bluuebunny/crossref_metadata_2025 huggingface dataset:
Potential mechanism of cyclosporine A-induced vascular smooth muscle contraction.
Authors: Meyer-Lehnert H , Schrier R W
Published: June 2012

Arterial hypertension is a common side effect of cyclosporine A therapy; however, the cellular mechanism of cyclosporine A-induced hypertension is still unknown. The present study, therefore, examined the effect of cyclosporine A on Ca2+ kinetics and contraction in primary cultures of vascular smooth muscle cells. Cyclosporine A (10 micrograms/ml) did not affect resting intracellular free Ca2+ ([Ca2+]i) levels (151 +/- 10 vs. 146 +/- 5 nM, NS), but augmented the 10(-8) M arginine vasopressin-induced increase of [Ca2+]i (delta 76 +/- 4 vs. delta 172 +/- 6 nM, p less than 0.001). This effect of cyclosporine A was also observed in Ca2+-free medium. Arginine vasopressin-stimulated [Ca2+]i efflux within 30 seconds compared with baseline efflux rates (1,644 +/- 146 vs. 2,591 +/- 373 cpm/mg prot/30 sec, p less than 0.005), but this transient effect was significantly greater (p less than 0.001) with arginine vasopressin plus cyclosporine A (1,702 +/- 133 vs. 5,605 +/- 1235 cpm/mg prot/30 sec, p less than 0.01). Basal 45Ca2+ efflux rates were not affected by cyclosporine A, and prior incubation of the cells with cyclosporine A was required to elicit the augmentory effect. 45Ca2+ uptake was measured to examine the mechanism by which cyclosporine A may affect [Ca2+]i stores. Cyclosporine A increased Ca2+ uptake when compared with control (6.38 +/- 0.69 vs. 10.99 +/- 0.59 x 10(3) cpm/mg prot/5 min, p less than 0.001). This effect was not blocked by the Ca2+ antagonist verapamil. Arginine vasopressin (10(-8) M) induced contraction of smooth muscle cells with 25.5% of the cells responding.(ABSTRACT TRUNCATED AT 250 WORDS)
Hydrocortisone-induced hypertension in humans: pressor responsiveness and sympathetic function.
Authors: Sudhir K , Jennings G L , Esler M D , Korner P I , Blombery P A , Lambert G W , Scoggins B , Whitworth J A
Published: June 2012

Oral hydrocortisone increases blood pressure and enhances pressor responsiveness in normal human subjects. We studied the effects of 1 week of oral hydrocortisone (200 mg/day) on blood pressure, cardiac output, total peripheral resistance, forearm vascular resistance, and norepinephrine spillover to plasma in eight healthy male volunteers. Although diastolic blood pressure remained unchanged, systolic blood pressure increased from 119 to 135 mm Hg (SED +/- 3.4, p less than 0.01), associated with an increased cardiac output (5.85-7.73 l/min, SED +/- 0.46, p less than 0.01). Total peripheral vascular resistance fell from 15.1 to 12.2 mm Hg/l/min (SED +/- 1.03, p less than 0.05). Resting forearm vascular resistance remained unchanged, but the reflex response to the cold pressor test was accentuated, the rise in resistance increasing from 10.5 mm Hg/ml/100 ml/min (R units) before treatment to 32.6 R units after treatment (SED +/- 6.4, p less than 0.025). The rise in forearm vascular resistance accompanying intra-arterial norepinephrine (25, 50, and 100 ng/min) was also significantly greater after hydrocortisone, increasing from an average of 14.9 +/- 2.4 R units before treatment to 35.1 +/- 5.5 R units after hydrocortisone (SED +/- 6.0, p less than 0.05). A shift to the left in the dose-response relation and fall in threshold suggested increased sensitivity to norepinephrine after treatment. Measurement of resting norepinephrine spillover rate to plasma and norepinephrine uptake indicated that overall resting sympathetic nervous system activity was not increased. The rise in resting blood pressure with hydrocortisone is associated with an increased cardiac output (presumably due to increased blood volume).(ABSTRACT TRUNCATED AT 250 WORDS)
Nonpeptide angiotensin II receptor antagonists. IV. EXP6155 and EXP6803.
Authors: Wong P C , Price W A , Chiu A T , Thoolen M J , Duncia J V , Johnson A L , Timmermans P B
Published: June 2012

EXP6155 (2-n-butyl-1-[4-carboxybenzyl]-4-chloroimidazole-5-acetic acid) and EXP6803 (methyl 2-n-butyl-1-[4-(2-carboxybenzamido)benzyl]-4-chloroimidazole -5-acetate, sodium salt) are shown to be novel, nonpeptide, antihypertensive, specific angiotensin II receptor antagonists. In rabbit aorta, they competitively inhibited the contractile response to angiotensin II with pA2 values of 6.54 and 7.20 and did not alter the response to norepinephrine or KCl. In guinea pig ileum, both agents blocked the responses to angiotensin I and II and did not alter the responses to bradykinin and acetylcholine. A similar specific angiotensin II antagonism was shown in vivo in the spinal pithed rat model. In renal artery-ligated rats, a high renin hypertensive model, EXP6155 and EXP6803 given intravenously, decreased blood pressure with ED30 of 10 and 11 mg/kg, respectively. Both compounds did not alter blood pressure when given orally at 100 mg/kg. Unlike saralasin, EXP6155 and EXP6803 given intravenously did not cause a transient increase in blood pressure in the renal artery-ligated and normotensive rats. Our results indicate that EXP6155 and EXP6803 are selective angiotensin II receptor antagonists and antihypertensive agents. Since neither compound had partial agonist activities or bradykinin potentiation effects, unlike the existing peptide angiotensin II receptor antagonists and angiotensin converting enzyme inhibitors, respectively, they may represent preferred probes for studying the physiological roles of angiotensin II.
Neural control of renal function: cardiovascular implications.
Authors: DiBona G F
Published: June 2012

The innervation of the kidney serves to function of its component parts, for example, the blood vessels, the nephron (glomerulus, tubule), and the juxtaglomerular apparatus. Alterations in efferent renal sympathetic nerve activity produce significant changes in renal blood flow, glomerular filtration rate, the reabsorption of water, sodium, and other ions, and the release of renin, prostaglandins, and other vasoactive substances. These functional effects contribute significantly to the renal regulation of total body sodium and fluid volumes with important implications for the control of arterial pressure. The renal nerves, both efferent and afferent, are known to be important contributors to the pathogenesis of hypertension. In addition, the efferent renal nerves participate in the mediation of the excessive renal sodium retention, which characterizes edema-forming states such as congestive heart failure. Thus, the renal nerves play an important role in overall cardiovascular homeostasis in both normal and pathological conditions.
Role of vasopressin in cardiovascular response to central cholinergic stimulation in rats.
Authors: Imai Y , Abe K , Sasaki S , Minami N , Munakata M , Yumita S , Nobunaga T , Sekino H , Yoshinaga K
Published: June 2012

The cardiovascular effects of centrally administered cholinomimetics were examined in conscious Long-Evans and Brattleboro rats. Carbachol (1 microgram/kg) or physostigmine (50 micrograms/kg) induced a long-lasting increase in blood pressure and a decrease in heart rate in Long-Evans rats whereas no bradycardia was observed in Brattleboro rats, and the pressor response was significantly less than that in Long-Evans rats. The cardiovascular responses to nicotine (30 micrograms/kg) in Brattleboro rats were not different from those in Long-Evans rats. Intravenous vasopressin antagonist, d(CH2)5Tyr(Me) arginine vasopressin, significantly attenuated the pressor response and eliminated the bradycardic response to carbachol in Long-Evans rats. However, the pressor response to carbachol in Brattleboro rats was still significantly less than that in Long-Evans rats treated with vasopressin antagonist. Intravenous phentolamine partially inhibited the pressor response to carbachol in Long-Evans rats and completely eliminated it in Brattleboro rats. Combined intravenous treatment with phentolamine and vasopressin antagonist completely eliminated the pressor response to carbachol in Long-Evans rats. Centrally administered methylatropine eliminated either the hypertensive or bradycardic response to carbachol in Long-Evans rats. These results indicate that the pressor and bradycardic response to carbachol or physostigmine is mediated by the central muscarinic receptor mechanism. Hypertensive response to intracerebroventricularly administered carbachol in normal rats is mediated both by an increase in central sympathetic outflow and in circulating vasopressin. The bradycardia seems to be mediated mainly by vasopressin.
Salt-induced hypertension in Dahl salt-sensitive rats. Hemodynamics and renal responses.
Authors: Simchon S , Manger W M , Carlin R D , Peeters L L , Rodriguez J , Batista D , Brown T , Merchant N B , Jan K M , Chien S
Published: June 2012

This study was performed with Dahl salt-sensitive (DS) and Dahl salt-resistant (DR) rats to detect differences in cardiovascular hemodynamics and renal responses that might be involved in initiating salt-induced hypertension in DS rats. The effects of 4 weeks of 8% NaCl diet were studied in conscious, male DR and DS rats in which vascular and urinary catheters had been previously implanted. Results were compared with those obtained from control groups of DR and DS rats on 4 weeks of 1% NaCl diet. DR rats on 8% salt diet did not develop hypertension, and cardiac output and blood volume were unchanged; glomerular filtration rate, urinary flow, sodium excretion, and plasma atrial natriuretic factor (ANF) increased. DS rats on 8% salt diet developed hypertension, and cardiac output and blood volume increased; glomerular filtration rate, urinary flow, and sodium excretion did not change, despite an increase in ANF. DS and DR rats on 1% NaCl diet were subjected to ANF infusion. After ANF infusion DR rats had a decreased blood volume and an increased glomerular filtration rate, urinary flow, and sodium excretion; DS rats showed no significant changes in blood volume, glomerular filtration rate, urinary flow, or sodium excretion. ANF caused vasodilation in all regions studied in DR rats; DS rats showed vasodilation in all regions except the kidney. After acute volume expansion, although both DR and DS rats responded by an increase in cardiac output, only DS rats developed prolonged hypertension. This finding suggests an inadequate vasodilatory mechanism in DS rats. In response to acute volume expansion, renal resistance decreased in DR rats but not in DS rats. It is concluded that the primary hemodynamic disturbance in DS rats with salt-induced hypertension is an increase in cardiac output caused by blood volume expansion in the absence of any vasodilation. Comparison of the responses of DS and DR rats to high salt diets, ANF infusion, and acute volume expansion indicates that the salt-induced hypertension in DS rats is initiated by a diminished renal response to ANF.
Endothelium and control of vascular function. State of the Art lecture.
Authors: Vanhoutte P M
Published: June 2012

The response of isolated blood vessels to a variety of vasoactive agonists is modulated by the presence of endothelial cells. Indeed, these cells can release both dilator and constrictor substances. The major endothelium-derived relaxing factor may be nitric oxide, which activates soluble guanylate cyclase in the smooth muscle, although the endothelial cells also secrete an unidentified hyperpolarizing factor. Among the natural stimuli for the release of endothelium-derived relaxing factors are circulating hormones, platelet products, thrombin, shear stress, and certain autacoids. Endothelium-derived relaxing factors may contribute to the regulation of the release of atrial natriuretic factor and renin. The endothelial cells can also release constricting factors; among the likely candidates are superoxide anions or the peptide endothelin. In hypertensive blood vessels, the ability to release endothelium-derived relaxing factors but not endothelium-derived contracting factors is blunted.
Responsiveness of noradrenergic neurons in rat experimental hypertension.
Authors: Debinski W K , Kuchel O G
Published: June 2012

We investigated possible abnormalities of cholinergic-noradrenergic neurotransmission in superior cervical ganglia in vitro in spontaneously hypertensive, Dahl salt-sensitive and deoxycorticosterone-salt-hypertensive rats by measuring the de novo synthesis of catecholamines from their labeled precursor tritiated tyrosine in response to cholinergic stimulation. Labeled tyrosine was incorporated into dopamine and its main neuronal metabolite dihydroxyphenylacetic acid as well as into norepinephrine. Dihydroxyphenylacetic acid and norepinephrine, but not dopamine, generation was linear with time under basal and stimulated conditions. However, norepinephrine incorporation remained similar before and after cholinergic stimulation of ganglionic neurons. Only young, prehypertensive spontaneously hypertensive rats showed altered responses when compared with their controls. Although endogenous dihydroxyphenylacetic acid content and baseline tyrosine incorporation into dihydroxyphenylacetic acid were lower in 4-week-old spontaneously hypertensive rats than in age-matched Wistar-Kyoto rats, cholinergic stimulation increased labeled dopamine and dihydroxyphenylacetic acid generation significantly more in juvenile spontaneously hypertensive rats. Such a hyperresponsiveness was not observed in either young Dahl rats or in any of the other models when they became hypertensive. These results probably reflect a genuine hyperreactivity of postganglionic noradrenergic neurons to acetylcholine or their increased catecholamine-synthesizing ability after centrally evoked enhanced sympathetic outflow known to occur during the early development of hypertension in spontaneously hypertensive rats.
Dietary calcium and cell membrane abnormality in genetic hypertension.
Authors: Furspan P B , Rinaldi G J , Hoffman K , Bohr D F
Published: June 2012

Adult stroke-prone spontaneously hypertensive rats (SHRSP) and Wistar-Kyoto (WKY) rats were maintained for 10 weeks on one of two diets: 1.0% calcium content and 2.5% calcium content. At the end of this time rats were anesthetized, and blood pressure was determined by means of aortic cannulation; then the rats were exsanguinated. Lymphocytes were isolated for determination of intracellular sodium and potassium concentrations, net sodium influx, net potassium efflux, and intracellular free calcium concentration. Serum ionized calcium was also measured. The increase in calcium content of their diet had no effect on intracellular sodium and potassium concentrations in lymphocytes from WKY rats and SHRSP. In lymphocytes from WKY rats, none of the parameters was affected by the change in dietary calcium intake. In contrast, in lymphocytes from SHRSP the increase in dietary calcium from 1.0 to 2.5% led to significant decreases in net potassium efflux (13.3 +/- 2.3 vs. 19.7 +/- 1.4 mmol/kg dry wt/hr, p less than 0.05, analysis of variance), intracellular free calcium concentration (114.5 +/- 10.2 vs. 166.2 +/- 11.2 nM, p less than 0.001), and systolic blood pressure (125.3 +/- 13.6 vs. 183.3 +/- 16.6 mm Hg, p less than 0.01). Serum ionized calcium increased in SHRSP (2.40 +/- 0.04 vs. 2.16 +/- 0.03, p less than 0.01) but not in WKY rats (2.34 +/- 0.05 vs. 2.31 +/- 0.05) fed the high calcium diet.(ABSTRACT TRUNCATED AT 250 WORDS)
Combined renin and converting enzyme inhibition in rats.
Authors: Mento P F , Holt W F , Murphy W R , Wilkes B M
Published: June 2012

The effects of combined renin inhibition and converting enzyme inhibition on mean arterial pressure and the plasma renin-angiotensin system were studied in conscious rats. In sodium-replete rats the infusion of the renin inhibitor CP71362 (100 micrograms/kg/min) decreased blood pressure by 13 +/- 1 mm Hg (p less than 0.0001), reduced plasma renin activity to undetectable levels, but did not lower plasma angiotensin II. In rats treated chronically with enalapril (30 mg/kg/day), CP71362 decreased blood pressure by an additional 5 +/- 2 mm Hg (p less than 0.025) and reduced plasma renin activity and angiotensin II concentrations to undetectable levels. The effects of renin inhibition were also tested under conditions where the renin-angiotensin system was stimulated. In rats on a low sodium diet, CP71362 decreased blood pressure by 15 +/- 2 mm Hg (p less than 0.0001), a decrease similar to that in rats on a normal diet. Plasma renin activity was decreased below detectable limits, but plasma angiotensin II concentrations were not reduced. In rats on a low sodium diet treated chronically with enalapril, CP71362 did not further decrease blood pressure although angiotensin II levels were significantly reduced. An additive effect of combined converting enzyme and renin inhibition on blood pressure lowering and inhibition of plasma angiotensin II was found in rats anesthetized with Inactin.(ABSTRACT TRUNCATED AT 250 WORDS)
Kinin antagonist reverses converting enzyme inhibitor-stimulated vascular prostaglandin I2 synthesis.
Authors: Beierwaltes W H , Carretero O A
Published: June 2012

Treatment with a converting enzyme inhibitor has been shown to stimulate aortic prostaglandin I2 synthesis. We studied whether converting enzyme inhibitor-stimulated prostaglandin I2 synthesis might be mediated by kinins. Anesthetized male Sprague-Dawley rats were given a continuous 70-minute infusion of either saline or a kinin analogue antagonist, [DArg0-Hyp3-Thi5-DPhe7-Thi8]bradykinin, 8 micrograms/kg/min. After 10 minutes, rats were given an intravenous bolus of either vehicle or the converting enzyme inhibitor enalaprilat (30 micrograms/100 g body wt). After 70 minutes, aorta and renal cortical slices were harvested and incubated in vitro in buffer without drugs at pH 7.4, 37 degrees C for 60 minutes. The buffer was then sampled for measurement of 6-keto prostaglandin F1 alpha (an index of prostaglandin I2), prostaglandin E2, and renin release (angiotensin I generation) by radioimmunoassay. The aortic prostaglandin I2 from rats treated with converting enzyme inhibitor was significantly elevated (36.7 +/- 5.0 ng/mg dry wt/hr) compared with aorta from rats treated with either vehicle (25.6 +/- 2.2 ng/mg/hr), kinin antagonist (25.1 +/- 2.4 ng/mg/hr), or kinin antagonist plus converting enzyme inhibitor (23.0 +/- 2.0 ng/mg/hr), p less than 0.02. There were no differences in aortic prostaglandin E2, renin release, or prostaglandin E2 from renal cortical slices. Direct in vitro incubation of aorta with molar concentrations of converting enzyme inhibitor from 10(-9) to 10(-4) had no effect on prostaglandin I2. These results suggest that kinins may mediate the effect of converting enzyme inhibition on aortic prostaglandin I2 synthesis and thereby may account for part of the hemodynamic responses resulting from treatment using converting enzyme inhibitors.
Hemodynamic and humoral effects of the new renin inhibitor enalkiren in normal humans.
Authors: Delabays A , Nussberger J , Porchet M , Waeber B , Hoyos P , Boger R , Glassman H , Kleinert H D , Luther R , Brunner H R
Published: June 2012

The effect of the renin inhibitor enalkiren (Abbott-64662) was evaluated in eight normal volunteer subjects on a standardized sodium diet (100 mmol/day) by measurement of various components of the renin-angiotensin system and drug levels in plasma. On day 1, vehicle and doses of 0.001, 0.003, and 0.01 mg/kg i.v. were administered within 2 minutes at 90-minute intervals. On day 2, vehicle and doses of 0.01, 0.03, and 0.1 mg/kg i.v. were given. With the higher doses, blood pressure tended to decrease slightly with no change in heart rate. Plasma renin activity and plasma angiotensin-(1-8)octapeptide (angiotensin II) fell markedly in a dose-dependent manner. Inhibition of plasma renin activity was maximal 5 minutes after administration of the drug and persisted 90 minutes after the doses of 0.03 and 0.1 mg/kg. Not surprisingly, there was a close correlation between plasma renin activity and plasma angiotensin II levels (r = 0.81, n = 28, p less than 0.001). In contrast, active and total renin measured directly by monoclonal antibodies rose in dose-related fashion in response to renin inhibition. Pharmacokinetic parameters were calculated using the plasma drug concentrations obtained up to 6 hours after the 0.1 mg/kg dose. By means of a two-compartment model, plasma mean half-life of the drug was estimated at 1.60 +/- 0.43 hours.
1,25-Dihydroxyvitamin D3 and rat vascular smooth muscle cell growth.
Authors: Carthy E P , Yamashita W , Hsu A , Ooi B S
Published: June 2012

Recent studies from several laboratories have shown perturbations of 1,25-dihydroxyvitamin D3 [1,25(OH)2D3] metabolism in hypertension. While these perturbations may exert their effect on blood pressure via their actions on calcium metabolism, it is possible that this vitamin D metabolite may have direct effects on vascular smooth muscle cell (VSMC) physiology. To examine this, we studied the effect of 1,25(OH)2D3 on VSMC growth and found that this substance suppressed VSMC [3H]thymidine uptake; furthermore, this vitamin D metabolite also suppressed the stimulatory effect of epidermal growth factor (EGF) on VSMC proliferation. The concomitant presence of this substance appeared to be required for its action on VSMC growth since cells pretreated with the vitamin D metabolite for up to 72 hours and then washed of the substance grew normally and responded to EGF. Studies were also done to determine if 1,25(OH)2D3 had any effect on the function of EGF receptors on VSMC. Experiments using Iodine-125-labeled EGF showed no differences in the binding of this ligand to VSMC, either untreated or treated with 1,25(OH)2D3, which indicates the effect of the vitamin D metabolite on VSMC growth (when exposed to EGF) was not mediated by an alteration of EGF receptor function. The results of these studies have implications for the pathogenesis of vascular diseases such as hypertension and atherosclerosis.
Remodeling of cerebral arterioles in chronic hypertension.
Authors: Baumbach G L , Heistad D D
Published: June 2012

Chronic hypertension impairs dilatation of cerebral arterioles. Impairment of dilatation generally has been attributed to hypertrophy of the vessel wall with encroachment on the vascular lumen. In this study, we tested the hypothesis that a reduction in external diameter may contribute to encroachment on the vascular lumen during chronic hypertension. We examined 10-12-month-old, anesthetized Wistar-Kyoto (WKY) rats and stroke-prone spontaneously hypertensive rats (SHRSP). External diameter, stress, and strain of pial arterioles were calculated from measurements of pial arteriolar pressure (servo null), diameter, and cross-sectional area of the arteriolar wall. During maximal dilatation produced with ethylenediaminetetraacetic acid, cross-sectional area of the arteriolar wall was greater in SHRSP than in WKY rats (2,038 +/- 57 vs. 1,456 +/- 61 micron 2, p less than 0.05). External, as well as internal, diameter was less in SHRSP than in WKY rats (101 +/- 3 and 88 +/- 3 micron in SHRSP vs. 111 +/- 3 and 102 +/- 3 micron in WKY rats for external and internal diameter, respectively, p less than 0.05). Reduction in external diameter accounted for 76% of encroachment on the lumen in SHRSP, and hypertrophy per se accounted for only 24%. Distensibility of deactivated pial arterioles was increased in SHRSP. These findings suggest that reduction in external diameter plays an important role in impairment of maximal dilatation of cerebral arterioles in SHRSP, and reduction in vascular diameter in SHRSP cannot be accounted for by altered distensibility. We propose that, during chronic hypertension, cerebral arterioles undergo structural remodeling that results in a smaller external diameter and encroachment on the vascular lumen.(ABSTRACT TRUNCATED AT 250 WORDS)
Aortic compliance in human hypertension.
Authors: Liu Z R , Ting C T , Zhu S X , Yin F C
Published: June 2012

Aortic compliance in normotensive and hypertensive Chinese subjects undergoing diagnostic cardiac catheterization was compared by using a newly described method that allows for determination of the pressure dependence of compliance if one assumes a value for the exponential coefficient of the pressure-volume relation of the large arteries. Under baseline conditions in the normotensive and hypertensive groups at mean aortic pressures of 96.3 and 128.6 mm Hg, aortic compliance averaged 1.47 and 0.80 ml/mm Hg, respectively. Compliance in the hypertensive group at a diastolic pressure of 99.4 mm Hg (which was nearly equal to the mean normotensive pressure) was 1.072 ml/mm Hg--still significantly lower than in the normotensive group. During nitroprusside infusion, however, the compliances in the hypertensive group increased to levels equal to or greater those in the normotensive group. Thus, these data confirm that aortic compliance is lower in hypertensive than in normotensive humans. They further demonstrate that the lower compliance cannot be attributed entirely to the elevated blood pressure, suggesting that excess smooth muscle tone may be partly responsible.
Isolation and characterization of single vascular smooth muscle cells from spontaneously hypertensive rats.
Authors: Bolzon B J , Cheung D W
Published: June 2012

To study the properties of vascular smooth muscle in hypertension without the influence of the nerves and endothelium, a procedure was developed to isolate single smooth muscle cells from tail arteries of spontaneously hypertensive rats (SHR) and Wistar-Kyoto (WKY) normotensive control rats. Perfusion of intact arteries with a solution of papain and collagenase produced dense populations of viable cells (more than 10(4) cells/ml) that remained relaxed in the presence of physiological levels of calcium. Contractile responses of smooth muscle cells from the SHR were significantly more sensitive to noradrenaline, potassium depolarization, and the calcium channel agonist Bay K 8644 compared with those from WKY rats. Enhanced sensitivity to calcium in the SHR was also observed on readdition of calcium to cells preincubated in noradrenaline or KCl in a calcium-free medium. These results provide evidence for alterations in the properties of vascular smooth muscle in the SHR at the single cell level.
Impairment of baroreceptor reflex control of heart rate but not sympathetic efferent discharge by central neuroadministration of ethanol.
Authors: Zhang X , Abdel-Rahman A A , Wooles W R
Published: June 2012

We investigated the acute hemodynamic effects of ethanol microinjection into brain areas known to influence cardiovascular function and reflexes. In chloralose-anesthetized rats, ethanol had no effect on baseline mean arterial pressure, heart rate, or sympathetic efferent discharge when microinjected into the nucleus tractus solitarius, the dorsal motor nucleus of the vagus, the rostral ventrolateral medulla, or the posterior hypothalamus. On the other hand, ethanol microinjection into the anterior hypothalamus caused a site-dependent pressor effect and an increase in sympathetic efferent discharge. Baroreceptor heart rate response but not sympathetic efferent discharge response was impaired by ethanol microinjection into the nucleus tractus solitarius, the dorsal motor nucleus of the vagus, and the rostral ventrolateral medulla, suggesting that ethanol involves one or more of these areas in its inhibitory effect on baroreceptor heart rate response and that ethanol has a selective action on baroreceptor reflex control of heart rate. The findings that 1) the effect was dose dependent and 2) injection of ethanol outside of, or an equal volume of cerebrospinal fluid into, the nucleus tractus solitarius had no effect on the response strongly suggest that the observed effect on baroreceptor heart rate response was ethanol mediated. Ethanol microinjection into the dorsal motor nucleus of the vagus impaired the heart rate response, thus raising the possibility that leakage of ethanol to that area from the nucleus tractus solitarius might have contributed to its effect. These findings show that ethanol has a pressor and sympathoexcitatory site of action within the anterior hypothalamus and that it selectively impairs baroreceptor heart rate response via a central site of action; the mechanisms by which ethanol produces these effects remain to be elucidated.
Insulin and renal sodium retention in obese adolescents.
Authors: Rocchini A P , Katch V , Kveselis D , Moorehead C , Martin M , Lampman R , Gregory M
Published: June 2012

The effect of insulin on the renal handling of sodium was studied in obese and nonobese subjects by using euglycemic hyperinsulinemia. Seven water-loaded obese (14-19 years old) and five nonobese young adults (18-21 years old) had insulin given intravenously at a rate of 40 munits/m2/min. Blood glucose and creatinine clearance were not altered by euglycemic hyperinsulinemia in either the obese or the nonobese group. Hyperinsulinemia resulted in a significant decrease in urinary sodium excretion in both groups of subjects (by 54.2 +/- 3% [mean +/- SEM] in the obese and by 50.9 +/- 3.1% in the nonobese group). However, the amount of glucose required to maintain euglycemia was significantly less in the obese versus nonobese group, 89.5 +/- 6.2 versus 329.2 +/- 16 mg glucose/m2/min (p less than 0.001). There was no relation in either group between the amount of glucose required to maintain euglycemia and the change in urinary sodium excretion. On a separate day, all of the obese subjects underwent 3 hours of water diuresis but without insulin. There was no change in urinary sodium excretion with sustained water diuresis alone. However, when compared with the nonobese group, the obese group of subjects had a significantly higher resting mean arterial pressure, heart rate, and plasma norepinephrine concentration; during the insulin clamp, neither group experienced a significant change in mean arterial pressure or heart rate, and only the nonobese group experienced an increase in plasma norepinephrine. In obese subjects, we have found, despite the presence of insulin resistance to carbohydrate metabolism, that euglycemic hyperinsulinemia was associated with a normal decrease in urinary sodium excretion.(ABSTRACT TRUNCATED AT 250 WORDS)
Angiotensin-induced hypertension in the rat. Sympathetic nerve activity and prostaglandins.
Authors: Luft F C , Wilcox C S , Unger T , Kühn R , Demmert G , Rohmeiss P , Ganten D , Sterzel R B
Published: June 2012

To elucidate mechanisms of angiotensin II (Ang II)-related hypertension, we infused angiotensin (76 ng/min s.c.) into rats with minipumps for 10-14 days. Control rats received sham pumps. We measured blood pressure by tail-cuff, and the excretion of aldosterone and prostaglandins (PG) (PGE2, prostacyclin derivative 6kPGF1 alpha, and thromboxane [Tx] derivative TxB2). Angiotensin II increased blood pressure by 20 mm Hg by day 2 and by 90 mm Hg by day 10. Aldosterone excretion increased from 10 to 70 ng/day in Ang II rats by day 7. Urine PGE2 did not increase in angiotensin rats; however, both 6kPGF1 alpha and TxB2 excretion increased with angiotensin. Control rats had no changes in any of these parameters. A sympathetic component was tested in a separate group of angiotensin rats that received phenoxybenzamine (300 micrograms/kg/day) during angiotensin infusion; their increase in blood pressure of 40 mm Hg at 10 days was less than in those rats with angiotensin alone but more than in control rats. Phenoxybenzamine did not influence the angiotensin-induced increases in excretion of 6kPGF1 alpha or TxB2. Additional groups of conscious angiotensin and control rats were equipped with splanchnic nerve electrodes on day 14 for recording of sympathetic nerve activity. Angiotensin rats had greater basal sympathetic nerve activity than the control rats. Incremental methoxamine injections demonstrated altered baroreceptor reflex function in rats receiving angiotensin. We conclude that increased blood pressure with chronic angiotensin infusion is accompanied by increased production of aldosterone and increased sympathetic tone. The latter may be modulated by PG.
Impaired renorenal reflexes in two-kidney, one clip hypertensive rats.
Authors: Kopp U C , Buckley-Bleiler R L
Published: June 2012

In normotensive rats, stimulation of renal mechanoreceptors by an increase in ureteral pressure results in a contralateral inhibitory renorenal reflex response with contralateral natriuresis. Similar effects are produced by stimulation of renal chemoreceptors by renal pelvic perfusion with 0.9 M NaCl. However, in spontaneously hypertensive rats the renorenal reflex responses to renal mechanoreceptor and chemoreceptor stimulation are impaired. The present study was performed to examine whether the renorenal reflexes were altered in two-kidney, one clip hypertensive rats, a model of hypertension in which it has been suggested that the afferent renal nerves contribute to the enhanced peripheral sympathetic nervous activity. A 0.2 mm silver clip was placed around one renal artery 4 weeks before the study. At the time of study, mean arterial pressure was 156 +/- 4 mm Hg. Renal mechanoreceptor and chemoreceptor stimulation of either the nonclipped or clipped kidney failed to affect ipsilateral afferent renal nerve activity, contralateral efferent renal nerve activity, and contralateral urine flow rate and urinary sodium excretion. Renal denervation of the nonclipped kidney increased ipsilateral urinary sodium excretion from 0.65 +/- 0.13 to 1.50 +/- 0.42 mumol/min/g and decreased contralateral urinary sodium excretion from 0.18 +/- 0.03 to 0.13 +/- 0.03 mumol/min/g (p less than 0.05). Thus, denervation of the nonclipped kidney resulted in a similar contralateral excitatory renorenal reflex response as in normotensive rats. However, denervation of the clipped kidney increased both ipsilateral and contralateral urinary sodium excretion, from 0.14 +/- 0.04 to 0.27 +/- 0.5 mumol/min/g and from 1.29 +/- 0.33 to 2.09 +/- 0.59 mumol/min/g (p less than 0.01), respectively. Taken together these data suggest that the lack of inhibitory renorenal reflexes from the clipped kidney may enhance efferent sympathetic nervous activity and thereby contribute to the hypertension in two-kidney, one clip hypertensive rats.
Calcium channel alterations in genetic hypertension.
Authors: Hermsmeyer K , Rusch N J
Published: June 2012

We proposed earlier that voltage-dependent calcium (Ca2+) current is altered in single azygos venous cells from Wistar-Kyoto (WKY) rats and spontaneously hypertensive rats (SHR). In this study, the effects of different intracellular concentrations of ethylene glycol-bis-N,N,N',N',-tetraacetic acid (EGTA) on Ca2+ currents were investigated. Vascular muscle cells from SHR and WKY rats were equilibrated with pipette solution containing 0.1 mM or 10 mM EGTA. Increasing the EGTA concentration from 0.1 to 10 mM in SHR vascular cells significantly enhanced the peak amplitude of the longer lasting (L) current from 87 +/- 12 pA to 152 +/- 8 pA, while the transient (T) current amplitude was not significantly different (52 +/- 7 pA and 36 +/- 7 pA, respectively). In WKY rat vascular muscle cells, the amplitudes of the T and L currents were not significantly different with the same comparison of intracellular EGTA concentrations. These observations suggest that relatively low intracellular Ca2+ concentrations can more strongly modulate Ca2+ current through the L channel in SHR than WKY rat vascular muscle cells.
Impaired reflex response to volume expansion in NaCl-sensitive spontaneously hypertensive rats.
Authors: Thornton R M , Wyss J M , Oparil S
Published: June 2012

Abnormal baroreceptor reflex function that antedates or is a consequence of NaCl loading could contribute to the NaCl-induced exacerbation of hypertension in NaCl-sensitive spontaneously hypertensive rats (SHR-S). The current study tested the hypothesis that an impairment in cardiopulmonary baroreceptor reflex function exists in SHR-S before NaCl loading. The reflex response to volume expansion was compared in SHR-S, NaCl-resistant SHR (SHR-R), and normotensive Wistar-Kyoto (WKY) and Sprague-Dawley rats maintained on a normal NaCl diet. Conscious, free-moving SHR-S, SHR-R, WKY, and Sprague-Dawley rats were volume expanded with whole blood to 15% of blood volume within 6 minutes, and mean arterial pressure, heart rate, and lumbar sympathetic nerve activity were recorded. Heart rate and lumbar sympathetic nerve activity decreased significantly in SHR-R, WKY, and Sprague-Dawley rats after volume expansion. In contrast, in SHR-S neither heart rate after volume expansion nor lumbar sympathetic nerve activity was significantly different from levels before volume expansion. The blunted reflex response of heart rate and lumbar sympathetic nerve activity to volume expansion suggests impaired cardiopulmonary volume receptor function in SHR-S. This likely contributes to NaCl-induced hypertension in SHR-S on a high NaCl diet.
Reversal by ethanol of the hypotensive effect of clonidine in conscious spontaneously hypertensive rats.
Authors: Abdel-Rahman A A
Published: June 2012

We studied the acute effect of ethanol on the hypotensive response to clonidine in conscious spontaneously hypertensive rats. When administered during the hypotensive response to clonidine, ethanol not only reversed the response but also caused a slight but significant short-lived pressor effect. The maximal hypotensive effect of graded doses of clonidine was significantly (p less than 0.05) attenuated by a dose of 1 g/kg ethanol, which resulted in a peak blood ethanol concentration of 54.2 +/- 6.3 mg/dl. The data strongly suggest the adverse effect of ethanol on the hypotensive response to clonidine is ethanol mediated and that their antagonistic interaction is both reversible and reproducible because: 1) an equal volume of saline had no effect on the hemodynamic responses to clonidine and 2) crossing over ethanol and saline treatments on days 2 and 3, which allowed longitudinal comparisons, showed that the effect of ethanol was similar both in naive rats (day 1) and in rats that were pre-exposed to ethanol (day 3). Whether this negative effect of ethanol also involves other antihypertensive agents that do not act primarily by a central nervous system mechanism was investigated. The same dose of ethanol had little or no effect on the hypotensive response to hydralazine, suggesting the negative effect of ethanol is selective to centrally acting antihypertensive agents. Although the mechanism by which ethanol reverses the hypotensive effect of clonidine is not known, it is possible that it involves an ethanol-evoked increase in plasma catecholamine levels, which are known to be decreased by clonidine. That ethanol did not reverse the hypotensive effect of hydralazine, which is also known to be associated with increased plasma catecholamine levels, supports this notion. The findings of the present study may explain, at least in part, why regular use of alcohol is associated with an inadequate control of blood pressure in treated hypertensive patients who are regular consumers of alcohol.
Race and gender influence ambulatory blood pressure patterns of adolescents.
Authors: Harshfield G A , Alpert B S , Willey E S , Somes G W , Murphy J K , Dupaul L M
Published: June 2012

The purpose of this study was to examine ambulatory blood pressure and heart rate patterns in healthy, normotensive adolescents and to determine the influence of race and gender on these patterns. Ambulatory blood pressure recordings were performed on 199 adolescents; 42 were black males, 55 were white males, 65 were black females, and 37 were white females. The mean age (+/- SD) was 13 +/- 2 years. Blood pressure readings were obtained with an automatic, noninvasive recorder. Black adolescents and white adolescents had similar blood pressures while awake (116/69 vs. 116/69 mm Hg), with boys having higher levels of systolic blood pressure (118 vs. 114 mm Hg) and comparable levels of diastolic blood pressure (69 vs. 69 mm Hg) relative to girls. The patterns while the adolescents were asleep, however, were different. White boys (106 mm Hg), white girls (105 mm Hg), and black girls (105 mm Hg) had similar systolic blood pressures during sleep. Black boys (112 mm Hg), however, had significantly higher systolic blood pressures while asleep. Black adolescents, as a group, had significantly higher diastolic blood pressures than white adolescents while asleep (64 vs. 61 mm Hg). Changes in blood pressure from awake to asleep were not related to changes in heart rate. Results of this study indicate that both race and gender are important determinants of the diurnal pattern of blood pressure and heart rate in adolescents.
A lack of genetic linkage of renin gene restriction fragment length polymorphisms with human hypertension.
Authors: Naftilan A J , Williams R , Burt D , Paul M , Pratt R E , Hobart P , Chirgwin J , Dzau V J
Published: June 2012

Because renin is an important enzyme in blood pressure regulation, we studied the possibility that an alteration in the structure of the human renin gene is genetically linked to human essential hypertension or associated with levels of plasma renin activity or blood pressure. By using specific DNA probes, we have identified four polymorphisms in the human renin gene with the restriction enzymes Taq I, HindIII, Bgl I, and Bgl II. The gene location of all of these polymorphisms except for the Bgl II polymorphism has been determined, and their frequencies were initially estimated in a population of 50 random subjects. To test the clinical significance of these polymorphisms, we studied 68 persons from a large Utah pedigree with a high incidence of hypertension. Among nine relatives with hypertension, genetic linkage without recombination was ruled out by observing several obligate recombinants. We also found no significant association of the restriction fragment length polymorphisms with quantitative measurements of sitting or standing, systolic or diastolic blood pressures, or plasma renin activity in 59 untreated members of this pedigree. Although we found no genetic linkage in this set of study subjects, the characterization of the restriction fragment length polymorphisms for the renin gene may be useful in future studies of other selected pedigrees for the presence of one or more of these to be a genetic marker in hypertension.
Reflex control of sympathetic nerve activity in dopamine beta-hydroxylase deficiency.
Authors: Rea R F , Biaggioni I , Robertson R M , Haile V , Robertson D
Published: June 2012

Patients with autonomic failure secondary to dopamine beta-hydroxylase deficiency lack the enzyme activity necessary for the conversion of dopamine to norepinephrine in sympathetic nerve terminals and the adrenal medulla. These patients have virtually undetectable norepinephrine and epinephrine in plasma and cerebrospinal fluid. The presence of intact sympathetic nerve activity in these patients has been suggested by the enhanced release of dopamine (but not norepinephrine) in response to maneuvers that augment sympathetic outflow in normal subjects. In the present study, we recorded sympathetic nerve traffic by using microneurography in a patient with dopamine beta-hydroxylase deficiency and measured sympathetic neural responses to static exercise, the cold pressor test, and pharmacological alterations of blood pressure. At rest, sympathetic nerve activity was abundant and was modulated in a normal manner by handgrip (+278%), the cold pressor test (+169%), hypotension induced with isoproterenol (+102%), and hypertension induced with phenylephrine (-85%). These results provide the first electrophysiological evidence for intact regulation of sympathetic neural outflow in a patient with dopamine beta-hydroxylase deficiency and suggest that central norepinephrine and epinephrine pathways believed essential for the control of sympathetic neurotransmission in humans may be supplanted by alternative redundant mechanisms.
Atrial natriuretic factor plays a significant role in body fluid homeostasis.
Authors: Blaine E H
Published: June 2012

Atrial natriuretic factor (ANF) is a hormone with the physiological characteristics of a regulator of body fluid volume. It is potent, has a short duration of action, and responds to a physiologically relevant stimulus in a negative feedback-controlled system. It can act directly or indirectly (via inhibition of aldosterone biosynthesis) on the kidney to alter sodium transport and may regulate fluid distribution within the extracellular space. The peptide circulates at low (nanomolar) levels, and recent studies with renal inner medullary cells document relevant receptor binding and second messenger activation in this concentration range. In vivo data support a direct action on the kidney to enhance natriuresis, and blockade of a primary catabolic pathway for ANF within the kidney results in augmented natriuresis at concurrent endogenous peptide concentrations. Long-term, low dose infusion directly into the renal artery of conscious dogs supports a physiological action of ANF to promote urinary sodium excretion. Nevertheless, under certain circumstances, natriuresis does not occur even at high circulating levels of ANF. Apparently other factors such as renal perfusion pressure, volume status, and renal nerve activity are important in determining the natriuretic response to a given level of peptide. We hypothesize that the role played by ANF in volume regulation is highly complex, and the kidney responds with increased sodium excretion only when a constellation of variables is appropriately arrayed. That is, ANF is a necessary, but not sufficient, condition to induce natriuresis.
Metabolism and production of angiotensin I in different vascular beds in subjects with hypertension.
Authors: Admiraal P J , Derkx F H , Danser A H , Pieterman H , Schalekamp M A
Published: June 2012

To study the metabolism and production of angiotensin I, highly purified monoiodinated [125I] angiotensin I was given by constant systemic intravenous infusion, either alone (n = 7) or combined with unlabeled angiotensin I (n = 5), to subjects with essential hypertension who were treated with the angiotensin converting enzyme inhibitor captopril (50 mg b.i.d.). Blood samples were taken from the aorta and the renal, antecubital, femoral, and hepatic veins. [125I]Angiotensin I and angiotensin I were extracted from plasma, separated by high-performance liquid chromatography, and quantitated by gamma counting and radioimmunoassay. Plasma renin activity was measured at pH 7.4. The plasma decay curves after discontinuation of the infusions of [125I]angiotensin I and unlabeled angiotensin I were similar for the two peptides. The regional extraction ratio of [125I]angiotensin I was 47 +/- 4% (mean +/- SEM) across the forearm, 59 +/- 3% across the leg, 81 +/- 1% across the kidneys, and 96 +/- 1% across the hepatomesenteric vascular bed. These results were not different from those obtained for infused unlabeled angiotensin I. Despite the rapid removal of arterially delivered angiotensin I, no difference was found between the venous and arterial levels of endogenous angiotensin I across the various vascular beds, with the exception of the liver where angiotensin I in the vein was 50% lower than in the aorta. Thus, 50-90% of endogenous angiotensin I in the veins appeared to be derived from regional de novo production. The blood transit time is 0.1-0.2 minute in the limbs and in the kidneys and 0.3-0.5 minute in the hepatomesenteric vascular bed. This is too short for plasma renin activity to account for the measured de novo angiotensin I production. It was calculated that less than 20-30% in the limbs and in the kidneys and approximately 60% in the hepatomesenteric region of de novo-produced angiotensin I could be accounted for by circulating renin. These results indicate that a high percentage of plasma angiotensin I may be produced locally (i.e., not in circulating plasma).