ISSN:0194-911X    

出版商:OVID    

年代:1995

数据来源: OVID

ISSN:0194-911X    

出版商:OVID    

年代:1995

数据来源: OVID

摘要:

Hypertension is a risk factor for the development of atherosclerosis, although the mechanisms have not been well elucidated. As the cellular and molecular mechanisms of the pathogenesis of atherosclerosis and the effects of hypertension are being more clearly defined, it becomes apparent that the two processes have certain common mechanisms. The endothelium is a likely central focus for the effect of both diseases. There is increasing evidence that atherosclerosis should be viewed fundamentally as an inflammatory disease. Atherogenic stimuli such as hyperlipidemia appear to activate the inflammatory response by causing expression of mononuclear leukocyte recruiting mechanisms. The gene for one of these, the vascular cell adhesion molecule-1, is controlled at least in part by transcriptional factors regulated by oxidative stress, which modifies the redox state of the endothelial cell. Alterations in the redox state of the arterial wall also may contribute to vascular smooth muscle cell growth. In a somewhat parallel fashion, there is evidence that hypertension may also exert oxidative stress on the arterial wall. This article reviews evidence that leads to the postulate that hypertension predisposes to and accelerates atherosclerosis at least in part because of synergy between elevated blood pressure and other atherogenic stimuli to induce oxidative stress on the arterial wall. (Hypertension. 1995;25:155-161.)

ISSN:0194-911X    

出版商:OVID    

年代:1995

数据来源: OVID

摘要:

Brief angiotensin-converting enzyme (ACE) inhibition in young spontaneously hypertensive rats (SHR) causes a persistent reduction in blood pressure. Bradykinin accumulation may contribute to these long-term effects, and to test this hypothesis we studied the consequences of bradykinin B2receptor antagonism during ACE inhibitor treatment in young SHR. Male SHR were treated from 6 to 10 weeks of age with water, ramipril (1 mg/kg per day), Hoe 140 (0.5 mg/kg per day), or both ramipril and Hoe 140. Systolic blood pressure and body weight were measured each week from 6 to 20 weeks of age. During treatment, Hoe 140 treatment resulted in lower blood pressures than in controls. Ramipril caused a larger fall in blood pressure over the same period. The ramipril plus Hoe 140 group had the lowest blood pressures of any group during treatment. After treatment, the blood pressure of Hoe 140-treated SHR was similar to that of untreated SHR. After ramipril, blood pressure rose but plateaued significantly below values in controls. In contrast, withdrawal of combined ramipril and Hoe 140 treatment caused a rapid rise of systolic blood pressure to levels significantly higher than in ramipril-treated SHR but less than in controls. The antihypertensive effects of Hoe 140 during the development of genetic hypertension may represent a direct effect of the drug or some alteration in the normal relation between bradykinin and blood pressure. The antagonism by Hoe 140 of the long-term blood pressure reduction after ramipril withdrawal indicates that the persistent effects of ACE inhibitors may in part be due to the accumulation of bradykinin during a critical stage of development. (Hypertension. 1995;25:162-165.)

ISSN:0194-911X    

出版商:OVID    

年代:1995

数据来源: OVID

摘要:

Heme oxygenase is a mammalian enzyme that converts heme to biliverdin and carbon monoxide. Carbon monoxide activates soluble guanylate cyclase and relaxes vascular smooth muscle, and it has been implicated as a potential neuromessenger. The regulatory functions of endogenous carbon monoxide on hemodynamics are not known. Zinc deuteroporphyrin 2,4-bis glycol (ZnDPBG) inhibits heme oxygenase in rats and thus permits assessment of the hemodynamic response to inhibition of endogenous carbon monoxide synthesis. In chronically instrumented, awake male Sprague-Dawley rats, ZnDPBG (45 micro mol/kg IP) increased mean arterial pressure (19 plus/minus 2%, P < .05) and total peripheral resistance (47 plus/minus 4%, P < .05), decreased cardiac output (-16 plus/minus 2%, P < .05), but did not affect heart rate. Another heme oxygenase inhibitor, zinc protoporphyrin IX (45 micro mol/kg IP), also increased arterial pressure (17 plus/minus 5%, P < .05), with no effect on heart rate. In contrast, neither the nonmetallic deuteroporphyrin 2,4-bis glycol (45 micro mol/kg IP) nor biliverdin (45 micro mol/kg IP) had any effect on blood pressure or heart rate. These findings suggest that ZnDPBG and zinc protoporphyrin IX increase arterial pressure by inhibiting heme oxygenase activity. After pretreatment with chlorisondamine (5 mg/kg IP) or prazosin (5 mg/kg IP) to inhibit autonomic ganglionic or alpha1-adrenoceptor functions, respectively, ZnDPBG did not affect arterial pressure or heart rate. This suggests that ZnDPBG-induced increases in blood pressure rely on autonomic nervous function. We conclude that the pressor response to heme oxygenase inhibitors results from withdrawal of the inhibitory influence of endogenous carbon monoxide on a pressor mechanism mediated by the autonomic nervous system. (Hypertension. 1995;25:166-169.)

ISSN:0194-911X    

出版商:OVID    

年代:1995

数据来源: OVID

摘要:

Angiotensin I (Ang I), Ang II, angiotensinogen, and renin are formed locally in the vasculature. We undertook this study to determine whether the rat mesenteric artery produces aldosterone and to investigate the effects of adrenalectomy, an angiotensin-converting enzyme inhibitor, Ang II, or potassium on aldosterone production in vascular tissue. Isolated rat mesenteric arteries were perfused with Krebs-Ringer solution for 4 hours. The perfusate was collected and chromatographed in a reversed-phase high-performance liquid chromatographic (HPLC) system. The fraction corresponding to synthetic aldosterone was collected and analyzed by mass spectrometry. The aldosterone concentration in the perfusate from the adrenalectomized rats and rats treated with an angiotensin-converting enzyme inhibitor was measured using radioimmunoassay after HPLC separation. The mass spectra of synthetic aldosterone and aldosterone isolated from the perfusate of rat mesenteric arteries were identical. Aldosterone production in the mesenteric arteries of adrenalectomized rats was increased and of rats treated with an angiotensin-converting enzyme inhibitor was reduced compared with that of controls. Ang II (1.9 x 10 (-10) mol/L) and potassium (6.0 mmol/L) increased aldosterone production in mesenteric arteries. This study shows that the rat mesenteric artery produces aldosterone and that the intravascular renin-angiotensin-aldosterone system may contribute to vascular tone. (Hypertension. 1995;25:170-173.)

ISSN:0194-911X    

出版商:OVID    

年代:1995

数据来源: OVID

摘要:

It is well established that two-kidney, one clip renovascular hypertension can be rapidly reversed by unclipping. We hypothesized that rapid renal reperfusion and the subsequent fall in blood pressure are mediated in part by nitric oxide, the endothelium-derived relaxing factor. We tested whether the hypotensive response to unclipping could be blocked by nitric oxide synthesis inhibition using a bolus of 10 mg/kg body wt Nomega-nitro-L-arginine methyl ester. Rats were made hypertensive by placing a silver clip on the left renal artery. After 4 weeks, they were anesthetized and either not treated (controls) or had nitric oxide synthesis blockade. After 10 minutes, the clip was removed and blood pressure monitored over 60 minutes. Initial pressure in controls was 157 plus/minus 8 mm Hg, and heart rate was 310 plus/minus 21 beats per minute. Unclipping resulted in pressure falling to 125 plus/minus 6 mm Hg within 45 minutes (P < .005). Heart rate was unchanged (312 plus/minus 9 beats per minute). In contrast, nitric oxide synthesis inhibition increased blood pressure from 149 plus/minus 6 to 174 plus/minus 9 mm Hg (P < .001). Unclipping did not change blood pressure, which was 167 plus/minus 8 mm Hg after 60 minutes (P < .005 versus controls), and heart rate remained unchanged (282 plus/minus 13 versus 276 plus/minus 16 beats per minute). We determined the blood flow to the clipped kidneys using radioactive microspheres. Unclipping untreated hypertensive rats resulted in a 10-fold increase in renal blood flow (P < .001), concomitant with a decrease in blood pressure. In rats with nitric oxide synthesis inhibition, unclipping resulted in an increase in renal blood flow that was only a third of that seen in untreated rats, with no change in blood pressure. Our results show that nitric oxide synthesis inhibition eliminates the acute reversal of renovascular hypertension caused by unclipping. This suggests that endothelium-derived nitric oxide may be an important component in the reversal of two-kidney, one clip renovascular hypertension, either by facilitating renal reperfusion or by mediating the systemic response secondary to renal reperfusion. (Hypertension. 1995;25:174-179.)

ISSN:0194-911X    

出版商:OVID    

年代:1995

数据来源: OVID

摘要:

Nitric oxide (NO) is an important molecular messenger accounting for endothelium-derived relaxing factor. Recently, NO synthase (NOS) from cultured endothelial cells has been purified and molecularly cloned. To evaluate the effect of phosphorylation by protein kinase C (PKC) and cyclic AMP-dependent protein kinase (PKA) on endothelial constitutive NOS catalytic activity, we incubated purified endothelial NOS with PKC or PKA. Endothelial NOS was stoichiometrically phosphorylated by PKC and PKA. In intact bovine aortic endothelial cells (BAECs), NOS was phosphorylated by stimulation with 12-O-tetradecanoylphorbol-13-acetate (TPA). NOS activity measured by the conversion of [(3) Hydrogen]arginine to [(3) Hydrogen]citrulline in homogenates of BAECs treated with TPA or phorbol 12,13-dibutyrate was reduced by 30%, whereas dibutylyl cyclic AMP did not affect NOS activity. Moreover, we measured NO release from cultured BAECs by a chemiluminescence method to examine the effect of PKC and PKA on endothelial NOS activity. In cultured BAECs, ATPgammaS and A23187 induced NO release in time- and dose-dependent manners. Phorbol esters such as TPA and phorbol 12,13-dibutyrate dose dependently inhibited NO release stimulated by A23187 as well as ATPgammaS. Reduction of NO release by TPA was almost completely prevented by pretreatment with staurosporine, an inhibitor of PKC. NO release by A23187 was increased in PKC-downregulated BAECs. In contrast, dibutylyl cyclic AMP or 8-bromo cyclic GMP had no effect on NO release from BAECs induced by A23187 or ATPgammaS. These results indicate that phosphorylation of NOS by PKC is associated with a reduction of its catalytic activity in vascular endothelial cells. (Hypertension. 1995;25:180-185.)

ISSN:0194-911X    

出版商:OVID    

年代:1995

数据来源: OVID

摘要:

In arterial hypertension, coronary flow reserve, expressed by the difference between autoregulated and maximal coronary flow, is frequently impaired. Previous experimental and clinical investigations using acetylcholine as a stimulus for the production of endothelium-derived relaxing factor suggested that an impaired endothelium-dependent vasodilation, presumably caused by a decreased formation of nitric oxide (NO), may account for this microvascular dysfunction. However, so far no study has been performed that quantifies the formation of NO within the coronary circulation of hypertensive hearts to assess its role in setting coronary vascular tone in the hypertensive heart. We therefore quantified NO formation within the coronary circulation of constant flow-perfused, isolated hearts from spontaneously hypertensive rats (SHR, 16th to 26th week), as a model for hypertensive heart disease, and from the normotensive control strain (Wistar-Kyoto, WKY) using the oxyhemoglobin technique. Coronary perfusion pressure and vascular resistance were almost 30% higher in SHR compared with WKY hearts. Intracoronarily applied NO decreased coronary vascular resistance by maximally 45% of resting values in a concentration-dependent manner in both groups. The bradykinin-induced decrease in coronary vascular resistance and the parallel increase in NO release were comparable in SHR and WKY hearts and fell within the vasodilator range of exogenously applied NO. Moreover, basal release of NO normalized to heart wet weight was 50% higher in SHR compared with WKY hearts. Rates of basal NO release were correlated inversely with changes in coronary perfusion pressure and vascular resistance in both groups (r = -.85 and -.84, respectively, P < .05). This relation between resting coronary vascular resistance and NO formation, as a critical determinant of coronary flow, was shifted significantly to higher levels in SHR. From the present data we conclude that in the coronary circulation of SHR, NO formation is preserved under basal and stimulated conditions and critically determines resting coronary resistance. Moreover, the enhanced basal release of NO may serve the purpose of compensating the higher coronary vascular resistance of hypertensive hearts. (Hypertension. 1995;25:186-193.)

ISSN:0194-911X    

出版商:OVID    

年代:1995

数据来源: OVID

摘要:

We analyzed the effects and mechanisms of aging in aortic endothelium and vascular smooth muscle of 12-week-old (adult) and 72-week-old (senescent) normotensive Wistar-Kyoto rats (WKY) and spontaneously hypertensive rats (SHR). Aortas were suspended in organ chambers filled with physiological salt solution (95% O2/5% CO2; 37 degrees Celsius), and isometric tension was measured. In WKY, endothelium-dependent relaxations to acetylcholine were diminished with aging (P < .05); in SHR, they were reduced compared with WKY (P < .05) but unchanged with aging. The thromboxane/endoperoxide receptor antagonist SQ 30741 increased relaxations only in adult SHR. Relaxations to sodium nitroprusside were slightly enhanced with age in WKY and SHR (P < .05). Endothelium-dependent contractions to acetylcholine were unmasked by NG-nitro-L-arginine methyl ester (P < .05) and prevented by SQ 30741 or endothelium removal. In WKY, contractions increased with age. In adult SHR, marked endothelium-dependent contractions occurred (P < .05 versus WKY), which diminished with age (P = NS versus senescent WKY). The thromboxane analogue U46619 elicited similar contractions in adult and senescent WKY and adult SHR, whereas responses in senescent SHR were weaker (P < .05). In WKY and SHR, contractions to norepinephrine were similar and unaltered by aging. In WKY, contractions to endothelin-1 remained unaffected by aging. Adult SHR exhibited contractions to endothelin-1 comparable to those in WKY, whereas senescent SHR contracted less (P < .05). Bosentan, a combined endothelin-A/endothelin-B receptor antagonist, inhibited endothelin-1 markedly, especially in SHR (P < .05). Thus, aging causes different alterations in endothelium and smooth muscle in WKY and SHR aorta. In adult SHR, endothelium-dependent relaxations are reduced because of formation of prostaglandin H2, whereas in senescent SHR and senescent WKY, impaired formation or increased inactivation of nitric oxide must be involved. Contractions to endothelin but not to norepinephrine are reduced with aging only in SHR. (Hypertension. 1995;25:194-200.)

ISSN:0194-911X    

出版商:OVID    

年代:1995

数据来源: OVID