摘要:

Studies in experimental models suggest that endothelium-derived nitric oxide is reduced with aging, and this circumstance may be relevant to atherogenesis. The aim of this study was to determine whether increasing age resulted in altered endothelium-dependent vasodilation in the forearm resistance vessels of healthy humans. Forearm blood flow was measured in 119 healthy subjects, aged 19 to 69 years, by venous occlusion plethysmography. Brachial artery infusions of methacholine chloride (0.03 to 10.0 micro gram/min) were used to assess endothelium-dependent vasodilation and of sodium nitroprusside (0.03 to 10.0 micro gram/min) to assess endothelium-independent vasodilation. The slope of the dose-blood flow response relation was calculated in each subject for each drug. Univariate and multiple stepwise regression analyses were used to relate vascular reactivity to selected variables, including age, lipids, and blood pressure. Endothelium-dependent vasodilation was progressively impaired with increasing age, assessed as a reduction in slope from 2.25 plus/minus 0.16 to 0.34 plus/minus 0.11 (mL/100 mL tissue per minute)/(micro gram/min) (P < .001). The decline in endothelium-dependent vasodilation was already evident by the fourth decade (age 30 to 39 years). Endothelium-independent vasodilation did not change with age. Age, total cholesterol, and low-density lipoprotein cholesterol were univariate predictors of endothelium-dependent vasodilation. Age remained the most significant predictor of endothelium-dependent vasodilator responses by multiple stepwise regression analysis. From these observations, it can be concluded that endothelium-dependent vasodilation declines steadily with increasing age in healthy human subjects. Age is a strong univariate and multivariate predictor of endothelium-dependent vasodilation. This finding may be a marker for more widespread endothelial dysfunction. (Hypertension. 1996;27:849-853.)

ISSN:0194-911X    

出版商:OVID    

年代:1996

数据来源: OVID

摘要:

Insulin sensitivity may be improved with the angiotensin-converting enzyme inhibitor captopril, suggesting that inhibition of angiotensin II (Ang II) improves insulin resistance. However, the administration of systemic Ang II has also been associated with an improvement in rather than worsening of glucose utilization. Since both stimulating and antagonizing the renin-angiotensin system improve glucose uptake and both angiotensin-converting enzyme inhibitors and intravenous Ang II elicit skeletal muscle vasodilation, it is conceivable that hemodynamic factors rather than a direct effect of either Ang II or angiotensin-converting enzyme inhibitors on skeletal muscle metabolism modulate the increase in glucose utilization. The direct effects of Ang II on glucose extraction in intact human skeletal muscle have not been previously described. We investigated the effects of local infusion of Ang II on glucose uptake in the forearm of 20 healthy subjects. With the use of the isolated insulin-perfused forearm model, local plasma insulin values were raised to 100 mU/mL over fasting values and maintained there for a 90-minute infusion period. After the first 60 minutes of insulin alone, Ang II was infused into the brachial artery for the last 30 minutes. Intra-arterial Ang II infusion caused a 38% decrease in forearm blood flow (P < .05) and 59% increase in the arteriovenous glucose gradients (P < .05) to maintain a steady glucose utilization (a decrease of 4%, P = NS). Thus, local Ang II infusion does not impair insulin-stimulated glucose utilization. Furthermore, glucose extraction increases to compensate for the decrease in forearm blood flow (as the Fick principle would predict for freely diffusible substances). We conclude that the described increase in glucose utilization from systemic infusion of Ang II and during angiotensin-converting enzyme inhibitor treatment is mediated by hemodynamic factors rather than a direct effect of Ang II on skeletal muscle metabolism. (Hypertension. 1996;27:854-858.)

ISSN:0194-911X    

出版商:OVID    

年代:1996

数据来源: OVID

摘要:

Vascular myocytes from the spontaneously hypertensive rat (SHR) demonstrate elevated Sodium+-Hydrogen+exchanger activity associated with increased cell proliferation and hyperresponsiveness to agonists such as phorbol esters. Since the Sodium (+) -Hydrogen+exchanger isoform 1 (NHE-1) is stimulated by protein kinase C, we have investigated the effects of phorbol esters on NHE-1 activity and its phosphorylation in vascular myocytes of these rats. SHR cells demonstrated a larger alkalinization response to 12-O-tetradecanoylphorbol 13-acetate than Wistar-Kyoto rat (WKY) cells. Kinetic analyses indicated that whereas 12-O-tetradecanoylphorbol 13-acetate increased the maximal transport capacity of NHE-1 in both cell types, affinity for Hydrogen+was increased in WKY cells and cooperativity for Hydrogen+at the internal modifier site was reduced in SHR cells. In neither cell type was the subcellular distribution of NHE-1 altered by phorbol ester stimulation. NHE-1 phosphorylation was markedly reduced in WKY cells stimulated by the phorbol ester, an effect abolished by inhibition of protein kinase C. In contrast, NHE-1 phosphorylation in quiescent SHR cells was approximately double that of WKY cells and was reduced after phorbol ester treatment. Inhibition of protein kinase C in SHR cells led to a marked elevation of NHE-1 phosphorylation that was not associated with a change in exchanger activity, but WKY cells exhibited a small, insignificant rise in NHE-1 phosphorylation. Thus, the kinetic responses of NHE-1 to phorbol esters in vascular myocytes of these rat strains are different, the changes in exchanger kinetics of SHR resembling those described in human hypertension. NHE-1 phosphorylation has an inverse relationship with protein kinase C activity. However, modulation of NHE-1 phosphorylation may not be associated with concurrent alterations in activity, indicating a role for non-phosphorylation-dependent mechanisms. (Hypertension. 1996;27:859-866.)

ISSN:0194-911X    

出版商:OVID    

年代:1996

数据来源: OVID

摘要:

The objective of this study was to examine the role of dexamethasone on the expression of angiotensin II (Ang II) receptors in cultured rat mesangial cells. Dexamethasone caused concentration- and time-dependent decreases in125Iodine-[Sar1, Ala8]Ang II binding that were prevented by glucocorticoid receptor inhibition with mifepristone. A lag time of 24 hours and a dexamethasone concentration of at least 10 nmol/L were necessary for this effect to occur. Dexamethasone-induced reduction of125Iodine-[Sar1, Ala8]Ang II binding resulted from decreased Ang II type 1 (AT1) receptor density. No change in the apparent dissociation constant was observed. Dexamethasone also markedly inhibited Ang II-dependent inositol phosphate accumulation. Both reverse transcription-polymerase chain reaction and Northern blot analysis using specific short probes from the 3' noncoding region of the cDNA demonstrated the presence of AT (1A) and AT1Breceptor mRNAs in rat mesangial cells, with a slight predominance of AT1B. Therefore, we studied the effect of dexamethasone on the expression of these two subtypes in rat mesangial cells. Dexamethasone produced a time-dependent decrease of AT1Breceptor mRNA that was apparent after 6 hours of incubation, whereas AT (1A) receptor mRNA did not change. Mifepristone also suppressed the dexamethasone-induced decrease in AT1Breceptor mRNA. In conclusion, glucocorticoids diminish Ang II receptor density at the mesangial cell surface through a mechanism that implies successive interaction with the glucocorticoid receptor and specific reduction in AT1Breceptor mRNA expression. This differential regulation of both AT1receptor subtypes might allow glucocorticoids to exert adjusted effects in their various target tissues. (Hypertension. 1996;27:867-874.)

ISSN:0194-911X    

出版商:OVID    

年代:1996

数据来源: OVID

摘要:

In this study we evaluated the possibility that angiotensin-(1-7) [Ang-(1-7)] acts as an endogenous osmoregulatory peptide by determining the effect of acute administration of its selective antagonist [D-Ala7]Ang-(1-7) (A-779) on renal function parameters in rats. In addition, we investigated the physiological mechanisms involved in the antidiuretic effect of Ang-(1-7). The antidiuretic effect of Ang-(1-7) (40 pmol/0.05 mL per 100 g BW) in water-loaded rats was completely blocked by A-779 (vehicle-treated, 3.34 plus/minus 0.43 mL/h; Ang-(1-7), 1.48 plus/minus 0.23; A-779, 2.72 plus/minus 0.35; Ang-(1-7) plus A-779, 3.26 plus/minus 0.49). In contrast, the antidiuretic effect of Ang-(1-7) was not significantly changed by a vasopressin V2receptor antagonist in a dose that completely blocked the antidiuresis produced by an equipotent dose of vasopressin. In addition, Ang-(1-7) administration did not significantly change vasopressin plasma levels in water-loaded rats. The antidiuretic effect of Ang-(1-7) in water-loaded rats was associated with a reduction of creatinine clearance (0.68 plus/minus 0.04 versus 1.38 plus/minus 0.32 mL/min in vehicle-treated rats, P < .05) and an increase in urine osmolality (266.8 plus/minus 32.7 versus 182.8 plus/minus 14 mOsm/kg in vehicle-treated rats,P < .05). An effect of Ang-(1-7) in tubular water transport was demonstrated in vitro by a fourfold increase in the hydraulic conductivity of inner medullary collecting ducts in the presence of 1 nmol/L Ang-(1-7). Subcutaneous administration of A-779 (2.3 to 9.2 nmol/100 g) produced a significant increase in urine volume (4.6 nmol/100 g, 0.45 plus/minus 0.12 mL/h; vehicle-treated rats, 0.16 plus/minus 0.03 mL/h; P < .05) comparable to that of acute administration of a vasopressin V2receptor antagonist. The diuretic effect of A-779 was associated with an increase in creatinine clearance and decrease in urine osmolality. In contrast, no significant effects on urine volume were observed after systemic administration of angiotensin subtype 1 or 2 receptor antagonists (DuP 753 and CGP 42112A, respectively). These findings suggest that endogenous Ang-(1-7), acting on specific receptors, participates in the control of hydroelectrolyte balance by influencing especially water excretion. (Hypertension. 1996;27:875-884.)

ISSN:0194-911X    

出版商:OVID    

年代:1996

数据来源: OVID

摘要:

Mesangial cell growth and accumulation of extracellular matrix proteins constitute key features of progressive glomerular injury. Endothelin-1 (ET-1) and angiotensin II (Ang II), two potent vasoconstrictor agents, evoke a number of similar responses in mesangial cells. In rat mesangial cells, we compared ET-1 and Ang II effects on matrix protein production and cell proliferation as well as the potential interaction between the two hormones. When cells in 0.5% fetal calf serum were incubated for 24 hours with various concentrations of ET-1 or Ang II, both peptides stimulated, in a dose-dependent manner, fibronectin and type IV collagen mRNA expression, fibronectin synthesis, and mitogenesis. Incubation with specific receptor antagonists of both hormones demonstrated that endothelin subtype A (ETA) and angiotensin type 1 (AT1) receptors were involved. Preincubation of cells with two different protein kinase C inhibitors or with a neutralizing anti-transforming growth factor-beta antibody, but not an unrelated IgG, diminished the peptide-induced fibronectin synthesis. A dual interrelation seems to exist between ET-1 and Ang II. Thus, the AT (1) receptor antagonist losartan and the angiotensin-converting enzyme inhibitors quinaprilat and captopril diminished the ET-1-mediated effects, whereas the ETAreceptor antagonist BQ-123 diminished the Ang II-induced fibronectin synthesis and mesangial cell proliferation. Our results suggest that ET-1 and Ang II stimulate matrix protein synthesis and mesangial cell mitogenesis through ETAand AT1receptors, respectively, by complicated mechanisms, implicating protein kinase C activation, synthesis of transforming growth factor-beta, and release of one peptide by the other. These data could be important for a better understanding of the participation of vasoactive substances in the pathogenesis of glomerulosclerosis. (Hypertension. 1996;27:885-892.)

ISSN:0194-911X    

出版商:OVID    

年代:1996

数据来源: OVID

摘要:

The objective of this study was to test the hypothesis that administration of L-arginine, a substrate for nitric oxide synthase, restores acetylcholine-induced dilatation of the basilar artery in chronically hypertensive rats. Basilar artery diameter was measured through a cranial window in anesthetized stroke-prone spontaneously hypertensive rats (SHRSP) and normotensive Wistar-Kyoto rats (WKY) aged 6 to 7 months (adult) and 12 months (older adult). Under control conditions, baseline basilar artery diameter was smaller in SHRSP (adult, 239 plus/minus 30 micro meter; older adult, 198 plus/minus 13 micro meter) (mean plus/minus SE) than in WKY (adult, 261 plus/minus 10 micro meter; older adult, 259 plus/minus 7 micro meter) (P < .05 versus SHRSP). Topical application of acetylcholine (10-5mol/L) produced dilatation of the basilar artery in WKY, which was impaired in both adult and older SHRSP (P < .05). Topical L-arginine (10-3mol/L for 30 minutes) did not affect responses to acetylcholine in adult SHRSP but enhanced vasodilatation in response to acetylcholine (10-5mol/L) in older SHRSP without affecting responses to sodium nitroprusside. In contrast, D-arginine did not affect acetylcholine-induced vasodilatation in older SHRSP. These results suggest that impaired dilatation of the basilar artery in response to acetylcholine in older SHRSP is restored toward normal by L-arginine, a substrate for nitric oxide synthase. (Hypertension. 1996;27:893-896.)

ISSN:0194-911X    

出版商:OVID    

年代:1996

数据来源: OVID

摘要:

Angiotensin II (Ang II) has growth-stimulatory properties on different renal cell types. However, possible growth effects of this vasoactive peptide on endothelial cells isolated from the glomerular microvasculature have not formally been investigated. Therefore, we isolated and characterized primary cultures of rat glomerular endothelial cells. We used a simple technique in which collagenase-treated glomeruli were sparsely plated in several 96-well culture plates and microscopically screened for cobblestone-like outgrowth. After two limiting dilutions, homogeneous cultures were obtained. Cells were characterized by positive staining for the endothelial markers factor VIII, CD 31, endothelial leukocyte adhesion molecule-1, and the lectin Bandeiraea simplificifolia. Ang II stimulated the synthesis and release of endothelin-1 in culture supernatants. Moreover, in contrast to syngeneic mesangial cells, glomerular endothelial cells expressed angiotensin-converting enzyme. Ang II stimulated a mild but significant proliferation of quiescent cells, as measured by [(3) Hydrogen]thymidine incorporation and direct cell counting. This mitogenesis was transduced by losartan-blockable angiotensin type 1 receptors. Moreover, Ang II mediated phosphorylation of mitogen-activated protein kinase 2 and induction of transcripts for the immediate early gene Egr-1. Our results indicate that Ang II is a moderate mitogen for primary cultures of rat glomerular endothelial cells and activation of these metabolically active cells may play a role in the pathophysiology of several types of glomerulonephritis. Moreover, remodeling of glomerular endothelial cells by Ang II may be important in the progression of structural renal damage during the course of hypertensive injury. (Hypertension. 1996;27:897-905.)

ISSN:0194-911X    

出版商:OVID    

年代:1996

数据来源: OVID

摘要:

Plasma concentrations of both atrial natriuretic peptide (ANP) and brain natriuretic peptide (BNP) are elevated in severe hypertension, acute myocardial infarction, and heart failure. In the current study of individuals with essential hypertension, we have documented the hemodynamic, hormonal, and endocrine effects of infusions of these two peptides given alone or in combination in equimolar doses calculated to induce increments in plasma peptides to concentrations (30 to 60 pmol/L) observed in these disease states. The metabolic clearance rate of ANP (4.56 plus/minus 0.62 L/min) was greater than that for BNP (3.4 plus/minus 0.23 L/min, P < .001). Infusions of each cardiac hormone impaired the clearance of coinfused peptide. All peptide infusions enhanced natriuresis (17% to 70% above preinfusion levels versus placebo, 6%; P < .001), lowered blood pressure (10 to 18 mm Hg fall in mean arterial pressure below placebo levels; P < .001), increased hematocrit, suppressed the renin-angiotensin-aldosterone system, and enhanced plasma norepinephrine concentrations. The natriuretic and blood pressure-lowering effects of BNP were twofold to threefold those of ANP. In contrast, ANP-induced increments in plasma and urinary second messenger (cGMP) levels were greater than those for BNP. Both peptides suppressed the renin-angiotensin-aldosterone system (approximately one-third fall in renin activity and plasma aldosterone) and enhanced plasma norepinephrine concentrations (+30%) to a similar degree. Increments in plasma ANP and BNP that occur simultaneously in cardiovascular disease states appear capable of causing hemodynamic, endocrine, and renal effects that would tend to ameliorate conditions such as hypertension or heart failure. (Hypertension. 1996;27:906-913.)

ISSN:0194-911X    

出版商:OVID    

年代:1996

数据来源: OVID

摘要:

We analyzed the hypotensive mechanisms of a thiazide-type diuretic, mefruside, on the basis of the pressure-natriuresis relationship. We performed a 5-week study in eight patients with essential hypertension who were given a high sodium diet (15 to 18 g NaCl per day) during the 1st and 5th weeks, a severely sodium-restricted diet (1 to 3 g/d) during the 2nd week, and a mildly sodium-restricted diet (5 to 7 g/d) during the 3rd and 4th weeks. Mefruside (25 mg/d) was administered during the 4th and 5th weeks. Urinary sodium excretion rate and mean arterial pressure were measured at the end of each week, and the pressure-natriuresis relationship was drawn by plotting urinary sodium excretion rate on the ordinate and mean arterial pressure on the abscissa before and after mefruside treatment. Before treatment, the pressure-natriuresis relationship was linear, and mean arterial pressure was changed as a consequence of sodium intake alteration (1st week, 117 plus/minus 9 mm Hg; 2nd week, 105 plus/minus 7; 3rd week, 109 plus/minus 9). After treatment, however, the change in mean arterial pressure was very small (4th week, 102 plus/minus 8 mm Hg; 5th week, 104 plus/minus 7). Mefruside steepened the slope of the relationship (20.8 plus/minus 10.5 versus 143 plus/minus 85 [mmol/d]/mm Hg, P < .005) without significantly shifting the x intercept (104 plus/minus 6 versus 101 plus/minus 9 mm Hg, P = NS) of the relationship. The increase in the slope was greater in patients whose slope had been depressed and blood pressure was sodium sensitive before mefruside treatment. The hypotensive effect of mefruside during a high sodium diet correlated positively with both the hypotensive effect of sodium restriction (r = .84, P < .01) and the increase in the slope by mefruside (r = .83, P < .02). Thus, mefruside lowers blood pressure especially in patients with high sodium sensitivity mainly by making blood pressure sodium insensitive through its diuretic action. Strict sodium restriction seems unnecessary when diuretics are administered for blood pressure control. (Hypertension. 1996;27:914-918.)

ISSN:0194-911X    

出版商:OVID    

年代:1996

数据来源: OVID