bluuebunny/crossref_metadata_2025 huggingface dataset:
Vascular muscle membrane cation mechanisms and total peripheral resistance.
Authors: Hermsmeyer R K
Published: September 2013

Passive and active carrier-mediated transport of sodium across vascular muscle membranes has been suggested to be more important in the increased total peripheral resistance found in genetic hypertension. Using manipulations of ion gradients and recordings of ion currents, membrane potentials, and tension, I have found evidence for calcium regulation as the central pathophysiological mechanism in spontaneously hypertensive rats. Increased sodium pump activity, which may be a partial compensation for the increased sodium influx in hypertension, may thus be secondary to altered calcium channel regulation in hypertension. The calcium channel, and the membrane potentials governing it, seem to be the most immediately important membrane mechanisms for hypertension research.
The Li+-Na+ exchange and Na+-K+-Cl- cotransport systems in essential hypertension.
Authors: Canessa M , Brugnara C , Escobales N
Published: September 2013

This review examines the physiological functions of the Li+-Na+ exchanger and Na+-K+-Cl- cotransport system in human red blood cells. Both transporters are family aggregated and determined mainly by genetic factors; they are present in kidney and vascular cells, where they are regulated by vasoactive substances. To assess the physiological function of these two transporters, we investigated their kinetic and equilibrium properties, and their modulation by vasoactive substances. Recent studies in red blood cells indicate that the Li+-Na+ exchanger may be a mode of operation of the Na+-H+ exchanger, which plays an important role in the regulation of cell pH, cell volume, and transtubular sodium transport. In vascular cells, Na+-H+ exchanger is modulated by vasoconstrictors such as growth factors and angiotensin, while Na+-K+-Cl- cotransport is modulated by vasodilators such as atrial natriuretic factor and bradykinin. Kinetic studies in red blood cells of hypertensive patients and their offspring indicate the presence of subsets with elevated Vmax of Li+-Na+ exchange or high Km for cell sodium for outward Na+-K+-Cl- cotransport. The latter alteration is found most frequently in young blacks born of hypertensive parents, and it appears to be dependent on their level of sodium intake. The relationship between the alterations of the red blood cell sodium exchanger and Na+-K+-Cl- cotransport and risk factors for hypertension indicates that they can provide a tool to examine the interaction of genetic, hormonal, and environmental factors in human hypertension.
The possible role of digitalislike factors in pregnancy-induced hypertension.
Authors: Graves S W
Published: September 2013

A group of small, digitalislike compounds has been implicated in some forms of essential hypertension. Because of similarities between these forms of essential hypertension and pregnancy-induced hypertension, the presence of digitalislike factors in pregnancy-related fluids has been investigated. The factors are found in maternal sera with significantly higher levels of digitalislike activity, as monitored by digoxin radioimmunoassay, in the sera of third-trimester women with pregnancy-induced hypertension as compared to normotensive third-trimester controls (315 vs 195 pg digoxin equivalents/ml; p less than 0.001). Similarly, they are found in amniotic fluid, and significantly higher levels, as measured by radioimmunoassay (760 vs 540 pg digoxin equivalents/ml; p less than 0.0008) and by inhibition of ouabain-sensitive Na+,K+-adenosine triphosphatase (ATPase) (12.8 vs 2.7% inhibition; p less than 0.002), are found in those women whose pregnancies are complicated with hypertension. With purification, several digoxinlike immunoactive compounds are detected. Of these, some have a marked ability to inhibit ouabain-sensitive Na+,K+-ATPase. While as yet unidentified, these compounds have properties suggesting that they are not peptides, steroids, or fatty acids and lipids.
The vascular Na+-K+ pump in experimental hypertension.
Authors: Overbeck H W
Published: September 2013

We assessed the role of putative circulating ouabainlike factor(s) on in vivo arteriolar function in rats with very early (less than 7 days; mean, 3 days) and chronic (greater than 4 weeks) benign, one-kidney, one clip (1K1C) hypertension. Thus, we measured vascular responses in vasodilated (nitroprusside or adenosine), vascularly isolated, innervated hindlimb vascular beds of chloralose-anesthetized 1K1C rats perfused with their own blood at 1 ml/min. Complete norepinephrine dose-response curves in 8 rats with chronic and 28 with early 1K1C hypertension, compared with appropriate normotensive control rats, showed unchanged thresholds and ED50 values. Magnitude of ouabain-induced leftward shifts of the norepinephrine dose-response curve in 18 rats with chronic and 21 with early 1K1C hypertension, compared with appropriate normotensive control rats, was unchanged. Blockade of neural uptake of norepinephrine by desimipramine (10(-7) M) in 8 1K1C rats did not alter these results. These findings provide no evidence in this form and these stages of hypertension that humoral ouabainlike inhibitors of the Na+-K+ pump evoke physiologically significant inotropic effects in arterioles in vivo. It is possible, however, that induction of vascular Na+-K+-adenosine triphosphatase by circulating inhibitors modified the vascular responses to norepinephrine and ouabain in these rats.
Effects of prostaglandin F2 alpha on vasoconstrictor responses in the mesenteric vascular bed.
Authors: Aristegui P M , Enero M A
Published: September 2013

Prostaglandin F2 alpha (PGF2 alpha) in a concentration that did not induce vascular contraction (10(-8) M) potentiated the dose-response curves to norepinephrine and 5-hydroxytryptamine and the contractile response induced by potassium (60 or 100 mM) in isolated mesenteric vascular bed of the rat. After prostaglandin inhibitor treatment with indomethacin (10(-6) M), the dose-response curve to norepinephrine was reduced, and the dose (10(-10) M) of PGF2 alpha, which was ineffective in control tissues, facilitated the norepinephrine contractile response. In contrast, indomethacin did not change either the contractile response induced by potassium or the PGF2 alpha potentiation of this response. Calcium antagonists diltiazem or flunarizine reduced the potassium-induced contractile response. After diltiazem treatment, 10(-10) M of PGF2 alpha was also effective in facilitating this response. The PGF2 alpha postjunctional effect was conserved after phosphoinositide hydrolysis inhibition. These results suggest that PGF2 alpha potentiation of the contractile response may be independent of PGF2 alpha contraction. Low doses of endogenous prostaglandins could be able to facilitate the norepinephrine contractile response in this tissue. This process may be independent of calcium influx and phosphoinositide hydrolysis.
The central pressor effect of bradykinin in normotensive and hypertensive rats.
Authors: Lindsey C J , Fujita K , Martins T O
Published: September 2013

The site of action for the pressor response to bradykinin administered into the lateral ventricle has been reported to be either in the septal area or in the ventral portion of the third ventricle. We obtained dose-response curves for the pressor effect of bradykinin injected into the lateral ventricle or the posterior region of the fourth ventricle of normotensive Wistar and spontaneously hypertensive rats (SHR). Responses to fourth ventricle injections had a shorter latency and larger maximal effect, and were 20 to 100 times greater than those to lateral ventricle injections, suggesting that the site of bradykinin's action is in the caudal region of the brain, probably close to the area postrema. Maximal effects were similar for lateral and fourth ventricle injections in both SHR and normotensive rats, but SHR were much more sensitive to bradykinin. The ED50 values for the lateral ventricle route in normotensive rats and SHR were 1.3 and 0.35 nmol, respectively, and, for the fourth ventricle route, 60 and 3.4 pmol, respectively. Responses to Lys-Lys-bradykinin, a kininase-resistant bradykinin analogue, showed that kininase activity is lower in SHR than in normotensive rats and that SHR are four times more sensitive to Lys-Lys-bradykinin than are normotensive rats. The responses of all rats were inhibited by a specific bradykinin receptor blocker [Thi5,8,DPhe7]bradykinin. Our results show that there is a site of bradykinin action that is far more caudal than those previously described. The shorter latency and higher sensitivity of the fourth ventricle injection suggest that bradykinin injected into the lateral ventricle diffuses to the fourth ventricle where it exerts its effects.
Increased DNA replication in the arterial adventitia after aortic ligation.
Authors: Chatelain R E , Dardik B N
Published: September 2013

After microsurgical dissection of the thoracic aorta of normotensive rats, biochemical and morphological comparisons were performed between the intima-media and adventitia. The DNA content, wet weight, and dry defatted weight of the adventitia were half that of the intima-media. Collagen was the main component of the adventitia (collagen greater than nonfibrous protein greater than elastin) whereas elastin was the main protein in the intima-media (elastin greater than nonfibrous protein greater than collagen), and the results correlated with morphological observations. Hypertension induced by aortic ligation between the renal arteries resulted in rapid elevations in circulating humoral factors and blood pressure. A sixfold increase in DNA synthesis was observed in the adventitia (p less than 0.001), resulting in a significant increase in DNA content as early as 6 days after aortic ligation (75% increase; p less than 0.001). Increased DNA replication was accompanied by elevations in nonfibrous protein and elastin contents. Autoradiograms showed labeled adventitial fibroblasts throughout the thickness of the adventitia and along the entire length of the aorta and smaller vessels. DNA synthesis and content and labeled smooth muscle cells were increased in the intima-media. These studies indicate that the adventitia participates in the development of vascular hypertrophy and arterial disease produced by aortic ligation.
Converting enzyme activity and angiotensin metabolism in the dog brainstem.
Authors: Santos R A , Brosnihan K B , Chappell M C , Pesquero J , Chernicky C L , Greene L J , Ferrario C M
Published: September 2013

The concentrations of angiotensin converting enzyme (ACE) activity, norepinephrine, and serotonin were measured in microdissected regions of the dog's brainstem and spinal cord. In addition, we determined the in vitro metabolism of 125I-angiotensin I (Ang I) in homogenates of the same brain punch regions. High ACE-specific activity was found in the monoamine-containing regions of the brainstem and in the intermediolateral column of the spinal cord. In brainstem homogenates 125I-Ang I was metabolized to angiotensin II (Ang-[1-8]) and the N-terminal heptapeptide Ang-(1-7). In the presence of MK 422 (50 microM), Ang-(1-7) was still generated, while the production of Ang-(1-8) was inhibited. This study revealed the presence of high ACE activity in monoamine regions of dog brainstem and spinal cord, and showed that the metabolite Ang-(1-7) is the major product generated from Ang I in the presence and absence of ACE inhibition.
The ventrolateral medulla. A new site of action of the renin-angiotensin system.
Authors: Andreatta S H , Averill D B , Santos R A , Ferrario C M
Published: September 2013

High-affinity binding sites for angiotensin II (Ang II) in the ventrolateral medulla suggest that Ang II may act at cell groups that are known to modulate blood pressure. This hypothesis was investigated by the topical application of angiotensin I (Ang I), Ang II, the Ang II antagonist [Sar1, Thr8]Ang II, and the Ang I converting enzyme inhibitor MK 422 to a restricted region of the ventral medullary surface known as the glycine-sensitive area. Both Ang I (100 pmol) and Ang II (100 pmol) produced significant (p less than 0.01) increases in blood pressure (+20 +/- 4 and +31 +/- 5 mm Hg, respectively) that were associated with no change in heart rate. Furthermore, the relationship between the peak increases in blood pressure and Ang II was dose-dependent. Blockade of endogenous Ang II by [Sar1, Thr8]Ang II (13 nmol) produced a significant decrease in baseline blood pressure (-8 +/- 1 mm Hg; p less than 0.001). Similarly, topical application of MK 422 prevented the pressor effect of Ang I. Taken together, these experiments indicate that at least some components of the renin-angiotensin system exist in the ventrolateral medulla and they may modulate vasomotor outflow.
Baroreceptor reflex modulation by angiotensin II at the nucleus tractus solitarii.
Authors: Campagnole-Santos M J , Diz D I , Ferrario C M
Published: September 2013

This study characterized the effect of nucleus tractus solitarii (NTS) microinjection of the angiotensin II (Ang II) antagonist [Sar1, Thr8]Ang II on the baroreceptor control of heart rate in anesthetized rats. Reflex changes in heart rate were elicited by bolus intravenous injections of either phenylephrine or sodium nitroprusside before and after bilateral microinjection of [Sar1, Thr8]Ang II (100 pmol) or vehicle into the NTS. The slope of the relationship between the change in pulse interval and the change in mean arterial pressure was used as an index of baroreceptor reflex sensitivity. Bradycardia elicited by phenylephrine-induced increases in pressure was significantly greater after NTS injection of [Sar1, Thr8]Ang II. The slope of the pulse interval-arterial pressure relationship was 0.60 +/- 0.09 ms/mm Hg after injection, as compared with 0.42 +/- 0.07 ms/mm Hg before. In contrast, the baroreceptor reflex sensitivity index generated by decreases in pressure with nitroprusside was similar before and after injection. Vehicle injections did not alter the baroreceptor reflex index. Collectively, the data suggest that inhibition of endogenous Ang II in the NTS facilitates the baroreceptor reflex sensitivity to increases, but not decreases, in pressure. This new finding reveals the NTS as one site of action for the tonic effects of endogenous Ang II.
Characteristics of hormonal and neurogenic mechanisms of deoxycorticosterone-induced hypertension.
Authors: Ueno Y , Mohara O , Brosnihan K B , Ferrario C M
Published: September 2013

We characterized the hemodynamic and endocrine changes associated with the evolution of steroid-induced hypertension in conscious, trained, instrumented dogs given intramuscular injections of deoxycorticosterone (DOC) pivalate on Days 1 (20 mg/kg) and 14 (10 mg/kg) of the study. Because hypertension could be produced in these dogs without salt loading and unilateral nephrectomy, the research afforded a novel opportunity to determine the primary effects of DOC excess on the renin-angiotensin and sympathetic nervous systems, and on vasopressin levels. Both before and during 28 days of DOC treatment, regular measurements of mean arterial pressure, heart rate, cardiac output, and total peripheral resistance were coupled with serial determinations of plasma and cerebrospinal fluid levels of angiotensin II, vasopressin, norepinephrine, and electrolytes. DOC induced a progressive rise in mean arterial pressure associated with increased cardiac output and no change in heart rate. These hemodynamic changes were accompanied by sustained decreases in plasma renin activity, and in plasma, but not cerebrospinal fluid, angiotensin II. In contrast, plasma and cerebrospinal fluid vasopressin rose transiently on the 7th and 14th days of the study, respectively. After anesthesia with morphine and chloralose, the hemodynamic response to occlusion of a sole innervated carotid artery was evaluated on the 5th week before and after cervical vagotomy. Compared to normal animals, dogs with DOC-induced hypertension showed a reduced pressor response to carotid occlusion associated with suppression of reflex tachycardia; vagotomy partially restored the pressor response to normal levels. The data suggest that DOC-induced hypertension changes central hormonal influences of cardiovascular function, and also alters cardiopulmonary baroreceptor reflex control of peripheral sympathetic nerve activity.
The effect of a community hypertension control program.
Authors: Macías I , del Collado F , Forte G
Published: September 2013

A hypertension detection and control program sponsored by the Pan-American Health Organization and the World Health Organization (PAHO/WHO) was carried out in an urban health district of Havana City, Cuba. A baseline (initial) survey was conducted on a random sample of the population (greater than or equal to 15 years of age) to assess the problem of hypertension in that community. Subsequently, we extended the program in the same area by taking the blood pressure of as many people as we could, and a health education program on hypertension was developed and implemented. All hypertensive persons were treated. We surveyed about 90% of the adult population (29,640) over a 5-year period. We then conducted a final survey on a second random sample of the population to assess the effect of the program. The response rate to the letter of invitation to visit the hypertension clinic was 50%; 30% of the recall appointments were missed, and the dropout rate was 18.6%. Seventy percent of the hypertensive persons had Stage I disease (PAHO/WHO) with normal electrocardiograms. Before the program, 15.7% of the total number of hypertensive persons surveyed in the area had the disease under good control, and this increased to 31% after the program. Mortality due to cerebrovascular disease was reduced from 11/10,000/yr to 7/10,000/yr, whereas mortality caused by myocardial infarction did not change.
Nitrendipine in severe hypertension. Satellite symposium on calcium antagonists.
Authors: Mroczek W J , Burris J F , Allenby K S
Published: September 2013

We report the results of a multicenter trial in which nitrendipine, alone or in combination with a diuretic, a beta-blocker, or both, was administered to 114 patients with severe hypertension (greater than or equal to 115 mm Hg). Nitrendipine was titrated in doses of 5 to 30 mg b.i.d. If blood pressure was not controlled with nitrendipine alone, hydrochlorothiazide or propranolol or both were added. After a mean of 29 days in the study, 96 (90%) of 107 patients reached the initial goal of therapy; in 44 (41%) given nitrendipine alone the mean decrease in supine blood pressure was 38/25 mm Hg. After a mean of 91 days, 69 (72%) of 96 patients achieved the final goal of therapy; in 24 (25%) patients given nitrendipine alone the mean supine blood pressure decrease from baseline was 49/33 mm Hg. Falls in blood pressure were comparable in the patients given drug combinations. Seventy-two of 114 patients given study drug(s) had adverse experiences; headache and edema were the most frequent complaints. Only four patients dropped out of the study because of adverse effects. Most abnormal laboratory values occurred when nitrendipine was given with hydrochlorothiazide or propranolol or both. Analysis of severely hypertensive patients followed up in our Virginia center revealed continued control of blood pressure after long-term follow-up (43 +/- 3 [SD] months). Average supine blood pressure was reduced from 180/121 +/- 21/5 to 140/90 +/- 16/9 (SD) mm Hg (p less than 0.001). It was concluded that the calcium antagonist nitrendipine, alone or in combination with a diuretic or beta-blocker or both, is effective in the treatment of severe hypertension.
Vasopressin and arterial pressure regulation. Special lecture.
Authors: Cowley A W , Liard J F
Published: September 2013

Data from conscious rats, dogs, and humans show that plasma arginine vasopressin (AVP) begins to exert vasoconstrictor activity at concentrations in the same range as those associated with maximum antidiuretic activity. Minimum pressor responses are observed with elevated plasma AVP, due in part to decreases of cardiac output and in part to withdrawal of sympathetic neural tone to various regions of the systemic circulation. These responses appear to some extent to be species-dependent. In conscious dogs, but not in rats, the fall of cardiac output is mediated by AVP stimulation of baroreceptor reflex pathways. Studies in rats indicate that AVP inhibits the sympathetic nervous system by direct action on the central nervous system. No evidence was found for inhibition at peripheral sites such as autonomic ganglia or vascular smooth muscle receptors. Also, AVP plays an important role in the regulation of arterial pressure with blood loss by direct vasoconstriction and by AVP enhancement of the strength of the baroreceptor reflex responses. The role of AVP in the long-term control of arterial pressure and in hypertension remains controversial, but plasma AVP is elevated in many experimental and human forms of hypertension. The link between plasma AVP and hypertension remains unclear because long-term elevation of AVP alone cannot sustain volume expansion or hypertension, and excess AVP does not enhance hypertension produced by sodium-retaining hormones or other vasoconstrictor agents. It appears that AVP plays mainly a permissive role by its fluid-retaining effects in most forms of hypertension. It is also possible that it acts as a central nervous system neural transmitter and modifies autonomic pathways in some forms of hypertension.
Implication of leumorphin in inhibitory control of vasopressin secretion in conscious rats.
Authors: Yamada T , Nakao K , Itoh H , Morii N , Shiono S , Sakamoto M , Sugawara A , Saito Y , Mukoyama M , Arai H
Published: September 2013

The effects of leumorphin, a kappa-agonist derived from proenkephalin B (neoendorphin and dynorphin precursor), on vasopressin secretion were studied under basal and stimulated conditions in conscious, unrestrained rats. Intracerebroventricular injection of leumorphin (60 or 600 pmol) significantly inhibited basal vasopressin secretion. The vasopressin response induced by intracerebroventricular injection of angiotensin II (100 pmol) was significantly suppressed, in a dose-dependent fashion, by the simultaneous intracerebroventricular injection of leumorphin (6, 60, or 600 pmol). Intravenous pretreatment with naloxone (0.5 mg/kg body weight) diminished the inhibitory action of leumorphin (60 pmol) on vasopressin secretion. Moreover, naloxone (0.5 mg/kg body weight) prolonged the vasopressin secretion induced by intracerebroventricular injection of angiotensin II (100 pmol). These results indicate that leumorphin possesses a potent inhibitory effect on vasopressin secretion and that, alone or in combination with other endogenous opioid peptides, it plays an important role in the control of vasopressin secretion.
Effects of a kinin antagonist on mean blood pressure.
Authors: Carbonell L F , Carretero O A , Madeddu P , Scicli A G
Published: September 2013

Administration of high doses of a kinin antagonist produces an increase in blood pressure. Thus, endogenous kinins may be involved in the regulation of blood pressure. Kinins can induce the release of vasoactive substances such as catecholamines, renin, vasopressin, histamine, and prostaglandins. To determine whether the blood pressure changes induced by high doses of kinin antagonist are due to agonistic activity mediated by these vasoactive substances, we studied the effect on blood pressure of a kinin antagonist (DArg0-Hyp3-Thi5,8-DPhe7-bradykinin) administered to control, nephrectomized, and adrenalectomized rats, and to rats treated with vasopressin V1-receptor antagonist, ganglionic and alpha- and beta-adrenergic receptor blockers (either separately or combined), histamine H1- and H2-receptor blockers, and indomethacin, a prostaglandin synthesis inhibitor. Blood pressure changes were monitored on awake, restrained rats. In the control rat, the kinin antagonist injected as a bolus (4 mg/kg) into the ascending aorta produced a transient biphasic blood pressure response, first a pressor effect (delta BP = 7 +/- 1 mm Hg; p less than 0.05), then a depressor effect (delta BP = -20 +/- 6 mm Hg; p less than 0.05). The pressor response to the kinin antagonist was not affected by any of the treatments; however, the depressor effect of the kinin antagonist appeared to be caused by the release of vasodilator prostanoids from the kidney, since it was not observed in the nephrectomized rats or in those treated with indomethacin. The pressor effect induced by the kinin antagonist suggests that kinins may contribute to the regulation of blood pressure.
Left ventricular function in mild hypertension after adrenergic blockade.
Authors: Dianzumba S B , DiPette D , Joyner C R , Townsend R , Weber E , Mauro K , Cornman C
Published: September 2013

We previously used the Doppler transmitral flow velocity ratio A/E (A = late ventricular filling peak velocity; E = early ventricular filling peak velocity) and the age-adjusted ratio A/E/Age to detect left ventricular filling abnormalities in untreated mild hypertension. This study is a double-blind assessment of the effect of combined alpha- and beta-blockade (labetalol) and beta-blockade alone (atenolol) on left ventricular filling in mild hypertension. Twenty-seven patients blindly randomized to labetalol (12 patients) and atenolol (15 patients) treatment completed the echocardiographic and Doppler studies. Clinical and echo-Doppler data obtained at baseline and 6 weeks after initiation of therapy showed no difference between the two groups for age (49 +/- 10 vs 46 +/- 10 years), mean blood pressure (before therapy, 118 +/- 9 vs 117 +/- 8 mm Hg; after therapy, 108 +/- 12 mm Hg), left ventricular dimensions, wall thickness, systolic function, and mean late filling velocity A. There was no significant change in left ventricular mass and mass index with labetalol (left ventricular mass, 211 +/- 36 vs 216 +/- 38; mass index, 110 +/- 17 vs 112 +/- 16) or atenolol (245 +/- 41 vs 271 +/- 65; 120 +/- 18 vs 130 +/- 35). The mean velocity E, A/E, and A/E/Age ratios significantly improved with labetalol (p less than 0.05) but did not change significantly with atenolol. The improvement in A/E and A/E/Age ratios was primarily due to an increase in early filling velocity E.(ABSTRACT TRUNCATED AT 250 WORDS)
Drug interactions in hypertension.
Authors: Wood A J
Published: September 2013

Interactions between drugs and antihypertensive agents can result in either increased or decreased antihypertensive effects. These interactions may be pharmacokinetic or pharmacodynamic in type, resulting in either altered plasma drug concentrations or altered drug effects at similar plasma concentrations. Drugs may limit the absorption of antihypertensive agents, alter their metabolism through either enzyme inhibition or induction, or change renal excretion. In addition, by altering cardiovascular and volume homeostasis, changes in antihypertensive response may be produced.
An algorithm for the management of resistant hypertension.
Authors: Gifford R W
Published: September 2013

Before hypertension can be considered resistant to a rational triple drug regimen in maximal doses, the physician should rule out poor adherence to the regimen (including diet), adverse drug interactions, pseudotolerance (due to fluid retention), office hypertension, pseudohypertension, and an unrecognized secondary cause (e.g., renovascular disease, primary aldosteronism, and pheochromocytoma). When these have been excluded, hemodynamic measurements are indicated to identify the mechanism(s) at fault so that the therapeutic regimen can be modified appropriately.
Beta-adrenergic receptor blockers. Adverse effects and drug interactions.
Authors: Frishman W H
Published: September 2013

Adverse effects of beta-adrenergic receptor blocking drugs can be divided into two categories: 1) those that result from known pharmacological consequences of beta-adrenergic receptor blockade; and 2) other reactions that do not appear to result from beta-adrenergic receptor blockade. Adverse effects of the first type include bronchospasm, heart failure, prolonged hypoglycemia, bradycardia, heart block, intermittent claudication, and Raynaud's phenomenon. Neurological reactions include depression, fatigue, and nightmares. It is not yet proven whether the beta 1-selective adrenergic blockers or those with partial agonist activity reduce the overall frequency of adverse reactions seen with propranolol. Patient age does not appear, in itself, to be associated with more beta-blocker side effects. Side effects of the second category are rare. They include an unusual oculomucocutaneous reaction and the possibility of oncogenesis. There are also many drugs that interact with beta-blockers, which may increase toxicity. Finally, there are specific patient characteristics where one beta-blocker may be more effective and safer than another.
Side effects of sympatholytic antihypertensive drugs.
Authors: Engelman K
Published: September 2013

Antihypertensive drugs with pharmacological action due to sympatholytic activity have been second only to diuretics in their use and efficacy in normalizing blood pressure. Their pharmacological actions have resulted in the notable absence of chemical toxicity, but because of symptomatic side effects, their use has been limited relative to some of the newer antihypertensive agents. Most prominent among undesirable side effects are the central nervous system findings of sedation, altered thought process, depression, and orthostatic or exercise hypotension. Sexual problems, especially in men, are also prominent. Special toxicity is discussed with reference to methyldopa, clonidine, monoamine oxidase inhibitors, and metyrosine.
Side effects of vasodilator therapy.
Authors: Pettinger W A , Mitchell H C
Published: September 2013

Vasodilating antihypertensive drugs have in common the capacity to activate the peripheral sympathetic nervous system through the carotid sinus baroreceptor reflex mechanism, thereby increasing heart rate, renin release, and sodium and water retention. They differ in their tendencies to augment cardiac output and to relieve or precipitate cardiac failure and arrhythmias. Vasodilating antihypertensive drugs can produce an array of side effects and toxicity including headache, facial changes, hair growth, varying degrees of sodium and water retention, and rarely systemic lupus erythematosus and allergic reactions. Detailed knowledge of these effects is a prerequisite to skillful individualization of antihypertensive regimens.
Angiotensin converting enzyme inhibitors. Properties and side effects.
Authors: Gavras H , Gavras I
Published: September 2013

The purpose of this brief review is to separate the characteristic properties and side effects attributable to the pharmacology of the whole class of angiotensin converting enzyme (ACE) inhibitors from those attributable to the chemical structure and kinetics of each particular ACE inhibitor. The former would be predictable and probably similar for all agents and, therefore, would be expected to recur with each agent, whereas the latter are likely to be characteristic of individual compounds and may be avoidable by changing to another compound with similar pharmacology but different molecular structure.
Antihypertensive drug side effects in the Hypertension Detection and Follow-up Program.
Authors: Curb J D , Schneider K , Taylor J O , Maxwell M , Shulman N
Published: September 2013

The 5485 participants in the Hypertension Detection and Follow-up Program, Stepped-Care group form one of the largest groups to date on which detailed surveillance of long-term antihypertensive therapy and drug side effects has been reported. During a 5-year period, among all hypertensive persons (mild, moderate, and severe combined) who were not taking antihypertensive medications at the beginning of the study and who attended the clinic at least once during the 5-year trial, a total of 9.3% had definite or probable side effects severe enough to cause discontinuation of the drug treatment in question. Less than 1% of active participants required hospitalization for side effects. No death that could be attributed to side effects was detected. Thus, the Hypertension Detection and Follow-up Program data, which have previously demonstrated the beneficial effects of antihypertensive therapy, confirm the relative safety of such therapy.
Enhanced alpha-adrenoreceptor-mediated vasoconstriction in essential hypertension.
Authors: Amann F W , Bolli P , Kiowski W , Bühler F R
Published: September 2013

Forearm blood flow (FAF) has been determined using venous occlusion plethysmography in 24 patients with essential hypertension (EHT) and in 16 age-matched normotensive subjects (NT) under basal resting conditions, following nonspecific vasodilatation with sodium nitroprusside and after intraarterial infusion of the postjunctional alpha-blocking drug, prazosin. Under basal conditions, FAF was significantly higher in EHT than in NT. Infusion of sodium nitroprusside produced a similar absolute increase in FAF in both groups, whereas postjunctional alpha-blockade with prazosin led to a significantly greater increase in FAF in EHT than in NT. A positive correlation was found between plasma epinephrine concentration and prazosin-induced FAF in EHT but not in NT. These results suggest an enhanced postjunctional alpha-adrenoreceptor-mediated vasoconstrictor component in established EHT.
Direct action of kallikrein and other proteases on the renin-angiotensin system.
Authors: Suzuki S , Franco-Saenz R , Tan S Y , Mulrow P J
Published: September 2013

Kallikrein is present in the renal tubule near the macula densa, and it has recently been shown to activate inactive renin in human plasma. We recently showed that kallikrein was a potent stimulus of renin release and increased renin secretion in a dose-dependent fashion. To study its effect on renal renin release, we superfused rat renal cortical slices with purified rat urinary kallikrein. Kallikrein-stimulated renin release was completely abolished by trasylol and by amiloride, but was not affected by soybean trypsin inhibitor. Indomethacin did not block kallikrein action, indicating that kallikrein's effect is not mediated via kinin generation and prostaglandins. Kallikrein-stimulated renin release was not blocked by propranolol, trasylol did not block isoproterenol, and dibutyryl cyclic AMP stimulated renin release, indicating that kallikrein may not play a role in the beta-adrenergic mechanism of renin release. There was no demonstrable acid-activatable or kallikrein activatable renin in the superfusate, suggesting that all of the renin release was in the active form. Cathepsin D and plasmin also stimulated renin release from kidney slices in pH 6.0 buffer, whereas trypsin and pepsin did not. Our results support the hypothesis that kallikrein may play a role in the secretion of renin by the kidney. Other proteases can also release renin from the kidney.
Renin-angiotensin and adrenergic mechanisms in control of blood pressure in fowl.
Authors: Nishimura H , Nakamura Y , Taylor A A , Madey M A
Published: September 2013

Many avian species demonstrate atherosclerosis and high blood pressure (BP) that are influenced by age, sex, diet, and environment, but show no arteriosclerosis in small vessels. Thus, we aimed to define neural and humoral control of BP in conscious, 32-wk-old female chickens, Gallus gallus. Mean aortic pressure (determined by chronically implanted catheter) was 137.6 +/- 2.0 mm Hg; heart rate was 295 +/- 4 beats/min. Plasma renin activity (PRA), measured by radioimmunoassay of fowl angiotensin I ([Asp1, Val5, Ser9]AI), and plasma angiotensinogen levels were 3.55 +/- 0.31 ng/ml/hr and 1229 +/- 66 ng/ml respectively. Repeated injection of propranolol (4 to 8 mg/kg/day, i.m.) decreased (p less than 0.01) the BP 19.1 +/- 3.0 mm Hg and heart rate 76 +/- 6 beats/min. Acute infusion of propranolol also markedly reduced BP and heart rate, and increased plasma levels of norepinephrine and epinephrine. SQ 14,225 (20 mg/kg/day) reduced BP (p less than 0.01), but BP returned towards original levels unless a higher dose was given. PRA increased 2- to 6-fold. BP also decreased 31.0 +/- 2.1 mm Hg after reserpine treatment, but not after [Sar1, Ile8]AII. These results suggest that in maintaining BP in fowl the beta-adrenergic function is important, whereas the renin-angiotensin system may not have a primary role.
Inhibition of human converting enzyme in vitro by a novel tripeptide analog.
Authors: Weare J A , Stewart T A , Gafford J T , Erdös E G
Published: September 2013

We have studied inhibition of homogeneous human converting enzyme by a new inhibitor, a ketomethylene derivative of the blocked tripeptide substrate, Bz-Phe-Gly-Pro (ketoACE). KetoACE inhibited the hydrolysis of Hip-His-Leu and Hip-Phe-Arg at different concentrations (I50 values were 4 X 10(-8) M and 2 X 10(-7) M, respectively). Kinetic studies indicated that ketoACE inhibits the hydrolysis of both substrates by a similar, non-competitive mechanism. At the lowest enzyme concentration tested, using 3H-Hip-Gly-Gly as substrate, the I50 of ketoACE was 6 X 10(-9) M. KetoACE protected a functional tyrosine residue in the active site of human converting enzyme from modification with N-acetylimidazole. It is proposed that there are alternate (hydrophobic) binding sites for both inhibitors and substrates in the active site of human converting enzyme. It should be possible to develop other high-affinity inhibitors of this class that bind to hydrophobic sites and do not require metal binding via a sulfhydryl group.
Methylprednisolone-induced hypertension. Role for the autonomic and renin angiotensin systems.
Authors: Kohlmann O , Ribeiro A B , Marson O , Saragoça M A , Ramos O L
Published: September 2013

The role of the autonomic nervous system (ANS) in the pathogenesis of hypertension induced by methylprednisolone (20 mg/kg/week subcutaneously) was studied in rats before and during chronic renin angiotensin system (RAS) blockade with captopril (20 mg/kg/every 8 hrs by mouth). Sympathetic nervous system (SNS) blockade was accomplished by the intravenous (i.v.) administration of propranolol (0.20 mg/100g) plus phentolamine (1.25 mg/100g/i.v.) and ganglionic (G) blockade by the use of pentolinium tartarate (0.5 mg/100g/i.v.). After 4 weeks, methylprednisolone-treated animals showed significant decreases in mean arterial pressure (MAP) with both SNS (-34 +/- 2 mm Hg) and G (-56 +/- 3 mm Hg) blockades; during chronic RAS blockade, even greater falls in MAP were observed (SNS = -43 +/- 2 mm Hg and G = -75 +/- 3 mm Hg). Nevertheless, for both groups the levels of MAP obtained during SNS and G blockades were higher than those observed in their control groups. At the end of second week, however, in captopril-treated hypertensive rats the values of MAP obtained during ANS blockade were lower than those observed in the control group. An increased responsiveness to exogenous administration of norepinephrine (NE) was observed in animals receiving methylprednisolone and captopril. It is concluded that methylprednisolone hypertension in the rat may be initially explained by activation of RAS and ANS. At later phases, a third mechanism has to be postulated to explain the hypertensive state.
Neurogenic hypertension produced by lesions of the nucleus tractus solitarii alone or with sinoaortic denervation in the dog.
Authors: Ferrario C M , Barnes K L , Bohonek S
Published: September 2013

The cardiovascular effects of bilateral lesions of the nucleus tractus solitarii (NTS) were compared with those of subsequent sinoaortic denervation in the same dogs. Destruction of the lateral but not the medial component of the NTS between + 0.5 and 3 mm anterior to the obex produces mild hypertension and tachycardia, not always sustained for more than 2 weeks. Rises in pressure were accompanied by increased lability which was not present regularly in all dogs but correlated with the baseline level of arterial pressure. On the other hand, sinoaortic denervation following lateral NTS lesions produced the first demonstration of fulminant hypertension in the dog, which led to death within hours. These data suggest that, while NTS lesions in the dog probably only partially interrupt central baroreceptor pathways, the addition of sinoaortic denervation completely disrupts baroreceptor inputs to the central nervous system, thus releasing central sympathetic outflow completely from baroreceptor inhibition.
Role of the anteroventral third ventricle region and the renin angiotensin system in methylprednisolone hypertension.
Authors: Marson O , Ribeiro A B , Tufik S , Filho G A , Saragoço M A , Ramos O L
Published: September 2013

Methylprednisolone (M, 10 mg/kg/week subcutaneously) was administered to cause hypertension in rats, and the role of AV3V region was assessed before and after development of the hypertensive state. Participation of the renin angiotensin system (RAS) was evaluated by changes in mean arterial pressure (MAP) induced by administration of saralasin (S, 10 micron g/kg/min i.v.) or captopril (C, 20 mg/kg/p.o).aAnaAV3V lesion before M administration partially prevented and delayed the beginning appearance of M hypertension. Furthermore, a prior AV3V lesion abolished an angiotensin II (AII)-dependent pressor component normally identified by S and C administration in this type of hypertension. During the maintenance phase of the hypertension, an AV3V lesion caused a partial reduction in blood pressure. A spontaneous disappearance of a vasoconstrictor component mediated by AII was observed in the late phases of M hypertension. It is concluded that the AV3V region is essential to the full development and maintenance of M hypertension in the rat. Also in this model, integrity of the AV3V area is essential to the expression of the AII-mediated pressor component. Finally it is apparent tha M can cause hypertension even in the absence of the AV3V area or during chronic renin angiotensin blockade, indicating multiple pathogenetic mechanisms in this experimental model.
Angiotensin I, II, and II tachyphylaxis in the mesenteric vascular circuit of the rat.
Authors: Fasciolo J C , Binia A
Published: September 2013

Angiotensin tachyphylaxis is rapidly induced in the mesenteric vascular circuit of the rat perfused with a saline solution. there is crossed tachyphylaxis among angiotensins (AI, AII, and AIII). The angiotensin antagonist Sar 1-Ileu 8-AII is ineffective when the vascular preparation is previously rendered tachyphylactic to AII, showing that the AII receptors are not available during tachyphylaxis. This finding supports the theory that angiotensin tachyphylaxis is caused by receptor occupancy by the agonist. By perfusing the vascular preparation with aII solutions that were too diluted to produce vasoconstriction, tachyphylaxis to AII was induced. Therefore, AII receptors can be slowly saturated without producing vasoconstriction. The recoveries of the vasoconstrictor effect of AII and AIII at 30 and 60 minutes after tachyphylaxis are similar; thus, the dissociation constants of the AII- and AIII-receptor complexes should be alike. After three bolus injections of AI, the vascular preparation is completely refractory to AI, AII, and AIII. When the conversion of AI to AII is inhibited with captopril, AI no longer induces tachyphylaxis to AII and AIII. Thus, tachyphylaxis to AII and AIII induced by AI seems to be due not to the occupancy of AII receptors by AI but to the AII formation from AI "in situ."
Vascular structural changes in DOC-salt hypertensive rats.
Authors: Mangiarua E , Basso N , Ruiz P , Taquini A C
Published: September 2013

Vascular alterations in DOC-salt hypertensive rats 10 and 30 days after the onset of the treatment were studied and compared with those from rats receiving only DOC, rats drinking salt, and control rats. Wet weight and absolute amounts of deoxyribonucleic acid (DNA) and ribonucleic acid (RnA) of the artery wall were significantly increased in DOC-salt rats 10 and 30 days after the onset of the treatment. RNA/DNA and protein/DNA ratios were similar in all the experimental groups. The arteries of DOC-salt animals incorporated tritiated thymidine at a higher rate 10 days after beginning the treatment, while the uptake was similar in all the animals at the end of the experimental period. These results would indicate that, in this type of hypertension, the increase in artery mass is mainly the result of cellular hyperplasia, which is active during the early phase of the process; afterward the vascular wall reaches a new steady state characterized by a greater number of cells and no further cell proliferation.
Initial mechanisms in hypertension after bilateral renal ischemia in the rat.
Authors: de la Riva I J , Morera S , Rosón M I , Mon M D , Basso N , Taquini A C
Published: September 2013

Cumulative water- and electrolyte balance, plasma creatinine (PC), plasma renin activity (PRA), urinary prostaglandins (PGs) E2, and F2alpha and kallikrein (K) were studied in 40 male Wistar CHbb THOM rats (250 +/- 4 g SE). A solid silver clip (0.25 mm lumen) was applied to both renal arteries in 18 animals; 13 rats were sham-operated and nine remained intact. The analyses were performed during a control period and up to 10 days after surgery. Blood pressure (BP) recorded on the 10th and 12th day of the study increased significantly in clipped rats with respect to sham rats (p less than 0.001);PC and PRA measured on the 11th day were not significantly different. A positive cumulative water "balance" )p less than 0.01) and sodium balance (p less than 0.02) was found in clipped rats when compared with sham rats in the first 5 days of the experimental period. Significantly higher values of PGE2 urinary excretion were observed in sham rats vs clipped rats on the 2nd and 5th day after surgery (p less than 0.02). On the 2nd day after surgery, K urinary excretion was significantly lower in clipped rats than in sham rats (p less than 0.02). No significant changes were observed in PGF2alpha excretion. The absence of significant difference in PRA 10 days after bilateral renal artery stenosis points to a lack of any fundamental role of circulating angiotensin II at this stage of the development of hypertension. The significant water- and salt retention in the first 5 days after clipping suggests that it might be involved in the pathogenesis of this model. Early changes in PGs E2 and F2alpha and K appear to be related more to intrarenal adjustments soon after surgery than to the increase in BP.
Effects of captopril on vascular reactivity of SHR in vivo and in vitro.
Authors: Antonaccio M J , Rubin B , Kotler D
Published: September 2013

The effect of captopril treatment (100 mg/kg by mouth daily for up to 6 months) on pressor responses to norepinephrine (NE) and angiotensin II (AII) was examined in spontaneously hypertensive rats (SHR). Also, helical strips of rat aorta were removed from rats that had been similarly dosed. The aortic strips were suspended for isometric recording in modified Krebs' solution kept at 37 degrees C and bubbled with 95% O2-5% CO2. Pressor responses of both NE and AII in vivo were inhibited by captopril in SHR treated for all treatment periods. Responses to NE were more significantly and consistently inhibited than those for AII. Aortic strips from SHR previously dosed with captopril showed equivalent or greater contractile responses to potassium chloride (KCl) and NE, when compared with strips from untreated age-matched controls. In aortic strips from untreated Sprague-Dawley rats incubated with captopril, 30 micron g/ml for 1 hour ( a concentration 6000 times higher than that needed to inhibit angiotensin-covering enzyme by 50% in vitro), captopril had no effect on nitroglycerin-induced relaxation or NE-induced contractions, whereas ethacrynic acid (25 micron g/ml) reduced both the NE contractile response as well as the nitroglycerin-induced relaxation. These results suggest that captopril has no direct effect on the ability of isolated vascular smooth muscle to contract or relax despite causing a significant inhibition of pressor responses in vivo. It is suggested that this effect is related to an interaction of captopril with blood-borne elements necessary for the full expression of vasoconstriction, but unrelated to angiotensin-converting enzyme inhibition.