bluuebunny/crossref_metadata_2025 huggingface dataset:
Dopamine fails to inhibit renal tubular sodium pump in hypertensive rats.
Authors: Chen C , Beach R E , Lokhandwala M F
Published: June 2012

We have previously reported that dopamine-1 receptor-mediated activation of phospholipase C is diminished in renal cortical slices of adult spontaneously hypertensive rats. To determine the potential consequences of this phenomenon, we performed the present studies in which renal proximal tubule suspensions obtained from spontaneously hypertensive and Wistar-Kyoto rats of 10-12 weeks of age were used. The tubule suspensions were incubated with dopamine in the presence or absence of dopamine receptor antagonists, and sodium, potassium adenosine trisphosphatase (sodium pump) activity was measured as the ouabain-sensitive adenosine trisphosphate hydrolysis. We found that dopamine produced a concentration-related inhibition of sodium pump activity in the normotensive rats but not in the hypertensive rats. Dopamine-induced inhibition of sodium pump activity in the normotensive rats was abolished by the phospholipase C inhibitor U-73122 or the protein kinase C inhibitor sphingosine, suggesting the involvement of a phospholipase C-coupled protein kinase C pathway in this response. Dopamine-induced inhibition in the normotensive rats was attenuated by the dopamine-1 receptor antagonist SCH 23390 but not by the dopamine-2 receptor antagonist domperidone. To identify possible sites of defect in dopamine-1 receptor-coupled signaling pathways in the hypertensive rats, we incubated the proximal tubules with phorbol 12,13-dibutyrate or the synthetic diacylglycerol analogue 1-oleoyl-2-acetyl-rac-glycerol. The results showed that both compounds inhibited sodium pump activity as effectively in the hypertensive as in the normotensive rats, suggesting that the protein kinase C-coupled sodium pump pathway was not defective in the hypertensive animals.(ABSTRACT TRUNCATED AT 250 WORDS)
Effects of hypertension and aging on coronary arteriolar density.
Authors: Vitullo J C , Penn M S , Rakusan K , Wicker P
Published: June 2012

Coronary reserve has been shown repeatedly to be depressed in hypertension and aging. The underlying mechanisms remain elusive, but structural alterations of the coronary vasculature have been implicated. In this study, we measured maximal coronary dilator capacity and structural characteristics relevant to coronary resistance in aging normotensive (Wistar-Kyoto, n = 22) and spontaneously hypertensive rat (SHR) strains (n = 25) at 1.5, 4, 11, 16, and 22 months of age. Coronary flow measurements, using radiolabeled microspheres, demonstrated a significant (p < 0.01) hypertension- and age-related decline in maximal coronary dilator capacity. After flow measurements, vascular dimensions and arteriolar density were obtained from 1-micron sections prepared from perfusion-fixed hearts. A total of 10,012 arterioles were analyzed, 4,820 in hypertensive and 5,192 in normotensive rats. There was an 18-28% reduction in arteriolar density in hypertensive rats that specifically affected the terminal arteriolar bed at 1.5-11 months. However, the decrement in arteriolar density stabilized at 10% and 6% in 16- and 22-month-old hypertensive rats, respectively. Arteriolar density was not affected by aging. In both strains, there was a significant (p < 0.01) age-related decrease in the ratio of lumen diameter to wall thickness in arterioles > 50 microns. In addition, there was an overall 30% decrease (p < 0.01) in the ratio of lumen diameter to wall thickness in hypertensive compared with normotensive rats. These data indicate that both hypertension and aging are accompanied by structural alterations of the coronary resistance vasculature. These structural alterations may contribute to the depression in coronary reserve that complicates hypertension and aging.
Estrogen receptor variant and hypertension in women.
Authors: Lehrer S , Rabin J , Kalir T , Schachter B S
Published: June 2012

Eighty-eight women visiting a gynecologist were tested for an estrogen receptor B-variant allele. The women were ethnically and racially homogeneous to a large degree. They were from a suburb of Long Island, and most were white. The 12% incidence of hypertension in women with the estrogen receptor wild-type allele is comparable to the 13-32% incidence in the general population of women aged 55-64 years. However, the 48% incidence of hypertension in women with the estrogen receptor B-variant allele is considerably higher than in the general population of women in this age group. We conclude that the presence of the estrogen receptor B-variant allele might have increased the prevalence of hypertension in the women in this study.
Membrane sodium-proton exchange and primary hypertension.
Authors: Rosskopf D , Düsing R , Siffert W
Published: June 2012

Recent studies have revealed that an enhancement of sodium-proton exchange is a frequently observed ion transport abnormality in essential hypertension. An altered antiport activity not only is measurable in blood cells of hypertensive subjects ex vivo but also is detectable in skeletal muscle in vivo. Several lines of argument suggest that the altered antiport activity is not an epiphenomenon of hypertension: 1) the increased activity is found only in a subgroup of patients with high blood pressure, 2) it is not tightly correlated to the severity or duration of hypertension, and 3) high sodium-proton exchange activity persists over time and is not affected by antihypertensive treatment. Available evidence suggests that enhanced sodium-proton exchange is associated with or a cause for the structural alterations found in resistance vessels of hypertensive individuals (media hypertrophy) and left ventricular hypertrophy. This review summarizes some of the physiological properties and roles of the sodium-proton exchanger and discusses its kinetic properties in essential hypertension. Furthermore, the reasons for the enhanced antiport activity and its potential implications regarding the pathogenesis of hypertension are discussed.
Elevated hepatic insulin extraction in essential hypertension.
Authors: Kautzky-Willer A , Pacini G , Weissel M , Capek M , Ludvik B , Prager R
Published: June 2012

Insulin resistance, hyperinsulinemia, and dyslipidemia are common characteristics of patients with untreated hypertension. However, the link between the vascular and metabolic disturbances is still unclear. To provide further insights into the metabolic picture of subjects with hypertension, we evaluated insulin resistance, pancreatic secretion, and hepatic extraction of the hormone in 16 untreated patients with essential hypertension before and after 12-16 weeks of drug treatment in comparison with 16 age-, sex-, and body weight-matched normotensive control subjects. All subjects underwent an oral and a frequently sampled intravenous glucose tolerance test. Metabolic parameters were calculated by the minimal model technique. The hypertensive patients exhibited a highly reduced tissue insulin sensitivity (2.6 +/- 0.4 versus 9.6 +/- 1.9 10(4) min-1/[microunits/mL]; p < 0.001). The basal secretion rate (70 +/- 11 versus 35 +/- 5 pmol/L per minute) and the total amount of prehepatically secreted insulin (32 +/- 4 versus 16 +/- 2 nmol/L in 4 hours) were significantly increased in the hypertensive patients compared with the control subjects (p < 0.01), whereas the posthepatic insulin delivery rate was not significantly different between the two groups (4.9 +/- 0.6 versus 3.5 +/- 0.3 nmol/L in 4 hours). Hepatic insulin extraction was found to be significantly elevated in the hypertensive patients compared with control subjects (81 +/- 4% versus 69 +/- 3%, p < 0.04). Increased hepatic insulin extraction partially ameliorated B cell hypersecretion in hypertensive patients. After 12-16 weeks of drug treatment, the blood pressure was normalized, but the metabolic profile of the patients remained unchanged. We conclude that elevated insulin extraction in the liver is a specific characteristic of individuals with essential hypertension and partially compensates pancreatic B cell hypersecretion.
Psychosocial stress can induce chronic hypertension in normotensive strains of rats.
Authors: Henry J P , Liu Y Y , Nadra W E , Qian C G , Mormede P , Lemaire V , Ely D , Hendley E D
Published: June 2012

We report on five 6-month experiments during which five colonies of four male and four female rats were exposed to psychosocial stress. Monthly blood pressure measurements by a tail-cuff method showed a modest (10 mm Hg) increase in two studies using Sprague-Dawley rats. In two further studies using the more aggressive Long-Evans strain, terminal direct carotid arterial pressures were taken as well, and in one study the differences exceeded 20 mm Hg. A fifth study used the Wistar-Kyoto, hyperactive (WKHA) strain developed by Hendley, and no differences were observed. Heart and adrenal weights; adrenal catecholamine synthetic enzymes; and heart, aortic, and kidney histology were measured and showed significant changes, which for the most part paralleled blood pressure changes. Social instability and the associated blood pressure changes were made more severe by periodic mixing of males from different colonies. This had no effect on the peaceable WKHA rats, some effect on the Sprague-Dawley rats, and a severe effect on the Long-Evans rats. The WKHA rats failed to show blood pressure changes despite stress-induced increases in heart and adrenal weights. Thus, different types of psychosocial stress and different genetics combine to induce a variety of neuroendocrine changes, not all of which necessarily lead to increased blood pressure.
Role of transforming growth factor-beta 1 in the cellular growth response to angiotensin II.
Authors: Koibuchi Y , Lee W S , Gibbons G H , Pratt R E
Published: June 2012

We have shown that angiotensin II (Ang II)-induced hypertrophy of vascular smooth muscle cells is dependent on the balance between proliferative and antiproliferative growth factors, specifically basic fibroblast growth factor and transforming growth factor-beta 1 (TGF-beta 1), respectively. We now present evidence, based on two phenotypically distinct cell cultures, that the ability to secrete the biologically active form of TGF-beta 1 is central to the growth response to Ang II. Two separate cultures were examined, one in which Ang II induces hypertrophy and the other in which Ang II induces hyperplasia. Ang II induces the expression of basic fibroblast growth factor twofold to fivefold in both cultures. Furthermore, both cultures express TGF-beta 1. In the culture that responds with hypertrophy, Ang II induces the expression of the active form of TGF-beta 1 twofold to threefold. However, in the culture that responds with hyperplasia, no active TGF-beta 1 was detected either at baseline or after Ang II exposure. Interestingly, all the TGF-beta 1 present was in the inactive, latent form. In the culture that responded with hyperplasia, Ang II induced a fourfold to fivefold increase in DNA synthesis. This increase could be abolished by the addition of active TGF-beta 1. Thus in these two cultures the ability to activate TGF-beta 1 dictates the cellular response to Ang II. These results support our hypothesis that a balance of proliferative and antiproliferative autocrine signals mediates the growth control of vascular smooth muscle cells.
Salt loads attenuate potassium-induced vasodilation of forearm vasculature in humans.
Authors: Fujita T , Ito Y
Published: June 2012

To evaluate the role of the sodium pump in resistance control in vivo, we studied vascular responses to potassium, which produces vasodilation by the activation of vascular Na+, K(+)-ATPase, in normotensive volunteers receiving a high salt diet compared with volume-depleted subjects receiving diuretic treatment. Forearm blood flow was measured by strain-gauge plethysmography during small increments in local concentrations of potassium with intrabrachial arterial infusions of KCl. Infusions of 0.12 and 0.24 mEq/min KCl increased forearm blood flow and decreased forearm vascular resistance in a dose-dependent fashion. But the simultaneous intrabrachial arterial infusion of 2 micrograms/min ouabain, a Na+,K(+)-ATPase inhibitor, could blunt the decremental response of vascular resistance to 0.12 mEq/min KCl. The decrements of vascular resistance with KCl infusions divided by the initial resistance were significantly less with ouabain compared with those without ouabain (43 +/- 4% versus 57 +/- 3%, p < 0.01). This suggests that potassium produces vasodilation by the activation of vascular Na+,K(+)-ATPase activity. Similarly, salt loading (180 mEq NaCl for 7 days) after treatment with diuretics could attenuate percent decrements of resistance with KCl infusions (39 +/- 3% versus 53 +/- 2%, p < 0.01), whereas vascular resistance responses to sodium nitroprusside, a nonspecific vasodilator, and to verapamil, a calcium antagonist, did not change with salt loading after volume depletion. Therefore, salt loading could attenuate forearm vascular response to potassium specifically, as did the administration of ouabain.(ABSTRACT TRUNCATED AT 250 WORDS)
Microalbuminuria in essential hypertension. Reduction by different antihypertensive drugs.
Authors: Erley C M , Haefele U , Heyne N , Braun N , Risler T
Published: June 2012

The effects of four different antihypertensive drugs (the Ca(2+)-channel blocker felodipine, the beta-blocker metoprolol, the angiotensin converting enzyme inhibitor ramipril, and the alpha-blocking agent doxazosin) on microalbuminuria and renal hemodynamics were evaluated in a double-blind, crossover study in 17 patients (10 women, seven men, aged 39 +/- 14 years) with mild-to-moderate essential arterial hypertension and microalbuminuria. Patients were studied after a 2-week placebo phase preceded by 2 weeks off all medication and after 12 weeks of treatment with each drug. Between each drug treatment, there was another 14-day placebo washout period. At the end of the study, we performed two additional 2-week placebo periods. After each placebo and treatment period, we measured albumin excretion during a 3-day collecting period. Renal hemodynamics were assessed by clearance techniques (inulin and p-aminohippurate clearance) at the end of the first and last placebo periods and after each treatment period. All drugs reduced mean arterial pressure and microalbuminuria to a similar and statistically significant (p < 0.05) extent (mean arterial pressure: placebo phase, 116 +/- 5 mm Hg; felodipine, 101 +/- 4 mm Hg; metoprolol, 101 +/- 5 mm Hg; ramipril, 101 +/- 4 mm Hg; doxazosin, 102 +/- 5 mm Hg; urinary albumin excretion: placebo phase, 46 +/- 50 mg/day; felodipine, 18 +/- 23 mg/day; metoprolol, 14 +/- 12 mg/day; ramipril, 16 +/- 16 mg/day; doxazosin, 14 +/- 14 mg/day). Mean arterial pressure levels and urinary albumin excretion returned to baseline after the last placebo period (110 +/- 6 mm Hg and 40 +/- 46 mg/day, respectively).(ABSTRACT TRUNCATED AT 250 WORDS)
Adrenal kallikrein.
Authors: Nolly H , Saed G , Carretero O A , Scicli G , Scicli A G
Published: June 2012

Kallikrein was identified in the adrenal glands of the rat. The enzyme was present in active and inactive forms (n = 9), since preincubation with trypsin increased kininogenase activity from 54.8 +/- 11.8 to 230 +/- 23 pg bradykinin per milligram protein per minute. Adrenal kininogenase activity was inhibited by 91% by phenylmethylsulfonyl fluoride (2 mM), 81% by D-Phe-Phe-Arg-chloromethyl ketone (1 microM), 88% by aprotinin (1,000 KIU), and only 16% by soybean trypsin inhibitor (50 microM). Preincubation with antibodies against rat urinary kallikrein resulted in over 90% inhibition of kininogenase activity. Immunoreactive glandular kallikrein was 30.7 +/- 4.8 ng/mg protein (n = 11). The apparent molecular weight of the adrenal kininogenase on gel filtration chromatography was 33,000 +/- 500 D. Both the adrenal enzyme and the purified submandibular gland kallikrein used as a control had the same mobility on alkaline polyacrylamide gel electrophoresis. To determine whether messenger RNA (mRNA) for glandular kallikrein is present in adrenal gland RNA, we used the polymerase chain reaction employing oligonucleotide primers and glandular kallikrein 32P complementary DNA (cDNA) as a probe, which should give a cDNA fragment of 370 bp. Southern blots of the amplified products revealed a fragment of the predicted size. In conclusion, glandular kallikrein has been identified in the adrenal glands. The presence of mRNA for glandular kallikrein suggests that kallikrein is synthesized locally in this tissue. This provides an anatomic basis for possible participation of a local kallikrein-kinin pathway in the regulation of adrenal function.
Inactivation of endothelin-1 by an enzyme of the vascular endothelial cells.
Authors: Jackman H L , Morris P W , Rabito S F , Johansson G B , Skidgel R A , Erdös E G
Published: June 2012

We previously investigated the inactivation of endothelin-1 by deamidase (lysosomal protective protein), present in many cells, including vascular smooth muscle cells. This enzyme, which we originally purified from human platelets, preferentially hydrolyzes peptides at the C-terminus with hydrophobic amino acids in the P1 or P1' position or both and thereby inactivates endothelin-1, which has a C-terminal sequence of Ile19-Ile20-Trp21-OH. We tested for the presence of deamidase in cultured bovine aortic endothelial cells. The final supernatant of the homogenized cells (S3) cleaved the deamidase substrate dansyl-Phe-Leu-Arg at a rate of 1.3 nmol/min per 10(6) cells at pH 5.5 at 37 degrees C. Endothelin-1 was completely inactivated by the S3 fraction as determined on rat thoracic aorta strips. The major site of inactivation was the Ile20-Trp21 bond, established by high performance liquid chromatography and by amino acid analysis where the main product was des-Trp21-endothelin-1. The hydrolysis of endothelin-1 (5.9 nmol/min per milligram of protein at pH 5.5 at 23 degrees C) by S3 was blocked mainly by inhibitors of deamidase, including diisopropyl fluorophosphate, but not by inhibitors of some other peptidases. This is the first report of a novel pathway of endothelin-1 metabolism in endothelial cells. Thus, endothelial cells, besides being the source of endothelin-1, contain an enzyme that inactivates it.
Genomic analysis and expression patterns reveal distinct genes for endothelial and brain nitric oxide synthase.
Authors: Sessa W C , Harrison J K , Luthin D R , Pollock J S , Lynch K R
Published: June 2012

Constitutively active nitric oxide synthases (NOS) are a unique class of NADPH-dependent, calcium/calmodulin-dependent enzymes that catalyze the conversion of L-arginine to nitric oxide and L-citrulline. However, little is known about the molecular similarities or differences between the two prototypical constitutive NOS enzymes, endothelial NOS (ECNOS) and brain NOS (bNOS). The aims of this study were to begin characterizing the gene structure and tissue distribution of messenger RNAs (mRNAs) for ECNOS and bNOS and to examine the immunological resemblance of the proteins by Western blotting. Full-length complementary DNAs (cDNAs) encoding bovine ECNOS and rat bNOS hybridized, under high stringency, to different-sized fragments of endonuclease-digested bovine, rat, and human genomic DNA. In addition, more than one fragment was detected with both cDNAs, suggesting that ECNOS and bNOS genes contained multiple introns. Tissue distribution of ECNOS mRNA (4.4 kb) and bNOS mRNA (9.5 kb) in the rat was detected by Northern blotting. Patterns among tissue extracts were strikingly different, with ECNOS mRNA being most abundant in aorta, heart, lung, kidney, adrenal gland, spinal cord, and urogenital tissues and bNOS mRNA most prominent in brain regions, intestine, stomach, spinal cord, adrenal gland, and aorta. Interestingly, ECNOS cDNA detected two equally abundant RNA transcripts (4.4 and 4.0 kb) in most brain regions tested, suggesting an alternative splicing of the ECNOS pre-mRNA. Western blotting, using an ECNOS monoclonal antibody, recognized ECNOS protein from native bovine endothelial cells, cultured bovine endothelial cells, and COS cells transfected with ECNOS cDNA but did not recognize purified bNOS.(ABSTRACT TRUNCATED AT 250 WORDS)
Effect of low sodium diet or potassium supplementation on adolescent blood pressure.
Authors: Sinaiko A R , Gomez-Marin O , Prineas R J
Published: June 2012

The roots of essential hypertension extend back into the first two decades of life, suggesting that effective intervention during those years may lead to a reduction in the incidence of adult hypertension. Decreasing the dietary sodium/potassium ratio offers a potentially effective approach to blood pressure reduction. This study tested the feasibility of 3-year sodium reduction or potassium supplementation in adolescents and the effect of these interventions on the rate of rise of blood pressure during adolescence. After 19,452 5th to 8th grade students were screened, 210 from the upper 15 percentiles of blood pressure distribution (105 boys, 105 girls) were randomly assigned to one of three groups: low sodium diet (70 mmol sodium intake per day), potassium chloride supplementation (normal diet plus 1 mmol/kg potassium chloride per day), or placebo (normal diet plus placebo capsule). Capsules for the potassium chloride and placebo groups were administered in a double blind protocol. Blood pressure was measured every 3 months for 3 years. The effect of the intervention was determined by comparing the rate of rise (slope) of blood pressure among the groups using a random-coefficient growth curve model. The boys groups and the girls placebo group had similar positive blood pressure slopes that were significantly different from zero. The girls low sodium group had a slightly negative slope (significantly lower than the slope of the girls placebo group), and the girls potassium group had a slightly positive slope. Both of these slopes were not significantly different from zero and were significantly lower than the slopes of the respective boys groups.(ABSTRACT TRUNCATED AT 250 WORDS)
Cardiovascular responses to long-term blockade of nitric oxide synthesis.
Authors: Manning R D , Hu L , Mizelle H L , Montani J P , Norton M W
Published: June 2012

The goal of this study was to determine if there is a basal release of nitric oxide that affects long-term arterial pressure regulation in dogs. Studies were conducted over a 23-day period in eight conscious dogs with indwelling catheters. Nitric oxide synthesis was blocked by continuous intravenous infusion of nitro-L-arginine-methyl ester at 37.1 nmol/kg per minute for 11 days. Arterial pressure increased to 120 +/- 4% of control on the first day, decreased for a few days, and then increased to a maximum value of 122 +/- 6% of control on day 7. Bradycardia was sustained throughout the entire nitro-arginine period. Blockade of nitric oxide synthesis was evidenced by attenuated pressure and flow responses to systemic acetylcholine infusion. The pressor response to phenylephrine was increased for only 1 day, and the hypotensive effects of nitroprusside were enhanced. Also, the variability of arterial pressure was significantly increased during nitro-arginine. Sodium and water balances were positive the first day of nitro-arginine infusion but were unchanged for the entire nitro-arginine period. In conclusion, the data suggest that blockade of the basal release of nitric oxide in dogs causes an increase in the long-term level of arterial pressure without any sustained sodium or water retention.
Salt-induced increase in arterial pressure during nitric oxide synthesis inhibition.
Authors: Salazar F J , Alberola A , Pinilla J M , Romero J C , Quesada T
Published: June 2012

The objective of this study was to determine in conscious dogs the role of endothelium-derived nitric oxide in mediating the arterial pressure and renal response to a prolonged increment of sodium intake. After a control period of 3 days, an inhibitor of nitric oxide synthesis, NG-nitro-L-arginine-methyl ester, was infused intravenously during 5 consecutive days (0.1 micrograms/kg per minute). Sodium intake (80 mmol/d) did not change throughout the experiment in one group (n = 4). In another group (n = 6), 1 day after infusion of this inhibitor was started, sodium intake increased from 80 to 300 mmol/d during 4 consecutive days. Inhibition of nitric oxide synthesis in dogs with normal sodium intake induced a significant decrease in natriuresis and diuresis (P < .05) without changes in arterial pressure. However, in dogs treated with the nitric oxide synthesis inhibitor, mean arterial pressure increased from 95.2 +/- 3.3 to 106.2 +/- 4.0 mm Hg (P < .01) the first day that sodium intake was elevated and remained increased the following 3 days. In a different group of dogs (n = 5), the increment of sodium intake during 4 days did not induce changes in arterial pressure when nitric oxide synthesis was not inhibited. Cumulative sodium balance was higher (P < .01) in dogs treated simultaneously with the nitric oxide synthesis inhibitor and high sodium intake (158 +/- 21 mmol sodium) than in those treated only with the nitric oxide synthesis inhibitor (82 +/- 19 mmol sodium) or with high sodium intake (36 +/- 13 mmol sodium).(ABSTRACT TRUNCATED AT 250 WORDS)
Intra-arterial infusion of insulin attenuates vasoreactivity in human forearm.
Authors: Sakai K , Imaizumi T , Masaki H , Takeshita A
Published: June 2012

Hyperinsulinemia may contribute to the development of hypertension. The aim of the present study was to determine whether hyperinsulinemia modulates vascular reactivity to phenylephrine or angiotensin II. In 10 young, healthy volunteers, the left brachial artery was cannulated for drug infusion and direct measurements of arterial pressure. We measured forearm blood flow by a strain-gauge plethysmograph while infusing phenylephrine (0.2, 0.8, and 2.4 micrograms/min) and angiotensin II (5, 10, and 20 ng/min) locally into the brachial artery before and during simultaneous intra-arterial infusion of insulin (0.15 mU/kg per minute). Forearm vascular resistance was calculated from directly measured arterial pressure and forearm blood flow. Intra-arterial infusion of insulin raised the local plasma insulin level from 10.3 +/- 1.4 to 133.3 +/- 21.1 microU/mL (P < .01) and did not change blood glucose level in the venous effluents of the forearm. Insulin infusion slightly but not significantly increased basal forearm blood flow (4.6 +/- 1.5 to 5.5 +/- 0.9 mL/min per 100 milliliters, NS) and decreased forearm vascular resistance (22.1 +/- 2.1 to 20.3 +/- 2.8 U, NS). Phenylephrine and angiotensin II increased forearm vascular resistance dose dependently before and during simultaneous insulin infusion (P < .01 for both). Intra-arterial infusion of insulin attenuated vascular reactivity to phenylephrine (P < .01) and angiotensin II (P < .01). None of these drugs changed blood pressure or heart rate. Our results suggest that hyperinsulinemia attenuates vascular reactivity in the forearm resistance vessels in healthy humans.
Comparative effects of three different potent renin inhibitors in primates.
Authors: Clozel J P , Fischli W
Published: June 2012

The goal of the present study was to compare the effects of three potent reference renin inhibitors (remikiren, CGP 38560A, and enalkiren) in sodium-depleted normotensive squirrel monkeys. In these monkeys, arterial pressure was measured in the conscious state with a telemetry system. Oral and intravenous maximal effective doses of the three renin inhibitors were compared in parallel groups of monkeys. In additional experiments, remikiren was given on top of either CGP 38560A or enalkiren in the same animals. Finally, the three drugs were compared with the angiotensin converting enzyme inhibitor cilazapril. The effects of the three drugs on the plasma components of the renin-angiotensin system (plasma renin activity, immunoreactive renin, and immunoreactive angiotensin II concentrations) were also measured. Our results show that remikiren was as effective as cilazapril and markedly more effective than CGP 38560A or enalkiren in reducing arterial pressure in our monkey model. Interestingly, these differences in arterial pressure could not be explained by differences of in vitro potency or different biochemical changes of the plasma components of the renin-angiotensin system, because the inhibitors all reduced immunoreactive angiotensin II to similarly low levels. One possible explanation is that, in our model, remikiren in contrast to CGP 38560A and enalkiren is able to inhibit renin in a functionally important extraplasmatic compartment.
Circadian blood pressure variation in transgenic hypertensive rats.
Authors: Lemmer B , Mattes A , Böhm M , Ganten D
Published: June 2012

Automatic, around-the-clock blood pressure measurements have increased our understanding of hypertension in humans. Patients with essential hypertension display patterns similar to those observed in normotensive subjects, whereas those with secondary hypertension frequently show abnormal circadian rhythms characterized by a failure to reduce blood pressure at night. We have modeled this situation in rats. Normotensive Wistar-Kyoto and Sprague-Dawley rats, spontaneously hypertensive rats, and rats made hypertensive by transgenic implantation of the mouse salivary gland renin gene (TGR[mRen-2]27) underwent chronic implantation of a device that telemetrically monitored their blood pressures, heart rates, and motor activities. In either normotensive or hypertensive rats, motor activity peaked during the dark phase, indicating that animals from all strains were nocturnal. In both normotensive and spontaneously hypertensive rats, the 24-hour blood pressure and heart rate profiles showed peak values during the rats' active phase at night, ie, between midnight and 3 AM. In the transgenic rats, on the other hand, blood pressure values were at maximum during the day around noon, when the rats were in their resting phase. The heart rate of the transgenic rats nevertheless still peaked around midnight. These data suggest that normotensive rats and those with primary and secondary hypertension display circadian rhythms of blood pressure and heart rate analogous to those observed in normotensive and primary or secondary hypertensive humans, respectively. The TGR(mRen-2)27 strain may be a useful model with which to investigate the mechanisms responsible for alterations in circadian rhythms of blood pressure and heart rate in forms of secondary hypertension.
Red blood cell sodium-proton exchange in hypertensive blacks with insulin-resistant glucose disposal.
Authors: Canessa M , Falkner B , Hulman S
Published: June 2012

To define the potential pathogenic role of hyperinsulinemia as a mediator of alterations in sodium transport, we have examined red blood cell Na(+)-H+ and Na(+)-Li+ exchanges in a young adult black population characterized for blood pressure and insulin-mediated glucose disposal. Normotensive and mildly hypertensive blacks (blood pressure, 120 +/- 2/76 +/- 2 and 139 +/- 3/94 +/- 2 mm Hg, respectively) with a mean age of 26.1 years were studied for insulin sensitivity with the euglycemic hyperinsulinemic clamp (molar index of insulin sensitivity, M/I = moles glucose metabolized/insulin in milliliters of plasma). Na(+)-H+ exchange (U = mmol/L cell.h) was measured before and after the insulin clamp as a function of cell pH to determine the maximum transport rate. In the normotensive subjects, 18 were insulin sensitive (M/I = 9.37 +/- 0.6 x 10(4)) and 4 were insulin resistant (M/I = 3.64 +/- 0.6 x 10(4)). In the hypertensive subjects, 4 were insulin sensitive (M/I = 9.15 +/- 1.1 x 10(4)) and 16 were insulin resistant (M/I = 3.02 +/- 0.3 x 10(4)). The maximum rate of Na(+)-H+ exchange was significantly higher in all hypertensive vs normotensive individuals (35 +/- 3 vs 23 +/- 3 U, P < .005). Na(+)-H+ exchange activity was higher in insulin-resistant vs insulin-sensitive hypertensive subjects (40 +/- 3 vs 20 +/- 2 U, P < .001) but not in insulin-resistant normotensive subjects. Na(+)-Li+ exchange was not different in hypertensive and normotensive individuals but was higher in all insulin-resistant compared with all insulin-sensitive subjects (0.26 +/- 0.03 vs 0.16 +/- 0.02 U, P < .01). Na(+)-Li+ exchange also was higher in insulin-resistant vs insulin-sensitive normotensive subjects (0.35 +/- 0.03 vs 0.15 +/- 0.02 U, P < .001) and in insulin-resistant hypertensive subjects vs insulin-sensitive normotensive subjects (0.24 +/- 0.03 vs 0.15 +/- 0.02 U, P < .001). A stepwise multiple regression analysis for all variables revealed that with Na(+)-H+ exchange as a dependent variable the main determinant was blood pressure, which in turn had insulin sensitivity as the main determinant. In conclusion, these results indicate that in hypertensive blacks, insulin-resistant glucose disposal is strongly associated with elevated red blood cell Na(+)-H+ exchange activity. Thus, despite impaired insulin-mediated glucose disposal, cellular Na+ gain via enhanced activity of Na(+)-H+ exchange is not blunted in hypertensive blacks.
Renal nitric oxide and angiotensin II interaction in renovascular hypertension.
Authors: Sigmon D H , Beierwaltes W H
Published: June 2012

In two-kidney, one clip (2K1C) renovascular hypertension, blood flow is reduced to the clipped but not to the nonclipped kidney, despite elevated angiotensin II. To determine possible interactions between endothelium-derived nitric oxide and angiotensin, we studied bilateral renal blood flow using radioactive microspheres in anesthetized 2K1C hypertensive rats 4 weeks after clipping. We studied the response to nitric oxide synthesis inhibition with 10 mg/kg body wt NG-nitro-L-arginine- methyl ester (L-NAME) in hypertensive rats untreated (n = 5) or treated (n = 5) with 10 mg/kg body wt of the angiotensin II antagonist losartan. 2K1C rats had a blood pressure of 159 +/- 9 mm Hg, and renal blood flow to the clipped kidney was reduced 87% compared with the nonclipped kidney. L-NAME increased blood pressure 36 +/- 5 mm Hg and decreased renal blood flow in the nonclipped kidney 61% (4.9 +/- 0.5 to 1.9 +/- 0.4 mL/min per gram kidney weight, P < .001). Renal vascular resistance increased 200% (33.4 +/- 2.2 to 100.7 +/- 15.0 resistance units [RU], P < .005). Renal blood flow and resistance in the clipped kidney were unchanged by L-NAME. Treatment of 2K1C rats with losartan reduced blood pressure (154 +/- 8 to 116 +/- 11 mm Hg, P < .01), did not change blood flow in the nonclipped, but normalized it in the clipped kidney (4.8 +/- 0.8 mL/min per gram kidney weight).(ABSTRACT TRUNCATED AT 250 WORDS)
Flow regulation of vascular tone. Its sensitivity to changes in sodium and calcium.
Authors: Bevan J A
Published: June 2012

Our hypothesis is that flow-through hydraulic drag or shear stresses the extracellular elements in the vascular wall. When the endothelium is intact, this results in the release of endothelium-derived relaxing factor and other substances, eg, prostanoids, from the endothelium. As in some reports, after inhibition of nitric oxide synthase, flow effects are still observed although diminished; the shear effect is extended mechanically to the subendothelial tissues. Shear causes conformational changes in the glycosaminoglycans by extending them from a randomly coiled aggregated state to a more elongated condition along the line of flow. This elongation and the consequent exposure of an increased number of cationic binding sites on the glycosaminoglycans lead to changes in sodium binding. The extent of the conformational change is influenced by the concentration of calcium, an ion that not only competes with sodium at specific binding sites but possibly cross-links the polysaccharide chains of the protein saccharide complex. These complex interactions might account for the cooperative, nonantagonistic interaction of sodium and calcium over the physiological concentration range. Sodium binding is influenced by changes in external sodium concentration, and this presumably accounts for the sodium sensitivity of the flow response. Although glycosaminoglycans are possibly the most studied in this regard, they are not the only candidates. Other extracellular proteins, either in conjunction with glycosaminoglycans or independently, might be involved. By mechanisms not yet identified, these changes are signaled to the cell. We have proposed that in part, at any rate, this may be related to the sodium concentration gradient.
Effects on blood pressure of omega 3 fats in subjects at increased risk of cardiovascular disease.
Authors: Vandongen R , Mori T A , Burke V , Beilin L J , Morris J , Ritchie J
Published: June 2012

This study was conducted to compare the effects of omega 3 fatty acids, taken as fish or fish-oil supplements in the setting of a high- or low-fat dietary background, on blood pressure and heart rate in men with moderate cardiovascular risks. One hundred twenty men were randomly allocated to five high-fat (40% of daily energy) and two low-fat (30% of energy) groups to undertaken a 12-week dietary intervention period involving fish, fish oil, or a combination of these. Sodium intake was restricted to less than 90 mmol/d. The five high-fat groups were assigned to take either 6 or 12 fish-oil capsules daily, fish or a combination of fish oil and fish, or placebo capsules. The two low-fat groups took either fish or placebo capsules. Fish meals were devised to provide 1.3 g of eicosapentaenoic acid daily, equivalent to that contained in 6 fish-oil capsules. Subjects were instructed to eat a selection of fish that provided an average of 3.65 g/d (range, 3.2 to 4.1 g/d) of total omega 3 fatty acids. Subjects were seen at regular intervals during the baseline and dietary intervention periods for measurement of weight, blood pressure, heart rate, dietary compliance, urinary electrolyte excretion, platelet phospholipid fatty acids, blood glucose, and insulin concentration. There was a greater fall in both systolic and diastolic blood pressures in subjects allocated fish or fish oil, particularly in the low-fat groups, compared with control subjects. However, there was no significant group effect.(ABSTRACT TRUNCATED AT 250 WORDS)
Cardiac weight in hypertension induced by nitric oxide synthase blockade.
Authors: Arnal J F , el Amrani A I , Chatellier G , Ménard J , Michel J B
Published: June 2012

Wistar rats given a nitric oxide synthase inhibitor, NG-nitro-L-arginine-methyl ester (L-NAME), for 4 weeks develop time- and dose-dependent hypertension without cardiac hypertrophy. This initial study of the relation between left ventricular weight and L-NAME-induced hypertension has now been extended by giving 50 mg/kg per day L-NAME to Wistar rats (n = 30) for 8 weeks and comparing results with those from control rats (n = 10) and two-kidney, one clip rats (n = 14). Although L-NAME rats and two-kidney, one clip rats had increased systolic blood pressures during the last 3 weeks of the experiment (202 +/- 24 and 224 +/- 16 mm Hg, respectively), the ratio of left ventricular weight to body weight of L-NAME rats (2.12 +/- 0.32 mg/g) was not statistically different from that of control rats (1.93 +/- 0.13 mg/g), whereas that of two-kidney, one clip rats was increased (2.85 +/- 0.20 mg/g). The plasma renin activity of L-NAME rats was not significantly different from that of control rats. Two L-NAME rat subgroups were defined according to the presence of left ventricular hypertrophy (ratio of left ventricular weight to body weight > 2.19 mg/g, control mean +2 SD) (6 of 25) or its absence (19 of 25). Systolic blood pressure, plasma renin activity, and cardiac angiotensin converting enzyme activity of L-NAME rats with left ventricular hypertrophy were significantly higher than those of the subgroup without.(ABSTRACT TRUNCATED AT 250 WORDS)
In vivo hypothalamic release and synthesis of catecholamines in spontaneously hypertensive rats.
Authors: Pacák K , Yadid G , Jakab G , Lenders J W , Kopin I J , Goldstein D S
Published: June 2012

Juvenile spontaneously hypertensive rats (SHR) have higher plasma levels of catechols and markedly larger catechol responses to yohimbine than do normotensive Wistar-Kyoto rats, indicating increased sympathoadrenal outflow and increased alpha 2-adrenergic receptor-mediated restraint of peripheral catecholamine release during hypertension development in SHR. Yohimbine-induced catecholamine release and metabolism in the posterolateral hypothalamus of the brain were assessed in juvenile (6 to 7 weeks) and adult (15 to 16 weeks) SHR and Wistar-Kyoto rats. In vivo microdialysis was used to obtain samples for measurements of norepinephrine, dihydroxyphenylglycol, methoxyhydroxyphenylglycol, and dihydroxyphenylacetic acid in conscious animals before and after yohimbine injection (1 mg/kg IV) beginning 24 hours after probe implantation. Catecholamine synthesis was examined from elevations of 3,4-dihydroxyphenylalanine levels after probe perfusion with NSD-1015, an inhibitor of L-aromatic acid decarboxylase. In adults, SHR had higher dialysate norepinephrine (277 +/- 38 versus 181 +/- 35 pg/mL), dihydroxyphenylglycol (3260 +/- 509 versus 2231 +/- 201 pg/mL), methoxyhydroxyphenylglycol (2659 +/- 369 versus 1890 +/- 144 pg/mL), and dihydroxyphenylacetic acid (46,312 +/- 5512 versus 13,187 +/- 1963 pg/mL) levels and markedly larger increases in 3,4-dihydroxyphenylalanine levels after NSD-1015 than Wistar-Kyoto rats. In juveniles, SHR had larger proportionate increments in microdialysate norepinephrine levels after yohimbine than Wistar-Kyoto rats (85% versus 25%). Although juvenile SHR and Wistar-Kyoto rats had similar NSD-1015-elicited increments in 3,4-dihydroxyphenylalanine levels, systemic yohimbine enhanced the NSD-1015-elicited 3,4-dihydroxyphenylalanine elevations in juvenile SHR but not in Wistar-Kyoto rats. These findings suggest augmented norepinephrine release and catecholamine synthesis in the posterolateral hypothalamus of adult SHR and augmented alpha 2-adrenergic receptor restraint of both norepinephrine release and catecholamine synthesis in juvenile SHR.
Nuclear angiotensin receptors induce transcription of renin and angiotensinogen mRNA.
Authors: Eggena P , Zhu J H , Clegg K , Barrett J D
Published: June 2012

The observation that nuclei from hepatic tissue exhibit specific angiotensin II (Ang II) binding led us to explore whether Ang II modulates mRNA in general, mRNA specific for renin system components, or both. Nuclei from hepatic tissue exhibited a single high-affinity (Kd = 0.4 nmol/L) Ang II-specific binding site, which was associated with increased RNA transcription. Whereas total RNA extracted from nuclei increased 1.5-fold in response to Ang II (10(-9) mol/L), specific mRNA for renin and angiotensinogen increased 7.8- and 2.5-fold, respectively. Ang II binding and induced transcription showed parallel Ang II dose responses that were both inhibited by 10(-5) mol/L DuP 753 or saralasin. Maximum Ang II binding and RNA transcription occurred at the same Ang II concentration (10(-9) mol/L). Higher doses of Ang II resulted in a progressive decrease in RNA transcription. Together, these results demonstrate that hepatic nuclei have functional Ang II-specific receptors. It is concluded that Ang II may elicit responses at nuclear receptors, which heretofore were associated only with Ang II receptors located on plasma membranes. However, the individual contribution of plasma and nuclear membrane Ang II receptors to the overall cellular Ang II transcriptional response and their possible interactions remain to be determined.
Histology of subcutaneous small arteries from patients with essential hypertension.
Authors: Korsgaard N , Aalkjaer C , Heagerty A M , Izzard A S , Mulvany M J
Published: June 2012

The purpose of the present study was to determine the cellular basis for the increased ratio of media thickness to lumen diameter (media-lumen ratio) consistently found in the peripheral resistance arteries from patients with essential hypertension using an unbiased stereological principle (the "disector"). Segments of subcutaneous resistance arteries (approximately 200 microns internal diameter) were isolated from gluteal biopsies of skin and subcutaneous fat taken from 16 untreated patients with essential hypertension and 16 age- and sex-matched normotensive control subjects. Measured under standardized conditions (ie, relaxed and under controlled mechanical conditions) on an isometric myograph, vessels from hypertensive patients had a significant (P < .05) reduction in lumen diameter and an increase in media-lumen ratio (P < .05) compared with vessels from normotensive control subjects. These changes were not associated with alterations in the estimated media volume per segment length. After these measurements had been made, the arteries were fixed, serial sectioned, and stained. The volume fraction of smooth muscle cells within the media was estimated by point counting on photomicrographs of the vessels. Using the disector principle, we determined the numerical density (number per unit volume) of smooth muscle cells within the media of each vessel and calculated the average smooth muscle cell volume (1775 +/- 122 [mean +/- SEM] and 1532 +/- 112 microns 3, hypertensive and normotensive, respectively, P > .05) on the basis of these measurements.(ABSTRACT TRUNCATED AT 250 WORDS)
Purinergic endothelium-dependent and -independent contractions in rat aorta.
Authors: Mombouli J V , Vanhoutte P M
Published: June 2012

The role of endothelium-derived contracting factor or factors in modulating relaxations and contractions to adenine nucleotides was examined in aortas from spontaneously hypertensive rats (SHR) and normotensive Wistar-Kyoto (WKY) and Wistar rats. During contractions to phenylephrine, the relaxations to ATP were impaired significantly in SHR compared with WKY aortas with endothelium. In rings treated with NG-nitro-L-arginine (to inhibit nitric oxide synthase), the endothelium significantly augmented contractions evoked by ATP; this enhancement was greater in SHR compared with WKY aortas. Indomethacin (inhibitor of cyclooxygenase) and SQ 29,458 (antagonist of thromboxane/prostaglandin endoperoxide receptors) but not dazoxiben (inhibitor of thromboxane synthase) significantly augmented the maximal relaxation in WKY rats, abolished the impairment of the relaxation in SHR, and prevented the potentiation by the endothelium of the contractions evoked by ATP. In older animals (10 to 12 months old), the endothelium-dependent concentration-relaxation curves to ATP in SHR and WKY aortas treated with indomethacin were superimposable, as were the concentration-contraction curves (with NG-nitro-L-arginine present). Endothelium-dependent concentration-relaxation and -contraction curves to ADP obtained in these preparations overlapped also. In Wistar rats, the magnitude of the endothelium-dependent relaxations to either ATP or ADP were significantly smaller compared with the other strains, and the endothelium-dependent contractions were even smaller. Results show that adenine nucleotides stimulate the production of both endothelium-derived relaxing and contracting factors. Although there is no obvious age-related alteration in the capacity of aortas to release endothelium-derived relaxing factor, aging enhances endothelium-derived contracting factor activity in WKY rats.