ISSN:0194-911X    

出版商:OVID    

年代:1990

数据来源: OVID

ISSN:0194-911X    

出版商:OVID    

年代:1990

数据来源: OVID

ISSN:0194-911X    

出版商:OVID    

年代:1990

数据来源: OVID

摘要:

Adrenergic receptors are prototypic models for the study of the relations between structure and function of G protein-coupled receptors. Each receptor is encoded by a distinct gene. These receptors are integral membrane proteins with several striking structural features. They consist of a single subunit containing seven stretches of 20–28 hydrophobic amino acids that represent potential membrane-spanning a-helixes. Many of these receptors share considerable amino acid sequence homology, particularly in the transmembrane domains. All of these macromolecules share other similarities that include one or more potential sites of extracellular N-linked glycosylation near the amino terminus and several potential sites of regulatory phosphorylation that are located intracellularly. By using a variety of techniques, it has been demonstrated that various regions of the receptor molecules are critical for different receptor functions. The seven transmembrane regions of the receptors appear to form a ligand-binding pocket Cysteine residues in the extracellular domains may stabilize the ligand-binding pocket by participating in disulnde bonds. The cytoplasmic domains contain regions capable of interacting with G proteins and various kinases and are therefore important in such processes as signal transduction, receptor-G protein coupling, receptor sequestration, and down-regulation. Finally, regions of these macromolecules may undergo posttranslational modifications important in the regulation of receptor function. Our understanding of these complex relations is constantly evolving and much work remains to be done. Greater understanding of the basic mechanisms involved in G protein-coupled, receptor-mediated signal transduction may provide leads into the nature of certain pathophysiological states.

ISSN:0194-911X    

出版商:OVID    

年代:1990

数据来源: OVID

摘要:

The forearm vasoconstrictor response to lower body negative pressure (LBNP), a reflex stimulus to norepinephrine release, can be augmented by a prior brachial artery infusion of epinephrine. We wished to determine whether this sustained aftereffect of epinephrine could be replicated by systemic infusion and, if so, whether it could be prevented by prior uptake-1 blockade with desipramine. Eight normal men (mean age 30 years) were studied on two separate study days at least 1 week apart, 2.5 hours after taking, at random, either desipramine 125 mg p.o.) or placebo. Forearm vascular resistance was measured at rest and at the end of 6 minutes of LBNP at ‐40 mm Hg. This was done both before and 30 minutes after a 60 -minute infusion of epinephrine (1.5 /ttg/min i.v.). From similar baselines, the forearm vasoconstrictor response to LBNP was significantly augmented 30 minutes after epinephrine on the placebo day (+17±4 vs. +12±3 resistance units, mean±SEM,p< 0.01) but not on the desipramine day (+14±2 vs. +16±3 resistance units). The heart rate response to LBNP was also greater after epinephrine on the placebo day (+20±3 vs. +16±2 beats/min,p< 0.05). Mean arterial pressure was higher after epinephrine infusion on the placebo (p< 0.01) but not on the desipramine day. Thus, transient increases in epinephrine, which has a plasma half-life of only minutes, can have sustained aftereffects, increasing mean arterial pressure and augmenting vasoconstrictor and chronotropic responses to a reflex stimulus to norepinephrine release 30 minutes after its infusion. These effects appear to be mediated through the uptake of epinephrine by sympathetic nerves and its corelease with norepinephrine on subsequent nerve stimulation. Epinephrine then could act on prejunctional /3-adrenergic receptors to facilitate norepinephrine release and augment neurogenic vasoconstriction. These observations provide further support for the concept that increases in plasma epinephrine concentration might contribute to the pathogenesis of essential hypertension by this mechanism.

ISSN:0194-911X    

出版商:OVID    

年代:1990

数据来源: OVID

摘要:

The predisposition of black people to salt (NaCl) -sensitive essential hypertension may relate to racial differences in cellular Na+ metabolism. This tenet was investigated by examining the Na+-H+ antiport in serially passed skin fibroblasts from blacks and whites. Na+-dependent stimulation of the Na+-H+ antiport by cellular acidification resulted in a greater maximal velocity (VJ(mean±SEM) of this transport system in quiescent fibroblasts from blacks than fibroblasts from whites; the V ⁁ for recovery from cellular pH (pHJ of 6.6 was 5.84±0.50 versus 439±034 mmol H+/lx20 seconds for blacks and whites, respectively (/?<0.05). Although the Na+ concentration producing 50% stimulation of the Na+-H+ antiport for blacks (35.1 ±5.7 mM) was greater than for whites (24.1 ±3.5 mM), this difference was not statistically significant No racial differences were observed in the Hill coefficient (n, U5±0.21 for blacks and 1.46±0.28 for whites). Compared with whites, cells from blacks exhibited a greater response to cytoplasmic acidification over the range of pH, values 6.20–6.60, as exhibited by an augmented rate of recovery in the pH,. These differences were not due to different basal pH, values or cellular buffering capacities, which were similar for blacks and whites. Na+-H+ antiport activity was not correlated with family history of hypertension. Increased activity of the Na+-H+ antiport in fibroblasts from blacks was confirmed without cellular acidification by stimulating quiescent cells with 10% human serum. This study demonstrates innate racial differences in cellular membrane Na+-H+ antiport activity.

ISSN:0194-911X    

出版商:OVID    

年代:1990

数据来源: OVID

摘要:

We studied the binding properties of [3H]ouabain to erythrocytes from normotensive children (n=83) between the ages of 10 and 18 years (mean resting arterial pressure: 102/57 mm Hg) from normotensive and essential hypertensive parents. Arterial blood pressures of 101/57 and 104/57 mm Hg (subjects with normotensive and hypertensive parents, respectively) were not significantly different between the two groups. Forty-four children had normotensive parents and 39 had hypertensive parents, 51 were white and 32 were black, and 41 were girls and 42 were boys. By using the [3H]ouabain-binding technique, we determined the density of sodium pump sites and the equilibrium dissociation constants in erythrocytes from these children. Possible effects of race, sex, or parental hypertension status on pump sites and dissociation constants were tested with a three-way analysis of variance (ANOVA). Race had a major effect on the dissociation constant: blacks had a significantly higher value than did whites (p=0.002). We also found a race by sex by parental hypertension status interaction (p=0.04) with black girls with hypertensive parents having the highest value. There was no effect of race, sex, or status on sodium pump site density. Age, height, weight, resting arterial blood pressure, and plasma Na+ and K+ concentrations did not correlate with the dissociation constants. These data suggest that, among the groups we studied, black girls with hypertensive parents had erythrocytes with the lowest binding affinity for ouabain. In addition, race had a strong effect on the binding affinity of ouabain to human erythrocytes, with blacks having lower affinities than whites. Because the black population has a much higher prevalence of hypertension than the white population and black women have the highest prevalence of hypertension, this decrease in the affinity of ouabain-binding to the erythrocyte sodium pump molecule may be a possible predictor of adult hypertension.

ISSN:0194-911X    

出版商:OVID    

年代:1990

数据来源: OVID

摘要:

The effects of SCH 34826, an orally active neutral metalloendopeptidase inhibitor, on responses to atrial natriuretic factor-(103–125) or -(99–126) and on blood pressure were evaluated in rats. SCH 34826 (10,30, and 90 mg/kg s.c. and 90 mg/kg p.o.) potentiated the antihypertensive action of atrial natriuretic factor (30 /tg/kg i.v.) in conscious spontaneously hypertensive rats. SCH 34826 (90 mg/kg) also potentiated the diuretic and natriuretic responses to atrial natriuretic factor (30 /tg/kg i.v.) as well as the plasma levels achieved after pcptide injection. SCH 34826 significantly reduced blood pressure in the conscious deoxycorticosterone acetate-salt hypertensive rat, at doses of 90 mg/kg s.c. (−35±12 mm Hg), 10 mg/kg p.o. (−30±7 mm Hg), and 90 mg/kg p.o. (−45±6 mm Hg). SCH 34826 was devoid of acute antihypertensive activity in the spontaneously hypertensive rat but reduced blood pressure by day 3 of a 5-day treatment schedule. SCH 34826 (90 mg/kg s.c.) enhanced urine volume output in the deoxycorticosterone acetate-salt rat (2.78±0.6 vs. l27±03 ml/100 g/3 hr in vehicle-control rats,p< 0.05). SCH 34826 (90 mg/kg s.c) increased plasma levels of atrial natriuretic factor at 1 hour (753±89 vs. 451 ±79 pg/ml in vehicle-treated rats, p< 0.05) but not 3 hours after dosing. The renal excretion of atrial natriuretic factor (3,092 ±1,089 vs. 21 ±6 pg/100 g/3 hr in vehicle-treated rats, p< 0.05) and cyclic guanosine monophosphate (2,131 ±509 vs. 879±168 pg/100 g/3 hr in vehicle-treated rats,p< 0.05) was markedly elevated by SCH 34826 in deoxycorticosterone acetate-salt rats. These studies suggest that neutral endopeptidase inhibition may represent a new approach to treatment of some forms of hypertension.

ISSN:0194-911X    

出版商:OVID    

年代:1990

数据来源: OVID

ISSN:0194-911X    

出版商:OVID    

年代:1990

数据来源: OVID

摘要:

Our previous studies demonstrated that acute infusion of atrial natriuretic factor (ANF) produces an enhanced depressor response in NaCI-sensitive spontaneously hypertensive rats (SHR-S) fed a high (8%) NaCl diet compared with control SHR-S fed a normal (1%) NaCl diet and that dietary NaCl loading increases circulating ANF levels in Wistar-Kyoto (WKY) rats but not in SHR-S. The current study tested the hypotheses that 1) long-term infusion of ANF at a dose that elevates plasma ANF to levels comparable with those seen in high NaCl-fed WKY rats prevents the NaCl-induced exacerbation of hypertension in SHR-S and 2) ANF lowers blood pressure in this model by a sympatholytic effect Male SHR-S received infusions of ANF (0.1 (ig/hr) or vehicle intravenously via osmotic minipump for 3 weeks beginning immediately before initiation of 1% or 8% NaCl diets at age 7 weeks. Chronic ANF infusion prevented the increase in arterial pressure in response to a high NaCl diet in SHR-S but had no effect in 1% NaCl-fed SHR-S. Thus, the NaCI-sensitive component of hypertension in SHR-S was more sensitive to ANF than the non-NaCl-sensitive component Plasma norepinephrine was significantly increased in ANF-treated, 8% NaCl-fed SHR-S compared with vehicle controls, suggesting that ANF did not prevent NaCI-sensitive hypertension by a sympatholytic effect During ANF infusion, plasma ANF was increased by only 36% and 40% in the 1% and 8% NaCl groups, respectively, so that long-term infusion of exogenous ANF in a dose that resulted in plasma ANF levels well within the physiological range abolished the NaCl-induced exacerbation of hypertension in SHR-S. The data suggest that a deficiency in circulating endogenous ANF may play a role in NaCI-sensitive hypertension in this model.

ISSN:0194-911X    

出版商:OVID    

年代:1990

数据来源: OVID