ISSN:0194-911X    

出版商:OVID    

年代:1997

数据来源: OVID

摘要:

Our objective was to compare cardiovascular event rates in patients with mild or moderate hypertension who received nifedipine with active drug controls. We performed a MEDLARS search using the MeSH heading "hypertension" and the text word "nifedipine" to identify all articles that were published between 1966 and August 1995 in English, French, German, Italian, and Spanish languages and that involved human subjects. The computerized search was supplemented by a manual search of article bibliographies. Review of 1880 citations revealed 98 randomized controlled clinical trials that met protocol criteria. Articles were extracted independently by two doctors who were blinded for author, institution, and treatment regimen, using a structured, pretested extraction form. Differences of opinion were resolved by consensus. Fourteen events occurred in 5198 exposures (0.27%) to nifedipine and 24 events in 5402 exposures (0.44%) to other active drug controls. Unadjusted odds ratios for nifedipine versus controls were 0.49 (95% confidence interval [CI], 0.22-1.09) for definitive events (death, nonfatal myocardial infarction or stroke, revascularization procedure) and 0.61 (95% CI, 0.31-1.17) for all events (definitive plus increased angina). The odds ratio for nifedipine monotherapy (sustained- or extended-release in 91% of exposures) was nonsignificantly higher for definitive and all events (odds ratio, 1.40; 95% CI, 0.49-4.03 and odds ratio, 1.39; 95% CI, 0.59-3.32, respectively). The odds ratio for nifedipine in combination with another drug was significantly lower for definitive and all events (odds ratio, 0.09; 95% CI, 0.01-0.66 and odds ratio, 0.15; 95% CI, 0.03-0.65, respectively). Differences in odds ratio for nifedipine monotherapy and combined therapy were statistically significant (P = .02 for definitive events and P = .001 for all events). Results support the safety of sustained- and extended-release nifedipine in the treatment of mild or moderate hypertension when it is used in combination with other drugs. (Hypertension. 1997;30[part 1]:7-14.)

ISSN:0194-911X    

出版商:OVID    

年代:1997

数据来源: OVID

摘要:

The potential role of endothelin-1 (ET-1) in essential hypertension in humans is still subject to debate. We recently reported strong sodium retention and renal vasoconstriction during pathophysiological increments in plasma ET-1. Apart from this vasoconstrictor action, ET-1 also has mitogenic properties that play a role in the pathophysiology of hypertension. On the other hand, some data refute an important role of ET-1 in hypertension. We therefore investigated in nine subjects with essential hypertension the constrictor actions of ET-1 by challenging these subjects with a systemic infusion of ET-1 (0.5 ng/kg per minute for 60 minutes, then 1.0 ng/kg per minute for 60 minutes, and finally 2.0 ng/kg per minute for 60 minutes). Furthermore, we studied whether these effects of ET-1 could be modulated by oral use of the angiotensin-converting enzyme inhibitor enalapril (20 mg BID) or the calcium channel blocker nifedipine (60 mg OD). ET-1 infusion increased plasma ET-1 levels from 2.5 +/- 0.4 to 11.6 +/- 1.0 pmol/L (P < .05). Blood pressure rose by approximately 10 mm Hg (P < .05). Cardiac index decreased by 21 +/- 2%, whereas calculated systemic vascular resistance increased by 27 +/- 6% (P < .05). Renal blood flow decreased from 1051 +/- 94 to 707 +/- 60 mL/min at the end of the ET-1 infusion (P < .05), and calculated renal vascular resistance increased from 118 +/- 19 to 189 +/- 19 mm Hg [center dot] min/L (P < .05). Sodium excretion decreased from 227 +/- 39 to 111 +/- 15 micro mol/min (P < .05). Both enalapril and nifedipine treatment prevented the systemic effects of ET-1 infusion in these subjects. However, during enalapril treatment, despite renal predilatation, ET-1 reduced renal blood flow (from 1119 +/- 132 to 701 +/- 75 mL/min, P < .05) and increased renal vascular resistance (from 111 +/- to 187 +/- 28 mm Hg [center dot] min/L, P < .05) to the same levels as during ET-1 infusion alone. Nifedipine pretreatment attenuated the ET-1-induced fall in renal blood flow (from 1088 +/- 93 to 907 +/- 68 mL/min) and increase in renal vascular resistance (from 105 +/- 9 to 133 +/- 10 mm Hg [center dot] min/L). Although neither drug modulated the antinatriuretic effect of ET-1, nifedipine increased basal sodium excretion (P < .05), which compensated for the decrease during ET-1 infusion. In conclusion, essential hypertensive subjects are sensitive to the vasoconstrictor effects of ET-1. Both enalapril and nifedipine can prevent the systemic effects of ET-1, but nifedipine seems more effective in attenuating the renal constrictor effects of ET-1. (Hypertension. 1997;30[part 1]:15-21.)

ISSN:0194-911X    

出版商:OVID    

年代:1997

数据来源: OVID

摘要:

To assess whether acute nitric oxide (NO) blockade could unmask the vascular actions of endogenous endothelin, we tested the effects of the endothelin type A/type B (ETA/ETB) receptor antagonist bosentan and the selective ETAantagonist FR 139317 on blood pressure, plasma volume, and albumin escape after inhibition of NO synthesis with NG-nitro-L-arginine methyl ester (L-NAME). Conscious, chronically catheterized rats received L-NAME in the absence and presence of 17.4 micro mol/kg (10 mg/kg) bosentan or 3.8 micro mol/kg (2.5 mg/kg IV, 10 minutes before L-NAME) FR 139317. Red blood cell volume and plasma volume were determined with chromium-51-tagged erythrocytes and iodine-125-labeled albumin, respectively. L-NAME (0.46 to 7.42 micro mol/kg [0.125 to 2 mg/kg]) induced a dose-dependent increase in blood pressure, which was attenuated by 60% and 48% with bosentan and FR 139317, respectively (P < .01). L-NAME (7.42 micro mol/kg) also increased hematocrit. This effect was associated with an increase in total-body albumin escape, which is reflected by a 14% reduction in plasma volume. Red blood cell volume remained unchanged. L-NAME promoted albumin escape primarily in the lung, heart, liver, kidney, and gastrointestinal tract. Both bosentan and FR 139317 markedly reduced these effects of L-NAME. Furthermore, L-NAME increased plasma levels of immunoreactive endothelin-1 from 8.6 +/- 0.4 (n = 10) to 14.7 +/- 1.4 pg/mL (n = 9, P < .01). These results demonstrate that the pressor response, losses in plasma volume, and increase in albumin escape observed after inhibition of NO synthesis are in part the consequence of unmasking the actions of endogenous endothelin, which are mediated predominantly via ETAreceptors. These findings suggest a role for endogenous endothelin in the regulation of vascular functions in conditions when NO formation by endothelial cells is impaired. (Hypertension. 1997;30[part 1]:22-28.)

ISSN:0194-911X    

出版商:OVID    

年代:1997

数据来源: OVID

摘要:

Experiments in cultured vascular smooth muscle cells have shown that angiotensin II (Ang II) stimulates expression of endothelin-1. We sought to examine role of endothelin-1 in the effects of Ang II in vivo. Ang II infusion in rats (0.7 mg/kg per day for 5 days) was associated with marked increases in vascular smooth muscle endothelin-1 levels, as assessed by immunostaining. Administration of the selective endothelin type A (ETA) receptor antagonist PD 155080 (50 mg/kg per day) abrogated the hypertensive response to a 5-day infusion of Ang II (0.7 mg/kg per day), as did losartan (25 mg/kg per day). ETAreceptor blockade during Ang II-mediated hypertension was associated with marked elevations of plasma endothelin-1 levels. Ang II-mediated hypertension was associated with heightened vascular responsiveness to a variety of vasoconstrictor agents except endothelin-1. Blockade of ETAreceptor invariably corrected this vasoconstrictor hyperresponsiveness. We conclude that some of the vascular effects of Ang II thought to be unique to this hormone are likely mediated by endothelin-1. (Hypertension. 1997;30[part 1]:29-34.)

ISSN:0194-911X    

出版商:OVID    

年代:1997

数据来源: OVID

摘要:

Although various cytokines are known to be expressed in atherosclerotic lesions, it is not known how these cytokines affect receptors for the peptide hormone angiotensin II (Ang II). We therefore examined the effects of interleukin-1alpha (220 U/mL [10 ng/mL]), tumor necrosis factor-alpha (280 U/mL [100 ng/mL]), and interferon gamma (100 U/mL) on Ang II type 1 (AT1) receptors expressed in rat vascular smooth muscle cells. Treatment with interleukin-1alpha caused a 1.4- to 1.7-fold increase in AT1binding after 24 hours (P < .01) and a 2.3-fold increase in AT1mRNA (P < .05). Tumor necrosis factor-alpha and interferon gamma did not cause a significant change in AT1binding when administered alone but caused a 30% reduction in binding when administered together (P < .05). The maximal decrease in AT1binding (60%, P < .01) was seen with the combination of interleukin-1alpha with tumor necrosis factor-alpha and interferon gamma. Although the upregulation of AT1by interleukin-1alpha was unaffected by pretreatment of cells with N-monomethyl-L-arginine or indomethacin, downregulation of AT1by interleukin-1alpha combined with tumor necrosis factor-alpha/interferon gamma was inhibited by N-monomethyl-L-arginine (P < .01). Interleukin-1alpha treatment enhanced Ang II-induced [(3) H]uridine incorporation, whereas treatment with interleukin-1alpha combined with tumor necrosis factor-alpha/interferon gamma attenuated Ang II-induced [(3) H]uridine and [(3) H]leucine incorporation. These results demonstrate that interleukin-1alpha upregulates AT1receptors and enhances Ang II-stimulated hypertrophic responses. However, a combination of interleukin-1alpha with tumor necrosis factor-alpha and interferon gamma downregulates AT1receptors by a nitric oxide-dependent mechanism and reduces Ang II-stimulated trophic responses in vascular smooth muscle cells. (Hypertension. 1997;30[part 1]:35-41.)

ISSN:0194-911X    

出版商:OVID    

年代:1997

数据来源: OVID

摘要:

Angiotensin II (Ang II) is internalized by various cell types via receptor-mediated endocytosis. Little is known about the kinetics of this process in the whole animal and about the half-life of intact Ang II after its internalization. We measured the levels of125I-Ang II and125I-Ang I that were reached in various tissues and blood plasma during infusions of these peptides into the left cardiac ventricle of pigs. Steady-state concentrations of125I-Ang II in skeletal muscle, heart, kidney, and adrenal were 8% to 41%, 64% to 150%, 340% to 550%, and 680% to 2100%, respectively, of the125I-Ang II concentration in arterial blood plasma (ranges of six experiments). The tissue concentrations of125I-Ang I were less than 5% of the arterial plasma concentrations.125I-Ang II accumulation seen in heart, kidney, and adrenal was almost completely blocked by a specific Ang II type 1 (AT1) receptor antagonist. Steady-state concentrations of125I-Ang II were reached within 30 to 60 minutes in the tissues and within 5 minutes in blood plasma. The in vivo half-life of intact125I-Ang II in heart, kidney, and adrenal was approximately 15 minutes, compared with 0.5 minute in the circulation. Thus, Ang II, but not Ang I, from the circulation is accumulated by some tissues, and this is mediated by AT1receptors. The time course of this process and the long half-life of the accumulated Ang II support the contention that this Ang II has been internalized after its binding to the AT1receptor, so that it is protected from rapid degradation by endothelial peptidases. The results of this study are in agreement with growing evidence of an important physiological role for internalized Ang II. (Hypertension. 1997;30[part 1]:42-49.)

ISSN:0194-911X    

出版商:OVID    

年代:1997

数据来源: OVID

摘要:

It is unknown whether basal release of endothelium-derived nitric oxide in the coronary artery is altered in heart failure in humans. The aim of the present study was to evaluate the effect of inhibition of nitric oxide synthesis on basal tone of the conduit and resistance coronary arteries in awake patients. Coronary blood flow velocity (Doppler guide wire) and coronary arterial diameter (quantitative coronary angiography) were measured in 14 patients with heart failure caused by nonischemic left ventricular dysfunction (7 idiopathic dilated cardiomyopathy and 7 valvular insufficiency) and 7 patients with normal ventricular function (controls). Intracoronary NG-monomethyl-L-arginine (L-NMMA), an inhibitor of nitric oxide synthesis, at graded doses decreased coronary blood flow in both groups. However, the magnitude of flow reduction was smaller in patients with heart failure than in control patients (P < .0001). The magnitude of coronary blood flow reduction in response to L-NMMA inversely correlated to indexes of left ventricular contractile function (P < .01) but was not affected by the cause of heart failure. Constriction of the large epicardial coronary artery with L-NMMA also tended to be attenuated in patients with heart failure. In summary, vasoconstricting response to L-NMMA was blunted in the coronary resistance artery in heart failure in vivo. These findings suggest that basal release of nitric oxide in the coronary circulation is decreased in patients with heart failure. (Hypertension. 1997;30[part 1]:50-56.)

ISSN:0194-911X    

出版商:OVID    

年代:1997

数据来源: OVID

摘要:

Hypercholesterolemic and hypertensive patients have impaired endothelium-dependent vasorelaxation because of decreased nitric oxide activity, but the mechanism underlying this abnormality is unknown. This study sought to determine whether an increased breakdown of nitric oxide by xanthine oxidase-generated superoxide anions could participate in these forms of endothelial dysfunction. We studied vascular responses to intrabrachial infusion of acetylcholine (an endothelium-dependent vasodilator, 7.5 to 30 micro gram/min) and sodium nitroprusside (a direct smooth muscle dilator, 0.8 to 3.2 micro gram/min) by strain-gauge plethysmography before and during the combined administration of oxypurinol (300 micro gram/min), a xanthine oxidase inhibitor, in 20 hypercholesterolemic patients, 20 essential hypertensive patients, and 20 normal subjects. The vasodilator response to acetylcholine was blunted in hypercholesterolemic (highest flow, 8.2 +/- 8 mL [center dot] min-1[center dot] dL-1) and hypertensive (8.5 +/- 4 mL [center dot] min (-1) [center dot] dL-1) patients compared with control subjects (13.8 +/- 6.6 mL [center dot] min-1[center dot] dL-1) (both P < .001); however, no differences were observed in the response to sodium nitroprusside. Oxypurinol did not change the response to acetylcholine in control subjects (P = .26) and improved, but did not normalize, its vasodilator effect in hypercholesterolemic patients (P < .01). Oxypurinol did not affect the response to acetylcholine in hypertensive patients (P = .34) and did not modify the response to sodium nitroprusside in any group. These results suggest that xanthine oxidase-generated superoxide anions are partly responsible for the impaired endothelial vasodilator function of hypercholesterolemic patients. In contrast, this mechanism does not appear to play a significant role in essential hypertension. (Hypertension. 1997;30[part 1]:57-63.)

ISSN:0194-911X    

出版商:OVID    

年代:1997

数据来源: OVID

摘要:

Studies in anesthetized animals have advanced the theory that there is an important neurogenic component to the hypertension caused by pharmacological inhibition of nitric oxide, but studies in conscious animals have produced conflicting evidence for and against this theory. To try to reconcile the seemingly contradictory data, we hypothesized that the neurogenic component of this hypertension is time dependent such that the sympathetic nervous system is involved primarily in the maintenance, rather than the initiation, of the hypertension. We measured intra-arterial pressure in conscious, unrestrained rats with and without guanethidine-induced sympathectomy during varying durations of intravenous Nomega-nitro-L-arginine methyl ester (L-NAME). The major new finding is that sympathectomy had no effect on the hypertensive response to bolus injections of L-NAME but in the same rats it produced a greater than 50% attenuation in the hypertension seen after 6 days of continuous L-NAME (change in mean arterial pressure, 23 +/- 4 versus 55 +/- 4 mm Hg, P <.01, sympathectomy versus control). Using 8-hour infusions of L-NAME, we found that 60 minutes was the minimum time required for detecting a sympathectomy-sensitive component of L-NAME-induced hypertension. Furthermore, we demonstrate that the magnitude of this component increases further between 8 hours to 6 days of continuous L-NAME: it accounted for only 18% of the total hypertensive response at 8 hours but 61% after 6 days. From these experiments, we conclude that the importance of the sympathetic system in the pathogenesis of L-NAME-induced hypertension accrues slowly over hours and days, and thus its importance can be overlooked by focusing on the initial phase of the hypertension. (Hypertension. 1997;30[part 1]:64-70.)

ISSN:0194-911X    

出版商:OVID    

年代:1997

数据来源: OVID