bluuebunny/crossref_metadata_2025 huggingface dataset:
Converting-enzyme inhibition corrects the altered adrenal response to angiotensin II in essential hypertension.
Authors: Taylor T , Moore T J , Hollenberg N K , Williams G H
Published: June 2012

Of patients with essential hypertension, 30% to 50% do not modulate adrenal and renovascular responsiveness to angiotensin II (AII) with changes in sodium intake. To define the role of AII in mediating these altered responses, the adrenal and renal vascular responses to AII infusion (0.3, 1.0, 3.0 ng/kg/min) were assessed on a sodium-restricted intake in 31 patients with essential hypertension and 13 normotensive controls before and after 72 hours of converting-enzyme inhibition. Forty percent of the hypertensive patients had a subnormal adrenal response to AII. There were no differences between the normal and abnormal responding hypertensive patients in a number of clinical and biochemical factors except that the "abnormal responders" had a significantly (p less than 0.03) greater control AII level (37 +/- 3 vs 29 +/- 3 pg/ml) and lower control plasma aldosterone level (14 +/- 2 vs 22 +/- 3 ng/dl) than the "normal responders." When a converting-enzyme inhibitor was administered, no change in adrenal responsiveness to AII occurred in the normotensive controls or the hypertensive normal responders. In the hypertensive abnormal responders, both the threshold sensitivity and the entire dose response curve was significantly (p less than 0.01) enhanced following short-term converting-enzyme inhibition. This increased sensitivity could not be explained by differences in AII increment with AII infusions, in basal aldosterone levels, or in blood pressure or basal AII response to converting-enzyme inhibition. Since they occurred whether captopril or enalapril (MK 421) were used, this phenomenon is likely to be a specific effect of converting-enzyme inhibition.(ABSTRACT TRUNCATED AT 250 WORDS)
Antihypertensive effect of MK-421 in rats. Role of the renal kallikrein-kinin system.
Authors: Yasujima M , Abe K , Tanno M , Kasai Y , Tajima J , Seino M , Chiba S , Sato K , Goto T , Omata K
Published: June 2012

To study the hypotensive mechanism of the new oral converting-enzyme inhibitor, MK-421, we evaluated the antihypertensive effect of MK-421 in rats with hypertension induced by chronic administration of norepinephrine (NE) or vasopressin and measured urinary kallikrein and kinin excretions as indices of the renal kallikrein-kinin system. When 6 mg/kg/day of MK-421 was administered simultaneously with 1.8 mg/kg/day of NE, the systolic blood pressure of conscious rats rose on Day 1 to only 122.6 +/- 3.4 mm Hg compared with the rise to 146.3 +/- 1.6 mm Hg when NE alone was infused (p less than 0.001). Similarly, when the same dose of MK-421 was administered simultaneously with 7.2 U/kg/day of vasopressin, the systolic blood pressure of conscious rats rose on Day 1 to only 117.4 +/- 3.8 mm Hg compared with the rise to 141.6 +/- 3.4 mm Hg when vasopressin alone was infused (p less than 0.01). The antihypertensive effect of MK-421 was sustained for 6 days in rats infused with NE or vasopressin. Infusion of NE alone resulted in a small but significant increase in urinary kallikrein excretion and no change in urinary kinin excretion. The combined administration of NE with MK-421 induced additional increases in urinary kallikrein and kinin excretions. Vasopressin alone resulted in marked decreases in urinary kallikrein and kinin excretions. The combined administration of vasopressin with MK-421 induced no additional changes in urinary kallikrein and kinin excretion. These results indicate that the hypotensive effect of MK-421 may depend on a reduced sensitivity of the peripheral arteries to vasoconstrictor substances.(ABSTRACT TRUNCATED AT 250 WORDS)
Additive effects of aldosterone with vasopressin or angiotensin.
Authors: Friedman S M
Published: June 2012

Rat tail arteries were incubated overnight in potassium (K)-free physiological saline solution (PSS) at 10 degrees C, then returned to normal aerated PSS at 37 degrees C for a 3-hour recovery period followed by standard chemical analysis. Cell sodium (Na) was measured following replacement of extracellular Na by lithium (Li) at 3 degrees C. The addition of aldosterone at 10(-7) M reduced free cell Na by about 3 mmol/kg dry weight (about 20%). Arginine vasopressin also lowered cell Na to the same degree. The minimal effective dose was about 25 pM (25 pg/ml, 0.01 mU/ml), and the maximal dose was about 250 pM. No effect was seen with higher doses (greater than 1.5 nM or 0.5 mU/ml). Tissues incubated in media containing 10(-7) M aldosterone showed an exaggerated response to vasopressin evidenced by a near doubling of the maximum fall in cell Na produced by a tenfold smaller dose (25 pM). No significant change in cell K was observed while cell water tended to increase with lower doses. Angiotensin produced a similar reduction of cell Na at the same dose levels as vasopressin and was similarly additive with aldosterone. We suggest that these hormones enhance the transport of Na from luminal to basal sides of polarized cells and from cells to environment in symmetrical cells.
Alterations in vascular sensitivity to vasoactive agents after discontinuation of propranolol in SHR.
Authors: Kubota T , Yamada T
Published: June 2012

Spontaneously hypertensive rats (SHR) were treated with propranolol (P) (70 mg/kg) daily for 2 or 4 weeks and then the effects of vasoactive substances on blood pressure were studied 10 or 36 hours after the last dose of P. At 10 hours after the last dose of P, vascular hyperresponsiveness to norepinephrine (NE) and angiotensin II (AII) had largely disappeared, but the hypotensive action of isoproterenol and prostacyclin was still blocked in P-treated SHR. An increase of cyclic AMP (cAMP) in response to isoproterenol was blocked in the thoracic aorta. Similarly, an increase of circulating cAMP and blood glucose in response to epinephrine (E) was depressed. At 36 hours after the last dose of P, an elevation of blood pressure in response to NE and AII was significantly reduced in P-treated SHR. Although basal blood pressure with or without anesthesia was the same in P-treated SHR and control SHR, a decrease of blood pressure in response to isoproterenol and prostacyclin was augmented significantly in P-treated SHR. This was also true in normal rats similarly treated. In addition, an increase of cAMP in the thoracic aorta in response to isoproterenol and prostacyclin was augmented significantly in P-treated SHR. An increase in blood glucose in response to E was not blocked, but an increase of circulating cAMP in response to E was blocked. These data suggest that cAMP synthesis in the vessels is somehow related to the production of peculiar vascular responses during escape from P action.(ABSTRACT TRUNCATED AT 250 WORDS)
Management of hypertension during lactation.
Authors: White W B
Published: June 2012

There has been a dramatic increase in the number of women breast-feeding during the last decade. Since little is known about the excretion of antihypertensive drugs into human breast milk, the management of hypertension during lactation can be problematical. To enable the clinician to better advise the hypertensive, lactating mother, the published literature on the excretion of antihypertensive agents into human milk has been reviewed and is presented in this report.
Increased plasma norepinephrine in young patients with essential hypertension under three sodium intakes.
Authors: Masuo K , Ogihara T , Kumahara Y , Yamatodani A , Wada H
Published: June 2012

Increased sympathetic nerve activity may play an important role in the pathogenesis of essential hypertension. It is well known that both dietary sodium intake and age influence the plasma norepinephrine (NE) concentration. The present study was undertaken to evaluate the effects of age on sympathetic nerve activity in patients with essential hypertension and normal control subjects under low-, regular-, and high-sodium regimens (mean 24-hour sodium excretions: 30 +/- 4, 116 +/- 7,280 +/- 15 mEq, respectively). Plasma NE and epinephrine (E) were analyzed by trihydroxyindole methods after high-performance liquid chromatography separation. Subjects were categorized by age into young (less than or equal to 40 yrs), middle-aged (40-60 years), and old (greater than or equal to 60 years) subgroups. Mean plasma NE in hypertensive patients was significantly higher (p less than 0.01) than in normal subjects on each of the sodium regimens. In normal control subjects, there was a significant positive correlation between age and plasma NE with all three sodium intakes. However, no correlation was seen in hypertensive patients on any of the sodium regimens, because in the young subgroup of hypertensive patients the mean plasma NE was significantly higher than that of normal control subjects. These results suggest that the increased sympathetic nerve activity plays an important role in the pathogenesis of essential hypertension, especially in young patients.
Polyuria, polydypsia, and hypertension produced by a six-day intravenous infusion of prostaglandin E1 in the conscious dog.
Authors: Rocchini A P , Behrendt D
Published: June 2012

The effects of a continuous intravenous infusion of prostaglandin E1 (PGE1) on mean arterial pressure (MAP), sodium and water balance, and plasma renin activity (PRA) were examined in 10 conscious dogs maintained on a 70 to 75 mEq/day sodium intake. In a crossover pattern, each dog received 6 days of intravenous PGE1 (0.1 micrograms/kg/min) and 6 days of intravenous diluent. When compared to diluent, intravenous PGE1 resulted in a mild sustained rise in MAP. By Day 6 the intravenous PGE1, MAP had increased from 98 +/- 4 to 112 +/- 5 mm Hg (mean +/- SE) (p less than 0.04). Concurrent with the MAP increase, PRA increased from 0.6 +/- 0.2 to 3.1 +/- 0.7 ng angiotensin I (AI)/ml/hr (p less than 0.03). To assess the role of the renin-angiotensin system in the maintenance of the systemic hypertension. AI converting-enzyme inhibitor was given to four dogs on Day 6 of both intravenous PGE1 and diluent. Only when the dogs were receiving PGE1 did the administration of converting-enzyme inhibitor result in a significant decrease in MAP (-19 +/- 5 mm Hg). In addition to increasing arterial pressure, the chronic infusion of PGE1 also produced changes in salt and water balance. When compared to diluent, PGE1 resulted in a twofold increase in both water intake and urine output, an increase in urinary sodium excretion (from 72 +/- 3 to 84 +/- 6 mEq/day, p less than 0.05, on Day 1), and a decrease in urine osmolality (from 942 +/- 82 to 586 +/- 61 mOsmol/kg H2O/day, p less than 0.05, on Day 1).(ABSTRACT TRUNCATED AT 250 WORDS)
Location of the area postrema pressor pathway in the dog brain stem.
Authors: Barnes K L , Ferrario C M
Published: June 2012

Electrical stimulation of the dog's area postrema (AP) induces a response that mimics the pressor response produced by intravertebral infusion of low-dose angiotensin II, which causes an increase in mean arterial pressure associated with transient tachycardia and increased peripheral resistance. The present study investigated in morphine-chloralose anesthetized dogs whether: 1) the characteristics of the AP pressor response are influenced by the presence of carotid sinus afferents; 2) structures rostral to the medulla influence the AP pressor response; and 3) the pressor pathway is initiated by neurons within the AP. Since bilateral cervical sinovagal denervation, which potentiated the phenylephrine pressor response, did not affect the pressor response to AP stimulation, the data provide evidence for an inhibitory influence exerted upon the central baroreflex mechanism by the AP pressor mechanism. The unaltered AP pressor response after midcollicular transection suggests that the efferent pathway is contained within the brain stem caudal to the pons. Finally, the elimination of the pressor response following kainic acid microinjection into the AP provides evidence that the AP pressor mechanism is initiated by neurons within the AP, rather than by fibers of passage from other pressor centers. These results suggest that the AP produces its facilitation of central sympathetic vasomotor outflow via a pathway contained within the medulla.
Pressor hyperresponsiveness in saline-infused rabbits.
Authors: Sakamaki T , Johnson J A , Zeigler D W , Koivunen D G , Siripaisarnpipat S , Fowler W L , Payne C G
Published: June 2012

Conscious rabbits infused intravenously (i.v.) with isotonic saline at 1.5 to 1.8 ml/min for 24 hours had greater pressor responses to norepinephrine (NE) than did normal control rabbits. Infusion of the angiotension II (ANG II) antagonist [Sar1, Ile8] ANG II did not decrease the exaggerated pressor responses to NE in saline-infused rabbits. Measurements of cardiac output (CO) as well as the pressor responses to NE before and after saline infusion revealed that, although saline infusion increased the CO and decreased total peripheral resistance (TPR), CO did not change during NE infusion either before or after saline infusion, but NE produced significantly greater increases in mean arterial pressure (MAP) and TPR after saline infusion than before the saline infusion. The cross-circulation of blood at 10 ml/min for 5 minutes between saline-infused donor rabbits and normal recipient rabbits resulted in pressor hyperresponsiveness to NE in the normal recipients. Similar cross-circulation experiments between pairs of normal rabbits did not alter the pressor responses to NE. These studies provided direct evidence that expansion of body fluid volumes by saline infusion results in pressor and vascular hyperresponsiveness. There was no evidence to indicate that ANG II was involved in the mechanisms producing this pressor hyperresponsiveness. Some circulating hormonal factor, however, was involved in mediating the pressor hyperresponsiveness following saline infusion. The results of this study are compatible with the concept that natriuretic hormone may play a role in promoting pressor hyperresponsiveness in saline-expanded animals.
Increased urinary kallikrein-like activity during ADH-induced hyponatremia in rats.
Authors: Tomita K , Shiigai T , Saito H , Iino Y , Takeuchi J
Published: June 2012

The urinary kallikrein system was studied during hyponatremia associated with water and vasopressin administration in rats. Two groups of animals were studied. In the experimental group (n = 5), vasopressin (0.4 U/day) was injected intramuscularly for 7 days, and water (15%-20% body weight per day) was given via a stomach tube. The control group (n = 6) received only vasopressin. In the experimental group, plasma sodium concentration (PNa) decreased from 143.2 +/- 0.5 to 130.8 +/- 1.8 (m +/- SEM) mmol/liter (5th day, p less than 0.01) along with plasma osmolality. Urinary kallikrein-like activities (UkaV) increased from 99.1 +/- 7.5 to 172.6 +/- 23.5 mumol X min/day (100 g body weight) (5th day, p less than 0.05; 6th day, p less than 0.05; and 7th day, p less than 0.05) after the administration of vasopressin. Uric acid clearance (Cua) increased from 0.153 +/- 0.014 to 0.275 +/- 0.041 ml/min (5th day, p less than 0.05; 7th day, p less than 0.05). No change was observed in urinary aldosterone excretion (UAldV), creatinine clearance, or blood pressure. UkaV correlated with Cua (r = 0.81, p less than 0.01) and with the degree of change of PNa (r = --0.79, p less than 0.01), respectively. In the control group, no change was observed in the above parameters. A significant relationship between UkaV and fractional Na clearance (r = 0.60, p less than 0.01) was observed. We conclude that the urinary kallikrein system in rats may be stimulated during hyponatremia when induced by water and vasopressin. This increased activity is probably the result of volume expansion associated with water and vasopressin and may have some relationship to fractional Na clearance in the kidney.
Erythrocyte Na+,K+ cotransport and Na+,K+ pump in black and caucasian hypertensive patients.
Authors: Tuck M L , Gross C , Maxwell M H , Brickman A S , Krasnoshtein G , Mayes D
Published: June 2012

Alterations in red blood cell (RBC) Na+,K+ pump and in Na+,K+ cotransport (CoT) have been described in essential hypertension (EH). We examined pump and CoT in 50 normotensive (NT) subjects and 58 EH subjects subdivided by race and family history of hypertension (+ FH). RBCs were preloaded with Na+ to obtain intracellular levels of 25 mM/liter cells by using the p-chloromercuribenzene sulfonic acid (pCMBS) method. Na+ and K+ efflux rates into a magnesium-sucrose medium were quantitated in the presence of ouabain and ouabain plus furosemide to define pump and CoT activity respectively. Mean intracellular Na+ content was higher (p less than 0.05) in black NT and HT subjects compared to Caucasians. Mean RBC CoT was lower in black EH compared to NT and compared to Caucasian NT and HT subjects. Conversely, Caucasian HT patients had higher mean CoT than NT subjects. Subdivision into + FH revealed very little effect of + FH on CoT in black NT and HT subjects. In Caucasian NT and HT subjects with + FH, mean CoT was significantly reduced (less than 0.3 mM/liter cells/hr) compared to those without + FH. A subgroup of Caucasian EH subjects displayed high CoT (greater than 0.6 mM/liter cells/hr); a + FH had little impact on the high CoT group. There was no correlation between RBC CoT activity and age, sex, severity of hypertension, urinary sodium excretion, and plasma aldosterone. There was a positive correlation (r = + 0.47; p less than 0.01) between CoT and upright plasma renin activity.(ABSTRACT TRUNCATED AT 250 WORDS)
Dilation of forearm blood vessels after angiotensin-converting-enzyme inhibition by captopril in hypertensive patients.
Authors: Johns D W , Ayers C R , Williams S C
Published: June 2012

In eight hypertensive patients, forearm vascular tone was assessed by water plethysmography following inhibition of angiotensin II-converting-enzyme (ACE) activity with captopril. Acute captopril administration increased venous distensibility (VV30) and decreased forearm vascular resistance (FVR), while it lowered systemic blood pressure (BP). Alpha-one adrenergic receptor blockade by prazosin did not prevent captopril from decreasing vascular tone or lowering blood pressure (BP). Thus, captopril dilated both veins and arterioles. The primary mechanism of captopril's acute antihypertensive action did not involve inhibition of alpha1-adrenergic receptor activity. Moreover, captopril and prazosin together produced a greater reduction in BP and peripheral resistance than occurred with either agent alone.
Vasomotion of renal blood flow in essential hypertension. Oscillations in xenon transit.
Authors: Hollenberg N K , Sandor T
Published: June 2012

To assess the frequency and magnitude of phasic renal blood flow changes in essential hypertension, we applied an analytical method based on the estimation of power spectral density to xenon transit through the kidney. Despite similar age and gender distribution of the patients and exclusion of those with accelerated hypertension, mean renal blood flow was significantly lower in 100 patients with essential hypertension (299 +/- 8 ml/100 g/min) than in the 144 normal subjects (335 +/- 6 ml/100 g/min; p less than 0.001). Normalized power, the index of oscillatory behavior, was more than twice normal in patients with essential hypertension (p less than 0.001), but there was no difference in the frequency or cycle length of the oscillation. Two maneuvers that induced renal vasoconstriction, the application of cuffs to the thighs which were then inflated to diastolic blood pressure and an emotional provocation, reduced renal blood flow much more in patients with essential hypertension (p less than 0.01) in association with a striking increase in normalized power (p less than 0.001). The oscillations, which reflected not the phasic blood pressure change but rather the phasic change in renal perfusion, provided additional evidence that renal vasoconstriction plays an active role in the pathogenesis of essential hypertension.
Chronic angiotensin II infusion decreases renal norepinephrine overflow in conscious dogs.
Authors: Carroll R G , Lohmeier T E , Brown A J
Published: June 2012

Sympathetic nerve activity and in particular renal sympathetic nerve activity were monitored in six conscious dogs subjected to 6 days of intravenous angiotensin (ANG II) infusion (20 ng/kg/min). This was accomplished by measurement of both arterial and renal venous plasma catecholamine concentration. During the initial 4 hours of ANG II infusion, mean arterial pressure (MAP) increased 35 +/- 8 mm Hg from a control value of 101 +/- 4 mm Hg. Although there were no significant changes in arterial plasma norepinephrine (NE) concentration at this time (control = 148 +/- 40 pg/ml), arterial plasma epinephrine (E) concentration increased threefold (control 42 +/- 15 pg/ml). After 24 hours of ANG II infusion, MAP remained elevated (132 +/- 5 mm Hg), but plasma E concentration returned to control levels. From Days 2 through 6 of ANG II infusion, MAP was elevated approximately 40 mm Hg, but there were no chronic increases in either arterial plasma E or NE concentrations. In contrast to arterial plasma catecholamine concentration, renal vein plasma NE concentration (control = 216 +/- 27 pg/ml) actually decreased during both the acute (122 +/- 12 pg/ml) and chronic (103 +/- 26 pg/ml) phases of ANG II infusion. Moreover, renal NE overflow (renal venous plasma NE concentration-arterial plasma NE concentration X effective renal plasma flow), an index of renal sympathetic nerve activity, was depressed during the chronic phase of ANG II hypertension. These results, therefore, do not support the contention that the sympathetic nervous system mediates the hypertension produced by elevated plasma levels of ANG II.(ABSTRACT TRUNCATED AT 250 WORDS)
Hypertension-producing factor in serum of hypertensive Dahl salt-sensitive rats.
Authors: Hirata Y , Tobian L , Simon G , Iwai J
Published: June 2012

To investigate whether serum in hypertensive Dahl salt-sensitive rats (S rats) contains a hypertensinogenic substance, we examined the effects of repeated injections of serum from such S rats on blood pressure (BP) and pressor responses. Serum was collected from either hypertensive or normotensive S rats (fed an 8% or 0.11% NaCl diet, respectively) and injected into uninephrectomized recipient S rats for 2 weeks (0.45 ml, twice a day, i.v.). Serum from hypertensive rats injected for 14 days significantly increased BP by 14 mm Hg (143 vs 129, p less than 0.05), pressor responses to angiotensin II (ANGII) by 45% (p less than 0.005), pressor responses to norepinephrine (NE) by 38% (p less than 0.025), and Na concentration in the aortic wall of recipient rats by 5.9% (p less than 0.05), compared to the effects of the injection of serum from normotensive S rats. These results imply that hypertensive S serum contains a hypertensinogenic substance and that this serum factor produces a mild hypertension in the recipient rats and also contributes importantly to the hypertension in donor S rats. Dahl salt-resistant rats (R rats) on either 8% or 0.11% NaCl had normal BP. Their sera produced no differences in BP or in pressor responses in recipient rats. Hence 8% NaCl, which produced no hypertension, also induced no hypertensinogenic serum factors in R rats. We sought to determine whether nephrectomy would alter these humoral factors. The BP averaged 139 mm Hg in rats receiving normotensive sham-nephrectomized S serum vs 154 in those receiving hypertensive sham-nephrectomized S serum, 15 mm Hg higher (p less than 0.05).(ABSTRACT TRUNCATED AT 250 WORDS)
Urinary excretion of renin and its biochemical properties in dogs.
Authors: Yukimura T , Miura K , Matsushima Y , Ikemoto F , Yamamoto K
Published: June 2012

The amount and biochemical properties of renin excreted by anesthetized dogs were investigated to elucidate the significance of urinary excretion in the metabolism of renin. Mean arterial blood pressure was 127 +/- 4 mm Hg, renal blood flow was 170 +/- 8 ml/min, glomerular filtration rate, 38.6 +/- 2.3 ml/min, and urine flow rate, 0.37 +/- 0.09 ml/min (n = 11). Urinary renin concentration (URC) was 9.2 +/- 2.1 ng angiotensin I (ANG I)/ml X hr (n = 11), as determined by radioimmunoassay for ANG I generated by incubation with semipurified homologous renin substrate. The ANG I-producing activity was inhibited by more than 90% by a specific antibody to dog kidney renin. The renin secretion rate from the left kidney into the renal vein was 76.4 +/- 13.3 ng ANG I/ml X hr per min (n = 11), and the simultaneous urinary excretion rate of renin was 2.3 +/- 0.4 ng ANG I/ml X hr per min (n = 11). Molecular weight of the urinary renin was 40,000 daltons. The pH dependent curves of the angiotensin-forming capacity of renin showed an optimum between pH 5.5 to 6.0, and the estimated Michaelis constant was 0.42 microM. These biochemical parameters were similar to the findings in the case of renin in the plasma and the kidney. Moreover, neither acid nor trypsin treatment altered the renin activity in the urine. Thus, the active form of renin with a molecular weight 40,000 was excreted into the urine in dogs. Urinary excretion of renin was a small percentage of the renin secretion rate, thereby indicating the minor role of urinary excretion in the metabolism of renin.
Cholinergic stimulation of vasopressin release in spontaneously hypertensive rats.
Authors: Sladek C D , Blair M L
Published: June 2012

Plasma vasopressin (VP) concentration is elevated in spontaneously hypertensive rats (SHRs) relative to their normotensive Wistar-Kyoto (WKY) controls. The possibility that this reflects altered responsiveness of the hypothalamo-neurohypophyseal system (HNS) in SHRs was examined by comparing VP release in response to acetylcholine from organ cultured HNS explants obtained from SHR and WKY donors. Explants were prepared from 5-, 8-, and 18-week-old animals. Blood pressure was significantly elevated in the 8- and 18-week-old SHR donors relative to their age-matched WKY donors. VP release was assessed on the 4th day of culture during a control hour and during the subsequent hour in the presence of acetylcholine. Acetylcholine caused a concentration-dependent stimulation of VP release from both types of explants, but the response was significantly greater in the explants from 5- and 8-week-old SHRs than in explants from age-matched WKYs. The explants from 18-week-old SHRs and WKYs demonstrated comparable sensitivity to acetylcholine. Basal VP release was not significantly different in explants from age-matched SHRs and WKYs, but it did increase with donor age in both strains. These studies indicate potential hyperresponsiveness of the HNS to excitatory stimuli in SHRs during the developmental phase of hypertension. The hyperresponsiveness disappears in the chronically hypertensive phase. Thus, increased sensitivity of the HNS during the development of hypertension may contribute to the elevation of plasma VP concentration in SHRs.
Construction of a model for the three-dimensional structure of human renal renin.
Authors: Carlson W , Karplus M , Haber E
Published: June 2012

The aspartyl proteases that have had their complete three-dimensional structures determined by x-ray diffraction techniques exhibit a high degree of structural homology and a correspondingly high degree of sequence homology. Using this homology, we constructed a model for the three-dimensional structure of human renal renin. We then refined and evaluated the model with the energy refinement program called CHARMM. We found that the model for human renin differs from that of mouse submaxillary gland renin in certain features, which may account for the differences in substrate specificity and antibody binding. Amino acid differences between human and mouse renin in the regions that bind the P1' side chain of the substrate appear to change only the shape of the S1' subsite of the enzyme, so that either valine or leucine side chains of the substrate can be accommodated by human renin. Amino acids in the solvent-accessible surface of the 75-85 flap appear to be distinctly different between the two structures and could account for the differences observed in antibody binding to human and mouse renin.
Acute vasodilator action of pindolol in humans.
Authors: Chang P C , van Brummelen P , Vermeij P
Published: June 2012

The local hemodynamic effect of pindolol, a nonselective beta-blocker with intrinsic sympathomimetic activity, was investigated in 17 healthy volunteers. Changes in forearm blood flow (FBF) in response to infusion of drugs into the brachial artery were measured by plethysmography. Pindolol increased FBF dose dependently to a maximal value of 62 +/- 8% (mean +/- SEM, p less than 0.001) without inducing changes in heart rate or blood pressure. For a single dose of pindolol the maximal effect on FBF was seen after approximately 4 minutes of infusion, and this effect persisted for at least 12 minutes after the infusion. The pindolol-induced increase in FBF was reduced by concomitant infusion of propranolol (p less than 0.001). Intra-arterial infusion of practolol did not influence FBF. No significant influence of pindolol was found on the vasoconstriction induced by the alpha 1-adrenergic receptor agonist methoxamine, the alpha 2-adrenergic receptor agonist BHT-933, or angiotensin II. Measurement of plasma pindolol concentrations in the venous effluent of the forearm suggested that vasodilatation occurred at drug levels within the therapeutic range. These results indicate that the beta-blocker pindolol has vasodilatory properties owing to stimulation of vascular beta 2-adrenergic receptors and that this effect may be of therapeutic relevance.
The effects of epinephrine on norepinephrine release in essential hypertension.
Authors: Nezu M , Miura Y , Adachi M , Adachi M , Kimura S , Toriyabe S , Ishizuka Y , Ohashi H , Sugawara T , Takahashi M
Published: June 2012

The effects of endogenous epinephrine (E), released by glucagon injection, and exogenously infused E on plasma norepinephrine (NE) and cardiovascular responses before and after beta-blockade were studied in patients with essential hypertension and in age-matched normotensive controls. The resting plasma NE and E levels were significantly higher in the borderline hypertensive subjects (NE: 251 +/- 21 pg/ml [SEM], p less than 0.005; E: 57 +/- 5, p less than 0.05, n = 18) than in controls (NE: 129 +/- 12; E: 39 +/- 5, n = 18). An intravenous injection of glucagon (1.0 mg) induced a transient rise of both plasma catecholamine levels and blood pressure in every subject studied. Plasma E levels rose transiently and returned to the basal levels by 20 minutes after the injection, whereas plasma NE levels showed a more prolonged rise over 20 minutes. beta-Blockade with propranolol did not affect the plasma E response to glucagon, but inhibited the prolonged rise of plasma NE levels. An intravenous infusion of exogenous E (1.25-1.50 micrograms/min) for 30 minutes caused an apparent rise of both plasma NE levels and blood pressure, which lasted more than 60 minutes after stopping the E infusion. Propranolol did not affect the time course of plasma E but again inhibited the prolonged rise of both plasma NE levels and blood pressure. No significant differences could be observed in the cardiovascular or plasma NE responses to glucagon or to E infusion between normal and hypertensive subjects. These findings lend support to the view that plasma E can act physiologically as a sustained stimulator of presynaptic beta-adrenergic receptors, which leads to an enhanced NE release from peripheral sympathetic nerve terminals and a rise of blood pressure in humans.
In vitro arterial responses to vasopressin in subjects with a family history of hypertension.
Authors: Wyse D G
Published: June 2012

Intrinsic vascular responsiveness was examined in isolated, helically cut strips of cystic artery from 32 normotensive women. Contractions were elicited by vasopressin, norepinephrine, 5-hydroxytryptamine and transmural electrical stimulation. Of the 32 subjects, 17 had a family history of hypertension in a first-degree relative (parent, sibling, or adult offspring) and 15 had no family history of hypertension. The ages and mean arterial blood pressures of the two groups were not different: 39 +/- 12 versus 35 +/- 11 years (mean +/- SD; p = 0.263) and 87 +/- 4 versus 85 +/- 5 mm Hg (p = 0.214) respectively. The vasopressin dose-response curve was significantly shifted to the left for arteries of those subjects with a family history of hypertension compared with that for arteries of subjects with no family history (e.g., response--percent of norepinephrine maximum--to 100 mU/ml = 31 +/- 23 versus 12 +/- 16; p = 0.014). All other responses were not significantly different, although in general the arteries of those subjects with a family history tended to have greater responses to all stimuli except norepinephrine. Arteries from the two groups did not differ with respect to physical dimensions (e.g., cross-sectional area), passive mechanical properties, or maximal responses to norepinephrine. The data indicate that altered intrinsic vascular responsiveness is linked to a family history of hypertension in normotensive subjects and thus could play a role in the familial aggregation of elevated blood pressure.
Selective antagonism of humoral versus neural vasoconstrictor responses by nisoldipine.
Authors: Lappe R W , Barron K W , Faber J E , Brody M J
Published: June 2012

The effects of nisoldipine administration on vascular reactivity to humoral and neural vasoconstrictor stimuli were examined in the intact rat. For these experiments, rats were instrumented with miniaturized pulsed Doppler flow probes to allow continuous measurement of renal, mesenteric, and hindquarters blood flow. In conscious and anesthetized rats, intravenous doses of angiotensin II (75 and 150 ng/kg), norepinephrine (0.6 and 1.2 microgram/kg), and epinephrine (0.6 and 1.2 microgram/kg) caused dose-dependent increases in arterial pressure and renal and mesenteric vascular resistance. Nisoldipine (0.7 microgram/min) administration significantly attenuated (p less than 0.05) the pressor and regional vasoconstrictor actions of all three circulating pressor agents; however, nisoldipine infusion had little effect on neurally mediated regional vasoconstrictor responses elicited by electrical stimulation of the posterior hypothalamus or greater splanchnic nerve. These data indicate that nisoldipine depressed vascular responsiveness to humoral vasoconstrictor agents, while neural vasoconstrictor responses were unaffected. Thus nisoldipine appears to exert preferential antagonistic effects on humoral rather than on neural vasoconstrictor stimuli.
alpha 1-Adrenergic receptor binding in the spontaneously hypertensive rat.
Authors: Pullen G L , Oltmans G A , Berenbaum S A , Hansen T R
Published: June 2012

Increased sympathetic outflow from the central nervous system to the periphery may contribute to the initiation of hypertension in spontaneously hypertensive rats (SHR). As this alteration in sympathetic activity may be mediated in part by alpha-adrenergic receptors in the central nervous system, the current study examined alpha 1-adrenergic receptors in various brain areas of SHR and normotensive Wistar-Kyoto control rats (WKY). The alpha 1-adrenergic receptor number and apparent affinity constants of brain sections of both young prehypertensive animals (4 weeks old) and mature hypertensive animals (12 weeks old) were studied with the alpha 1-adrenergic receptor antagonist [3H]WB-4101 to label the alpha-adrenergic receptor. Five brain regions were studied: rostral hypothalamus, caudal hypothalamus, locus ceruleus, nucleus tractus solitarius, and frontal cortical poles. In comparison to normotensive controls, mature hypertensive rats had a significantly greater density (p less than 0.05) of the alpha 1-adrenergic receptors in the rostral hypothalamus (+11%), caudal hypothalamus (+25%), and frontal cortical poles (+20%). Significantly greater (p less than 0.05) alpha 1-adrenergic receptor density was found in the rostral hypothalamus (+27%), caudal hypothalamus (+60%), and locus ceruleus (+39%) of the young prehypertensive SHR compared with age-matched WKY. These results indicate the presence of altered adrenergic receptor systems in the brains of genetically hypertensive animals and suggest that changes in the receptor systems take place during establishment of the hypertension.
Role of hypertension in progressive glomerular immune injury.
Authors: Raij L , Azar S , Keane W F
Published: June 2012

The relationship between hypertension, ferritin-antiferritin mesangial immune injury (FIC), and progressive glomerular damage was studied in hypertensive (8% NaCl chow) Dahl salt-sensitive rats (DS) and in spontaneously hypertensive rats (SHR). The glomeruli of SHR are protected from the increased perfusion pressure that accompanies systemic hypertension by preglomerular vasoconstriction, while the glomeruli of hypertensive DS are not. Blood pressure, serum creatinine levels, urinary protein excretion, and glomerular injury (assessed by semiquantitative morphometric analysis) were determined in 20-week-old SHR and DS with FIC. In addition, half of a group of 20-week-old SHR with FIC were uninephrectomized and progression of glomerular injury was assessed 12 weeks later. Control rats for each of the groups did not receive FIC. Our studies showed that more extensive mesangial expansion and glomerulosclerosis developed in hypertensive DS with FIC than in rats without FIC. Glomerular injury in DS with FIC affected cortical and deep glomeruli. Similarly, hypertensive SHR with FIC had minimal damage in cortical glomeruli. In deep glomeruli of SHR, mesangial expansion was similar to that of DS, but glomerulosclerosis was absent. In SHR, a 50% reduction in renal mass, a maneuver known to decrease preglomerular vasoconstriction, resulted in mesangial expansion similar to that in DS in cortical glomeruli while deep glomeruli developed mesangial expansion as well as glomerulosclerosis. Our results suggest that when hypertension and mesangial immune injury coexist with renal vasodilatation (as occurs in DS with 2 kidneys and in SHR after uninephrectomy), they act synergistically to induce progressive glomerular damage. Similar mechanisms may be operative in hypertensive humans with glomerulonephritis and may condition the rate of progression to renal insufficiency.
Erythrocyte membrane transport in hypertensive humans and rats. Effect of sodium depletion and excess.
Authors: Feig P U , Mitchell P P , Boylan J W
Published: June 2012

Sodium transport by erythrocyte membranes was studied in hypertensive and normotensive humans and in spontaneously hypertensive rats (SHR) and normotensive Wistar-Kyoto rats (WKY). The rate constants of sodium efflux were increased in both hypertensive humans and rats, and this increase was due mostly to an increase in the ouabain-resistant component of efflux. Both the furosemide-sensitive and furosemide-resistant components of efflux were increased. The ouabain-sensitive efflux was also increased, as confirmed by the ouabain-sensitive rubidium influx in rats. In rats, the intracellular sodium content was also increased in the SHR with respect to the WKY. The transport abnormalities of red cell membrane associated with hypertension were similar in humans and rats. In rats, sodium depletion failed to affect the transport abnormality, while sodium load made the difference in transport between SHR and WKY undetectable. Cross-incubation experiments, using plasma and erythrocytes of WKY and SHR, are more suggestive of a flux abnormality that is intrinsic to the cell membrane than of one that is humoral in nature.
Erythrocyte phosphate release in essential hypertension.
Authors: Walter U
Published: June 2012

In this study erythrocyte phosphate release depended on the intracellular hydrolysis of organic phosphate esters. Total phosphate release was increased in essential hypertension, which suggests an elevated phosphate ester metabolism. Ouabain-sensitive phosphate release was decreased, and the ratio of intracellular Na+/K+ concentrations was increased, a finding consistent with a diminished Na-K-ATPase activity. Furosemide in a concentration of 1.0 mmol/L inhibited erythrocyte phosphate release by half, probably owing to nonspecific membrane effects. The combination of ouabain and furosemide reduced phosphate transfer to a higher degree than did each substance individually. Because of the nonspecific alteration of erythrocyte membrane permeability by furosemide in a concentration of 1.0 mmol/L, ouabain-insensitive, furosemide-sensitive phosphate release and ouabain-insensitive, furosemide-sensitive Na+ efflux (Na-K cotransport) must not be regarded uncritically as specific transport systems.
Chronic ethanol consumption, stress, and hypertension.
Authors: Chan T C , Wall R A , Sutter M C
Published: June 2012

A reliable method of producing physical stress in the rat was developed using heat irradiation, and the possible interaction between chronic ethanol consumption and stress was investigated in a rat model of alcoholism. Chronic heat stress and chronic ethanol consumption each produced mild hypertension in rats. When combined, the two treatments resulted in hypertension more severe than that produced by either stress or ethanol consumption alone. The group of animals receiving both treatments also exhibited high mortality. Investigations into the mechanisms responsible for the apparent additive effects of the two treatments revealed that the animals in this group had the highest circulating norepinephrine levels. The plasma volumes, however, were not different between the stressed groups and their unstressed counterparts. As the plasma norepinephrine level usually reflects overall sympathetic tone of an animal, our results suggest that the additional hypertensive effect of chronic stress on the ethanol-treated animals is associated with increased sympathetic nervous activity and is not a result of expanded plasma volume. These findings may have clinical implications for human alcoholics and in the analysis of cardiovascular risk factors in hypertensive patients.
Systemic and coronary hemodynamic effects of pinacidil in awake normotensive and hypertensive dogs.
Authors: Kawashima S , Liang C S
Published: June 2012

We studied the systemic and coronary hemodynamic effects of a new antihypertensive agent, pinacidil, in nine morphine-sedated chronically instrumented dogs with one-kidney renal hypertension and eight similarly treated sham-operated normotensive dogs. The renal hypertensive dogs exhibited higher mean aortic blood pressure, total peripheral vascular resistance, and plasma renin activity before pinacidil administration than the sham-operated animals. The renal hypertensive dogs also had a lower left ventricular norepinephrine content, but the two groups did not differ significantly in plasma norepinephrine levels, cardiac output, or heart rate. Pinacidil decreased mean aortic pressure and total peripheral vascular resistance and increased cardiac output and heart rate in both groups. The changes in aortic pressure, total peripheral vascular resistance, and cardiac output were similar between the two groups, but the increase in heart rate was attenuated in renal hypertension. The peak rate of rise of left ventricular pressure (dP/dt), the ratio of left ventricular dP/dt and the developed pressure during isovolumic contraction (dP/dt/P), myocardial oxygen consumption, and plasma norepinephrine levels increased after pinacidil administration in the sham-operated dogs, but did not change in the renal hypertension group. The two groups did not differ in their responses of left ventricular dP/dt to intravenous isoproterenol. Pinacidil also caused coronary vasodilation in both groups, as evidenced by an increase in coronary blood flow and decreases in coronary vascular resistance and myocardial oxygen extraction. The decrease in myocardial oxygen extraction was similar in the two groups, but the increase in coronary blood flow was significantly less (p less than 0.05), probably because of the absence of an increase in myocardial oxygen consumption in the renal hypertensive dogs.(ABSTRACT TRUNCATED AT 250 WORDS)
Role of acetyl glyceryl ether phosphorylcholine in blood pressure regulation in rats.
Authors: Masugi F , Ogihara T , Saeki S , Otsuka A , Kumahara Y
Published: June 2012

The role of an endogenously occurring acetyl glyceryl ether phosphorylcholine (AGEPC) in blood pressure regulation was studied with an AGEPC antagonist in rats with hypertension of various etiologies. The hypotensive activity of an intravenously injected AGEPC was competitively suppressed by the intravenous infusion of 3-(N-n-octadecylcarbamoyloxy)-2-methoxypropyl-2-thiazolioethylphospha te (CV-3988) and was dose-dependent. The CV-3988 was infused intravenously into one- and two-kidney, one clip hypertensive, deoxycorticosterone-salt hypertensive, adrenal regeneration hypertensive, spontaneously hypertensive, and normotensive control rats. The increase in blood pressure caused by CV-3988 infusion in spontaneously hypertensive and normotensive control rats was significant (p less than 0.01 and p less than 0.001, respectively, at 60 min) compared with that caused by vehicle infusion. The increase was not seen in rats with secondary hypertension. In rats with two-kidney, one clip hypertension, the initial rapid decrease in blood pressure seen after unclipping was significantly (p less than 0.05) inhibited by CV-3988 infusion as compared with that by vehicle infusion. These results suggest that endogenous AGEPC may participate in the blood pressure regulation and pathophysiology of some forms of hypertension in rats.
Effects of alpha-human atrial natriuretic peptide in essential hypertension.
Authors: Richards A M , Nicholls M G , Espiner E A , Ikram H , Yandle T G , Joyce S L , Cullens M M
Published: June 2012

Because there is little published information on the effects of atrial peptides in hypertensive humans, 100 micrograms of alpha-human atrial natriuretic peptide was injected intravenously into six patients with essential hypertension in a double-blind, placebo-controlled study under standardized conditions of body posture and dietary sodium and potassium intake. The peptide increased urine sodium excretion sixfold in the first 30 minutes. Smaller increments occurred in urine volume and in calcium, magnesium, and phosphorus excretion; the rise in urine potassium concentration was not statistically significant. Most of these indices returned to time-matched placebo values within 1 hour, but urine sodium excretion remained high for 2 1/2 hours. Arterial pressure fell within 2 minutes of alpha-human atrial natriuretic peptide injection, then returned to matching placebo levels by 10 minutes. Conversely, heart rate increased rapidly and remained elevated for 3 hours. The peptide induced a prompt, brief rise in plasma norepinephrine concentration and a more sustained fall in epinephrine and aldosterone levels, but it did not affect plasma renin activity or cortisol concentration. Compared with normotensive volunteers studied previously under the same conditions, the hypertensive subjects had a greater response in urine volume and sodium, calcium, and magnesium excretion but a less sustained fall in arterial pressure.