bluuebunny/crossref_metadata_2025 huggingface dataset:
Renin system activity as a determinant of response to treatment in hypertension and heart failure.
Authors: Cody R J , Laragh J H , Case D B , Atlas S A
Published: September 2013

In hypertension, irrespective of its underlying etiology, the baseline pretreatment renin-sodium profile predicts the antihypertensive action or the lack of it for five major types of antihypertensive drugs: 1) diuretic agents; 2) beta-receptor blockers; 3) converting-enzyme inhibitors; 4) the alpha 1 postsynaptic blocker, prazosin; and 5) the calcium channel blockers, verapamil and nifedipine. Moreover, vigorous compensatory activation of the renin-angiotensin system in response to therapy often explains initial drug ineffectiveness or resistance to treatment by diuretics and nonspecific vasodilators. This correlation between renin system behavior and antihypertensive drug efficacy likely reflect basic pharmacologic-physiologic interactions. This correlation is also observed in congestive heart failure without hypertension, where operant renin-aldosterone profiles may help to explain both drug efficacy and drug resistance to commonly administered therapeutic agents. Accordingly, a control system analysis of the renin axis has broad applications in therapy. The analysis is also conceptually significant since it exposes the operation of fundamentally different mechanisms of increased vascular resistance to flow occurring in different patients with hypertension or heart failure. One form is renin-angiotensin-mediated whereas the other, in the absence of renin, is associated with sodium-volume excess and/or abnormal alpha-adrenergic and calcium channel activity. Further definition of these two mechanisms of increased peripheral resistance could lead to a better understanding of the pathogenesis of some forms of essential hypertension and congestive heart failure.
Cardiac factors in response to antihypertensive treatment.
Authors: Fouad F M , Tarazi R C
Published: September 2013

The cardiac status of hypertensive patients will influence not only the indications for and choice of antihypertensive agents but can also alter the effectiveness of antihypertensive therapy. The heart may interfere with adequate blood pressure control either because of marked increases in cardiac output or as result of decompensation activating various pressor mechanisms or through the generation of pressor reflexes. Reflex increases in cardiac output may blunt or even nullify the effect of reduction in peripheral resistance by vasodilators. Cardiac decompensation from incidental disease or secondary to some antihypertensive drugs can lead to hypertension rather than reduction in blood pressure. It is particularly liable to develop from excessive fluid retention, particularly when associated with reduction of cardioadrenergic support. Coronary insufficiency from either coexisting coronary disease or triggered by injudicious antihypertensive treatment can stimulate pressor reflexes leading to marked fluctuations in arterial pressure. Alterations in left ventricular relaxation and rapid filling have been reported with some antihypertensive drugs; these changes could conceivably influence blood pressure responses through their effect on reflexes from low pressure baroceptors.
Sodium and potassium intake and blood pressure.
Authors: MacGregor G A
Published: September 2013

There is increasing circumstantial evidence that the very high sodium diet combined with low potassium intake that most Western communities now eat may be, at least in part, responsible for the prevalence of high blood pressure. This circumstantial evidence combined with animal evidence has been considered sufficient in some countries to make a general recommendation to reduce sodium intake. If high sodium intake is an important cause of high blood pressure, it is not clear at the present time how it may do so. In this report, evidence is reviewed for one hypothesis suggesting an inherited defect in the kidney's ability to excrete sodium in patients who are going to develop essential hypertension, together with evidence for a raised concentration of an inhibitor of sodium transport. In patients with established hypertension, moderate restriction of sodium intake appears to lower blood pressure and moderate potassium supplementation to also lower blood pressure. While further evidence is required, particularly long-term studies, it would seem prudent to recommend to patients with essential hypertension or a strong family history of hypertension that they restrict dietary sodium intake moderately and increase dietary potassium intake by the consumption of more fruits and vegetables and, perhaps, the use of a potassium-based salt substitute. This regimen could obviate or reduce the need for drug treatment in some patients with mild to moderate hypertension.
Compliance of hypertensive patients with pharmacological treatment.
Authors: Breckenridge A
Published: September 2013

Failure of compliance with drug treatment is a major problem in all diseases requiring long-term therapy. The incidence of noncompliance is variously reported as between 5% and 60% in well-conducted investigations in hypertensive patients. Direct (objective) methods give a higher incidence of noncompliance than indirect (subjective) methods. Among factors associated with noncompliance, the complexity of the treatment regimen and the nature of the doctor-patient relationship are important; few demographic characters among the patient population can be identified. Improvement of noncompliance depends on understanding these facets of the problem.
Age and cardiovascular response adaptation. Determinants of an antihypertensive treatment concept primarily based on beta-blockers and calcium entry blockers.
Authors: Bühler F R
Published: September 2013

The patient's age has great impact on the development of hypertension, its duration, and severity. In patients with essential hypertension, sympathetic cardiovascular control changes from an early phase with increased beta-adrenoceptor-mediated responses, e.g., cardiac output and renin, into a later phase where these responses are blunted and alpha-adrenoceptor-mediated vasoconstriction prevails, associated with higher intracellular free sodium and calcium concentration. This pathophysiological view of essential hypertension has its corollary in the pharmacotherapeutic approach. Younger patients, who often have high renin levels, respond better to monotherapy with a beta-blocker or with a converting-enzyme inhibitor. Older patients, who often have low renin levels, respond less well to beta-blockers but particularly well to calcium entry blockers as an alternative to diuretics. Therefore, beta-blockers and calcium entry blockers form new cornerstones for antihypertensive treatment and strategy, with the potential of cardioprotection.
Red blood cell sodium in the DOCA hypertensive pig.
Authors: Guthe C C , Harris A L , Thio B , Moreland R S , Bohr D F
Published: September 2013

The influence of deoxycorticosterone acetate (DOCA) on the sodium content of the red blood cell was determined in the pig. DOCA (100 mg/kg), impregnated in Silastic, was implanted subcutaneously (s.c.) in six male pigs; seven additional pigs received Silastic implants without the DOCA. Those receiving DOCA had an increase in mean arterial pressure (MAP) that was significant in 48 hours and reached a plateau that was 24 mm Hg greater than that of the controls after 15 days. These animals also developed hypokalemia and polydipsia over approximately the same time course. Red blood cell sodium content increased in DOCA-treated pigs 24 hours after implant (5.57 +/- 0.17 vs 5.23 +/- 0.05, mEq/liter cells). The sodium content continued to rise, reaching a plateau 28% above that of control value by the 5th postimplant day (6.37 +/- 0.40 mEq/liter cells). In vitro tests of possible mechanisms that might have caused the in vivo increase in red blood cell sodium content gave the following results: 1) Incubations of red blood cells in a physiological salt solution (PSS) containing deoxycorticosterone failed to cause an increase in cell sodium content. 2) No ouabain-like factor was demonstrated in plasma from the DOCA hypertensive pigs. 3) An elevation in bicarbonate concentration in the PSS caused an increase in red blood cell sodium content. 4) A decrease in potassium concentration in the PSS also caused an increase in red blood cell sodium content.(ABSTRACT TRUNCATED AT 250 WORDS)
Studies of impaired aldosterone response to spironolactone-induced renin and potassium elevations in adenomatous but not hyperplastic primary aldosteronism.
Authors: Kater C E , Biglieri E G , Schambelan M , Arteaga E
Published: September 2013

Spironolactone (SPL) corrects hypertension, hypokalemia, and hyporeninemia in patients with primary hyperaldosteronism (PHA) by blocking mineralocorticoid (MCH) receptors. We evaluated the effect of continuous SPL treatment (100 to 300 mg/day for 7 days to 9 years) on plasma renin (PRC), potassium, aldosterone (PA), 18-hydroxycorticosterone (18-OHB), deoxycorticosterone (DOC), and corticosterone (B) concentrations and 24-hour urinary excretion of aldosterone (UA) in 24 patients with PHA (15 with an aldosterone-producing adenoma [APA] and nine with idiopathic PHA [IHA]). Despite the normalization of PRC and K in both APA and IHA patients by SPL, UA and PA failed to increase in APA (55.8 +/- 8.8 to 51.4 +/- 7.3 micrograms/24 hr and 54.0 +/- 9.4 to 44.6 +/- 6.2 ng/dl, respectively) in contrast to rises in IHA patients (22.3 +/- 2.5 to 69.3 +/- 10.3 micrograms/24 hr and 16.0 +/- 1.0 to 49.9 +/- 9.9 ng/dl). Similar corrections with amiloride (20-40 mg/day for 2 months) in one patient with APA produced a three- to fourfold increase in UA and PA. In addition, while on SPL the characteristic fall or no change in PA and 18-OHB during upright posture persisted in all APA patients despite further increases in PRC (4.48 +/- 1.15 to 7.86 +/- 1.89) and K (4.0 +/- 0.1 to 4.3 +/- 0.1). The patterns of the aldosterone precursors, DOC, B, and 18-OHB, and their ratios to acute stimulation with cosyntropin were not altered by SPL. Thus, SPL treatment causes a sustained impairment of the aldosterone secretory response to normalized PRC and K, but not to ACTH stimulation, only in patients with APA.
Tachycardic responses during the development of renal hypertension.
Authors: Machado B H , Salgado H C , Krieger E M
Published: September 2013

Basal heart rate (HR) of conscious rats under resting conditions was measured daily by electrocardiogram (ECG) during the development of one-kidney, one clip (1K1C) hypertension. A progressive increase in HR (mean +/- SEM) was observed from Day 1 to 7: 318 +/- 11; 330 +/- 18, 338 +/- 18; 344 +/- 19; 372 +/- 14; 374 +/- 11, and 388 +/- 12 bpm, respectively. During the same period, mean arterial pressure (MAP) also increase progressively: 126 +/- 2; 129 +/- 2; 134 +/- 4; 135 +/- 7; 144 +/- 2 and 157 +/- 4 mm Hg, respectively. From Day 7 onward, the HR declined, reaching values of 336 +/- 13 bpm on Day 9, with no further alterations for the next 21 days. The MAP continued to rise, however, being 158 +/- 4 on Day 8 and 175 +/- 7 mm Hg on Day 30. Sham-operated rats showed no changes in HR or MAP. During the development of hypertension, blockade of converting enzyme with captopril (10 mg/kg, i.v.) caused a significant blood pressure fall on Day 1 (-27 +/- 1 mm Hg) and Day 3 (-18 +/- 2 mm Hg), whereas on Day 6 (-9 +/- 3 mm Hg) and Day 14 (-8 +/- 3 mm Hg) the fall was not different from that of the normotensive control rats (NCR) (-6 +/- 1 mm Hg). Reflex bradycardia, produced by increasing doses of phenylephrine which elevated the MAP by 10 to 40 mm Hg, was studied in conscious NCR and renal hypertensive rats (RHR) 3 and 7 days after surgery during the development of renal hypertension.(ABSTRACT TRUNCATED AT 250 WORDS)
Basal levels of plasma epinephrine and norepinephrine in the dog.
Authors: Bridle P A , Brosnihan K B , Speth R C , Goormastic M , Ferrario C M
Published: September 2013

Conscious (n = 62) and anesthetized (n = 34) dogs were studied to establish basal levels and ranges for plasma epinephrine (E) and norepinephrine (NE) in this species. Trained conscious dogs were familiarized to recording conditions and personnel for 2 to 3 weeks and acclimatized to the laboratory for at least 15 minutes prior to blood sampling from a chronically implanted catheter. Their basal values were 65 +/- 47 pg/ml for E and 145 +/- 58 pg/ml for NE, which were significantly lower (p less than 0.05) than values in a second group of conscious dogs trained in the same manner but sampled soon after arrival to the laboratory (E = 144 +/- 93 pg/ml; NE = 193 +/- 86 pg/ml). Catecholamine levels in dogs anesthetized with one of three different regimes commonly used in cardiovascular studies were shown to be similar to the basal values found in conscious dogs acclimatized to the laboratory. The weak correlations found between basal plasma catecholamines and hemodynamic variables in all groups of conscious dogs reflect the complexity of factors interacting with the sympathetic nervous system in the maintenance of arterial pressure. These results document the variability that can be expected when using catecholamine levels as an index of sympathetic nervous system activity and the necessity of standardizing conditions for sample collection.
Immunoreactive glandular kallikrein in plasma during alterations of urinary kallikrein excretion.
Authors: Rabito S F , Scicli A G , Carretero O A
Published: September 2013

To determine whether maneuvers known to modify immunoreactive urinary kallikrein excretion (iUKK) also alter the concentration of immunoreactive glandular kallikrein (iGKK) in plasma, we measured iGKK in the plasma and urine of rats before, at 1 week, and at 3 weeks after induction of two-kidney, one clip hypertension, low sodium intake, and DOCA-salt hypertension. Glandular kallikrein in plasma and urine was measured by radioimmunoassay. Clipping of a renal artery decreased iUKK from 11.7 +/- 0.5 microgram/24 hr/100 g body weight (BW) to 7.8 +/- 0.5 and 8.2 +/- 0.5 at 1 and 3 weeks after surgery without significantly changing iGKK in plasma. The level of iGKK in the plasma did not correlate significantly with iUKK in the clipped group. Low sodium intake significantly increased iUKK, which rose from 6.6 +/- 0.3 microgram/24 hr/100 g BW to 9.6 +/- 0.5 and 13.9 +/- 0.7 after 1 and 3 weeks. In addition, low sodium intake appeared to increase iGKK in plasma, and a significant positive correlation was observed between iUKK and iGKK in plasma in the group on low sodium diet (r = 0.65, p less than 0.01). DOCA-salt treatment increased iUKK significantly from 10.4 +/- 0.6 microgram/24 hr/100 g BW to 17.1 +/- 1.4 and 22.6 +/- 2.3 at 1 and 3 weeks after. The iGKK in plasma increased from 13.8 +/- 0.5 to 15.4 +/- 0.7 ng/ml (p less than 0.05) at 1 week after the DOCA-salt treatment began, but it returned to pretreatment levels 3 weeks later (14.5 +/- 0.7 ng/ml, n.s.).(ABSTRACT TRUNCATED AT 250 WORDS)
Aldosterone-binding globulin-induced hypertension in the rat. A new experimental model.
Authors: Nowaczynski M , Nowaczynski W , Mavoungou D , Lioy F , Wilkins G , Fung K , Boyko W
Published: September 2013

A thermostable urinary homologue of the plasma aldosterone-binding globulin (ABG), designated ABG-TsU, was isolated and purified by differential ultrafiltration, ion exchange chromatography, and gel filtration to electrophoretic homogeneity. Scatchard plot analysis using highly purified ABG-TsU demonstrated reversible high-affinity low-capacity binding at separate sites for aldosterone and dehydroepiandrosterone sulfate (DHEA-SO4). ABG-TsU injected intraperitoneally (i.p.) in male rats resulted in sustained hypertension after 5 to 8 days, characterized after 12 days by no changes in plasma Na+ K+, aldosterone, or plasma renin activity (PRA). No histological changes could be detected in the kidneys, brains, or hearts, nor evidence of adrenocortical hyperplasia. This hypertension appears to be aldosterone-dependent since it is prevented by bilateral adrenalectomy or administration of a spironolactone, but not by adrenalectomy when aldosterone is given concomitantly with ABG-TsU. Hemodynamic characterization of this hypertension was carried out in rats after treatment with ABG-TsU or saline i.p. for 14 days. Cardiac output (CO) was measured using the reference sample microsphere method. ABG-TsU-treated rats had significantly higher mean arterial pressure (MAP), systolic blood pressure (SBP), diastolic blood pressure (DBP), and CO, while no difference in total peripheral resistance (TPR) was detected. This new animal model of borderline essential hypertension (EH) induced by ABG-TsU, which has a reversible high-affinity binding for aldosterone, results in adrenal-dependent hypertension due at this early phase to an increase in CO without any change in TPR, which remains inappropriately normal.
Acute changes in the renin-angiotensin system modify bradykinin and angiotensin reactivity and metabolism in conscious rats.
Authors: Salgado M C , Krieger E M
Published: September 2013

We have shown that angiotensin I (AI) conversion as well as bradykinin (BK) inactivation and reactivity are altered in chronic renal hypertensive rats. In the present experiments we tested the possibility that acute renal hypertension or AI and AII infusion cause alterations in both systems. Pulmonary inactivation of BK was estimated by comparing intravenous and intraaortic equipressor doses (20 mm Hg), and the extent of AI conversion was assessed by determining the equipressor doses of AI and AII that produced a 20 mm Hg rise in mean arterial pressure (MAP). Acute renal hypertension was produced by unclamping the renal pedicle (URP) occluded for 5 hours in conscious rats. Before URP, the MAP was already increased (131 +/- 2 mm Hg) and captopril (10 mg/kg, i.v.) produced a fall of 27 +/- 8 mm Hg, suggesting that the renin-angiotensin system was overactive. After URP, MAP rose to 151 +/- 3 mm Hg, and captopril completely abolished the hypertension. Before URP, reactivity to BK was increased [doses 6 times smaller than control (C), 34 +/- 5 ng], and URP produced no further elevation. Pulmonary BK inactivation (97.5% +/- 4%) was the same before and after URP. Before URP, doses of AII 5 times greater than C (2 +/- 4 pmol) were necessary, and hyporeactivity to AII was markedly increased after URP (doses 300 times larger than C). After URP, the conversion was maximal (104% +/- 2% vs 49% +/- 3% in C), and it was already elevated before URP (82% +/- 10%) when six of the nine rats studied had maximal extent of conversion.(ABSTRACT TRUNCATED AT 250 WORDS)
Angiotensinogen concentration in the cerebrospinal fluid in different experimental conditions in the rat.
Authors: Ruiz P , Basso N , Grinspon D , Mangiarua E , Cannata M A
Published: September 2013

Angiotensinogen is the most important component of the renin-angiotensin system present in the cerebrospinal fluid (CSF) of the rat. Its physiological significance as well as its origin have not been clearly elucidated. In this experiment we have examined plasma renin activity (PRA) and plasma and CSF angiotensinogen concentration under the following experimental conditions in male rats of the Wistar strain: 1) adrenalectomy (Adx) 4 days prior to sample collection; controls were sham Adx animals; 2) nephrectomy (Nx) 48 hours before blood and CSF collection; controls were sham Nx rats; 3) DOC-salt treatment (Cortexon depot, 50 mg/kg.s.c. twice a week) plus saline to drink was given during 4 weeks; controls were intact rats; 4) DOC-salt plus captopril: captopril (100 mg/kg/day) in the drinking fluid was added to the treatment of experimental and control animals of Group 3; 5) two-kidney, two clip hypertension: silver clips placed in both renal arteries 8 weeks before samples collection; control: sham-operated rats; 6) water deprivation: rats deprived of water for 5 days; controls: intact rats; 7) peripheral sympathectomy: 6-hydroxydopamine (6-HODA) injected s.c. from birth until 16 weeks of age, adrenodemedullectomy and adrenal denervation performed at 8 weeks; controls were vehicle-injected animals. Determination of angiotensinogen concentration in plasma and CSF was accomplished by incubation of the samples with excess hog renin. The angiotensin I released as well as PRA were evaluated using an specific radioimmunoassay technique. PRA was significantly increased by Adx, captopril treatment, and water deprivation, and was almost suppressed by Nx, DOC-salt, and DOC-salt plus captopril treatment.(ABSTRACT TRUNCATED AT 250 WORDS)
Maintenance of arterial pressure by vasopressin and angiotensin II after adrenalectomy.
Authors: Elijovich F , Kirchberger M , Barry C R , Krakoff L R
Published: September 2013

Participation of vasopressin and the renin-angiotensin system in the maintenance of systemic arterial pressure was evaluated in unanesthetized adrenalectomized rats. Adrenalectomized and sham-operated rats with implanted arterial and venous catheters were given 1% sodium chloride and 2.5% glucose as drinking fluid for 72 hours following adrenalectomy. Serum and urine samples were obtained for measurement of electrolyte and solute concentration. The pattern of serum electrolytes, serum osmolality, and renal excretion of electrolytes, solute, and water observed in the adrenalectomized rats was entirely consistent with previous observations in this model. Mean arterial pressure of unanesthetized unrestrained adrenalectomized rats was significantly lower than controls. In adrenalectomized rats, dPMeTyrAVP reduced mean arterial pressure 9 +/- 1 mm Hg, p less than 0.001; captopril then caused an additional reduction of 17 +/- 2 mm Hg, p less than 0.01. Neither antagonist altered arterial pressure in the control group. Our results indicate that vasopressin and the renin-angiotensin system play a compensatory pressor role in adrenal insufficiency, preventing a larger decrease of arterial pressure in this model of chronic hypotension.
Lesions of epinephrine neurons in the rostral ventrolateral medulla abolish the vasodepressor components of baroreflex and cardiopulmonary reflex.
Authors: Granata A R , Ruggiero D A , Park D H , Joh T H , Reis D J
Published: September 2013

Epinephrine-containing neurons of the rostral ventrolateral medulla (RVL) (the C1 group of Hökfelt) in the rat are primarily unilaterally innervated by neurons in the nucleus tractus solitarius (NTS) and in turn project to autonomic spinal neurons. In this study, we investigated whether the C1 area of the RVL mediates the vasodepressor responses (VDR) induced by either electrical stimulation of the vagus nerve or carotid sinus stretch. In all experiments, C1 neurons were localized immunocytochemically with antibodies to phenylethanolamine N-methyltransferase (PNMT). Bilateral lesions of the C1 area decreased arterial pressure (AP) and heart rate (HR) to spinal cord transection levels and blocked the VDR induced by vagal stimulation and carotid sinus stretch. Combined lesions of the contralateral NTS and C1 area ipsilateral to the stimulated vagus nerve maintained AP and HR at normal levels, and totally blocked the VDR to vagal stimulation and carotid sinus stretch. Since projections from the vagus nerve to NTS are bilateral and those from NTS to C1 unilateral, the combined contralateral NTS/ipsilateral C1 lesions isolated and interrupted the ipsilateral NTS-C1 pathway and, therefore, blocked the baroreceptor reflex. The results are consistent with the hypothesis that neurons in the NTS synapsing in or projecting through the C1 area mediate the baro- and cardiopulmonary mechanoreceptor reflex.
Effects of anterior hypothalamic disconnection on the evolution of Goldblatt renal hypertension. A dual response.
Authors: Castro A L , Almeida E F , Vadenal R , Lopes O U
Published: September 2013

The role of the central nervous system, in general, and of the hypothalamus, in particular, in the genesis of various forms of experimental hypertension has been the object of increased investigation. Lesions of the anteroventral area of the third ventricle (AV3V) in rats seem to block the development of various forms of hypertension. In the present experiments, AV3V was kept intact but its connections with the caudal neuroaxis were severed by means of a curved knife (2 mm radius), stereotaxically placed at the level of the arcuate nucleus. This disconnection, per se, induces polydipsia, and a reduction of the pressor effect of i.v.-infused angiotensin II. The interactions of simultaneously performed hypothalamic disconnection (HD) and Goldblatt one-kidney, one clip, (1K1C) or two-kidney, one clip (2K1C) hypertensions was studied. It was found that HD retards and attenuates the development of 1K1C hypertension but does not materially affect the evolution of the 2K1C model. Rats with established 1K1C or 2K1C hypertensions were not affected by HD, whereas rats with chronic HD (4 weeks) showed slight and slow developing hypertension in response to clipping. The possible significance of these results with respect to the neural connections of AV3V is discussed.
Arginine vasopressin modulates the central action of angiotensin II in the dog.
Authors: Michelini L C , Barnes K L , Ferrario C M
Published: September 2013

Endogenous vasopressin may interact with central autonomic nervous system factors in the regulation of cardiovascular function. In 25 morphine/chloralose-anesthetized dogs, we studied the magnitude of the pressor response produced by an infusion of angiotensin II (AII) into the vertebral arteries (VA), before and after intracisternal (n = 10), intravertebral (n = 9), or intravenous (n = 6) administration of a competitive antagonist of arginine vasopressin (AVP) [d(CH2)5Tyr(Me) AVP]. The dose response curve to vertebral artery infusion of AII (range 2-20 ng/kg/min) was significantly (p less than 0.05) shifted to the right of control after injection of the AVP antagonist (10 micrograms/kg) into the cisterna magna; the ED at 20 mm Hg being almost double after central AVP blockade. This effect of AVP blockade was confined only to the cardiovascular response mediated by AII via the vertebral arteries. When pressor doses of AII were injected into either a vein (i.v.) or the cisterna magna of these same dogs, the increases in mean blood pressure were the same before and after AVP antagonist treatment. In another group of anesthetized dogs, we investigated whether the reduced reactivity to intravertebral AII could be duplicated by giving the AVP antagonist either via the vertebral artery or i.v. Only the cisterna magna route was effective in causing a blunting of the pressor response to vertebral artery AII. These data demonstrate a previously unknown interaction between vasopressin and the centrally mediated pressor response to intravertebral AII.
Molecular biology of catecholamine neurons. Similar gene hypothesis.
Authors: Joh T H , Baetge E E , Reis D J
Published: September 2013

We have postulated that the catecholamine-synthesizing enzymes tyrosine hydroxylase (TH), dopamine beta-hydroxylase (DBH), and phenylethanolamine N-methyltransferase (PNMT) are coded for by similar genes. To analyze the structural relationship of genes coding for these enzymes, we have cloned DNAs complementary (cDNA) to DBH and PNMT messenger RNAs (mRNAs). Using hybrid selection analysis to identify the cDNA clones positively, we discovered cross-hybridization between DBH cDNA clones and PNMT mRNA and between PNMT cDNA clones and DBH mRNA. Further analysis by RNA blot hybridization revealed that the DBH cDNA probe hybridized predominantly to a 5500 nucleotide mRNA and less strongly to a 1100 nucleotide species, and the PNMT cDNA probe hybridized strongly to the 1100 nucleotide mRNA and weakly to the 5500 nucleotide message. DNA blot hybridization analysis demonstrated that DBH and PNMT cDNA probes hybridized to several common restriction fragments of total cellular DNA. The evidence presented here suggests the existence of homologous gene-coding regions in DBH and PNMT cDNAs. These homologies may be the result of duplication of a common ancestral gene. DNA blot analysis suggests that these enzymes are coded for by single genes, which may be located in close proximity to each other in the DNA, and points to the existence of either a single gene or linked genes coding for all catecholamine enzymes.
The hypotensive activity and side effects of methyldopa, clonidine, and guanfacine.
Authors: van Zwieten P A , Thoolen M J , Timmermans P B
Published: September 2013

Clonidine (Catapres, Catapresan), guanfacine (Estulic), and methyldopa (Aldomet) are the prototypes of centrally acting antihypertensive drugs. Clonidine and guanfacine are lipophilic drugs that readily penetrate into the brain, where they stimulate alpha-adrenergic receptors in the pontomedullary region. The stimulation of these central alpha-adrenergic receptors has been shown to activate an inhibiting neuron, which causes a reduction of peripheral sympathetic tone and a subsequent fall in arterial blood pressure and heart rate. Both a centrally initiated reduction of vagus reflex activity and the activation of presynaptic alpha 2-adrenergic blocking agents in the heart may contribute to the bradycardia. Studies indicate that methyldopa also penetrates into the brain, where it is converted into alpha-methylnorepinephrine. This amine may stimulate the same central alpha-adrenergic receptors as those activated by clonidine, which will result in a hypotensive effect. Possibly, alpha-methyldopamine might also play a role. Accordingly, the modes of action of clonidine and alpha-methyldopa probably are very similar at a basic level. The central adrenergic receptors probably are located postsynaptically. Their receptor demand corresponds more closely to that of the alpha 2-subtype. Central alpha 1-adrenergic receptors might possibly play a part in the modulation of vagally induced baroreflex bradycardia. A discussion on the pharmacological basis of the side effects of the centrally acting antihypertensives has been limited to those adverse reactions that are somehow related to alpha-adrenergic receptors. Sedation, a common side effect, appears to be mediated by central alpha 2-adrenergic receptors, at least in animal models.(ABSTRACT TRUNCATED AT 250 WORDS)
Antihypertensive metabolites of alpha-methyldopa.
Authors: Robertson D , Tung C S , Goldberg M R , Hollister A S , Gerkens J F , Oates J A
Published: September 2013

alpha-Methyldopa acts through a metabolite in the central nervous system. Of the three metabolites most prominently considered as potential mediators of alpha-methyldopa hypotension--alpha-methyldopamine, alpha-methylnorepinephrine (MNE), and alpha-methylepinephrine (ME)--ME is the most potent depressor agent following intravenous infusion into rats, following injection into the lateral ventricle, and following injection into the solitary tract nucleus (NTS). The depressor effect of ME in the NTS is attenuated as effectively by timolol as by yohimbine, while the combination of both timolol and yohimbine completely abolishes the pharmacological activity of ME in the NTS. ME is approximately eightfold more potent than MNE in the NTS and also has a greater susceptibility to timolol attenuation.
Central and peripheral autonomic mechanisms involved in the circulatory actions of methyldopa.
Authors: Korner P I , Head G A , Bobik A , Badoer E , Aberdeen J A
Published: September 2013

Intracisternal (i.c.) and intravenous (i.v.) administration of methyldopa in conscious rabbits produced closely similar changes in hemodynamics, heart rate, and falls in plasma norepinephrine levels. Two weeks after giving i.c. 6-hydroxydopamine (6-OHDA), when there is widespread destruction of central noradrenergic neurons, the effects of i.c. methyldopa virtually were abolished. This suggests that noradrenergic neurons are the major central site of biotransformation into active metabolites. The circulatory and norepinephrine effects of i.v. methyldopa were attenuated but not completely abolished after giving i.c. 6-OHDA. Hence, in the rabbit about 70% of the action of methyldopa was central and about 30% was peripheral in the human therapeutic range of methyldopa concentrations. Preliminary lesion experiments suggest that the A5 nucleus plays an important role in the bradycardia. Two weeks after giving 5,6-dihydroxytryptamine (5,6-DHT) to destroy serotonergic (5HT) neurons the effects of i.c. methyldopa on mean arterial pressure (MAP) and heart rate were attenuated to approximately 50% of control effects. Therefore, some of the central effects of methyldopa apparently are mediated through 5HT pathways. We also compared the effects of i.c. methyldopa with those of i.c. clonidine (an alpha 2-adrenergic receptor agonist) and with the effects of transmitter release from the endings of noradrenergic and 5HT neurons during the first few hours after either 6-OHDA or 5,6-DHT administration. Our findings suggest that after biotransformation of methyldopa its active metabolites increase the activity of the bulbospinal noradrenergic neurons that control MAP and heart rate and reduce the activity of bulbospinal 5HT neurons.
Brain stem catecholamine mechanisms in tonic and reflex control of blood pressure.
Authors: Reis D J , Granata A R , Joh T H , Ross C A , Ruggiero D A , Park D H
Published: September 2013

Neurons of the lower brain stem maintain resting levels of arterial pressure (AP), mediate reflex responses from cardiopulmonary receptors, and are an important site of the hypotensive actions of alpha 2-adrenergic agonists. Details of the pathways and transmitters that mediate tonic and reflex control of AP are emerging. Afferent fibers of cardiopulmonary receptors in the ninth and tenth nerves terminate bilaterally in the nucleus of the tractus solitarius (NTS). Although some neurons contain substance P, the primary neurotransmitter appears to be the excitatory amino acid L-glutamate (L-glu). Neurons in rostral ventrolateral medulla, which most probably comprise the C1 group of epinephrine neurons, are also critical in AP control. C1 neurons project to innervate cholinergic preganglionic sympathetic neurons in the spinal cord. Stimulation of the C1 area electrically or with L-glu increases AP, while lesions or local injection of the inhibitory amino acid gamma-aminobutyric acid (GABA) lowers AP to levels comparable to spinal cord transection. Lesions of C1 neurons or their pathways abolish vasodepressor reflexes from baroreceptors and vagal afferents. In contrast, noradrenergic neurons of the caudal ventrolateral medulla, the A1 group, project rostrally to innervate, in part, vasopressin neurons of the hypothalamus. Stimulation of A1 neurons lowers AP, while lesions or GABA elevates it. We propose that C1 neurons comprise the so-called tonic vasomotor center of the brain stem and also mediate, via a projection from the NTS, the vasodepressor limb of baroreflexes. The NTS-C1 projection may be GABAergic.
Fifteen-year survival of patients beginning treatment with methyldopa between 1962 and 1966.
Authors: Dollery C T , Hartley K , Bulpitt P F , Daymond M , Bulpitt C J
Published: September 2013

The 15-year survival of a group of 205 patients who started treatment in the period 1962 through 1966 and who received methyldopa for two-thirds or more of the time has been investigated. At entry these patients had severe hypertension with an average pretreatment pressure of 216/126 mm Hg. Twenty-one percent had retinal hemorrhages, cotton-wool spots, or papilledema. Blood pressure showed a large fall in the first year, followed by a small, progressive, further fall up to the sixth year. After 5 years of treatment the blood pressure averaged 144/90 mm Hg in men and 151/91 mm Hg in women. The average daily dose of methyldopa was approximately 1500 mg and changed little over the 15-year period. Survival was analyzed by life tables. Approximately 81% of men and women aged 30 to 49.9 years at entry were still alive 10 years later. In the age group 60 to 69.9 years, 53.8% of men and 63.2% of women were still alive 10 years later. Seventy-nine of the patients died during the follow-up period, 89% from cardiovascular or renal disease. Ischemic heart disease (40%) was the major cause of death, followed by stroke (19%). No patients died from drug toxicity.
Atrial natriuretic peptide in humans. Production and clearance by various tissues.
Authors: Crozier I G , Nicholls M G , Ikram H , Espiner E A , Yandle T G , Jans S
Published: September 2013

Although it is assumed that the human heart secretes atrial peptides, direct proof is not available. We therefore measured immunoreactive atrial natriuretic peptide levels in coronary sinus blood and simultaneously in femoral arterial and venous blood from patients before and during stepwise incremental atrial pacing of up to 200 beats per minute. Since the fate of circulating atrial peptides is unknown, we also measured immunoreactive atrial natriuretic peptide concentrations in arterial and venous blood across the liver, kidney, lower limb, and lung in patients undergoing cardiological investigation. Peptide levels in coronary sinus blood were higher than in samples from the femoral artery or vein. As the heart rate was accelerated by atrial pacing, peptide concentrations increased in coronary sinus blood and to a lesser extent in peripheral samples. Whereas the levels in venous blood draining the liver, kidney, and lower limb were approximately 50% of those in arterial blood, concentrations were similar in samples drawn simultaneously from the pulmonary artery and the aorta. These results show that the human heart produces immunoreactive atrial natriuretic peptide and that secretion increases with atrial tachycardia. The liver, kidney, and lower limb remove the peptide from arterial blood, but there is little change in its concentration during circulation of blood through the lungs.
Calcium-related abnormalities in lymphocytes from genetically hypertensive rats.
Authors: Furspan P B , Bohr D F
Published: September 2013

We examined the effect of various external calcium concentrations on net potassium efflux and net sodium influx in lymphocytes from spontaneously hypertensive rats (SHR), stroke-prone spontaneously hypertensive rats (SHRSP), and Wistar-Kyoto rats (WKY). Net potassium efflux was greater in lymphocytes from SHRSP than in those from WKY at external calcium concentrations of 0.1, 0.3, 1.0, and 3.0 mM but not at 0 mM (14.9 +/- 0.8 vs 13.0 +/- 0.7 mmol per kilogram of dry weight per hour, respectively). Net sodium influx in lymphocytes from SHRSP was greater than in those from WKY at all external calcium concentrations tested (0, 0.1, 1.0, and 3.0 mM). In contrast to lymphocytes from WKY, net potassium efflux and net sodium influx in lymphocytes from SHRSP were not significantly higher at 0 than at 0.1 mM external calcium concentration. Lymphocytes from SHRSP had elevated intracellular free calcium concentrations (173.6 +/- 7.4 nM, n = 8), as compared with lymphocytes from WKY (98.1 +/- 9.1 nM, n = 8). These data suggest that the interaction of calcium with the lymphocyte plasma membrane directly affects monovalent ion permeability and is altered in lymphocytes from SHRSP, as compared with those from WKY. Our findings support the hypothesis that in hypertension there is a generalized increase in cell membrane permeability to calcium and monovalent ions, which may result from a reduced number of calcium-binding sites on the plasma membrane.
Is low-dose hydrochlorothiazide effective?
Authors: Magee P F , Freis E D
Published: September 2013

In a double-blind crossover study, 13 patients with pretreatment diastolic blood pressure between 95 and 109 mm Hg received nadolol, 80 mg/day, plus placebo of hydrochlorothiazide and nadolol, plus three different doses of active hydrochlorothiazide. Patients remained on each active regimen for 3 weeks, with an intervening placebo period of 2 to 4 weeks. With 12.5 mg of hydrochlorothiazide daily plus nadolol, there was no greater reduction of blood pressure than with nadolol alone. A dose of 25 mg of hydrochlorothiazide was associated with a significantly greater decrease in systolic but not diastolic pressure, as compared with nadolol alone. A significantly greater reduction in both systolic and diastolic blood pressure was obtained only with the 50 mg/day dose of hydrochlorothiazide. Extension to 6 weeks of treatment with 12.5 mg/day failed to lower the blood pressure more than the level seen at 3 weeks. These results suggest that in combination with nadolol, 12.5 mg of hydrochlorothiazide per day has no significant antihypertensive effect. There was no evidence of a flat dose-response curve in the daily dose range of 12.5 to 50 mg. For most patients, a dose of 50 mg of hydrochlorothiazide was required to lower both systolic and diastolic blood pressure significantly below the level obtained with nadolol alone.
Role of inositol lipid breakdown in the generation of intracellular signals. State of the art lecture.
Authors: Williamson J R
Published: September 2013

Many hormones, neurotransmitters, and secretagogues act by increasing the intracellular free Ca2+ concentration in target cells. The initial event following binding of agonists to specific receptors in the plasma membrane involves a receptor-mediated activation of a guanosine nucleotide-binding protein (G protein), which induces a Ca2+-independent activation of phospholipase C. This novel, presently uncharacterized G protein is inactivated by pertussis toxin-catalyzed adenosine 5'-diphosphate ribosylation in some but not all cell types. Phospholipase C catalyzes the breakdown of inositol lipids, notably phosphatidylinositol 4,5-bisphosphate, with the production of inositol phosphates and 1,2-diacylglycerol. Inositol 1,4,5-trisphosphate (IP3) is responsible for a rapid mobilization of intracellular Ca2+ by activating Ca2+ efflux from a subpopulation of the endoplasmic reticulum. The properties of this process are consistent with its being a ligand-activated ion channel with electrogenic Ca2+ efflux being charge-compensated by K+ influx. Sustained hormonal responses require extracellular Ca2+ and a prolonged elevation of the cytosolic free Ca2+. This is brought about by hormone-mediated changes of Ca2+ flux across the plasma membrane involving both an inhibition of Ca2+ efflux and an activation of Ca2+ influx. This review summarizes recent findings concerning the role of G proteins in receptor coupling to phospholipase C; the regulation of enzymes of phosphoinositide metabolism; the evidence for IP3 being a Ca2+-mobilizing second messenger and its mechanism of action; the formation of new inositol phosphates and their possible significance; the relation of intracellular Ca2+ mobilization and plasma membrane Ca2+ fluxes to the kinetics of the hormone-induced cytosolic free Ca2+ transient; and the possible roles of protein kinase C in influencing the hormone-mediated functional response.
Platelet thromboxane inhibition by plasma polypeptides in prehypertensive Dahl rats.
Authors: Uehara Y , Tobian L , Iwai J
Published: September 2013

Plasma from Dahl rats susceptible to salt-induced hypertension (Dahl S rats) contains inhibitory factors that reduce the release of thromboxane A2 from thrombin-activated platelets. Platelet-rich plasma from Dahl S rats on either low salt (0.11 or 0.3% NaCl) or high salt (4% NaCl) diets released about 50% less thromboxane A2 than comparable plasma from Dahl rats that are resistant to hypertension (Dahl R rats). This inhibitory activity was present even in the blood of 4-week-old completely normotensive Dahl S rats on a diet containing 0.11% low NaCl. The inhibitory activity could be transmitted to platelets of normal Sprague-Dawley rats by incubating these platelets in boiled and dialyzed plasma from Dahl S rats. Moreover, the inhibitory activity could be completely washed off the Dahl S platelets by incubation in Dahl R plasma. Thus, Dahl S plasma contains inhibitory factors that reduce platelet thromboxane A2 release. The factors are found in low concentrations even in Dahl R plasma; and in Dahl S or Dahl R plasma the factors are increased 25 to 32% by a 4% high NaCl diet. Digestion of Dahl S and Dahl R plasma with either trypsin or chymotrypsin destroyed the inhibitory factors, which have a molecular weight between 2,000 and 3,500. Twenty-four hours after bilateral nephrectomy, dialyzed plasma from both Dahl S and Dahl R rats was completely devoid of thromboxane A2 inhibitory activity. Thus, the factors appear to be heat-stable polypeptides either produced in the kidney or greatly influenced by the presence of renal tissue.(ABSTRACT TRUNCATED AT 250 WORDS)
Biological actions of leukotrienes. State of the art lecture.
Authors: Ford-Hutchinson A , Letts G
Published: September 2013

Leukotrienes are novel mediators derived from arachidonic acid through the 5-lipoxygenase enzyme system. Leukotriene B4 has potent effects on leukocyte function and in vivo induces leukocyte accumulation and changes in vascular permeability and modulates pain responses. Peptido-lipid leukotrienes are potent smooth muscle--contracting agents. They may have important cardiovascular actions through mechanisms involving either vasoconstriction or indirect vasodilatation. Evidence for leukotriene production has been found in subjects with allergic conditions and psoriasis, indicating a putative role for these substances in human disease.
Blood flow through cerebral collateral vessels in hypertensive and normotensive rats.
Authors: Coyle P , Heistad D D
Published: September 2013

We tested the hypothesis that blood flow through cerebral collateral vessels is lower in stroke-prone spontaneously hypertensive rats (SHRSP) than in normotensive Wistar-Kyoto rats (WKY) after occlusion of the middle cerebral artery and during maximal vasodilatation. Cerebral blood flow, measured with microspheres, was similar in adult male SHRSP and WKY under control conditions. In both strains, occlusion of the middle cerebral artery reduced blood flow and vascular conductance to the territory of the occluded artery, as compared with homologous tissue on the side contralateral to the occlusion. The territory distal to the site of occlusion was identified by intravital demarcation with neutral red dye. In both strains, vasodilatation produced by seizures after occlusion of the middle cerebral artery produced minimal increases in blood flow to the territory of the occluded artery. Blood flow and vascular conductance to the territory of the occluded MCA were significantly lower in SHRSP than in WKY (p less than 0.05) after occlusion and during seizure after occlusion. We conclude that after occlusion of the middle cerebral artery, there is less blood flow through cerebral collateral vessels in SHRSP than in WKY. We speculate that the lower blood flow through collateral vessels in SHRSP may be related to structural differences in those vessels. Thus, the tendency toward infarction after occlusion of the middle cerebral artery in SHRSP may be related, at least in part, to a more limited dilator reserve of cerebral collateral vessels in SHRSP.