bluuebunny/crossref_metadata_2025 huggingface dataset:
Blood pressure in blacks. Twin studies in Barbados.
Authors: Grim C E , Wilson T W , Nicholson G D , Hassell T A , Fraser H S , Grim C M , Wilson D M
Published: June 2012

We have recently reported that there are significant genetic influences on the population variation in blood pressure in black twins in Los Angeles. The present cross-sectional study was undertaken to replicate these findings in a black twin population that lives in a different biosocial environment. We chose the Caribbean island nation of Barbados, where 96% of the population is black, the literacy rate is 99%, and the access to health care is guaranteed. The goals were 1) to test the feasibility of twin studies in blood pressure research in a developing country and 2) to estimate the relative contribution of genes and environment to blood pressure variability in blacks in the Caribbean. The names of 200 twin sets were obtained with the assistance of community resources including a twin club, by media advertisement, and by asking people at public blood pressure screenings if they knew any twins. By using these methods, we identified 200 sets of twins. Of these, 37.5% (75/200) met our criteria for study. Although 97% of the sets of twins (73/75) said they were willing to participate, only 69% (52/75) were able to be scheduled during the 1 week of the study when the full team of investigators was in Barbados. Of those scheduled, 83% (43/52) were examined. Examination included medical history, physical examination, recumbent blood pressure measurements by two observers, anthropometric measurements, 24-hour urine collections for sodium and potassium tests, and blood tests for zygosity.(ABSTRACT TRUNCATED AT 250 WORDS)
Sodium depletion increases calcium-activated left ventricular pressure in the rat.
Authors: Rossi G , Fouad-Tarazi F M
Published: June 2012

Left ventricular dP/dt has been reported to be enhanced in the perfused isovolumic paced heart (Langendorff preparation) isolated from sodium-depleted rats. In this study, we tested the hypothesis that this positive inotropic effect is caused by increased responsiveness of the contractile myofilaments to calcium. To address this question, the calcium-left ventricular pressure relation during tetanization of the whole heart at different extracellular calcium concentrations (2.5, 5.0, 7.5, 12.5, and 15.0 mM) was studied in 19 sodium-depleted (low sodium diet plus diuretics) and 18 control (regular sodium intake) Sprague-Dawley normotensive rats. Results showed that the maximum calcium-activated left ventricular pressure (induced by tetanization) was significantly higher in sodium-depleted than in control rats at 12.5 mM calcium concentration (170 +/- 27 [SD] mm Hg in sodium-depleted rats vs. 112 +/- 14 mm Hg in control rats, p = 0.0005). The calcium concentration at which half-maximal left ventricular pressure response was attained, however, was not different between the two groups. We conclude that long-term in vivo sodium depletion increased the maximum calcium-activated left ventricular pressure without altering the sensitivity of the contractile machinery to calcium.
Structural changes during microvascular rarefaction in chronic hypertension.
Authors: Hansen-Smith F , Greene A S , Cowley A W , Lombard J H
Published: June 2012

Previous physiological studies have suggested that loss of microvessels (anatomic rarefaction) occurs in the skeletal muscle microcirculation of rats with chronic hypertension. However, little is known of the exact structural changes that occur during the process of anatomic rarefaction. The purpose of this study was to examine the muscle at the ultrastructural level to search for evidence of microvessel degeneration that would correlate with the concept of anatomic rarefaction in chronic hypertension. Cremaster muscles were removed from normal rats and from rats with chronic reduced renal mass hypertension, which was produced by a 75% reduction in kidney mass followed by salt loading (4% NaCl chow with water ad libitum) for 4 weeks. The muscles were fixed and prepared for histological examination by light and electron microscopy. Atrophy and degeneration of both endothelial cells and vascular smooth muscle cells were observed in many arterioles of the hypertensive rats. Some arterioles of hypertensive rats were degenerated to such an extent that the original identity of the cells could not be determined. The hypertensive rats also exhibited degeneration of capillaries and extravasation and uptake of red blood cells into lymphatic vessels. In contrast, age-matched control rats exhibited normal histology. The results of this study support previous physiological evidence for anatomic rarefaction in the cremaster muscle of chronically hypertensive rats.
Hypertension-induced cardiac hypertrophy. Oxygen supply and consumption with pacing.
Authors: Cimini C M , Weiss H R
Published: June 2012

The purpose of this study was to determine if hypertrophied myocardium was associated with diminished cardiac function, restricted oxygen supply, or oxygen consumption during tachycardia. Myocardial oxygen supply and oxygen consumption were determined during baseline and atrial pacing conditions 30 days after New Zealand White rabbits were prepared as one-kidney, one clip Goldblatt hypertensive or uninephrectomized sham control rabbits. Coronary blood flow and cardiac output, using radioactive microspheres, and small vessel oxygen saturations, using microspectrophotometry, were measured in hypertrophied and nonhypertrophied hearts. After 30 days, baseline blood pressure was significantly higher in the Goldblatt rabbits compared with sham controls, and hypertension was maintained during pacing. The myocardium was hypertrophied in the Goldblatt hypertensive rabbits compared with sham controls. Baseline heart rates were not different between animal groups (242 +/- 32 and 244 +/- 24 beats/min, respectively). Both groups were paced 35% above baseline heart rates; during pacing, cardiac output was similar to baseline values in the sham controls (304 +/- 99 versus 321 +/- 116 ml/min, respectively) but reduced in the hypertensive rabbits (248 +/- 43 versus 325 +/- 62 ml/min). Myocardial oxygen consumption increased twofold in both nonhypertrophied and hypertrophied ventricles during tachycardia. Oxygen extraction was significantly elevated, but coronary blood flow was not altered during pacing in either animal group. Therefore, at the pacing level chosen the diminished function in cardiac hypertrophy was not associated with reduced oxygen consumption. Conversely, reduced efficiency during pacing in the hypertrophied myocardium was suggested.
Exaggerated natriuretic response to atrial natriuretic factor in rats developing spontaneous hypertension.
Authors: Pollock D M , Arendshorst W J
Published: June 2012

The present study was designed to evaluate the renal response to atrial natriuretic factor (ANF) in young rats developing spontaneous hypertension (SHR) and compare this response to age-matched, normotensive controls (WKY) and adult animals. At 6 weeks of age, intravenous infusion of ANF (0.25 micrograms/kg min) in anesthetized, euvolemic rats produced a significantly larger natriuresis and diuresis in SHR compared with WKY rats; this strain difference was not observed in rats 11 weeks of age. SHR showed no age-related change in the natriuretic response to ANF, whereas adult WKY rats exhibited a greater response than young WKY rats. To determine the effect of renal perfusion pressure on the magnitude of the renal response to ANF, additional groups of 6- and 11-week-old SHR were studied while renal perfusion pressure was lowered acutely by aortic constriction (SHR-AC) to values similar to age-matched WKY rats. In young rats, the diuretic and natriuretic response to ANF was greatest in SHR, intermediate in SHR-AC, and lowest in WKY rats. In adult animals, the natriuretic and diuretic response was similar in SHR and WKY rats and tended to be less in SHR-AC. These results in both 6- and 11-week-old SHR are consistent with previous reports that the magnitude of the response to ANF is directly related to acute changes in renal perfusion pressure.(ABSTRACT TRUNCATED AT 250 WORDS)
Enalapril can prevent vascular amplifier development in spontaneously hypertensive rats.
Authors: Adams M A , Bobik A , Korner P I
Published: June 2012

Three groups of spontaneously hypertensive rats (SHR) were given enalapril (25 mg/kg/day) from 4 to 9 weeks, 4 to 14 weeks, and 14 to 20 weeks of age. The drug was stopped and observations continued for another 16-21 weeks. At selected times, we measured blood pressure, in vitro hindquarter vascular resistance properties, left ventricular weight/body weight ratio, and skeletal muscle vessel norepinephrine kinetics in treated and untreated SHR and in Wistar-Kyoto (WKY) rats. At the end of each treatment period, all cardiovascular variables were close to values of WKY rats and well below those of untreated SHR, and the norepinephrine or fractional rate constant was about 25% below those levels. After enalapril was stopped, blood pressure and left ventricular weight/body weight ratio increased in parallel to levels ranging from 30% to 50% of the normal difference between untreated SHR and WKY rats. However, in SHR treated from 4 to 9 weeks and from 4 to 14 weeks of age, hindquarter resistance properties remained close to WKY rat levels for the entire observation period of 16-21 weeks after treatment, suggesting suppression of the enhanced resistance responses of SHR (amplifier properties). In SHR treated from 14 to 20 weeks of age, suppression of amplifier properties was more transient, and they redeveloped partially 5-6 weeks after cessation of therapy. When enalapril was given up to 14 weeks of age, the long-term suppression of amplifier properties was probably mainly through prevention of smooth muscle hypertrophy in resistance vessels and possibly through other mechanisms (e.g., "rarefaction").(ABSTRACT TRUNCATED AT 250 WORDS)
Inhibition of endopeptidase EC 24.11 in humans. Renal and endocrine effects.
Authors: Richards M , Espiner E , Frampton C , Ikram H , Yandle T , Sopwith M , Cussans N
Published: June 2012

The effects of an orally active inhibitor (UK 79300) of the neutral metalloendopeptidase EC 3.4.24.11 were investigated in six healthy male volunteers maintained on a constant diet (150 mmol sodium/day and 80 mmol potassium/day). Subjects were studied in a random order, single-blind study on two occasions, each 48 hours in length, when they were given UK 79300 (25 or 50 mg p.o.) or placebo at 12-hour intervals (each agent for 24 hours). The endopeptidase inhibitor enhanced plasma concentrations of atrial natriuretic factor in association with suppression of both plasma renin activity and aldosterone concentrations. Twenty-four-hour urinary excretion of sodium was doubled by UK 79300, and the urinary excretion rates of phosphorus, atrial natriuretic factor immunoreactivity, and cyclic guanosine monophosphate were also significantly enhanced, whereas urinary aldosterone excretion was halved. The profile of biological effects closely paralleled those previously reported with low dose infusions of atrial natriuretic factor in humans and animals. Therapeutic trials of such inhibitors are now indicated for hypertension or heart failure together with further studies to clarify the underlying mechanisms of action.
Time course of hemodynamic responses to sodium in elderly hypertensive patients.
Authors: Shimamoto H , Shimamoto Y
Published: June 2012

Thirty-one patients with essential hypertension (81.6 +/- 6.9 years old) were studied during two different regimens of sodium intake: 120 meq/day for 8 weeks and 344 meq/day for 2 weeks. Systemic hemodynamic data were measured with Doppler echocardiography from which the mitral flow velocity integral, cardiac index, and total peripheral resistance were calculated. The salt-sensitive patients in whom the increase in total peripheral resistance was greater than the increase in cardiac index with salt loading were termed SST. In the salt-sensitive patients termed SSC, the increase in cardiac index was greater than the increase in total peripheral resistance with increased sodium intake. All SST patients on day 7 of the high sodium diet remained in the SST group on day 14. Nine of 13 patients in the SSC group on day 7 remained in the SSC group on day 14, and the remaining four patients in the SSC group on day 7 fell into the SST group on day 14. Four of eight non-salt-sensitive (NSS) patients on day 7 of the high salt regimen remained in the NSS group on day 14, whereas the remaining four patients in the NSS group on day 7 fell into the SSC group on day 14. Our data suggest a changing pattern with sodium loading of initially high cardiac index followed by a persistently raised total peripheral resistance. The celiac, superior mesenteric, and renal arteries vasoconstricted with sodium repletion in both SST and SSC patients. With salt loading, the terminal aortic vascular bed vasodilated in the SSC patients and vasoconstricted in the SST patients.
Effects of angiotensin converting enzyme inhibitors and of hydralazine on endothelial function in hypertensive rats.
Authors: Clozel M , Kuhn H , Hefti F
Published: June 2012

The function of the endothelium is impaired in hypertension. In spontaneously hypertensive rats (SHR), acetylcholine-induced relaxation is decreased and serotonin-induced constriction is increased. The goal of our study was to evaluate the effect of a long-term treatment with cilazapril, a new angiotensin converting enzyme inhibitor, or hydralazine, a vasodilator, on the endothelium-dependent responses in aorta of SHR. Wistar-Kyoto rats were used as normotensive reference. Isolated aortic rings with or without endothelium were suspended in organ chambers. The rings with intact endothelium were contracted with norepinephrine. Acetylcholine-induced relaxation was markedly enhanced by cilazapril treatment. The tension achieved at maximal relaxation was 8 +/- 4% of norepinephrine contraction in the cilazapril-treated SHR versus 55 +/- 5% in the untreated SHR (p less than 0.001). Hydralazine had no significant effect. The effect of serotonin was also markedly modified by cilazapril. In untreated SHR, serotonin induced the release of a vasoconstrictor substance by the endothelium as assessed by the ratio of maximal tension induced by serotonin in rings with endothelium over maximal tension in rings without endothelium, which was greater than 1. This ratio was reversed in cilazapril-treated SHR but not in hydralazine-treated SHR. Captopril had effects similar to cilazapril. Finally, evaluation of carotid arteries showed that cilazapril also prevented morphological changes of the intima in SHR (i.e., infiltration by mononuclear cells). We conclude that angiotensin converting enzyme inhibitors prevent the functional and morphological alterations in endothelium that are found in hypertension and speculate that this action might participate in their antihypertensive effect.
Intrarenal de novo production of angiotensin I in subjects with renal artery stenosis.
Authors: Admiraal P J , Derkx F H , Danser A H , Pieterman H , Schalekamp M A
Published: June 2012

To estimate the renal extraction and de novo production of angiotensin I and to assess the contribution of blood-borne renin to renal angiotensin I production, the aortic and renal venous plasma levels of renin and intact [125I]angiotensin I and endogenous angiotensin I during continuous systemic intravenous infusion of monoiodinated [125I]angiotensin I were measured in subjects with unilateral renal artery stenosis (n = 8) who were treated with captopril (50 mg b.i.d.). Results demonstrated that 80% of angiotensin I delivered by the renal artery was extracted both by the affected and the unaffected kidney and that on both sides a major part of angiotensin I in the renal vein was derived from intrarenal de novo production. Production of plasma angiotensin I was in excess over extraction (p less than 0.01) on the affected side, whereas extraction was in excess over production (p less than 0.01) on the contralateral side. The plasma level of de novo intrarenally produced angiotensin I in the renal vein was seven times higher on the affected side than the contralateral side. This difference was by far too big to be explained by a difference in the transit time of blood between the two kidneys, by an augmented production of angiotensin I in the circulating blood passing through the affected kidney due to the higher level of venous plasma renin activity in that kidney, or by the combination of both.(ABSTRACT TRUNCATED AT 250 WORDS)
Pressor systems in hypertension and congestive heart failure. Role of vasopressin.
Authors: Gavras H
Published: June 2012

Elevated peripheral vascular resistance, which characterizes hypertension and congestive heart failure (the latter regardless of absolute blood pressure level) is maintained to a large extent by the combined effects of three major neurohormonal pressor mechanisms: the renin-angiotensin system, the sympathoadrenal system, and arginine vasopressin. Blockade of one of these mechanisms may lead to compensatory stimulation of the others, thus offsetting in part the hemodynamic benefits of a specific intervention. Combination therapy, designed to attack all three systems (with use of an angiotensin converting enzyme inhibitor, a sympathetic blocker such as clonidine, and an antagonist of the vasopressor action of vasopressin), may help in the treatment of such cases. To illustrate this strategy, two experimental studies, one case of malignant hypertension, and one case of congestive heart failure are presented.
Chronic atriopeptin regulation of arterial pressure in conscious hypertensive rats.
Authors: Koepke J P , Tyler L D , Blehm D J , Schuh J R , Blaine E H
Published: June 2012

Acute coadministrations of an inhibitor of endopeptidase 24.11 (thiorphan) and a ligand (SC-46542) selective for the non-guanylate cyclase-linked atriopeptin binding sites increases urinary sodium excretion to a greater degree in conscious spontaneously hypertensive rats than in normotensive Wistar-Kyoto rats. In the present study, we examined the effects of chronic 10-day intravenous infusions of SC-46542 (des[Phe106,Gly107,Ala115,Gln116] atriopeptin-(103-126] (0.1 mg/kg/hr), thiorphan (1.5 mg/kg/hr), and atriopeptin-(103-126) (100 ng/hr) alone or in combination on direct recording of mean arterial pressure in conscious spontaneously hypertensive rats. During an 11-day time-control infusion of isotonic saline vehicle (100 microliters/hr), mean arterial pressure remained stable. Chronic infusion of atriopeptin-(103-126) decreased mean arterial pressure progressively over the first 3 days; then mean arterial pressure progressively rose to control level over the following 3 days and remained at control level for the remainder of the experiment. Similarly, coinfusions of atriopeptin-(103-126) and SC-46542 or thiorphan, SC-46542 and thiorphan, or the triple infusion of atriopeptin-(103-126), SC-46542, and thiorphan had only transient effects on mean arterial pressure during 10-day infusions. SC-46542 alone had no effect on mean arterial pressure. Similarly, thiorphan alone had no effect on mean arterial pressure except at doses that blocked the acute pressor response to angiotensin I. Chronic infusions of atriopeptin-(103-126), SC-46542, and thiorphan alone or in combination are not effective long-term treatments for hypertension in spontaneously hypertensive rats.
Regression of cardiac hypertrophy in spontaneously hypertensive rats by enalapril and the expression of contractile proteins.
Authors: Childs T J , Adams M A , Mak A S
Published: June 2012

Several experimental models involving the development of cardiac hypertrophy in adult rats are characterized by the reexpression of the fetal isoform of myosin heavy chain (V3). To determine whether a similar adult-to-fetal shift in the expression of the thin-filament proteins occurs during cardiac hypertrophy, we have examined the expression of the isoforms of myosin, tropomyosin, and troponin T in the left ventricle of young spontaneously hypertensive rats (SHR) with and without treatment using enalapril, an angiotensin converting enzyme inhibitor. Phosphorylation of tropomyosin, which is predominant in the fetal state, was also analyzed. Twelve-week-old SHR were treated with enalapril for 2, 5, 8, and 9 weeks followed by withdrawal of treatment for 9 weeks. Control SHR, without drug treatment, were weight- and age-matched. After 9 weeks of enalapril treatment, mean arterial blood pressure was reduced (from 166 +/- 11 to 89 +/- 5 mm Hg), and left ventricular weight/body weight ratio was regressed (from 2.53 +/- 0.14 to 1.96 +/- 0.05 g/kg) to normotensive levels. During the 9-week treatment period, the percent V3 decreased in SHR substantially from 35 +/- 3% to 13 +/- 1%. There was a significant correlation between the left ventricular hypertrophy and the percent V3 myosin expression in the SHR during regression (r = 0.697, p less than 0.001). However, only the adult isoforms of tropomyosin and troponin T were detected in the SHR with or without enalapril treatment, and the level of tropomyosin phosphorylation remained constant irrespective of the degree of left ventricular hypertrophy.(ABSTRACT TRUNCATED AT 250 WORDS)
Effect of age on the efficacy of blood pressure treatment strategies.
Authors: Klag M J , Whelton P K , Appel L J
Published: June 2012

To study whether the proportion of excess cardiovascular events attributable to various levels of systolic blood pressure varies with age, we calculated the population-attributable risk of all-cause mortality, fatal and nonfatal cardiovascular events (stroke, coronary heart disease, angina, congestive heart failure, and peripheral vascular disease), and stroke incidence due to systolic blood pressure in men and women 45 years of age or older in the United States during 1980. Our estimates are based on US census counts, blood pressure prevalence distributions from the second National Health and Nutrition Examination Survey, and the annual risk of cardiovascular complications during 18 years of follow-up in the Framingham cohort. We then determined the impact of age on the relative efficacy of mass treatment and case-finding strategies in preventing systolic blood pressure-related events. At 45-54 years of age, only 30-40% of systolic blood pressure-related excess events occur in hypertensive individuals (systolic blood pressure greater than or equal to 160 mm Hg). With increasing age, however, the percentage of systolic blood pressure-related events that occur in hypertensive individuals rose substantially; in the older age group (greater than or equal to 75 years), 65-70% of fatal and nonfatal cardiovascular disease events occur in hypertensive persons. The pattern is similar for men and women. The potential impact of a mass treatment strategy designed to shift the distribution of blood pressure downward by a small amount is greater in younger than in older groups, whereas an opposite trend is seen for a high-risk, hypertensive case-finding and treatment approach.(ABSTRACT TRUNCATED AT 250 WORDS)
Renal manifestations of NaCl sensitivity in borderline hypertensive rats.
Authors: DiBona G F , Jones S Y
Published: June 2012

Compared with the normotensive Wistar-Kyoto rat, the spontaneously hypertensive rat exhibits exaggerated alterations in renal sympathetic nerve activity and excretory function during volume expansion (exaggerated natriuresis) and environmental stress (antinatriuresis). The borderline hypertensive rat is the first filial offspring of the spontaneously hypertensive rat and the Wistar-Kyoto rat and develops hypertension with increased dietary NaCl intake. The present investigation sought to determine whether the dietary NaCl intake-induced transition from the normotensive state of the Wistar-Kyoto parent to the hypertensive state of the spontaneously hypertensive parent in the borderline hypertensive rat was accompanied by a similar transition of the renal sympathetic nerve activity and excretory responses to volume expansion and environmental stress. Borderline hypertensive rats fed a 1% NaCl diet remained normotensive and exhibited renal sympathetic nerve activity and excretory responses to volume expansion and environmental stress that were similar to those of their Wistar-Kyoto parent. Borderline hypertensive rats fed an 8% NaCl diet developed hypertension and exhibited responses that were similar to those of their spontaneously hypertensive parent. Thus, the dietary NaCl intake-induced transition from the normotensive state of the Wistar-Kyoto parent to the hypertensive state of the spontaneously hypertensive parent in the borderline hypertensive rat was accompanied by a similar transition of the renal sympathetic nerve activity and excretory responses to volume expansion and environmental stress. The results suggest that increased dietary NaCl intake is able to induce or unmask the capabilities for these responses, which are genetically conveyed to the borderline hypertensive rat by the spontaneously hypertensive rat parent in latent forms.
Vasopressin response in collecting ducts of rats resistant to mineralocorticoid hypertension.
Authors: Jeffries W B , McArdle S , Bockman C , Abel P W , Pettinger W A
Published: June 2012

In previous studies we found that vasopressin stimulation of both cyclic AMP (cAMP) formation in cortical collecting tubules (CCT) and sodium reabsorption in isolated perfused kidneys was markedly exaggerated in rats with mineralocorticoid hypertension. In the present study, we tested the response (cAMP accumulation) of cortical and outer medullary collecting tubules (OMCT) to vasopressin in two rat models that are resistant to deoxycorticosterone acetate (DOCA)-induced hypertension, the Wistar-Furth strain and NaCl-deficient rats. The blood pressure of normal outbred Wistar rats rose to hypertensive levels (systolic pressure more than 165 mm Hg) during a 5-week treatment with DOCA (10 mg/week) and 1% saline to drink. Significant hypertrophy of the heart and kidneys was also observed. Vasopressin (10(-8) M)-induced cAMP formation was enhanced 3.4-fold in the CCT (OMCT unchanged) of hypertensive rats compared with normotensive controls. Significant hypertrophy (as indexed by tubule diameter) of the CCT but not the OMCT was also observed in DOCA-salt hypertensive rats. Restriction of dietary NaCl (0.13% in chow, tap water to drink) completely prevented DOCA-induced hypertension, organ and CCT hypertrophy, and enhancement of vasopressin-stimulated cAMP formation in the CCT. In Wistar-Furth rats, DOCA-salt treatment did not alter blood pressure or cause significant organ hypertrophy. However, DOCA-salt treatment enhanced vasopressin-stimulated cAMP formation by 4.1-fold in CCT of Wistar-Furth rats, with significant tubular hypertrophy in the CCT but not the OMCT. We conclude that DOCA-induced hypertension and changes in CCT function are dependent on excess dietary NaCl.(ABSTRACT TRUNCATED AT 250 WORDS)
Exclusion of the Na(+)-H+ antiporter as a candidate gene in human essential hypertension.
Authors: Lifton R P , Hunt S C , Williams R R , Pouysségur J , Lalouel J M
Published: June 2012

The primary abnormalities that contribute to the pathogenesis of human essential hypertension are unknown. The known genetic contribution to this disorder suggests the possible use of genetic linkage analysis to test whether specific candidate genes contribute to the pathogenesis of either essential hypertension or intermediate phenotypes. Among such phenotypes, elevated erythrocyte Na(+)-Li+ countertransport (SLC) is the best known, supporting major gene inheritance by pedigree analysis. Striking similarities between SLC and Na(+)-H+ exchange suggest that mutations at the Na(+)-H+ antiporter gene locus (APNH) might result in elevated SLC and contribute to the subsequent pathogenesis of hypertension. We have tested these hypotheses by genetic linkage analysis, with APNH as a candidate gene. By determining genotypes at APNH and flanking loci in pedigrees that support major gene segregation of elevated SLC, we have excluded linkage of APNH and the major SLC locus with a LOD score of -5.91, an odds ratio of almost 1,000,000:1 against linkage. In the analysis of 93 hypertensive sibling pairs, we have further demonstrated that APNH explains none of the variance in SLC in hypertensive individuals (r2 = 6 x 10(-7), p greater than 0.99). Finally, we have directly tested for linkage of APNH to genes predisposing toward hypertension by linkage in hypertensive sibling pairs. Mean allele sharing at APNH is not greater than expected from random assortment in hypertensive siblings (0.92 versus 1.0, p greater than 0.80), and the upper 95% confidence limit of this value (1.04) indicates that mutations at APNH rarely if ever contribute to the pathogenesis of hypertension in this population.(ABSTRACT TRUNCATED AT 250 WORDS)
Serotonin and the glomerular mesangium. Mechanisms of intracellular signaling.
Authors: Menè P , Pugliese F , Cinotti G A
Published: June 2012

Serotonin, a release product of activated platelets, stimulates proliferation and prostaglandin synthesis in cultured smooth muscle-like glomerular rat mesangial cells by activation of phospholipase and protein kinase C. To further characterize the signaling mechanisms used by serotonin, we monitored its effects on intracellular free Ca2+, pH, and membrane potential of cultured rat mesangial cells with sensitive fluorometric techniques. Activation of a 5-HT2 receptor, blocked by the specific receptor antagonists ketanserin and ritanserin, triggered immediate discharge of intracellular Ca2+ stores. The resulting rise of cytosolic free Ca2+ was accompanied by simultaneous membrane depolarization and followed within 30-60 seconds by prolonged cytosolic alkalinization. Depolarization and cytosolic free Ca2+ elevation were persistent in the continued presence of serotonin and were rapidly reversed by competitive receptor displacement with ketanserin or ritanserin. Depolarization is secondary to enhanced Cl- conductance, whereas it is relatively independent of Na+, K+, and Ca2+ fluxes. The putative Cl- channel is regulated by Ca2+ since ionomycin and other stimuli of cytosolic free Ca2+ mimic the effects of serotonin on membrane potential, whereas serotonin-induced depolarization is blunted in cells pretreated with the intracellular Ca2+ chelator BAPTA. Cytosolic alkalinization occurs in HCO3(-)-free solutions resulting from enhanced activity of a Na(+)-H+ exchanger and blocked by extracellular Na+ removal or amiloride. In the presence of HCO3-, serotonin elicits a persistent acidification, revealing simultaneous enhancement of a Na(+)-independent Cl(-)-HCO3- countertransport. These findings indicate multiple pathways for contraction and long-term functional changes induced by serotonin in mesangial cells, with potential relevance to glomerular and systemic hypertension.
Impaired insulin action on skeletal muscle metabolism in essential hypertension.
Authors: Natali A , Santoro D , Palombo C , Cerri M , Ghione S , Ferrannini E
Published: June 2012

Previous studies have shown that essential hypertension is frequently associated with insulin resistance. The tissues responsible for this metabolic alteration have not been defined. We tested the hypothesis that skeletal muscle is the site of insulin resistance of essential hypertension with the use of the perfused forearm technique. Eight hypertensive (age 42 +/- 3 years, body mass index 27 +/- 1 kg/m2, intra-arterial mean blood pressure 126 +/- 4 mm Hg) and seven normotensive (age 48 +/- 3 years, body mass index 26 +/- 1 kg/m2, mean blood pressure 95 +/- 4 mm Hg) male volunteers were studied. After glucose ingestion (40 g/m2), normal glucose tolerance in the patients was maintained at the expense of a heightened plasma insulin response, suggesting the presence of insulin resistance. During graded, local (intra-arterial) hyperinsulinemia encompassing the physiological range (12-120 milliunits/l), glucose uptake by forearm tissues was significantly (p less than 0.03) reduced in the hypertensive subjects as compared with the controls at each of five insulin steps, by 43% on the average. In addition, forearm lactate and pyruvate release were significantly less stimulated in the hypertensive than in the normotensive group (p less than 0.01 for both), presumably as a consequence of the decreased glucose influx. Forearm exchange of oxygen, carbon dioxide, lipid substrates (free fatty acids, glycerol, and beta-hydroxybutyrate), and potassium were similar in the hypertensive and normotensive groups in the basal state. Insulin had no effect on oxygen consumption, carbon dioxide production, and respiratory quotient in either study group, whereas it stimulated free fatty acids, glycerol, and potassium uptake to the same extent in the hypertensive and normotensive groups.(ABSTRACT TRUNCATED AT 250 WORDS)
Nicotine impairs reflex renal nerve and respiratory activity in deoxycorticosterone acetate-salt rats.
Authors: Whitescarver S A , Roberts A M , Stremel R W , Jimenez A E , Passmore J C
Published: June 2012

Smoking exacerbates the increase in arterial pressure in hypertension. The effect of nicotine on the baroreceptor-mediated reflex responses of renal nerve activity (RNA), heart rate, and respiratory activity (minute diaphragmatic activity [MDA]) after bolus injections of phenylephrine was compared in deoxycorticosterone acetate (DOCA)-salt sensitive and normotensive rats. Osmotic minipumps that dispensed either nicotine (2.4 mg/kg/day) or saline were implanted in DOCA and normotensive rats for 18 days. Anesthetized DOCA-nicotine, DOCA-saline, control-nicotine, and control-saline rats had mean arterial pressures (MAP) of 117 +/- 3, 110 +/- 9, 90 +/- 3, and 89 +/- 5 mm Hg, respectively. Nicotine decreased the sensitivity (p less than 0.05) of baroreceptor reflex control of RNA (% delta RNA/delta MAP) in the DOCA-nicotine rats (-0.92 +/- 0.08) compared with the DOCA-saline (-1.44 +/- 0.16), control-nicotine (-1.45 +/- 0.08), or control-saline (-1.45 +/- 0.21) rats. The reflex decrease in respiratory activity (% delta MDA/delta MAP x 100) was impaired (p less than 0.01) in both control-nicotine (-24.5 +/- 3.3) and DOCA-nicotine (-18.2 +/- 4.6) rats compared with control-saline (-59.2 +/- 9.1) and DOCA-saline (-52.5 +/- 9.9) rats. The reflex decrease in heart rate (absolute delta HR/delta MAP) in both DOCA-nicotine (1.56 +/- 0.17) and control-nicotine (1.54 +/- 0.24) rats was augmented compared with DOCA-saline and control-saline rats (0.91 +/- 0.12 and 0.97 +/- 0.14).(ABSTRACT TRUNCATED AT 250 WORDS)
Nephrotoxicity of allopurinol is enhanced in experimental hypertension.
Authors: Trachtman H , Valderrama E , Futterweit S
Published: June 2012

Hyperuricemia is present in 20-40% of pediatric and adult patients with essential hypertension. This metabolic abnormality may represent an additional risk factor for the development of cardiovascular disease. Therefore, we performed the following studies to determine 1) whether hyperuricemia is more prevalent in the spontaneously hypertensive rat (SHR) and 2) whether allopurinol treatment has a beneficial effect on the development of hypertension in this strain, based on its capacity to lower the serum uric acid concentration and to act as an antioxidant agent. SHR and control Wistar-Kyoto (WKY) rats were assigned to two groups, one given tap water to drink and the other provided water containing allopurinol (400 mg/l) to furnish an approximate daily dose equal to 100 mg/kg body wt. This treatment was maintained for 15 weeks. The serum uric acid levels were similar in untreated SHR and WKY rats (1.85 +/- 0.10 versus 1.66 +/- 0.14 mg/dl; p = 0.28). In the control WKY rat strain, allopurinol therapy did not adversely affect weight gain or hematocrit and did not cause an increase in mortality. It resulted in a moderate decrement in kidney function (creatinine clearance: allopurinol-treated group 0.32 +/- 0.09 versus control group 0.46 +/- 0.04 ml/min/100 g body wt, in conjunction with mild-to-moderate tubulointerstitial inflammation (allopurinol-treated group 0.9 +/- 0.4 versus control group 0).(ABSTRACT TRUNCATED AT 250 WORDS)
Significance of vascular renin for local generation of angiotensins.
Authors: Higashimori K , Gante J , Holzemann G , Inagami T
Published: June 2012

The effects of specific renin inhibitors, angiotensin converting enzyme inhibitors, indomethacin, and prostaglandin I2 analogue on the release of angiotensins from isolated and Krebs-Ringer-perfused rabbit mesenteric arteries were examined. Three different renin inhibitors suppressed release of angiotensins in dose-dependent manners. At the highest concentration (10(-7) M), the inhibitors EMD 52,620, EMD 54,388, and EMD 52,742 induced 46%, 52%, and 48% decreases, respectively, in the basal rate of immunoreactive angiotensin II release. These results provide clear evidence that released angiotensins are produced by the specific action of vascular renin and that the renin inhibitors suppress the vascular renin-angiotensin system as well as the circulating renin-angiotensin system and appear to provide a useful mode for the treatment of hypertension. Nonsulfhydryl angiotensin converting enzyme inhibitors cilazapril and delapril were more effective than captopril, and ramipril was equipotent to captopril, suggesting that the effectiveness of angiotensin converting enzyme inhibitors on the vascular renin-angiotensin system cannot be explained only by its inhibitory effect on angiotensin converting enzyme. Indomethacin, which was reported to suppress angiotensin II release from rat hind limbs, elicited a dose-dependent increase of angiotensin release from rabbit mesenteric arteries. These results suggest that a difference exists in the regulatory mechanisms in the release of angiotensins from diverse vascular beds.
DuP 753 is a specific antagonist for the angiotensin receptor.
Authors: Rhaleb N E , Rouissi N , Nantel F , D'Orléans-Juste P , Regoli D
Published: June 2012

2-n-Butyl-4-chloro-5-hydroxy-methyl-1-[(2'-(1H)-tetrazol-5-yl)biph enyl-4- yl)methyl]imidazol potassium salt (DuP 753) is a nonpeptide angiotensin II receptor antagonist that inhibits the contractile effects of angiotensin II competitively and shows pA2 values of 8.27 on the rabbit aorta and jugular vein, 8.66 on the rat portal vein and stomach, 8.19 on the rat urinary bladder, and 8.36 on human colon, ileum, and urinary bladder. This agent (more than 10(-5) M) exhibits no agonistic activity and does not affect the contractile effects of norepinephrine, acetylcholine, bradykinin, desArg9-bradykinin, substance P, neurokinin A, neurokinin B, or bombesin in the various tissues. The present results demonstrate that DuP 753 is a potent nonpeptide antagonist with high affinity, specificity, and selectivity for the angiotensin receptor.
Why do lean hypertensives have higher mortality rates than other hypertensives? Findings of the Hypertension Detection and Follow-up Program.
Authors: Stamler R , Ford C E , Stamler J
Published: June 2012

Specific causes of death were analyzed for 10,908 participants in the Hypertension Detection and Follow-up Program, to explore possible explanations for the observed excess 8.3-year mortality from all causes in hypertensives with low body mass. Although the cardiovascular mortality rate among men in the lowest decile of body mass (body mass index 21.96 or less) was 50% higher than that of men in the median class (body mass index 26.4-28.8), death rate for noncardiovascular deaths was more than 2 1/2 times higher in men with lean versus median body mass. The pattern was similar among women. Among noncardiovascular causes, striking differences in mortality rates between lean hypertensives and those of average body mass were observed for cirrhotic death (relative risk of 12+ in men and 11+ in women), for nonmalignant respiratory disease in men (relative risk of 7+), for violent death (both sexes), and for malignant neoplasms in men. Prevalence of smoking was almost twice as high in the lowest compared with the median body mass group; among the lean, excess deaths, particularly noncardiovascular deaths, were concentrated among smokers. Thus, male smokers in the lowest decile of body mass constituted only 3% of the study population, but contributed 8% of all deaths, 11% of all noncardiovascular deaths, and 22% of all cirrhotic deaths. A larger proportion of deaths occurred early in follow-up in the lean versus other hypertensives, suggesting occult disease among the lean at baseline. There was no evidence that more severe or treatment-resistant hypertension was present in or could explain excess mortality among the hypertensives with low body mass. The inference from the findings is not that overweight is protective for hypertensives nor that excess risk is due to leanness per se. Rather, a reasonable hypothesis, particularly from findings on specific causes of death, is that excess mortality in lean hypertensives is due to deleterious lifestyles, particularly smoking and excess alcohol intake, contributing to both leanness and risk of death.
Similar prevalence of renovascular hypertension in selected blacks and whites.
Authors: Svetkey L P , Kadir S , Dunnick N R , Smith S R , Dunham C B , Lambert M , Klotman P E
Published: June 2012

Renovascular hypertension is a potentially curable form of high blood pressure that is thought to be extremely rare among blacks. We demonstrate, however, that in a clinically selected population, the prevalence of renovascular hypertension is similar in blacks and whites. We prospectively evaluated 167 hypertensive subjects who had one or more clinical features known to be associated with renovascular hypertension. All subjects had captopril-stimulated peripheral renin measurements and conventional renal arteriography. All significant renal artery stenoses (greater than 50% luminal narrowing) were treated with percutaneous transluminal angioplasty or surgery. Renovascular hypertension was diagnosed if there was a blood pressure response to interventional therapy, according to the criteria established by the Cooperative Study of Renovascular Hypertension. Of the total group evaluated, 24% (39 of 167) had renal artery stenosis and 14% (23 of 167) had renovascular hypertension. Renal artery stenosis or occlusion was found in 27% (26 of 97) of whites and 19% (13 of 67) of blacks (p = 0.27). Renovascular hypertension was diagnosed in 18% (17 of 97) of whites and 9% (6 of 67) of blacks evaluated (p = 0.25). Renovascular hypertension was associated with severe or refractory hypertension and with smoking, but there were no racial differences in these associations. Blacks with renovascular hypertension tended to have low captopril-stimulated peripheral renin activity. We conclude that blacks with clinical features suggestive of renovascular hypertension should be evaluated with angiography. Captopril-stimulated plasma renin may not be useful in detecting blacks with renovascular hypertension, but this and other potential screening tests require further evaluation.
Insulin-like growth factor I gene expression in vascular cells.
Authors: Delafontaine P , Bernstein K E , Alexander R W
Published: June 2012

Insulin-like growth factor I (IGF I), a potent growth factor in vitro, is present in blood and in multiple tissues and is a major mediator of the effects of growth hormone on postnatal growth. IGF I is internalized and retained largely intact in cultured vascular endothelial cells. Neovasculature transiently expresses IGF I immunoreactivity, but it is not known whether this represents internalization of the circulating growth factor or vascular cell synthesis of IGF I. As an initial approach to defining the role of endogenous production of IGF I in the growth program of the vessel wall, Northern hybridizations were performed with RNA from cultured rat aortic smooth muscle cells and bovine aortic endothelial cells. Rat aortic smooth muscle cells expressed three primary IGF I messenger RNA transcripts sized 8.2, 1.7, and 0.9-1.2 kb. Bovine aortic endothelial cells expressed one major and one minor IGF I transcript of 2.1 and 1.6 kb, respectively. IGF I gene expression in smooth muscle cells was also demonstrated by ribonuclease protection assays using a rat exon 3 riboprobe. Both endothelial and vascular smooth muscle cells secreted IGF I, as detected by radioimmunoassay of conditioned medium after separation of IGF I from its binding proteins by gel filtration chromatography. Because IGF I stimulates growth of vascular cells, characterization of IGF I gene expression in blood vessels may be key to understanding developmental as well as abnormal growth in the cardiovascular system.
Norepinephrine overflow and renin pattern of the individual kidney in patients with unilateral renal artery stenosis.
Authors: Friberg P , Volkmann R , Jensen G , Aurell M
Published: June 2012

This study was performed to determine divided renal efferent sympathetic nerve activity from kidneys in seven patients with renin-positive, unilateral renal artery stenosis before and 30 minutes after an acute intravenous dose of 1.25 mg enalaprilat. Renal norepinephrine release was calculated from split renal plasma flow, venoarterial plasma concentration gradients across the kidney, and the fractional extraction of tritiated norepinephrine. All patients had unilateral renin secretion, the affected kidney increasing its plasma renin activity gradient 1.7-fold, whereas no statistically significant change was noted on the contralateral side in response to enalaprilat. Total norepinephrine release to plasma and norepinephrine plasma clearance (assessed by isotope dilution) were similar before and after administration of enalaprilat (approximately 400 ng/min and 1.0 l/min), despite a 26% fall in mean arterial pressure (from 125 mm Hg, p less than 0.01). Heart rate remained unchanged. After enalaprilat, norepinephrine venoarterial difference increased in the renin-secreting kidney (from 264 to 396, SED = 57 pg/ml, p less than 0.05), whereas it increased only slightly in the contralateral kidney (from 149 to 256, SED = 72 pg/ml, NS). Tritiated norepinephrine extraction fell approximately 25% (p less than 0.01) in both kidneys. Thus, renal norepinephrine spillover increased from 49 to 62, SED = 9 ng/min (NS) and from 81 to 129, SED = 17 ng/min (p less than 0.05) from the affected and the contralateral kidney, respectively. Hence, in this relatively small study in patients with renovascular hypertension, no evidence for increased renal nerve activity could be observed in the affected kidney, despite its marked renin production.(ABSTRACT TRUNCATED AT 250 WORDS)