bluuebunny/crossref_metadata_2025 huggingface dataset:
Delayed development of hypertension after short-term nitrendipine treatment.
Authors: Rizzoni D , Castellano M , Porteri E , Bettoni G , Muiesan M L , Agabiti Rosei E
Published: June 2012

In this study we evaluated the delayed effects of a calcium entry blocker on blood pressure and on vascular structural and functional alterations in mesenteric resistance arteries of spontaneously hypertensive rats (SHR). The calcium entry blocker nitrendipine was administered (30 mg/kg per day) according to three different schedules: in one group of SHR from 4 to 8 weeks of age (n = 12), in a second group from 8 to 12 weeks of age (n = 12), and in a third group from 4 to 12 weeks of age (n = 12). Twelve untreated SHR and 12 untreated Wistar-Kyoto rats served as controls. Half the animals of each group were killed at 13 weeks, and the remaining were killed at 38 weeks. After death, relative left ventricular mass was calculated. Vascular morphology and function (responses to norepinephrine and acetylcholine) in mesenteric small arteries were then assessed using a micromyographic technique. Nitrendipine treatment delayed the development of hypertension and determined the regression of structural alterations of mesenteric resistance arteries in SHR. These favorable effects were maintained for several weeks after treatment withdrawal, provided that treatment was started at 4 weeks of age. Considering the functional alterations of mesenteric arteries in SHR (responses to norepinephrine and acetylcholine), nitrendipine treatment determined an improvement of both these dysfunctions as long as reductions of the media-to-lumen ratio and blood pressure, respectively, were maintained.
Angiotensin II type 1 receptor gene polymorphisms in human essential hypertension.
Authors: Bonnardeaux A , Davies E , Jeunemaitre X , Féry I , Charru A , Clauser E , Tiret L , Cambien F , Corvol P , Soubrier F
Published: June 2012

We conducted the present study to determine whether the angiotensin II type I receptor (AT1) gene might be implicated in human essential hypertension by using case-control and linkage studies. The entire coding and 3' untranslated regions of the AT1 receptor gene (2.2 kb) were amplified by polymerase chain reaction and submitted to single-strand conformation polymorphism in 60 hypertensive subjects with a familial susceptibility. We identified five polymorphisms (T573-->C, A1062-->G, A1166-->C, G1517-->T, and A1878-->G). However, no mutations that alter the encoded amino acid sequence were detected. A case-control study performed on white hypertensive (n = 206; blood pressure, 168 +/- 16/103 +/- 9 mm Hg) and normotensive (n = 298; blood pressure, 122 +/- 10/75 +/- 9 mm Hg) subjects using three of five polymorphisms showed a significant increase in allelic frequency of C1166 in hypertensive subjects (0.36 versus 0.28 for normotensive subjects, chi 2 = 6.8, P < .01). Frequencies for the alleles of the other two polymorphisms (T573-->C, A1878-->G) were similar in both groups. We performed a linkage study using the affected sib pair method and a highly polymorphic marker of the AT1 receptor gene. There was no evidence for linkage in 267 sib pairs analyzed from 138 pedigrees. These findings would be compatible with a common variant of the AT1 receptor imparting a small effect on blood pressure; further studies will be needed to address this possibility.
Potassium inhibits free radical formation.
Authors: McCabe R D , Bakarich M A , Srivastava K , Young D B
Published: June 2012

We conducted this study to determine whether physiological changes in potassium concentration affect free radical formation by vascular cells. We assessed the effects of potassium on reactive oxygen species formed by cultured endothelial and monocyte/macrophage cells or freshly isolated human white blood cells by cytochrome c reduction or luminol chemiluminescence, respectively. Reducing potassium concentration of endothelial cell media (normally 5.1 to 6.1 mmol/L) to 3.0 mmol/L exponentially increased the rate of cytochrome c reduction, up to 8.4-fold at 2 hours; raising potassium concentration to 5.5 or 7.0 mmol/L at 1 hour reduced the maximal rate of cytochrome c reduction by 86% or 93%. Subsequent studies were done 30 to 75 minutes after media change. Potassium reduced the rate of cytochrome c reduction by 49% (endothelial cells) to 55% (monocytes/macrophages) between 3.0 and 7.0 mmol/L; the greatest decrement (20% to 26%) occurred between 3.0 and 4.0 mmol/L. Superoxide dismutase reduced the rate of cytochrome c reduction by 62% or 50% in endothelial or monocyte/macrophage cells. Potassium had no effect on the rate of cytochrome c reduction in the presence of superoxide dismutase. Increasing potassium concentration from 1.48 to 4.77 or 7.94 mmol/L also reduced luminol chemiluminescence in human white blood cells challenged by 1 to 10 mg/mL zymosan. We conclude that physiological increases in potassium concentration inhibit the rate of superoxide anion formation by cell lines derived from endothelium and from monocytes/macrophages and reactive oxygen species formation by human white blood cells.
Ciprokiren (Ro 44-9375). A renin inhibitor with increasing effects on chronic treatment.
Authors: Fischli W , Clozel J P , Breu V , Buchmann S , Mathews S , Stadler H , Vieira E , Wostl W
Published: June 2012

The present study characterizes the new transition-state renin inhibitor ciprokiren (Ro 44-9375) in squirrel monkeys. Arterial blood pressure was monitored by telemetry in freely moving, chronically instrumented conscious animals. In vitro at pH 7.4, ciprokiren inhibited human renin in buffer and human plasma with an IC50 of 0.07 and 0.65 nmol/L, respectively. It was equipotent against primate plasma renin and also inhibited plasma renin from dog and guinea pig in the nanomolar range (IC50, 29 and 65 nmol/L, respectively). After acute oral administration it reduced arterial blood pressure dose dependently in normotensive sodium-depleted and cyclosporin-induced hypertensive squirrel monkeys, starting with the minimal oral dose of 3 micrograms/kg. Daily oral doses of 1 microgram/kg showed a progressive blood pressure decrease, with a maximal response reached after 1 week. The drug could also be applied transdermally with similar hemodynamic effects without any decrease of plasma renin activity or plasma immunoreactive angiotensin II. Thus, ciprokiren is characterized in squirrel monkeys as a renin inhibitor with high in vivo potency that might act mainly in the tissular compartment.
Role of angiotensin II in renal injury of deoxycorticosterone acetate-salt hypertensive rats.
Authors: Kim S , Ohta K , Hamaguchi A , Omura T , Yukimura T , Miura K , Inada Y , Wada T , Ishimura Y , Chatani F
Published: June 2012

To investigate the role of angiotensin II (Ang II) in hypertension-induced tissue injury, we gave TCV-116 (1 mg/kg per day PO), a nonpeptide Ang II type I receptor antagonist, or enalapril (10 mg/kg per day PO) to deoxycorticosterone acetate (DOCA)-salt hypertensive rats for 3 weeks and examined the effects on tissue mRNA levels for transforming growth factor-beta 1 (TGF-beta 1) and extracellular matrix components. Tissue mRNA levels were measured by Northern blot analysis. Renal mRNA levels for TGF-beta 1; types I, III, and IV collagen; and fibronectin in DOCA-salt hypertensive rats were increased by severalfold (P < .01) compared with sham-operated rats. In the aorta of DOCA-salt hypertensive rats, TGF-beta 1 and fibronectin mRNA levels were increased, but types I, III, and IV collagen mRNAs did not increase. In the heart, increased mRNA was found only for fibronectin. Thus, these gene expressions are regulated in a tissue-specific manner. TCV-116 or enalapril did not lower blood pressure in DOCA-salt hypertensive rats. However, the increase in renal mRNAs for TGF-beta 1 and extracellular matrix components in DOCA-salt hypertensive rats was significantly inhibited by treatment with TCV-116 or enalapril, which was associated with a significant decrease in urinary protein and albumin excretions and histological improvement of renal lesions. In contrast, in the aorta and heart these gene expressions were not affected by TCV-116 or enalapril. Thus, local Ang II may contribute to renal injury of DOCA-salt hypertension by stimulating the gene expression of TGF-beta 1 and extracellular matrix components.
Angiotensin II exerts differential actions on renal nerve activity and heart rate.
Authors: Kumagai K , Reid I A
Published: June 2012

Angiotensin II (Ang II) exerts complex actions on sympathetic nerve activity and heart rate, but these actions are incompletely understood. We performed three series of experiments in conscious rabbits to analyze the actions of exogenous and endogenous Ang II on renal sympathetic nerve activity and heart rate. (1) Graded intravenous doses of phenylephrine and Ang II suppressed renal sympathetic nerve activity to the same degree, whereas Ang II decreased heart rate much less than phenylephrine. (2) Ang II infusion at 10 ng/kg per minute increased mean arterial pressure by 13 +/- 2 mm Hg (P < .01) and decreased renal sympathetic nerve activity by 67 +/- 13% (P < .01) but did not change heart rate. In the same rabbits, nitroprusside and phenylephrine infusions were used to generate baroreceptor reflex curves. Ang II shifted the heart rate-mean arterial pressure curve to the right but did not alter the renal nerve activity-mean arterial pressure curve. (3) The Ang II type 1 receptor antagonist losartan decreased mean arterial pressure by 8 +/- 3 mm Hg (P < .01) and increased renal sympathetic nerve activity by 63 +/- 15% (P < .05) but did not change heart rate. Losartan shifted the heart rate-mean arterial pressure curve to the left but did not alter the renal nerve activity-mean arterial pressure curve. These results demonstrate that whereas exogenous Ang II resets the baroreceptor reflex control of heart rate to a higher pressure, it does not increase resting renal sympathetic nerve activity or alter the baroreceptor reflex control of renal nerve activity.(ABSTRACT TRUNCATED AT 250 WORDS)
Augmented arterial pressure responses to cyclosporine in spontaneously hypertensive rats. Role of cytochrome P-450 3A.
Authors: Basu A K , Ghosh S , Mohanty P K , Watlington C O
Published: June 2012

Evidence to support a hypertensinogenic role of family 3A cytochrome P-450 (CYP3A) activity is that troleandomycin, a selective inhibitor of CYP3A, decreases both blood pressure and in vivo corticosterone 6 beta-hydroxylation in spontaneously hypertensive rats (SHR). Renal CYP3A activity is markedly increased in SHR compared with Wistar-Kyoto (WKY) rats. Cyclosporine acutely increases both systolic blood pressure and renal total cytochrome P-450 in SHR. We tested the hypothesis that the augmentation of blood pressure by cyclosporine is mediated by a further increase in renal CYP3A activity. Accordingly, we assessed the effect of troleandomycin administration on cyclosporine-induced systolic blood pressure increase and renal and hepatic microsomal CYP3A activity in SHR. Cyclosporine (5 mg/kg SC) given daily in 11-week-old SHR resulted in substantial augmentation of blood pressure after 6 days. This blood pressure increase was attenuated by troleandomycin (40 mg/kg) given either during or after development of hypertension. Cyclosporine increased renal (60%) but decreased hepatic (25%) microsomal CYP3A activity in SHR. In contrast, cyclosporine failed to produce any detectable increase in either blood pressure or renal CYP3A activity in WKY rats. Troleandomycin completely inhibited renal CYP3A activity measured after cyclosporine treatment of SHR, which correlated with its attenuation of the cyclosporine-induced blood pressure increase. These findings suggest that renal CYP3A could play an important role in acute cyclosporine-induced hypertension.
Effect of captopril and enalapril on endothelial function in hypertensive patients.
Authors: Creager M A , Roddy M A
Published: June 2012

Endothelium-dependent vasodilation is impaired in patients with essential hypertension. The objective of this study was to determine whether long-term treatment with angiotensin-converting enzyme inhibitors improves endothelium-dependent vasodilation in forearm resistance vessels of patients with hypertension. Furthermore, since tissue thiols may be relevant to nitric oxide-mediated vasodilation, we queried whether an angiotensin-converting enzyme inhibitor with a sulfhydryl group preferentially augments endothelium-dependent vasodilation in these individuals. The study included 24 patients with essential hypertension (mean age, 45 +/- 2 years) and 20 normotensive subjects (mean age, 47 +/- 1 years). Methacholine chloride (0.3 to 10 micrograms/min) was infused via the brachial artery to assess endothelium-dependent vasodilation in forearm resistance vessels. Nitroglycerin (1 to 30 micrograms/min) was administered to evaluate endothelium-independent vasodilation. Forearm blood flow was determined by venous occlusion strain-gauge plethysmography. Forearm vascular function studies were performed in hypertensive patients before and 7 to 8 weeks after randomization to either captopril or enalapril, angiotensin-converting enzyme inhibitors with and without a sulfhydryl moiety, respectively. Normotensive subjects were studied on only one occasion. Before treatment, the forearm vasodilative response to methacholine was attenuated in hypertensive compared with normotensive subjects (P < .01). The effects of nitroglycerin on forearm blood flow did not differ significantly between the two groups. Both captopril and enalapril reduced mean blood pressure in the hypertensive subjects (12 +/- 2 versus 15 +/- 3 mm Hg, respectively; P = NS).(ABSTRACT TRUNCATED AT 250 WORDS)
Tissue-specific expression of type 1 angiotensin II receptor subtypes. An in situ hybridization study.
Authors: Gasc J M , Shanmugam S , Sibony M , Corvol P
Published: June 2012

The angiotensin II type 1 (AT1) receptor in murine species exists as two isoforms (AT1A and AT1B) encoded by two different genes. Both subtypes have a 9/10 homology in the coding sequence of their mRNA. We examined organs of adult rats (liver, pituitary gland, adrenal gland, kidney, heart, and lung) to study the differential expression of these two genes in target tissues for angiotensin II. AT1A and AT1B mRNAs were detected by in situ hybridization using specific riboprobes for the 3' noncoding region of the mRNAs that have the lowest homology (approximately 6/10). Only AT1A was expressed in the liver, heart, and lung, and only AT1B was expressed in the anterior pituitary, where most cells were positive. In the adrenal gland, AT1A mRNA was detected in the zona glomerulosa and medulla and AT1B in the glomerulosa. In the kidney, AT1A mRNA was the predominant isoform (mesangial and juxtaglomerular cells, proximal tubules, vasa recta, and interstitial cells), but AT1B was also detected in mesangial and juxtaglomerular cells and in the renal pelvis. The results of this in situ detection suggest a tissue-selective regulation of AT1A and AT1B mRNAs. This tissue specificity may constitute a prerequisite condition if the two angiotensin II receptor subtypes, which are pharmacologically similar, are to selectively modulate the various effects of angiotensin II in the different target tissues.
Tissular expression and regulation of type 1 angiotensin II receptor subtypes by quantitative reverse transcriptase-polymerase chain reaction analysis.
Authors: Llorens-Cortes C , Greenberg B , Huang H , Corvol P
Published: June 2012

Recent studies have revealed that angiotensin II (Ang II) interacts with two pharmacologically different types of seven-transmembrane domain receptors, hence named Ang II type 1 and type 2 (AT1 and AT2) receptors. cDNAs for the AT1 receptor have been cloned, and the existence of two receptor subtypes, AT1A and AT1B, has been revealed in rat and mouse. This study presents a new approach for the specific quantification of AT1A and AT1B receptor mRNAs by reverse transcription and polymerase chain reaction amplification in the presence of an AT1 receptor mutant cRNA as internal standard. Absolute quantities of mRNA are then determined by extrapolation using the standard curve generated with the internal standard. Moreover, addition of this internal standard to each tube controls for both reverse transcription and polymerase chain reaction amplification in each sample. In male Wistar rats, the highest absolute AT1A receptor mRNA levels were found in liver and kidney and those for AT1B receptor mRNA in the pituitary. Expressed as a percentage of total AT1A+AT1B receptor mRNA content, AT1A receptor mRNA content was 100% in liver, 85% in lung, 73% in kidney, 65% in aorta, 48% in adrenals, and 15% in the hypophysis. Since this approach can determine absolute AT1A and AT1B receptor mRNA quantities in different organs, it allows the study of the regulation of their expression under different pathophysiological conditions. After sodium depletion, known to induce hyperactivity of the renin-angiotensin system, adrenal AT1A and AT1B receptor mRNA levels were increased by 60% and 110%, respectively. In contrast, in renovascular hypertension (two-kidney, one clip), also associated with elevated circulating plasma renin activity, adrenal AT1B receptor mRNA levels decreased by 50%, whereas there was no change in those of AT1A. Therefore, the differential distribution and regulation of these two receptor subtypes suggest that each of them might be involved in the mediation of different biological effects of Ang II.
Role of the renin-angiotensin system in neointima formation after injury in rabbits.
Authors: Janiak P , Libert O , Vilaine J P
Published: June 2012

We investigated the role of the renin-angiotensin system in neointima formation in a species in which converting enzyme inhibitors have been so far ineffective in suppressing abnormal vascular repair. The effects of converting enzyme inhibition by perindopril and selective blockade of angiotensin subtype 1 receptor by DuP 753 were assessed on neointima formation after balloon injury of rabbit carotid artery. Myointimal growth was measured by histomorphometric analysis. In rabbits treated 6 days before and for 14 days after injury, perindopril (2 mg/kg per day PO, n = 7) significantly reduced neointima formation (-51%, P < .01). DuP 753 (1 mg/d, n = 8) infused perivascularly for 14 days in the vicinity of injured carotid artery also markedly suppressed myointimal thickening (-60%, P < .01). To determine whether angiotensin subtype 2 receptor was implicated in this vascular response, we infused CGP 42112A, a specific subtype 2 receptor ligand, continuously for 14 days according to the same protocol of DuP 753 administration. CGP 42112A (1 mg/d) did not change the neointima-media ratio, indicating that angiotensin subtype 2 receptors were not involved in myointimal hyperplasia in rabbits. Thus in rabbits, the renin-angiotensin system plays a major role in neointima formation, and the protective effect of perindopril appears to be mediated mainly by inhibition of angiotensin II production, because blockade of the subtype 1 receptor reduced myointimal growth in a manner similar to that of converting enzyme inhibition and because intracarotid infusion of angiotensin II (500 ng/min) at the site of injury enhanced the vascular response (+39%, P < .05). Bradykinin (500 ng/min) administered in the same conditions as angiotensin II did not modify neointima formation.
Refeeding hypertension in obese spontaneously hypertensive rats.
Authors: Ernsberger P , Koletsky R J , Baskin J S , Foley M
Published: June 2012

Very-low-calorie diets lower blood pressure acutely in obese humans and rats. However, refeeding after dietary restriction produces mild hypertension in rats. Refeeding hypertension was characterized in genetically obese spontaneously hypertensive rats (obese SHR, Koletsky rat), a model of genetic obesity and hypertension. Obese SHR were fed a restricted diet (Optifast) for 12 days, refed ad libitum for 28 days, dieted again for 12 days, and then refed 4 days and killed. Control obese SHR and lean SHR littermates were fed ad libitum continuously. Dietary restriction led to rapid weight loss followed by prompt regain to baseline weight after return to unrestricted food intake. Heart rate fell with institution of the low-calorie diet and returned to baseline on refeeding. Blood pressure became elevated during refeeding in dieted obese SHR relative to ad libitum fed obese SHR controls. The fall in blood pressure after ganglionic blockade with chlorisondamine was exaggerated in refed obese SHR, and cardiac beta-adrenergic receptors were downregulated. Both of these findings imply increased sympathetic tone. The left ventricular wall was thicker in the refed obese SHR than in the ad libitum fed obese SHR. Shorter cycles of weight loss and regain in lean SHR led to transient increases in blood pressure and heart rate. Cycles of dietary restriction and refeeding in obese SHR elicit sustained blood pressure elevation via sympathetic activation and exacerbate cardiac hypertrophy. Drastic fluctuations in nutrient intake may not be advantageous in hypertension.
Tyrosine kinase inhibition prevents deformation-stimulated vascular smooth muscle growth.
Authors: Davis M G , Ali S , Leikauf G D , Dorn G W
Published: June 2012

The goal of this study was to determine the role of tyrosine phosphorylation in transducing deformation-stimulated vascular smooth muscle growth. Rat aorta-derived vascular smooth muscle cells were cultured on flexible silicone elastomer membranes and subjected to cyclic deformation (15 cycles per minute, deformed 2 seconds, relaxed 2 seconds). Deformation significantly increased proto-oncogene expression, [3H]thymidine incorporation, [3H]leucine incorporation, and cell number. Time course studies showed an 8-hour lag between initiation of cell deformation and onset of [3H]thymidine incorporation, with peak levels achieved after 18 to 24 hours. Western analysis of protein blots from deformed cells (10 minutes) demonstrated increased levels of phosphotyrosine-containing proteins having molecular weights of 110 to 130 and 70 to 80 kD. Deformation-stimulated tyrosine phosphorylation was prevented by the tyrosine kinase inhibitor Herbimycin A. Tyrosine kinase inhibition also prevented deformation-stimulated vascular smooth muscle cell growth as measured by [3H]thymidine incorporation. Cyclic deformation stimulates vascular smooth muscle proliferation through activation of tyrosine kinases. Inhibition of tyrosine phosphorylation is an effective means of preventing deformation-induced vascular smooth muscle growth in vitro.
Impaired leukocyte-endothelial cell interaction in spontaneously hypertensive rats.
Authors: Suzuki H , Schmid-Schönbein G W , Suematsu M , DeLano F A , Forrest M J , Miyasaka M , Zweifach B W
Published: June 2012

Hypertension is associated with a progressive organ injury whose etiology remains largely speculative. An increasing database shows that activated leukocytes, while affording an important immune protection, may be a contributing factor to several of the pathogenetic features of the hypertension syndrome. The purpose of this study was to determine the extent to which the glucocorticoid pathway may be involved in the atypical kinetics of leukocytes in spontaneously hypertensive rats (SHR) compared with normotensive Wistar-Kyoto (WKY) rats. The typical venular leukocyte adhesion induced by histamine application was significantly lower in SHR, and a comparison of normalized leukocyte rolling velocity (VWBC/VRBC) showed the values to be significantly higher in SHR relative to WKY controls. This abnormal trend in adherent leukocyte numbers and in VWBC/VRBC values could be counteracted when SHR were pretreated with RU 486, a synthetic glucocorticoid inhibitor, and restored to the levels observed in WKY rats. Anti-P-selectin monoclonal antibody (PB1.3) attenuated in SHR and WKY rats the increment of adherent leukocyte numbers as well as the decrement of VWBC/VRBC value that developed under combined histamine and RU 486 superfusion. Furthermore, an anti-intercellular adhesion molecule-1 monoclonal antibody (1A29) served to attenuate the increment of adherent leukocyte number induced by a combination of histamine and RU 486 superfusion in WKY rats and SHR. The results indicate that the deficient leukocyte-endothelial cell interaction in SHR can be circumvented by a glucocorticoid inhibitor.
Ambulatory blood pressure. An independent predictor of prognosis in essential hypertension.
Authors: Verdecchia P , Porcellati C , Schillaci G , Borgioni C , Ciucci A , Battistelli M , Guerrieri M , Gatteschi C , Zampi I , Santucci A , Santucci C , Reboldi G
Published: June 2012

To determine the prognostic significance of ambulatory blood pressure, we prospectively followed for up to 7.5 years (mean, 3.2) 1187 subjects with essential hypertension and 205 healthy normotensive control subjects who had baseline off-therapy 24-hour noninvasive ambulatory blood pressure monitoring. Prevalence of white coat hypertension, defined by an average daytime ambulatory blood pressure lower than 131/86 mm Hg in women and 136/87 mm Hg in men in clinically hypertensive subjects, was 19.2%. Cardiovascular morbidity, expressed as the number of combined fatal and nonfatal cardiovascular events per 100 patient-years, was 0.47 in the normotensive group, 0.49 in the white coat hypertension group, 1.79 in dippers with ambulatory hypertension, and 4.99 in nondippers with ambulatory hypertension. After adjustment for traditional risk markers for cardiovascular disease, morbidity did not differ between the normotensive and white coat hypertension groups (P = .83). Compared with the white coat hypertension group, cardiovascular morbidity increased in ambulatory hypertension in dippers (relative risk, 3.70; 95% confidence interval, 1.13 to 12.5), with a further increase of morbidity in nondippers (relative risk, 6.26; 95% confidence interval, 1.92 to 20.32). After adjustment for age, sex, diabetes, and echocardiographic left ventricular hypertrophy (relative risk versus subjects with normal left ventricular mass, 1.82; 95% confidence interval, 1.02 to 3.22), cardiovascular morbidity in ambulatory hypertension was higher (P = .0002) in nondippers than in dippers in women (relative risk, 6.79; 95% confidence interval, 2.45 to 18.82) but not in men (P = .91). Our findings suggest that ambulatory blood pressures stratifies cardiovascular risk in essential hypertension independent of clinic blood pressure and other traditional risk markers including echocardiographic left ventricular hypertrophy.(ABSTRACT TRUNCATED AT 250 WORDS)
Relationships Among Plasma Aldosterone, High-Density Lipoprotein Cholesterol, and Insulin in Humans
Authors: Goodfriend Theodore L. , Egan Brent , Stepniakowski Konrad , Ball Dennis L.
Published: June 2012

Abstract
To investigate the pathogenesis of hypertension in patients with obesity and insulin resistance and to explore the role of plasma lipids, we studied 30 subjects at the end of 7 days of low (20 mEq/d) then high (200 mEq/d) sodium diets. Glucose and insulin tolerance tests were performed at the end of each week and blood and urine collected for measurements of plasma aldosterone, renin activity, electrolytes, insulin, and lipoproteins. There was a strong negative correlation between plasma aldosterone and high-density lipoprotein cholesterol during both diets. There were weaker positive correlations between plasma aldosterone and insulin or triglycerides. When the aldosterone-renin ratio was the dependent variable and the correlation controlled for serum potassium, the inverse relationship with high-density lipoprotein cholesterol and the positive correlation with insulin remained, but only during the high salt diet. Subjects were divided into three groups based on high-density lipoprotein cholesterol. Subjects with the lowest high-density lipoprotein cholesterol levels showed the highest aldosterone, plasma triglycerides, body mass index, and waist-to-hip ratio. Those subjects also demonstrated the greatest resistance to insulin action on glucose and plasma unesterified fatty acids. There was a weak direct correlation between plasma aldosterone and systolic blood pressure during the high salt diet. These data suggest that high aldosterone levels may be a link between dyslipidemia, insulin resistance, and hypertension, a relationship made more evident by high salt intake.
Blood Pressure After Captopril Withdrawal From Spontaneously Hypertensive Rats
Authors: Kost Curtis K. , Li Ping , Jackson Edwin K.
Published: June 2012

Abstract
The purpose of the present study was to compare the effect of chronic captopril treatment on blood pressure in young and adult spontaneously hypertensive rats (SHR) and to assess the time course for development of hypertension after captopril withdrawal. SHR received drinking water or captopril solution from 4 weeks of age and were instrumented with radiotelemetry devices at 18 weeks of age to allow continuous monitoring of blood pressure. At 23 weeks of age, mean blood pressure in the captopril group was 100±1 mm Hg compared with 157±3 mm Hg in the water group. Pulse pressure also was significantly reduced in the captopril-treated rats. Infusion of angiotensin II into a subset of captopril-treated rats increased pulse pressure and restored blood pressure to levels of water-treated rats. Captopril treatment for 6 weeks in adult, 24-week-old SHR did not reduce blood pressure to the level of rats treated from 4 weeks of age. Ten weeks after cessation of captopril, blood pressure was 125±4 and 144±4 mm Hg in SHR treated with captopril from 4 to 30 and from 24 to 30 weeks of age, respectively, compared with control hypertensive rats with mean blood pressure of 160±6 mm Hg. Results from this radiotelemetry study confirm previous findings that captopril treatment prevents the development of hypertension and produces a persistent reduction of blood pressure after treatment in young SHR. Captopril treatment produced a persistent reduction of blood pressure after discontinuation in adult rats; however, the effect was less than that observed with captopril initiated in young rats.
A Heme Oxygenase Product, Presumably Carbon Monoxide, Mediates a Vasodepressor Function in Rats
Authors: Johnson Robert A. , Lavesa Manuel , Askari Bardia , Abraham Nader G. , Nasjletti Alberto
Published: June 2012

Abstract
Heme oxygenase is a mammalian enzyme that converts heme to biliverdin and carbon monoxide. Carbon monoxide activates soluble guanylate cyclase and relaxes vascular smooth muscle, and it has been implicated as a potential neuromessenger. The regulatory functions of endogenous carbon monoxide on hemodynamics are not known. Zinc deuteroporphyrin 2,4-bis glycol (ZnDPBG) inhibits heme oxygenase in rats and thus permits assessment of the hemodynamic response to inhibition of endogenous carbon monoxide synthesis. In chronically instrumented, awake male Sprague-Dawley rats, ZnDPBG (45 μmol/kg IP) increased mean arterial pressure (19±2%,
P
<.05) and total peripheral resistance (47±4%,
P
<.05), decreased cardiac output (−16±2%,
P
<.05), but did not affect heart rate. Another heme oxygenase inhibitor, zinc protoporphyrin IX (45 μmol/kg IP), also increased arterial pressure (17±5%,
P
<.05), with no effect on heart rate. In contrast, neither the nonmetallic deuteroporphyrin 2,4-bis glycol (45 μmol/kg IP) nor biliverdin (45 μmol/kg IP) had any effect on blood pressure or heart rate. These findings suggest that ZnDPBG and zinc protoporphyrin IX increase arterial pressure by inhibiting heme oxygenase activity. After pretreatment with chlorisondamine (5 mg/kg IP) or prazosin (5 mg/kg IP) to inhibit autonomic ganglionic or α
1
-adrenoceptor functions, respectively, ZnDPBG did not affect arterial pressure or heart rate. This suggests that ZnDPBG-induced increases in blood pressure rely on autonomic nervous function. We conclude that the pressor response to heme oxygenase inhibitors results from withdrawal of the inhibitory influence of endogenous carbon monoxide on a pressor mechanism mediated by the autonomic nervous system.
Blockade of the Renin-Angiotensin System in Cardiac Pressure-Overload Hypertrophy in Rats
Authors: Bruckschlegel Günter , Holmer Stephan R. , Jandeleit Karin , Grimm Daniela , Muders Frank , Kromer Eckhard P. , Riegger Günter A. J. , Schunkert Heribert
Published: June 2012

Abstract
Left ventricular hypertrophy in response to pressure overload may be modified by neurohumoral activation. To investigate the contribution of the renin-angiotensin system, we studied rats after banding of the ascending aorta that developed severe left ventricular hypertrophy associated with normal plasma renin but elevated cardiac angiotensin-converting enzyme (ACE) levels. Rats were treated with vehicle, ACE inhibitor (ramipril), angiotensin II type 1 receptor antagonist (losartan), or vasodilator (hydralazine) during weeks 7 through 12 after aortic banding. A significant regression of left ventricular mass index as determined by serial echocardiography was observed in ramipril- and losartan-treated groups during weeks 9 through 12 after banding, whereas hypertrophy further increased in vehicle- and hydralazine-treated groups. Twelve weeks after banding, relative left ventricular weights and myocyte widths were markedly increased in vehicle- and hydralazine-treated groups, whereas ramipril and losartan significantly reduced these parameters. In addition, molecular adaptations in left ventricular hypertrophy, such as upregulation of left ventricular atrial natriuretic peptide and downregulation of sarcoplasmic reticulum Ca
2+
-ATPase mRNA levels, were blunted by ramipril or losartan treatment. Hypertrophic regression was associated with reduced mortality in rats treated with ramipril (11%) and losartan (13%) versus hydralazine (20%) and vehicle (31%). Thus, the renin-angiotensin system may be involved in the maintenance of chronic left ventricular hypertrophy. Blockade of the system may result in regression of the hypertrophic phenotype and improve survival in rats despite persistent pressure overload.
Antisense Inhibition of Hypertension in the Spontaneously Hypertensive Rat
Authors: Wielbo Donna , Sernia Conrad , Gyurko Robert , Phillips M. Ian
Published: June 2012

Abstract
Phosphorothioated antisense oligodeoxynucleotide (ASODN) targeted to angiotensinogen mRNA was administered intracerebroventricularly in spontaneously hypertensive rats to test whether angiotensinogen reduction would lower their hypertensive blood pressures. The ASODN lowers hypertensive blood pressures to normotensive levels in spontaneously hypertensive rats; sense oligodeoxynucleotide had no effect. Administration of phosphorothioated ASODN produced a prolonged duration of lowered blood pressure. Injections of ASODN at the same dose that decreased hypertension when administered centrally did not result in blood pressure decreases when administered intra-arterially. Furthermore, angiotensinogen production was decreased in the brain stem and significantly decreased in the hypothalamus of the ASODN-treated rats (
P
<.05), supporting the concept of centrally mediated regulation of hypertension by an overactive brain angiotensin system. To determine the distribution of centrally administered oligodeoxynucleotides, fluorescein isothiocyanate–conjugated oligodeoxynucleotides were injected directly into the lateral ventricles. One hour later, oligodeoxynucleotides were distributed throughout the lateral and third ventricles, with tissue and cellular uptake observed in discrete cells at the injection site. This indicates that the oligodeoxynucleotides are taken up rapidly by brain cells and that they permeate the areas surrounding brain nuclei involved in central blood pressure regulation and volume homeostasis. The results confirm and extend our previous study with phosphodiester ASODN and show that phosphorothioation modification increases the duration of the response and is taken up in vivo. We conclude that with modification, ASODN inhibition of angiotensinogen mRNA translation can be used for a prolonged, profound decrease in mean arterial pressure in the spontaneously hypertensive rat through a central mechanism.
Enalapril Does Not Prevent Renal Arterial Hypertrophy in Spontaneously Hypertensive Rats
Authors: Kett Michelle M. , Alcorn Daine , Bertram John F. , Anderson Warwick P.
Published: June 2012

Abstract
Angiotensin-converting enzyme inhibitors prevent the development of vessel wall hypertrophy in some vascular beds in spontaneously hypertensive rats (SHR), but their effects on hypertrophy of renal arterial vessels have not been studied. We therefore used stereological techniques to study wall and lumen dimensions of the interlobular (cortical radial) and arcuate arteries in the kidneys of SHR (n=7), SHR treated from 4 to 10 weeks of age with enalapril (25 to 30 mg/kg per day; SHR-E, n=7), and Wistar-Kyoto rats (WKY, n=7). All kidneys were perfusion-fixed at 10 weeks. Systolic blood pressure was 199±9, 139±11, and 156±8 mm Hg in the SHR, SHR-E, and WKY groups, respectively. For the interlobular arteries, the volume density of artery wall, wall-to-lumen ratio, and wall thickness in the untreated SHR were significantly greater than in the WKY (0.84±0.09 versus 0.69±0.07×10
−3
, 0.75±0.20 versus 0.53±0.08, and 13.6±3.3 versus 10.6±0.8 μm, respectively), but values in the SHR-E were similar to those in the untreated SHR (1.10±0.20×10
−3
, 0.88±0.22, and 14.0±2.6 μm, respectively). For the arcuate arteries, wall thickness and volume density were significantly greater in SHR than WKY (17.3±3.0 versus 13.9±1.7 μm and 1.63±0.51 versus 1.14±0.27×10
−3
, respectively), and values in the SHR-E (15.7±1.7 μm and 1.69±0.50×10
−3
, respectively) were not significantly different from those in SHR. Thus, enalapril treatment did not prevent vessel wall hypertrophy of both the interlobular and arcuate arteries in SHR despite the normalization of arterial pressure. These results suggest that renal arterial hypertrophy in SHR is not caused by either angiotensin II or elevated arterial pressure.
Angiotensin II and Sympathetic Activity in Sodium-Restricted Essential Hypertension
Authors: Taddei Stefano , Virdis Agostino , Mattei Paola , Favilla Stefania , Salvetti Antonio
Published: June 2012

Abstract
Angiotensin II (Ang II) potentiates sympathetic neurotransmission by presynaptic facilitation of norepinephrine release. We investigated whether endogenous Ang II modulates peripheral sympathetic activity in sodium-depleted essential hypertensive patients. We evaluated the effect of intrabrachial infusion of saralasin, an Ang II antagonist (5 μg/100 mL forearm tissue per minute), and benazeprilat, an angiotensin-converting enzyme inhibitor (2 μg/100 mL forearm tissue per minute), on forearm vasoconstriction (measured by strain-gauge venous plethysmography) induced by the application of lower body negative pressure (−10 mm Hg for 5 minutes). Both saralasin and benazeprilat (n=6 for each group) blunted the vasoconstrictor action of lower body negative pressure, suggesting that circulating Ang II modulates peripheral sympathetic activity. In addition, since β-adrenoceptor stimulation can activate the production of vascular Ang II, the effect of saralasin and benazeprilat on lower body negative pressure application was evaluated in the presence of isoproterenol (0.09 μg/100 mL forearm tissue per minute) and propranolol (10 μg/100 mL forearm tissue per minute). In two other groups of hypertensive patients, isoproterenol infusion increased the release of Ang II in the forearm vasculature (arteriovenous values measured by radioimmunoassay). Furthermore, isoproterenol potentiated lower body negative pressure–induced vasoconstriction. This facilitating effect was abolished by either saralasin or benazeprilat (n=6 for each group). In contrast, in two further groups of patients (n=6 for each group), in the presence of the β-blocker propranolol, saralasin and benazeprilat did not alter the vasoconstrictor action of the endogenous sympathetic stimulus. The present data suggest that in sodium-depleted essential hypertensive patients, endogenous Ang II, activated by the stimulation of β-adrenergic receptors, can potentiate peripheral sympathetic neurotransmission.
Atrial Natriuretic Peptide and Hemodynamic Changes During Normal Human Pregnancy
Authors: Sala Carla , Campise Mariarosaria , Ambroso Giancarlo , Motta Tiziano , Zanchetti Alberto , Morganti Alberto
Published: June 2012

Abstract
We compared plasma atrial natriuretic peptide (ANP) and cGMP levels during normal pregnancy—a condition characterized by hypervolemia, high cardiac output, and decreased vascular resistance—with postpartum levels and assessed their relation to pregnancy-induced hemodynamic changes. Humoral and hemodynamic variables were measured in healthy women subjects in the supine and upright postures at each trimester of pregnancy and postpartum. Supine plasma ANP was increased throughout pregnancy (32±5, 21±3, and 19±2 versus 15±1 pmol · L
−1
, respectively, at each trimester versus postpartum), as was cGMP (8.6±1, 7.1±1, and 6.6±1 versus 5.6±1 nmol · L
−1
), and their increments were directly related (
r
=.68,
P
<.01). Both ANP and cGMP levels did not differ from postpartum levels after subjects stood. Supine stroke volume was initially increased but declined below postpartum levels in late pregnancy (69±4, 60±3, and 44±3 versus 58±4 mL · m
−2
), whereas after subjects stood it was always higher (56±3, 58±3, and 49±2 versus 44±2 mL · m
−2
); thus, stroke volume tended to increase in response to standing in late pregnancy. Supine cardiac index had a similar trend, which was opposite to that of total peripheral resistance (1213±62, 1265±79, and 1729±89 versus 1654±92 dyne · s
−1
· cm
−5
· m
−2
). The increments of supine ANP throughout pregnancy were directly related to the changes of stroke volume (
r
=.40,
P
<.01), and those of cGMP were inversely related to the changes of total peripheral resistance (
r
=−.46,
P
<.01). We conclude that in early pregnancy ANP secretion is stimulated by hypervolemia, which also increases stroke volume. In late pregnancy, these changes in the supine position wear off because of the impairment of venous return by the pregnant uterus, which is relieved after standing. The increased plasma ANP may contribute to the systemic vasodilation during pregnancy, and this effect is mediated by its second messenger cGMP.
Endogenous Human Renin Expression and Promoter Activity in CALU-6, a Pulmonary Carcinoma Cell Line
Authors: Lang Julie A. , Yang Gongyu , Kern Jeffrey A. , Sigmund Curt D.
Published: June 2012

Abstract
We have previously reported that transgenic mice containing the human renin gene express high levels of human renin mRNA in the lung. We show in this report that human renin expression in two lines of transgenic mice is developmentally regulated. Human renin expression is not evident in the transgenic mouse lung at 15.5 days of gestation, is detectable at 17.5 days of gestation, peaks around birth, and remains elevated into adulthood. In situ hybridization of mouse fetal lung samples at 18.5 days of gestation revealed that human renin was exclusively expressed in pulmonary type II epithelial cells. A survey of the medical literature revealed a number of clinical cases in which hypertension was caused by renin-secreting pulmonary tumors and a fairly widespread occurrence of immunoreactive renin in banked pulmonary tumors of diverse origin. This prompted us to examine a number of pulmonary tumor cell lines to determine whether they express human renin mRNA. One pulmonary carcinoma cell line, CALU-6, expressed human renin mRNA endogenously. Human renin expression in these cells was induced approximately 100-fold after treatment with forskolin, 8-bromoadenosine 3′:5′-cyclic monophosphate, or
N
6
,2′-
O
-dibutyryladenosine 3′:5′-cyclic monophosphate. Transfection analysis of human renin promoter–luciferase fusion constructs revealed the presence of cell-specific positive and negative regulatory elements in the human renin 5′-flanking DNA. This cell line is the only immortalized human cell line that expresses high levels of endogenous human renin mRNA and should provide an excellent tool for studying the regulation of human renin expression in vitro.
Muscle Delivery of Human Kallikrein Gene Reduces Blood Pressure in Hypertensive Rats
Authors: Xiong William , Chao Julie , Chao Lee
Published: June 2012

Abstract
We recently found that transgenic mice expressing human tissue kallikrein develop sustained hypotension. The result suggests that a continuous supply of human tissue kallikrein could have a prolonged effect on blood pressure reduction. In the present study, we investigated the potential of using human tissue kallikrein for gene therapy by injecting a kallikrein gene construct into the skeletal muscle of spontaneously hypertensive rats. Expression of the human tissue kallikrein messenger RNA in spontaneously hypertensive rats was identified by reverse transcription–polymerase chain reaction with Southern blot. Human tissue kallikrein was detected in the injected animals by an enzyme-linked immunosorbent assay. Injection of the human kallikrein gene into spontaneously hypertensive rats caused a significant reduction of systemic blood pressure, ranging from 15 to 26 mm Hg, compared with the control group. The differences were significant 1 week after the injection and continued for more than 2 months. Blood pressure reduction could be reversed after the administration of the bradykinin antagonist Hoe 140. The results indicate that somatic delivery of the human tissue kallikrein gene induces a sustained reduction of systemic blood pressure in spontaneously hypertensive rats. The present study raises the possibility of applying kallikrein gene therapy to the treatment of human hypertensive diseases.
Effect of Renal Perfusion Pressure on Renal Interstitial Hydrostatic Pressure and Sodium Excretion
Authors: Nakamura Tetsuya , Sakamaki Tetsuo , Kurashina Toshiaki , Sato Kunio , Ono Zenpei , Murata Kazuhiko
Published: June 2012

Abstract
Renal interstitial hydrostatic pressure (RIHP) has recently been cited as an important mediator of pressure natriuresis. Our objective was to determine the roles of vasopressin V
1
and V
2
receptors in mediating the effects of renal perfusion pressure (RPP) on RIHP and sodium excretion (U
Na
V). The effects of RPP on renal hemodynamics, RIHP, and U
Na
V were assessed in control Wistar rats (n=10) and in rats pretreated with intravenous infusion of the specific nonpeptide vasopressin V
1
antagonist OPC-21268 (100 μg · kg
−1
· min
−1
; n=8) and the V
2
antagonist OPC-31260 (40 μg · kg
−1
· min
−1
; n=10). Increasing RPP from 95 to 118 mm Hg in control rats increased RIHP (6.4±1.0 to 9.9±1.3 mm Hg), U
Na
V (0.29±0.03 to 0.52±0.05 μEq · min
−1
· g
−1
), urine flow rate (UFR) (5.2±0.3 to 7.6±0.6 μL · min
−1
· g
−1
), and the fractional excretion of sodium (FE
Na
). In rats pretreated with V
1
antagonist, similar results were obtained for urine osmolality and the responses of RIHP, U
Na
V, UFR, and FE
Na
to RPP. V
2
antagonist reduced urine osmolality (392±47 compared with 979±88 mOsm · kg
−1
in control rats) and enhanced the responses of U
Na
V (0.43±0.08 to 1.32±0.32 μEq · min
−1
), UFR (17.8±3.2 to 29.2±3.8 μL · min
−1
· g
−1
), and FE
Na
to RPP, but the RIHP response resembled that observed in the control and V
1
antagonist groups. Renal blood flow and glomerular filtration rate did not differ among the three groups.

Our findings indicate that neither V
1
nor V
2
receptor blockade influences the transmission of RPP into the renal interstitium, although V
2
receptor blockade enhances pressure natriuresis. The pressure natriuresis is mediated primarily by increased RIHP, and the enhanced natriuretic response to the V
2
antagonist is independent of RIHP.