bluuebunny/crossref_metadata_2025 huggingface dataset:
New perspectives in hypertension research. Potentials of vascular biology.
Authors: Dzau V J , Gibbons G H , Morishita R , Pratt R E
Published: June 2012

The vessel wall was once considered to be a passive conduit responding to the circulating endocrine system. However, the emergence of molecular and vascular biology in hypertension research has redefined our understanding of the role of the vasculature as a vital organ in the pathogenesis of hypertension. It is now recognized that the vasculature can regulate its own tone by a variety of previously unknown autocrine and/or paracrine vasoactive systems. Recent evidence indicates that the process of vascular remodeling in hypertension appears to be mediated by locally generated factors within the vessel wall. This review examines the implications of this new paradigm in hypertension, focusing on five topics that have developed through the emergence of molecular vascular biology: the discovery and characterization of novel biologically active molecules synthesized by the vessel wall, the molecular mechanisms and consequences of vascular remodeling, the developmental biology of the blood vessel and the relation to pathobiology, the use of in vivo gene transfer to test hypotheses in vivo, and novel treatment strategies based on gene therapy of the vessel wall.
Hypocalcemia and pregnancy-induced hypertension produced by low-calcium diet.
Authors: Prada J A , Tsang R C , Clark K E
Published: June 2012

Recent studies from our laboratory in fasting pregnant ewes with twin gestation have implicated low serum calcium concentration in the etiology of hypertension in pregnancy. We hypothesized that the reduction in serum calcium concentration produced by feeding of a calcium-deficient diet in twin gestation would lead to a significant increase in maternal arterial blood pressure, vascular resistance, and protein in the urine and decreased uterine blood flow. Twenty-five instrumented ewes were used in the present study. After surgery a calcium-deficient diet and deionized water (calcium ion free) were provided ad libitum to 19 animals. Blood pressure, cardiac output, heart rate, and uterine blood flow were monitored every other day. Six control animals were provided with standard Rumilab diet and tap water (group 1). Animals on a low-calcium diet (group 2) were subdivided according to the blood ionized calcium response to low dietary calcium intake. Non-hypocalcemic animals were assigned to group 2a (n = 10), and hypocalcemic animals (calcium concentration below two standard deviations from the control group) were assigned to group 2b (n = 9). In group 2b calcium concentration decreased from 1.03 +/- 0.04 mmol/L on day 110 of gestation to 0.77 +/- 0.03 mmol/L by day 125 of gestation. Arterial blood pressure increased significantly from 76 +/- 2 to 91 +/- 2 mm Hg, and uterine blood flow decreased from 950 +/- 53 to 579 +/- 48 mL/min. Urinary protein increased from 1.7 +/- 0.3 to 10.5 +/- 1.2 g/L.(ABSTRACT TRUNCATED AT 250 WORDS)
Blood pressure inversely correlates with thrombin-evoked calcium rise in platelets.
Authors: Gardner J P , Cho J H , Skurnick J H , Awad G , Gutkin M , Byrd L H , Lasker N , Aviv A
Published: June 2012

Earlier investigations showed a positive correlation between basal cytosolic free calcium in human platelets and blood pressure; however, recent studies have failed to show this relation. We undertook the present work to examine which platelet cytosolic calcium parameters (namely, cytosolic calcium in resting or stimulated states in calcium-containing and calcium-free media) present the least variability and best correlation with blood pressure. We studied 17 healthy white men on three different occasions separated by 1- and 4-week intervals. Their manual and ambulatory automated 24-hour blood pressure measurements were correlated with cytosolic calcium in resting and stimulated (thrombin-treated) fura 2-loaded platelets. The following cytosolic calcium parameters were measured in 1 mmol/L calcium and calcium-free media: basal cytosolic calcium, peak thrombin-evoked cytosolic calcium, and post-transient cytosolic calcium 5 minutes after thrombin treatment. The highest and lowest coefficients of variation were respectively shown by the basal cytosolic calcium (22.8%) and peak thrombin-evoked cytosolic calcium (10.1%) in calcium medium. Basal cytosolic calcium did not correlate with any of the blood pressure parameters. Of the cytosolic calcium parameters, peak thrombin-evoked cytosolic calcium in calcium medium demonstrated consistent (negative) correlations with blood pressure, with better correlations shown with diastolic than systolic blood pressure of both automated and manual blood pressure readings. Peak thrombin-evoked cytosolic calcium in calcium medium showed similar correlations with nighttime and daytime automated blood pressure measurements. There were no correlations between peak thrombin-evoked cytosolic calcium in calcium-free medium and blood pressure.(ABSTRACT TRUNCATED AT 250 WORDS)
Calcium dependency of frequency-stimulated atrial natriuretic peptide secretion.
Authors: Schiebinger R J , Li Y , Cragoe E J
Published: June 2012

In this study we examined the mechanism whereby atrial natriuretic peptide secretion is increased when the frequency of contraction is raised from 2 to 5 Hz. We tested the hypothesis that calcium plays a significant role in the frequency-stimulated response. Using superfused rat left atria, we found that lowering the superfusate calcium concentration from 1.8 to 0.2 mmol/L abolished the frequency-stimulated atrial natriuretic peptide secretory response. Superfusion with ryanodine (1 mumol/L), an inhibitor of sarcoplasmic reticulum calcium release, resulted in a minimal inhibitory effect. Superfusion with 50 mumol/L nitrendipine or 10 mumol/L diltiazem inhibited the frequency-stimulated response by 46% to 48%. The lack of total inhibition suggested that an additional mechanism of calcium influx was involved, namely, inward calcium movement carried by Na(+)-Ca2+ exchange. As intracellular sodium has been reported to rise with an increase in beat frequency, a fall in the sodium gradient would favor inward calcium movement by Na(+)-Ca2+ exchange. Because we could not directly assess the role of Na(+)-Ca2+ exchange in this experimental paradigm, we examined the effect of lowering the transmembrane sodium gradient on atrial natriuretic peptide secretion by superfusion with the sodium channel activator veratridine or the sodium ionophore monensin. Superfusion with 1 mumol/L veratridine increased atrial natriuretic peptide secretion by 2.3-fold, and 1, 5, and 10 mumol/L monensin increased secretion by 1.1-, 2.1-, and 15.7-fold, respectively. In addition, we examined the possibility that the reported rise in intracellular sodium associated with increased beat frequency was due to enhanced Na(+)-H+ antiporter activity.(ABSTRACT TRUNCATED AT 250 WORDS)
Vascular responsiveness to nitric oxide synthesis inhibition in hypertensive rats.
Authors: Pucci M L , Miller K B , Dick L B , Guan H , Lin L , Nasjletti A
Published: June 2012

We contrasted in normotensive and hypertensive rats the effect of inhibition of nitric oxide synthesis on isometric tension development by aortic rings bathed in Krebs' bicarbonate buffer. NG-Nitro-L-arginine methyl ester (L-NAME) (3 x 10(-4) mol/L) increased tension (82 +/- 11% of the response to 120 mmol/L potassium chloride) in rings of thoracic aorta taken from hypertensive rats 7 to 14 days after aortic coarctation, whereas rings of abdominal aorta from below the coarctation were unresponsive, as were rings of thoracic aorta from rats with deoxycorticosterone-salt-induced hypertension and from the corresponding normotensive controls of either model of hypertension. The contractile response to L-NAME in aortic rings of rats with aortic coarctation was reversed by L-arginine (1 mmol/L), attenuated by removal of the endothelium, and blunted by the protein kinase C inhibitor staurosporine but was unaffected by inhibition of cyclooxygenase, scavengers of superoxide anion, or blockade of receptors for angiotensin, norepinephrine, serotonin, or endothelin. In additional experiments we contrasted the effect of L-NAME (10 mg/kg IV) on the blood pressure of sham-operated rats and rats with aortic coarctation after pretreatment of animals in both groups with DuP 753 (30 mg/kg IV) to achieve blood pressure equalization. The pressor response to L-NAME was twofold greater in rats with aortic coarctation than in sham-operated controls. That pressor and aortic constrictor responsiveness to L-NAME are increased after aortic coarctation suggests that a mechanism of vasodilation, mediated by nitric oxide, is preferentially manifested in rats with aortic coarctation-induced hypertension.
Effects of lateral parabrachial nucleus lesions in chronic renal hypertensive rats.
Authors: Mortensen L H , Ohman L E , Haywood J R
Published: June 2012

Neuroanatomic studies describing forebrain projections to the lateral parabrachial nucleus suggest a central integrative role in cardiovascular regulation. We performed this study to examine the role of this pontine nucleus in the maintenance of one-kidney, figure-8 renal-wrap hypertension. Bilateral ibotenic acid ablation of the lateral parabrachial nucleus was performed 4 weeks after induction of hypertension or sham operation. In hypertensive rats, ablation produced a significant reduction in mean arterial pressure from 160 +/- 4 to 118 +/- 2 mm Hg and a transient but significant increase in heart rate from 381 +/- 5 to 408 +/- 8 beats per minute on the first day after ablation; arterial pressure returned to preablation values by day 5 after ablation. In sham-operated, normotensive animals, arterial pressure was not altered by ablation, and a transient but significant increase in heart rate from 384 +/- 8 to 419 +/- 7 beats per minute was again observed. Before ablation, trimethaphan administration produced a significantly greater drop in arterial pressure in hypertensive (delta-72.8 +/- 4.6 mm Hg) versus normotensive (delta-55.7 +/- 4.1 mm Hg) animals. This effect was eliminated on day 1 after ablation yet returned on day 4 after ablation. In blood samples obtained before ablation and on days 1 and 4 after ablation, circulating plasma catecholamine concentrations in both groups remained unchanged. These observations suggest that, because of possible alternate neural compensatory mechanisms, lateral parabrachial nucleus ablation produces a significant yet transient reversal of renal-wrap hypertension. Thus, the lateral parabrachial nucleus may contribute to the increased sympathetic nervous system function associated with this model.
Salt-induced hypertension in normotensive spontaneously hypertensive rats.
Authors: Wyss J M , Roysommuti S , King K , Kadisha I , Regan C P , Berecek K H
Published: June 2012

Lifetime treatment with oral captopril prevents the development of hypertension in spontaneously hypertensive rats (SHR). We tested the hypothesis that this treatment also prevents the hypertensive response that occurs when untreated NaCl-sensitive SHR are placed on a high NaCl diet. Female SHR were continuously treated with oral captopril before conception and throughout lactation, and the offspring were similarly treated with oral captopril throughout life. At 6 weeks of age, treated male SHR were placed on an 8% (or remained on a 1%) NaCl diet, and systolic arterial pressure, heart rate, and body weight were monitored for 2 weeks. The 8% NaCl diet caused a rapid increase in arterial pressure in the lifetime captopril-treated rats, and 18 days after the initiation of the diet, the mean arterial pressure of this group was 136 +/- 7 mm Hg compared with 100 +/- 2 mm Hg in the 1% NaCl diet rats. The results of a second experiment confirmed the hypertensive effect of the high NaCl diet in lifetime captopril-treated SHR and demonstrated that after 18 days on the diet the dietary NaCl-induced hypertensive response was greater in magnitude in lifetime captopril-treated compared with untreated SHR. The results also demonstrated that lifetime captopril-treated Wistar-Kyoto rats, which are normotensive irrespective of captopril treatment, display no significant increase in arterial pressure when given a high NaCl diet. A third experiment demonstrated that rapidly progressing NaCl sensitivity is also present in female lifetime captopril-treated SHR.(ABSTRACT TRUNCATED AT 250 WORDS)
Losartan inhibits sympathetic and cardiovascular responses to carotid occlusion.
Authors: Kumagai K , Reid I A
Published: June 2012

We have reported that inhibition of angiotensin-converting enzyme with captopril attenuates the cardiovascular responses to bilateral carotid occlusion in conscious rabbits and proposed that the attenuation results from removal of a facilitatory action of angiotensin II on the sympathetic nervous system. The aim of the present study was to assess the effect of carotid occlusion on renal sympathetic nerve activity in conscious rabbits and to investigate the effect of the angiotensin II subtype 1 (AT1) receptor antagonist losartan on the cardiovascular and renal sympathetic nerve activity responses to carotid occlusion. In seven conscious, aortic depressor nerve-sectioned rabbits, carotid occlusion elicited prompt and reproducible increases in mean arterial pressure from 75 +/- 2 to 124 +/- 5 mm Hg (P < .001), heart rate from 285 +/- 8 to 317 +/- 9 beats per minute (P < .01), and renal sympathetic nerve activity to 165 +/- 11% of control (P < .01). In the same rabbits, losartan (5 mg/kg i.v.) decreased mean arterial pressure by 9 +/- 2 mm Hg (P < .01), increased renal sympathetic nerve activity to 143 +/- 13% of control (P < .05), but did not alter heart rate. Losartan significantly attenuated (P < .01) the mean arterial pressure (66 +/- 2 to 81 +/- 2 mm Hg), heart rate (282 +/- 9 to 289 +/- 7 beats per minute), and renal sympathetic nerve activity (143 +/- 13% to 159 +/- 15% of control) responses to carotid occlusion.(ABSTRACT TRUNCATED AT 250 WORDS)
Vasomotor responses in cyclosporin A-treated rats after chronic angiotensin blockade.
Authors: Auch-Schwelk W , Duske E , Hink U , Betz M , Unkelbach M , Fleck E
Published: June 2012

Chronic angiotensin-converting enzyme (ACE) inhibition prevents endothelial dysfunction in hypertension and hypercholesterolemia. Long-term treatment with cyclosporin A impairs endothelium-dependent relaxations and augments contractions to angiotensin II in the rat aorta. The present study compares vasomotor responses to several vasoconstrictor and dilator stimuli after 6 weeks of oral treatment with either the angiotensin-converting enzyme inhibitor lisinopril (10 mg/kg per day), the angiotensin subtype 1 receptor antagonist D 8731 (10 mg/kg per day), cyclosporin A (15 mg/kg per day), or a combination of cyclosporin A with lisinopril or D 8731 (n = 15 rats per group). Twenty-four hours after the last treatment, aortic rings were mounted in organ chambers for measurement of isometric force. Endothelium-dependent relaxations to acetylcholine and calcium ionophore were impaired by cyclosporin A but not affected by the vasodilators. Cyclosporin A-induced endothelial dysfunction was prevented by cotreatment with lisinopril or D 8731. Relaxations to nitroglycerin, SIN-1, and forskolin were not affected by any treatment. Contractions to phenylephrine and serotonin were reduced by lisinopril but not by D 8731. In contrast, contractions to angiotensin II were augmented by cyclosporin A, lisinopril, and the combination of both but not by D 8731 or D 8731 plus cyclosporin A. The data suggest a role for angiotensin II in cyclosporin A-induced endothelial dysfunction. Chronic ACE inhibition reduces overall smooth muscle contractility. The selective augmentation of angiotensin II effects by ACE inhibition and cyclosporin A suggests upregulation of angiotensin receptors in the aortic smooth muscle by these treatments. Chronic angiotensin subtype 1 receptor blockade does not appear to affect angiotensin receptor function.
In vivo occupancy of angiotensin II subtype 1 receptors in rat renal medullary interstitial cells.
Authors: Zhuo J , Alcorn D , McCausland J , Casley D , Mendelsohn F A
Published: June 2012

Angiotensin II receptor binding sites in type 1 interstitial cells in the inner stripe of the outer medulla are readily labeled in vitro by the radioligand but not in vivo after systemic radioligand administration. In anesthetized rats, we investigated if reduced vascular delivery due to angiotensin II-induced renal vasoconstriction or, alternatively, prior occupancy of these sites by endogenous angiotensins modulates angiotensin II subtype 1 receptor binding to renal medullary interstitial cells in vivo using electron microscopic autoradiography. Using 125I-angiotensin II, administered systemically, as a radioligand, binding in control rats occurred predominantly in the glomeruli and proximal tubules, while only low binding was observed in the inner stripe of the outer medulla. Pretreatment of rats with unlabeled [Sar1,Ile8]angiotensin II or with the angiotensin II subtype 1 receptor antagonist losartan before receiving the radioligand completely abolished binding to all sites. Renal vasodilatation induced by sodium nitroprusside or use of the radiolabeled antagonist analogue 125I-[Sar1,Ile8]angiotensin II did not alter binding to the inner stripe. In contrast, chronic salt loading or inhibition of angiotensin-converting enzyme by perindopril significantly increased binding not only to the cortical sites but also to the sites in the inner stripe of the outer medulla. Electron microscopic autoradiographs of the inner stripe detected binding in the interstitial cells only in rats treated with chronic salt loading or perindopril. These results suggest that endogenous angiotensins may modulate binding of circulating angiotensin II to the interstitial cells in vivo, and these angiotensin II receptor-bearing cells are more likely to be more responsive to interstitial angiotensin II than to the circulating hormone.
Role of kinins and nitric oxide in the antihypertrophic effect of ramipril.
Authors: Rhaleb N E , Yang X P , Scicli A G , Carretero O A
Published: June 2012

We examined the effect of non-antihypertensive doses of the angiotensin-converting enzyme inhibitor ramipril, kinins, and/or nitric oxide on left ventricular hypertrophy in rats with aortic coarctation. We investigated the effect of either HOE 140, a specific B2 receptor antagonist, or NG-nitro-L-arginine methyl ester (L-NAME), a nitric oxide synthase inhibitor, on the antihypertrophic effect of ramipril at non-antihypertensive doses (10 micrograms/kg per day) failed to alter left ventricular hypertrophy significantly, although a small decrease was obtained. Given at a dose of 1 mg/kg per day for 6 weeks, ramipril prevented increased blood pressure and left ventricular hypertrophy after aortic coarctation. Neither of these effects was blocked by simultaneous administration of HOE 140 (500 micrograms/kg per day). In rats with aortic coarctation treated with L-NAME, blood pressure increased further but left ventricular weight did not. Ramipril (1 mg/kg per day) significantly reduced left ventricular hypertrophy, although blood pressure was still higher than in rats given water alone. The slope of the correlation between left ventricular weight and blood pressure in rats that received L-NAME was significantly lower than in rats that did not (0.52 versus 1.29; P = .008). This suggests that for each 1 mm Hg that the blood pressure increased, the increase in left ventricular weight was less in the L-NAME groups. Thus, only antihypertensive doses of ramipril possessed antihypertrophic activity. Kinins did not participate in the chronic antihypertensive and antihypertrophic effects of ramipril. In hypertension induced or aggravated by chronic nitric oxide synthase, L-NAME partially impaired development of left ventricular hypertrophy for reasons that are unclear.
A local kallikrein-kinin system is present in rat hearts.
Authors: Nolly H , Carbini L A , Scicli G , Carretero O A , Scicli A G
Published: June 2012

It has been reported that kinins mediate part of the beneficial cardiac effects induced by treatment with angiotensin-converting enzyme inhibitors in situations such as ischemia-reperfusion injury, myocardial infarction, and cardiac hypertrophy. However, it is not known whether the heart contains an independent kallikrein-kinin system. We measured kallikrein in tissue and in the incubation medium of heart slices. Heart slices released active and total (trypsin-activatable) kallikrein into the medium (46 +/- 5 and 380 +/- 18 pg bradykinin/mg, respectively, after 1 hour and 78 +/- 6 and 654 +/- 14 pg bradykinin/mg after 2 hours, n = 7). Release was not due to tissue damage because lactate dehydrogenase, a cytosolic marker, decreased from 8.9 +/- 2.9 to 2.9 +/- 1.0 U/mg per hour. Although kallikrein was released, total tissue kallikrein in the slices did not change (423 +/- 25 pg bradykinin/mg in nonincubated slices and 370 +/- 42 pg bradykinin/mg after 2 hours, P = NS), suggesting pool replenishment. Cardiac kallikrein activity was inhibited by incubation with anti-glandular kallikrein antibodies. Pretreatment with the protein synthesis inhibitor puromycin (10 mg IP) lowered release of active kallikrein from 78 +/- 6 to 22 +/- 4 pg bradykinin/mg and total kallikrein from 654 +/- 14 to 113 +/- 9 pg bradykinin/mg (P < .001). By using reverse transcription polymerase chain reaction with kallikrein family oligonucleotide primers and a specific kallikrein probe, we found that mRNA for tissue kallikrein is present in both atrial and ventricular RNA. Kallikrein activity was also detected in primary cultures of neonatal rat atrial and ventricular cardiocytes and their incubation medium.(ABSTRACT TRUNCATED AT 250 WORDS)
C-type natriuretic peptide upregulates vascular endothelin type B receptors.
Authors: Eguchi S , Hirata Y , Imai T , Marumo F
Published: June 2012

Cultured rat vascular smooth muscle cells (VSMCs) possess receptors for potent vasoconstrictor endothelin-1 (ET-1) as well as potent vasodilator natriuretic peptides (atrial, brain, and C-type natriuretic peptides [ANP, BNP, and CNP, respectively]). However, little is known about molecular interactions between endothelin receptors and natriuretic peptides in VSMCs. To elucidate whether natriuretic peptides regulate vascular endothelin receptors, we studied the effects of three natriuretic peptides on the capacity of 125I-ET-1 binding and expression of endothelin type A (ETA) and type B (ETB) receptor mRNAs in cultured rat VSMCs. CNP (10(-6) mol/L) increased 125I-ET-1 binding capacity in a time-dependent manner (6 to 48 hours) and stimulated cyclic GMP (cGMP) generation in a dose-dependent manner (10(-8)) to 10(-6) mol/L). Pretreatment with CNP (10(-8) to 10(-6) mol/L) and 8-bromo-cGMP (10(-5) to 10(-3) mol/L) for 24 hours resulted in dose-dependent increases in 125I-ET-1 binding in VSMCs. The three natriuretic peptides at the highest concentration (10(-6) mol/L) increased 125I-ET-1 binding and stimulated cGMP generation with almost the same rank order of efficacy (CNP > BNP > ANP). Scatchard analysis of binding studies revealed that CNP (10(-6) mol/L) and 8-bromo-cGMP (10(-3) mol/L) increased vascular endothelin receptor number by 28% and 88%, respectively, without changing its affinity. Pretreatment with both CNP and 8-bromo-cGMP increased ET-1-stimulated inositol 1,4,5-trisphosphate formation.(ABSTRACT TRUNCATED AT 250 WORDS)
Vascular hypertrophy in renal hypertensive spontaneously hypertensive rats.
Authors: Dilley R J , Kanellakis P , Oddie C J , Bobik A
Published: June 2012

Vascular smooth muscle cells isolated from spontaneously hypertensive rats (SHR) replicate faster in vitro than do cells from Wistar-Kyoto (WKY) rats, suggesting that the vascular hypertrophy seen early in the life of SHR might be at least partially caused by abnormal cellular growth properties in vivo. To test whether specific growth stimuli produce more extensive hypertrophy in SHR than WKY rats, we compared their cardiovascular growth responses to two-kidney, one clip renal hypertension. Six-week-old animals were subjected to either renal artery clipping or sham operation. Four weeks after renal artery clipping, there was a proportionately smaller rise in systolic blood pressure in SHR than WKY rats (21% and 44%, respectively); however, the overall level of systolic blood pressure achieved in the two rat strains differed by less than 10 mm Hg (4%). Limitations in the blood pressure responses of SHR to renal artery clipping were not due to inadequate development of left ventricular hypertrophy, as this was greater in SHR than WKY rats; however, aortic hypertrophy was similar in both strains. Aortic DNA content changes in SHR were consistent with a significant hyperplasia of medial smooth muscle cells, whereas in WKY rats, there was cellular hypertrophy. Small and medium-sized arteries of the mesenteric vasculature were also hypertrophied in SHR, and the medial cross-sectional area increased by 63% and 114%, respectively, compared with increases of only 15% and 23% in WKY rats. Strain differences between the sham-operated rat groups were small.(ABSTRACT TRUNCATED AT 250 WORDS)
Interrelation between renin mRNA levels, renin secretion, and blood pressure in two-kidney, one clip rats.
Authors: Schricker K , Holmer S , Hamann M , Riegger G , Kurtz A
Published: June 2012

To examine the interrelation between renin mRNA levels, renin secretion, and blood pressure in rats, we clipped the left renal arteries of rats and measured renin mRNA levels in both kidneys, plasma renin activity, and blood pressure. One and 2 days after clipping, renin mRNA levels increased 3-fold and 4.3-fold in the stenosed kidney and were suppressed to 52% and 26% of controls in the intact kidneys; plasma renin activity increased from 8 to 16.5 and to 30.5 ng angiotensin I.h-1.mL-1 and systolic blood pressure rose from 114 to 123 and to 137 mm Hg. We found a strong correlation (P < .001) between plasma renin activity and renin mRNA levels in the clipped kidneys. We also found significant correlations (P < .05) between mRNA levels in the clipped and intact kidneys and between plasma renin activity and blood pressure for the individual animals. Treatment of normal rats with the converting enzyme inhibitor ramipril (5 mg/kg twice a day) for 2 days increased renin mRNA levels in both kidneys fourfold. In animals with unilateral clips, additional treatment with ramipril increased renin mRNA levels 6.4-fold in the stenosed and 3.3-fold in the intact kidneys. These findings suggest that endogenous angiotensin II exerts an inhibitory effect on renin mRNA expression in normal kidneys, clipped kidneys, and their contralaterals. Suppression of the renin gene in contralateral kidneys seems not to be directly mediated by the rise of plasma renin activity or by the rise of blood pressure in two-kidney, one clip rats.
Lipids and lipoproteins during antihypertensive drug therapy. Comparison of doxazosin and atenolol in a randomized, double-blind trial: the Alpha Beta Canada Study.
Authors: Rabkin S W , Huff M W , Newman C , Sim D , Carruthers S G
Published: June 2012

A randomized double-blind trial comparing the alpha-adrenergic blocker doxazosin and the beta-adrenergic blocker atenolol was completed by 131 patients with mild to moderate hypertension. Blood pressure and fasting blood lipids were determined at baseline and 4, 12, and 24 weeks of treatment. At entry, plasma lipids and lipoproteins were similar in those patients randomized to doxazosin or atenolol. After 24 weeks of treatment with atenolol, there were significant (P < .05) decreases in high-density lipoprotein cholesterol (HDL-C) and increases in triglycerides and very-low-density triglycerides (VLDL-T). In contrast, doxazosin was associated with significant (P < .05) increases in HDL-C and decreases in triglycerides and VLDL-T. There were no significant differences in HDL apolipoprotein (apo) A-I or low-density lipoprotein apoB between the drugs, but atenolol decreased the ratio of HDL-C to apoA-I, and doxazosin increased this ratio, differences that were statistically significant (P < .002). Neither apoA-I nor apoB concentration at baseline nor apoE phenotype was predictive of the lipid responses during antihypertensive treatment with either drug. Thus, there are significant favorable changes in HDL-C, total triglycerides, and VLDL-T between patients with mild to moderate hypertension and normal plasma lipids when treated with the alpha-blocker doxazosin compared with the beta-blocker atenolol. Plasma lipid or apo concentrations were not predictive of their lipid response during antihypertensive therapy with either of these agents.
Analysis of the genetic contamination of salt-sensitive Dahl/Rapp rats.
Authors: Lewis J L , Russell R J , Warnock D G
Published: June 2012

Genetic contamination of Dahl/Rapp salt-sensitive rats (SS/JrHsd) was recently discovered in animals received from Harlan Sprague Dawley, Inc, the main supplier of this strain to researchers in the United States. We were interested in determining how this problem occurred and the extent of contamination in the breeding colony in hopes of quickly correcting the problem and reestablishing the supply of this important model of genetic hypertension. DNA was extracted from whole blood obtained from each rat in the Harlan foundation colony and their offspring, the pedigree expansion colony. Several microsatellite-based genetic markers that were polymorphic between the normal and contaminant alleles were used to test these two colonies. All 10 breeder pairs in the foundation colony were tested at six different loci and found to be homozygous for the normal allele in each case. All 60 members of the pedigree expansion colony were also tested, and several rats carrying contaminant alleles were found, thus localizing the origin of the contamination to this colony. We offer several recommendations regarding precautions researchers using inbred animals should take in designing future experiments.
Effects of atrial natriuretic peptide on left ventricular function in hypertension.
Authors: Semigran M J , Aroney C N , Herrmann H C , Dec G W , Boucher C A , Fifer M A
Published: June 2012

Atrial natriuretic peptide (ANP) has natriuretic and vasodilator actions that lower arterial pressure and may be beneficial to hypertensive patients. To assess the effects of ANP on left ventricular function in patients with hypertension, we compared it with the pure vasodilator nitroprusside. Simultaneous left ventricular micromanometer pressure and radionuclide volume were obtained at baseline, during nitroprusside infusion, during a second baseline period, and during ANP infusion in 10 patients with hypertension. Mean arterial pressure fell during ANP and nitroprusside. Heart rate and plasma norepinephrine levels increased by similar amounts during the two agents, whereas cardiac index and stroke volume index were unchanged during both. Peak positive left ventricular dP/dt fell similarly during ANP and nitroprusside, but left ventricular dP/dt at a developed pressure of 40 mm Hg, a less load-dependent index of contractility, was unchanged during both. The relation between end-systolic pressure and volume during ANP infusion was not shifted leftward or rightward from that during nitroprusside infusion, indicating no inotropic effect. Both ANP and nitroprusside shortened at time constant of isovolumic relaxation calculated by the logarithmic method but did not change the time constant calculated by the derivative method. Peak filling rate was unchanged from baseline during both agents. ANP did not shift the end-diastolic pressure-volume point away from the relation constructed from baseline and nitroprusside points. We conclude that ANP has no direct effect on myocardial contractile or diastolic function in patients with hypertension.
Early narrowed afferent arteriole is a contributor to the development of hypertension.
Authors: Nørrelund H , Christensen K L , Samani N J , Kimber P , Mulvany M J , Korsgaard N
Published: June 2012

The kidney is probably critically involved in the development of essential hypertension, as in many genetic models of hypertension. We have investigated whether a narrowed renal afferent arteriole is involved in the pathogenesis of hypertension in spontaneously hypertensive rats. Systolic blood pressure of 37 F2 generation spontaneously hypertensive rats/Wistar-Kyoto rats was measured at age 7 weeks. The right kidney was removed, and lumen diameter and media cross-sectional area of the afferent arterioles were measured after having been fixed while relaxed and under a transmural pressure of 100 mm Hg. The uninephrectomized rats continued until age 23 weeks, when mean blood pressure was measured. Mean blood pressure at 23 weeks was negatively correlated with lumen diameter at 7 weeks. Quartile analysis based on lumen diameter at 7 weeks showed that compared with rats in the top lumen diameter quartile, rats in the bottom lumen diameter quartile had a reduced media cross-sectional area at 7 weeks (17%), the same systolic blood pressure at 7 weeks, and an increased (16%) mean blood pressure at 23 weeks. We conclude that in spontaneously hypertensive rats a narrowed lumen of distal afferent arterioles at 7 weeks contributes to later development of increased blood pressure. This reduced lumen could be caused by inhibited renal afferent arteriole growth.
Effects of angiotensin II and angiotensin-(1-7) on the release of [3H]norepinephrine from rat atria.
Authors: Gironacci M M , Adler-Graschinsky E , Peña C , Enero M A
Published: June 2012

We examined the effects of angiotensin II (Ang II) and Ang-(1-7) on the release of [3H]norepinephrine elicited by nerve stimulation (2 Hz, 0.5 millisecond, for 2 minutes) in rat atria isolated with their cardioaccelerans nerves. The stimulation-induced release of [3H]norepinephrine was increased 50% by 3 x 10(-8) mol/L of either peptide. No further increase in [3H]norepinephrine release was observed with peptide concentrations up to 3 x 10(-7) mol/L. This effect was completely blocked by the nonselective angiotensin receptor antagonist saralasin (1 x 10(-7) mol/L). The type 1 angiotensin receptor antagonist DuP 753 (1 x 10(-6) mol/L) entirely prevented the increases in [3H]norepinephrine caused by Ang II and Ang-(1-7). On the other hand, the type 2 angiotensin receptor antagonist PD 123319 (1 x 10(-6) mol/L) prevented the increase in [3H]norepinephrine release elicited by Ang-(1-7) but not by Ang II. These results suggest that Ang-(1-7), like Ang II, could have a neuromodulatory function in rat atria via activation of specific angiotensin receptor subtypes, which could be the subtype 1 angiotensin receptor for Ang II and subtypes 1 and 2 for Ang-(1-7).
Modification of pressure natriuresis by long-term losartan in spontaneously hypertensive rats.
Authors: Kline R L , Liu F
Published: June 2012

The goal of this study was to determine how long-term treatment of spontaneously hypertensive rats with losartan affects the pressure-natriuresis curve. Rats were treated with losartan (12 to 15 mg.kg-1.d-1 in drinking water) starting at 4 to 5 weeks of age. At 8 to 9 weeks of age, pressure natriuresis was studied in treated and untreated anesthetized rats using a preparation involving volume expansion and fixed neural and hormonal influences on the kidney. In some untreated rats, losartan (10 or 30 mg.kg-1 i.v.) was given acutely. Average initial mean arterial pressure (+/- SEM) for untreated rats was 164 +/- 2 mm Hg (n = 13) and 131 +/- 3 mm Hg (n = 13) for rats treated chronically with losartan (P < .01). Short-term losartan did not alter arterial pressure significantly. Glomerular filtration rate was not altered significantly by losartan, and renal blood flow was increased modestly by long- and short-term (10 mg.kg-1) losartan at several levels of renal artery pressure. At renal artery pressures of 130 to 175 mm Hg, there were no significant differences between untreated and short-term losartan rats for urine flow, total and fractional sodium excretions, and renal interstitial hydrostatic pressure. The relation between renal artery pressure and urine flow, sodium excretion, or fractional sodium excretion was shifted to the left by long-term losartan treatment. At identical renal artery pressures, renal interstitial hydrostatic pressure was not significantly different among losartan-treated (short or long term) and respective control groups.(ABSTRACT TRUNCATED AT 250 WORDS)
Effect of isobaric hyperoxemia on erythropoietin secretion in hypertensive patients.
Authors: Kokot M , Kokot F , Franek E , Wiecek A , Nowicki M , Duława J
Published: June 2012

We assessed the influence of hyperoxemia on erythropoietin secretion in patients with various etiological forms of arterial hypertension (essential, n = 15; renoparenchymal, n = 16; renovascular, n = 15) and in 15 healthy subjects. On the first day of the study, blood was withdrawn at 1-hour intervals for the estimation of erythropoietin during a total of 6 hours and at 2-hour intervals for the assessment of PO2. Three days later the same parameters were assessed again at identical time intervals, but the subjects were breathing pure oxygen during the first 2 hours. Breathing with pure oxygen resulted in a significant increase of blood PO2 (184.85 +/- 4.47 versus 85.92 +/- 2.28 in essential, 185.21 +/- 5.52 versus 84.55 +/- 3.04 in renoparenchymal, and 181.7 +/- 3.14 versus 87.49 +/- 2.25 in renovascular hypertension groups and 189.84 +/- 5.2 versus 85.89 +/- 1.73 mm Hg in healthy subjects; P < .001 in all groups). Baseline plasma erythropoietin was not different among the groups (29.33 +/- 4.14 in essential, 24.56 +/- 3.09 in renoparenchymal, and 27.77 +/- 3.29 in renovascular hypertension groups and 24.23 +/- 2.70 mU/mL in the control group). The pattern of erythropoietin decline was different in the groups of hypertensive patients. In patients with essential hypertension, unlike in healthy subjects and patients with other etiological forms of arterial hypertension, only a very short-term suppression of erythropoietin levels was observed during hyperoxemia. No significant changes in blood pressure during breathing with pure oxygen were found in any of the studied groups.(ABSTRACT TRUNCATED AT 250 WORDS)
Renal apical membrane sodium-hydrogen exchange in genetic salt-sensitive hypertension.
Authors: Lewis J L , Warnock D G
Published: June 2012

Inbred Dahl/Rapp salt-sensitive and salt-resistant rats differ in their blood pressure response to dietary salt. We studied sodium-hydrogen (Na-H) exchanger kinetics in renal brush border membrane vesicles prepared from both strains on either a 1% or 8% NaCl diet. Kinetics measurements were made with the acridine orange fluorescence quenching technique in vesicles prepared at pH 6.0. The initial Na-H exchange rate was measured using preparations with similar initial quench values. The maximal transport rate (Vmax, fluorescence units per second per milligram protein [+/- SEM]) in salt-sensitive rats on a 1% NaCl diet was significantly lower than that in salt-resistant rats (36.9 +/- 4.4 versus 51.8 +/- 5.5, respectively, P < .0005). With the 8% NaCl diet for 1 week, the Vmax of salt-resistant rats decreased and became similar to that of salt-sensitive rats. The affinity for sodium (Km, millimoles per liter [+/- SEM]) was also lower in salt-sensitive rats than in salt-resistant rats while on a 1% NaCl diet (11.8 +/- 1.0 versus 19.6 +/- 2.3, respectively, P < .002). These values converged when both strains were fed an 8% NaCl diet for 1 week. Inhibition by 25 mumol/L amiloride was less in salt-sensitive rats than in salt-resistant rats on the 1% NaCl diet. These results show that salt-sensitive rats have lower renal apical membrane Na-H exchange activity than salt-resistant rats on a 1% NaCl diet.(ABSTRACT TRUNCATED AT 250 WORDS)
Inheritance of salt-dependent hypertension in the inbred Dahl rat.
Authors: Abbott R E , Schachter D
Published: June 2012

The mode of inheritance of salt-dependent hypertension in the inbred Dahl salt-sensitive rat strain was examined by genetic crosses with the corresponding salt-resistant strain. The blood pressure responses to ingestion of a high NaCl (8%) diet defined three phenotypes: early onset (within 17 days) of systolic hypertension, defined as greater than or equal to 140 mm Hg, the parental salt-sensitive phenotype; late onset of systolic hypertension requiring 50 to 60 days in males and more than 200 days in females, characteristic of the F1 progeny; and normotension, less than 140 mm Hg, the parental salt-resistant phenotype. The frequencies of the phenotypes observed among 91 F2 progeny and 45 progeny of the backcross to parental salt-sensitive animals agree well with values predicted by a model in which two autosomal, unlinked, allelic loci, termed alpha and beta, determine the inheritance. For F2 male progeny, the predicted frequencies of early-onset hypertension, late-onset hypertension, and normotension are 0.1875, 0.5625, and 0.25, respectively, and the corresponding observed frequencies were 0.156, 0.50, and 0.34 (X2 = 0.48, P > .50). F1 progeny of reciprocal parental crosses were maintained on the 8% NaCl diet for 255 days. Male F1 rats developed systolic hypertension sooner than did females. From 60 to 200 days, the average blood pressure value within each group remained approximately stable; the male values exceeded those for females (P < .01); and the direction of the parental cross significantly influenced (P < .05) the levels in males and females, suggestive of genomic imprinting.
Evidence of abnormalities in corticosteroid secretion leading to volume-dependent hypertension in Milan rats.
Authors: Fraser R , Ancil A K , Brown W B , Ingram M C , Holloway C D , Henderson I W , Kenyon C J
Published: June 2012

We examined corticosteroid secretory patterns and their relation to altered salt and water metabolism in Milan hypertensive and normotensive rats. Hypertensive rats had significantly higher blood pressures, exchangeable sodium (hypertensive, 41.2 +/- 0.3 mmol.kg-1; normotensive, 38.4 +/- 0.03 mmol.kg-1, P < .001), plasma volume (hypertensive, 5.39 +/- 0.12 mL.100 g-1; normotensive, 4.84 +/- 0.10 mL.100 g-1, P < .001), and plasma concentrations of atrial natriuretic peptide (hypertensive, 38.8 +/- 4.0 pg.mL-1, normotensive, 22.4 +/- 3.1 pg.mL-1, P < .02). These features coincide with those of mineralocorticoid-induced hypertension. Adrenal venous secretory rates (picomoles per minute) of corticosterone (hypertensive, 1696 +/- 202; normotensive, 873 +/- 139), 18-hydroxycorticosterone (hypertensive, 49.7 +/- 8.3; normotensive, 25.7 +/- 3.3), and aldosterone (hypertensive, 1.16 +/- 0.17; normotensive, 0.52 +/- 0.08) were higher in the hypertensive than the normotensive strain, but that of 11-deoxycorticosterone (DOC) (hypertensive, 94.4 +/- 14.9; normotensive, 114.3 +/- 33.9) was similar in the two strains. The corticosterone-DOC, 18-hydroxycorticosterone-DOC, and aldosterone-DOC ratios were higher in the hypertensive than the normotensive strain (P < .02), but the 18-hydroxycorticosterone-corticosterone and aldosterone-18-hydroxycorticosterone ratios were not. These results indicate increased activity of the "late" aldosterone biosynthetic pathway in the hypertensive compared with the normotensive strain caused by an increased conversion rate of DOC to corticosterone. The comparison of corticosterone secretion between the two strains indicates that 11 beta-hydroxylase rather than aldosterone synthase activity is more active in the hypertensive than the normotensive rats.
Cardiovascular autonomic modulation in essential hypertension. Effect of tilting.
Authors: Radaelli A , Bernardi L , Valle F , Leuzzi S , Salvucci F , Pedrotti L , Marchesi E , Finardi G , Sleight P
Published: June 2012

To better understand the role played by the autonomic nervous system in essential hypertension, we used autoregressive power spectrum analysis to study the noncasual oscillations in RR interval, blood pressure, and skin blood flow in 40 subjects with mild to moderate hypertension and in 25 age-matched control subjects at low frequency (index of sympathetic activity to the heart and the peripheral circulation) and high frequency, respiratory related (index of vagal tone to the heart). RR interval, respiration, noninvasive systolic blood pressure, and skin arteriolar blood flow were simultaneously and continuously recorded with subjects in the supine position and immediately after tilting. The low-frequency component was not significantly different in the two groups either at the cardiac level (control versus hypertensive subjects: 39.1 +/- 4.3 versus 39.9 +/- 3.7 normalized units [NU]) or at the vascular level (1.52 +/- 0.17 versus 1.69 +/- 0.13 ln mm Hg2). After head-up tilting, the RR interval fluctuations were less in hypertensive subjects (low-frequency components from 39.9 +/- 3.7 to 48.4 +/- 4.1 NU, P < .05; high-frequency components from 53.9 +/- 3.7 to 44 +/- 4 NU, P < .05) than in control subjects (low-frequency components from 39.1 +/- 4.3 to 64.4 +/- 4.9 NU, P < .001; high-frequency components from 56.0 +/- 4.5 to 31.2 +/- 4.6 NU, P < .001); the low-frequency components in systolic blood pressure increased similarly in hypertensive subjects (to 2.43 +/- 0.17 ln mm Hg2, P < .0001) and in control subjects (to 2.44 +/- 0.21 ln mm Hg2, P < .01), but the low-frequency components in skin blood flow increased only in control subjects (from 5.34 +/- 0.45 to 6.55 +/- 0.53 mm Hg2, P < .01), not in hypertensive subjects (from 5.55 +/- 0.34 to 5.60 +/- 0.35 ln mm Hg2). In hypertensive subjects with left ventricular hypertrophy, the low-frequency components in systolic blood pressure did not increase after tilting (from 1.75 +/- 0.33 to 2.05 +/- 0.41 ln mm Hg2). Baroreflex sensitivity, as assessed by spectrum analysis, was significantly lower in hypertensive than in control subjects (5.17 +/- 0.49 versus 13.18 +/- 2.44 ms/mm Hg, P < .001. Power spectrum analysis did not reveal an increased sympathetic activity or reactivity either at the cardiac or at the vascular level. The decreased baroreceptor sensitivity in hypertensive subjects could explain the reduced change in sympathovagal balance in the tilt position at the cardiac level. In hypertensive subjects without left ventricular hypertrophy, cardiopulmonary reflex deactivation induced by tilting and/or amplification of sympathetic nervous tone by arteriolar structural change could have preserved the sympathetic activation at the vascular level.
Hemodynamic predictors of incident hypertension. The Framingham Heart Study.
Authors: Post W S , Larson M G , Levy D
Published: June 2012

Previous reports indicate that cardiac output is increased early in the course of hypertension. The purpose of this study was to identify with echocardiography hemodynamic features in normotensive adults that predicted the development of hypertension. Framingham Heart Study subjects were eligible for this investigation if they were normotensive at the baseline examination (systolic blood pressure < 140 mm Hg, diastolic blood pressure < 90 mm Hg, and no antihypertensive medications) and if they were free of coronary heart disease, congestive heart failure, valvular heart disease, atrial fibrillation, hypertrophic cardiomyopathy, diabetes mellitus, and renal insufficiency. The study included 1118 men (mean age, 44 years) and 1559 women (mean age, 46 years). After 4 years of follow-up, of this normotensive cohort, 201 men (18.0%) and 257 women (16.5%) had developed hypertension. In separate, age-adjusted multivariable logistic regression analyses, increased cardiac index (men: odds ratio = 1.19 for one standard deviation increment, P = .03; women: odds ratio = 1.17, P = .02) and end-systolic wall stress (men: odds ratio = 1.24, P = .006; women: odds ratio = 1.43, P < .001) were related to the development of hypertension in both sexes. In addition, increased heart rate in men (odds ratio = 1.25, P = .006) was a significant predictor of hypertension. After adjustment for age and baseline blood pressure, none of the hemodynamic variables was a significant predictor of hypertension. In addition, load-independent indexes of contractility revealed only a minimally greater proportion of subjects with increased contractility at baseline in the group that developed hypertension compared with those who remained normotensive.(ABSTRACT TRUNCATED AT 250 WORDS)