摘要:

0.400 ng/mL had significantly poorer baseline hemodynamic parameters and tended to show more improvement with clonidine, although their data remained significantly worse than patients whose baseline norepinephrine was within the normal range. Sympathetic suppression with clonidine in congestive heart failure reduces preload, heart rate, and arterial pressure, all indexes of myocardial energy demand; the lack of significant reduction in systemic vascular resistance and increase in cardiac output might be attributable in part to enhanced release of vasopressin. The data suggest that suppression of activated pressor neurohormones is a rational approach to treatment of congestive heart failure. (Hypertension. 1995;26:719-724.)

ISSN:0194-911X    

出版商:OVID    

年代:1995

数据来源: OVID

摘要:

Defective vasodilator function could be important in the pathogenesis and/or maintenance of the hypertensive state and the predisposition of the elderly to hypertension. Impaired beta-adrenergic-mediated vasodilation and reduced lymphocyte beta-adrenergic activation of adenyl cyclase have been demonstrated both in aging and with hypertension. The cellular mechanisms responsible for these alterations remain unclear. To determine if these defects may be due to alterations in guanine nucleotide regulatory proteins (G proteins) that link receptor activation with effector function, we assessed (1) human lymphocyte adenyl cyclase activity, (2) stimulatory G proteins by cholera toxin-mediated [(32) Phosphorus]ADP ribosylation and, in hypertensive subjects, with alphas-specific and beta-subunit antisera, and (3) inhibitory G proteins by pertussis toxin-mediated [32Phosphorus]ADP ribosylation and, in older subjects, with alphai1,2- and beta-subunit-specific antisera. Lymphocytes from older subjects and from hypertensive subjects demonstrated a comparable reduction in isoproterenol-stimulated adenyl cyclase. However, aluminum fluoride-stimulated activity was reduced only in lymphocytes from hypertensive subjects. Furthermore, aluminum fluoride-stimulated activity was inversely correlated with mean arterial pressure. In lymphocytes from younger hypertensive subjects, cholera toxin-mediated labeling was significantly reduced; however, stimulatory G protein labeling by immunodetection was unaltered. In lymphocytes from older subjects, cholera toxin-mediated labeling was not altered; however, pertussis toxin-mediated labeling was significantly increased. In contrast, inhibitory G protein labeling by immunodetection was unaltered. Overall, the study suggests alterations of G protein function in hypertension and aging. In both conditions, stimulation of adenyl cyclase is impaired. However, these defects are associated with divergent alterations in stimulatory and inhibitory G proteins. (Hypertension. 1995;26:725-732.)

ISSN:0194-911X    

出版商:OVID    

年代:1995

数据来源: OVID

摘要:

The aim of this investigation was to examine the interrelation between renal mRNA levels of renin and angiotensin II receptor type 1 (AT1) in a renin-dependent form of experimental hypertension. Rats were studied 4 weeks after unilateral renal artery clipping. Mean blood pressure and plasma renin activity were significantly higher in the hypertensive rats (n = 10 206 plus/minus 8 mm Hg and 72.4 plus/minus 20.9 ng [centered dot] mL-1[centered dot] h-1, respectively) than in sham-operated controls (n = 10, 136 plus/minus 3 mm Hg and 3.3 plus/minus 0.5 ng [centered dot] mL-1[centered dot] h-1, respectively). Northern blot analysis of polyA+RNA obtained from the kidneys of renal hypertensive rats showed increased levels of renin mRNA in the clipped kidney, whereas a decrease was observed in the unclipped kidney. Plasma renin activity was directly correlated with renin mRNA expression of the poststenotic kidney (r = .94, P < .01). AT1mRNA expression was lower in both kidneys of the hypertensive rats. This downregulation was specific for the AT1Asubtype since the renal expression of the AT1Bsubtype remained normal in hypertensive rats. The downregulation of the renal AT1Areceptor may be due to high circulating angiotensin II levels. This is supported by the significant inverse correlation (r = -.71, P < .01) between plasma renin activity and AT1AmRNA expression measured in the clipped kidney of the hypertensive rats. (Hypertension. 1995;26:733-737.)

ISSN:0194-911X    

出版商:OVID    

年代:1995

数据来源: OVID

摘要:

To determine whether chronic angiotensin-converting enzyme (ACE) inhibition produces functional changes in the aorta of normotensive rats, four groups of rats were studied in parallel for 6 weeks. Group 1 orally received ramipril 10 mg/kg per day for 6 weeks; group 2, ramipril 10 mg/kg per day for 4 weeks and then a cotreatment with ramipril and beta (2) -kinin antagonist HOE140 500 micro gram/kg per day SC by injection for the remaining 2 weeks; group 3, hydralazine 100 mg/kg per day PO for 6 weeks; group 4 (control), subcutaneous injections of saline solution during the last 2 of 6 weeks. In aorta isolated from group 1 the relaxations induced by bradykinin, acetylcholine, and histamine were significantly potentiated compared with those of group 4. In group 3, despite a decrease in systolic blood pressure similar to that induced by ramipril treatment, the responses to these three endothelium-dependent vasodilators were not different from those of group 4. In group 2, bradykinin-induced relaxations were completely abolished whereas acetylcholine-induced and histamine-induced relaxations were similar to those of group 4. The inhibitory effect of the endothelium on serotonin-induced contractions was significantly increased in preparations of group 1 compared with those of groups 2 through 4. Indirect measurements of nitric oxide formation such as contractions evoked by N (G) -monomethyl-L-arginine (L-NMMA) and aortic cGMP content were also significantly enhanced in preparations from group 1 compared with those of groups 2 and 4. Moreover, because the relaxations to nitroglycerin and nitroprusside were similar in groups 1, 2, and 4 an alteration of the guanylate cyclase activity by ramipril treatment is quite unlikely. Thus long-term treatment with ramipril potentiates the endothelium-dependent responses in the rat aorta by enhancing nitric oxide availability. This effect seems to involve an inhibition of bradykinin breakdown facilitating nitric oxide release via endothelial beta2-receptors. (Hypertension. 1995;26:738-743.)

ISSN:0194-911X    

出版商:OVID    

年代:1995

数据来源: OVID

摘要:

Nitric oxide is an important regulator of vascular function and blood pressure. Chronic administration of nitric oxide inhibitors provides a new model of hypertension with pronounced target organ damage. We investigated the effects of oral treatment with Nomega-nitro-L-arginine methyl ester (L-NAME) for 6 weeks on vascular reactivity of the aorta in Wistar-Kyoto rats. Certain rats received verapamil or trandolapril in addition to L-NAME. Systolic blood pressure increased in the L-NAME group (by [nearly equal] 80 mm Hg systolic) but not in controls or rats treated with verapamil or trandolapril. Isometric tension changes of aortic rings were recorded. Endothelium-dependent relaxations to acetylcholine were reduced in the L-NAME group (58 plus/minus 6% versus 104 plus/minus 1% in placebo, P < .05) but were normalized by treatment with verapamil or trandolapril. In contrast, endothelium-independent relaxations to sodium nitroprusside were not significantly reduced in L-NAME hypertension but were slightly enhanced by trandolapril therapy (P < .05). Acute in vitro incubation of vessels with the thromboxane receptor antagonist SQ 30741 enhanced the relaxation to acetylcholine (P < .05) in the L-NAME group only. In quiescent rings, acetylcholine caused endothelium-dependent contractions in particular after in vitro incubation with L-NAME. These contractions tended to be enhanced in L-NAME hypertension (23 plus/minus 4% versus 14 plus/minus 3% in the placebo group; P = NS) and were significantly reduced after treatment with verapamil or trandolapril (P < .05). Contractions to norepinephrine and angiotensin I and II were unaffected by L-NAME hypertension, whereas those to endothelin-1 were reduced (P < .05). Thus, in the aorta, L-NAME-induced hypertension is associated with impaired endothelium-dependent relaxations, unmasking the effects of endothelium-derived vasoconstrictor prostanoids, and with a specific reduction of the contraction induced by endothelin-1. Chronic antihypertensive therapy with verapamil or trandolapril prevented this imbalance of endothelium-dependent relaxations and contractions and, in turn, normalized vascular function. (Hypertension. 1995;26:744-751.)

ISSN:0194-911X    

出版商:OVID    

年代:1995

数据来源: OVID

摘要:

The purpose of this study was to examine whether angiotensin II (Ang II) stimulates the release of endothelium-derived nitric oxide, which then impairs the contractions of vascular smooth muscle caused by the peptide, and to determine the receptor subtypes mediating these responses. Experiments were performed on isolated rings of rat carotid artery either incubated in the presence of phosphodiesterase inhibitor for the measurement of intracellular levels of cGMP or suspended in organ chambers for recording of changes in isometric force. Ang II (10 (-7) mol/L) caused a twofold increase in intracellular cGMP level in preparations with but not in those without endothelium. The presence of endothelium impaired the contractions evoked by the peptide and caused approximately 50% inhibition of the maximal response to Ang II (3 x 10-8mol/L); pD2values for Ang II were 8.9 plus/minus 0.1 and 9.6 plus/minus 0.2 in rings with and without endothelium, respectively. In rings with endothelium the contractions to Ang II were augmented by nitro-L-arginine (an inhibitor of nitric oxide synthase) but not indomethacin (an inhibitor of cyclooxygenase), to reach a response comparable to that of preparations without endothelium. In rings without endothelium losartan (a preferential angiotensin type 1 receptor antagonist) displayed competitive antagonism toward Ang II (pA2= 9.5); PD 123319 (a preferential angiotensin type 2 receptor antagonist; up to 10-7mol/L) did not affect the response to the peptide. Losartan (3 x 10-9mol/L) but not PD 123319 (10-7mol/L) impaired the endothelium-dependent component of the response to the peptide. These results suggest that in the rat carotid artery stimulation of an Ang II type 1 receptor causes the release of nitric oxide, which in turn inhibits the contractions to Ang II also mediated by type 1 receptors. (Hypertension. 1995;26:752-757.)

ISSN:0194-911X    

出版商:OVID    

年代:1995

数据来源: OVID

摘要:

Considerable evidence indicates an enhanced sympathetic innervation of resistance arterial smooth muscle in the spontaneously hypertensive rat (SHR) compared with its normotensive Wistar-Kyoto (WKY) control. In addition to sympathetic hyperinnervation, an increased vascular innervation by neuropeptide Y-containing fibers, which are known to exert a vasoconstrictive and trophic action in vascular smooth muscle, has also been described. In addition to genetic hypertension, the SHR expresses hyperactive behavior and hyperreactivity to stress. To determine whether the enhanced neuropeptide Y-immunoreactive vascular innervation is specifically associated with hypertension and/or these behavioral abnormalities, four genetically related, inbred rat strains were used: SHR, which are hypertensive and hyperactive; WKY rats, which are neither hypertensive nor hyperactive; WKHA, which are hyperactive but normotensive; and WKHT, which are hypertensive but not hyperactive. The present study demonstrated that whereas the hypertensive strains (SHR and WKHT) exhibited smooth muscle hypertrophy in both superior mesenteric and caudal arteries in adulthood (10 months) but not at a prehypertensive age (1 month), both arteries exhibited significantly increased neuropeptide Y-immunoreactive innervation at both ages. It was further observed that the mesenteric artery in WKHA, a normotensive strain, had significant smooth muscle hypertrophy at 10 months; however, neuropeptide Y innervation in this artery was no different from that of WKY controls. The findings indicate that there is a cosegregation of neuropeptide Y hyperinnervation of the vasculature with the hypertensive phenotype, evident as early as 1 month of life in the hypertensive strains, and this should be considered further as a contributory factor in genetic hypertension. Vascular smooth muscle hypertrophy, while evident in adult hypertensive rats, was also observed in the mesenteric artery (but not the caudal artery) of adult WKHA rats, suggesting that other factors besides genetic hypertension, possibly hyperreactivity to stress, are responsible for this specific hypertrophic change in WKHA rats. (Hypertension. 1995;26:758-763.)

ISSN:0194-911X    

出版商:OVID    

年代:1995

数据来源: OVID

摘要:

Many obese hypertensive individuals have a cluster of cardiovascular risk factors. This cluster includes plasma nonesterified fatty acid concentrations and turnover rates that are higher and more resistant to suppression by insulin than in lean and obese normotensive individuals. The higher fatty acids may contribute to cardiovascular risk in these patients by inhibiting endothelial cell nitric oxide synthase activity. To test this hypothesis, we quantified the effects of oleic (18:1[cis]) and other 18-carbon fatty acids on nitric oxide synthase activity in cultured bovine pulmonary artery endothelial cells by measuring the conversion of [(3) Hydrogen]L-arginine to [(3) Hydrogen]L-citrulline. Oleic acid (from 10 to 100 micro mol/L) caused a concentration-dependent decrease in nitric oxide synthase activity at baseline and during ATP and ionomycin (Calcium2+ionophore) stimulation. At 100 micro mol/L, linoleic (18:2[cis]) and oleic acids caused similar reductions of nitric oxide synthase activity, whereas elaidic (18:1[trans]) and stearic (18:0) acids had no effect. Oleic acid also inhibited the endothelium-dependent vasodilator response to acetylcholine in rabbit femoral artery rings preconstricted with phenylephrine (P < .05) but had no effect on the response to nitroprusside. The pattern of 18-carbon fatty acid effects on nitric oxide synthase activity in endothelial cells is consistent with activation of protein kinase C. Although oleic acid increased protein kinase C activity in endothelial cells, neither depletion of protein kinase C by 24-hour pretreatment with phorbol 12-myristate 13-acetate nor its inhibition with staurosporine eliminated the inhibitory effect of oleic acid on nitric oxide synthase. The vascular ring studies further indicate that oleic acid reduces the response to acetylcholine by inhibiting nitric oxide synthase activity rather than reducing the activation of guanylate cyclase or the effects of cGMP. Thus, elevated oleic acid values in obese hypertensive individuals may contribute to impaired endothelium-dependent vasodilation by a protein kinase C-independent mechanism. (Hypertension. 1995;26:764-770.)

ISSN:0194-911X    

出版商:OVID    

年代:1995

数据来源: OVID

摘要:

In the present study we describe the intracellular pathways for the transmission of growth signals by the potent vasoconstricting eicosanoids prostaglandin H2and thromboxane A2in smooth muscle cells from rat aorta. Carbocyclic thromboxane A2and U46619 are stable thromboxane A2mimetics acting at the common thromboxane A2/prostaglandinH2receptor. Carbocyclic thromboxane A2(10-6mol/L) induced an approximately 2.5-fold increase in [Ca2+]iabove the basal value at 25 seconds. Maximal stimulation of the 42-kD mitogen-activated protein kinase isoform by both thromboxane A2mimetics occurred at 5 minutes. Both thromboxane A2mimetics at a concentration of 10-6mol/L induced the expression of c-fos and early growth response gene-1 (egr-1) mRNA, with a maximum at 30 minutes. Carbocyclic thromboxane A2(10-6mol/L) induced a 3.3-fold increase in [(3) Hydrogen]thymidine incorporation into cell DNA above the basal value and produced a 3.5-fold elevation of platelet-derived growth factor-BB--dependent [(3) Hydrogen]thymidine incorporation into cell DNA. Similar effects of U46619 (10-6to 10 (-5) mol/L) alone and in combination with platelet-derived growth factor-BB on cell DNA synthesis were obtained. The thromboxane A2/prostaglandinH2receptor antagonist SQ29548 (10-6mol/L) completely suppressed the mitogenic effect of both thromboxane A2mimetics (10-6mol/L). Pertussis toxin (10 to 100 ng/mL) did not influence the mitogenic effects of the thromboxane A2mimetics. Carbocyclic thromboxane A2(10-6mol/L) and platelet-derived growth factor-BB (20 ng/mL) per se caused a 44% and 100% increase in cell number, respectively. In the presence of carbocyclic thromboxane A2(10-6mol/L), platelet-derived growth factor-BB induced a 152% increase in cell number. Similar results were obtained with U46619 alone or in combination with platelet-derived growth factor-BB. (Hypertension. 1995;26:771-780.)

ISSN:0194-911X    

出版商:OVID    

年代:1995

数据来源: OVID

摘要:

In previous studies investigators found that conditioned hypoventilatory breathing potentiated a sodium-sensitive form of hypertension in dogs that was not mediated by sympathetic nervous system arousal. Our study investigated effects of 30 minutes of voluntary hypoventilation, maintained by a respiratory gas monitor and feedback procedure, in 16 normotensive humans of both sexes on (1) plasma concentrations of endogenous digitalis-like factors (ouabain-like and marinobufagenin-like immunoreactivity), (2) activity of erythrocyte Sodium (+), Potassium+-ATPase, (3) inhibitory activity of plasma Sodium (+), Potassium+-ATPase, and (4) blood pressure. Increased end tidal PCO2(41 plus/minus 0.78 mm Hg versus 37.6 plus/minus 1.03 mm Hg) was associated with (1) an increase in plasma marinobufagenin-like immunoreactivity (1.23 plus/minus 0.47 versus 4.96 plus/minus 1.19 nmol/L), (2) an inhibition of Sodium+, Potassium+-ATPase in red blood cells (3.68 plus/minus 0.22 versus 2.15 plus/minus 0.25 mmol Pi[centered dot] mL-1[centered dot] h-1; P < .01), (3) increase in plasma Sodium+, Potassium+-ATPase inhibitory activity (34.9 plus/minus 4.0% versus 48.8 plus/minus 2.1%, P < .02), and (4) increases in systolic (112.4 plus/minus 2.6 versus 107.6 plus/minus 1.8 mm Hg) and diastolic (73.5 plus/minus 2.1 versus 68.8 plus/minus 2.1 mm Hg) blood pressures. Plasma levels of ouabain-like immunoreactivity did not increase significantly. Incubation of erythrocytes obtained during hypoventilation with antidigoxin antibody restored the Sodium+, Potassium+-ATPase activity (3.99 plus/minus 0.34 mmol Pi[centered dot] mL-1[centered dot] h-1). Cessation of hypoventilation was associated with decreases in diastolic blood pressure (70.5 plus/minus 2.2 mm Hg) and restoration of Sodium+, Potassium+-ATPase activity in erythrocytes (2.99 plus/minus 0.43 mmol Pi[centered dot] mL-1[centered dot] h-1). On the basis of organic extraction and thin-layer chromatography followed by separation with the use of reverse-phase high-performance liquid chromatography, the material coeluting with marinobufagenin was separated from human urine. This material cross-reacted with anti-marinobufagenin antibody. These results demonstrate the presence of a bufadienolide-like Sodium+, Potassium (+) -ATPase inhibitor in human plasma and support the view that breathing pattern may participate in blood pressure control via release of a rapidly acting circulating Sodium+, Potassium+-ATPase inhibitor. (Hypertension. 1995;26:781-788.)

ISSN:0194-911X    

出版商:OVID    

年代:1995

数据来源: OVID