摘要:

After transient episodes of ischemia, benefits of thrombolytic or angioplastic therapy may be limited by reperfusion injury. Angiotensin-converting enzyme inhibitors protect the heart against ischemia/reperfusion injury, an effect mediated by kinins. We examined whether the protective effect of the angiotensin-converting enzyme inhibitor ramiprilat on myocardial ischemia/reperfusion is due to kinin stimulation of prostaglandin and/or nitric oxide release. The left anterior descending coronary artery of Lewis inbred rats was occluded for 30 minutes, followed by 120 minutes of reperfusion. Immediately before reperfusion rats were treated with vehicle, ramiprilat, or the angiotensin II type 1 receptor antagonist losartan. We tested whether pretreatment with the kinin receptor antagonist Hoe 140, the nitric oxide synthase inhibitor NitrogenG-nitro-L-arginine methyl ester, or the cyclooxygenase inhibitor indomethacin blocked the effect of ramiprilat on infarct size and reperfusion arrhythmias. In controls, infarct size as a percentage of the area at risk was 79 plus/minus 3%; ramiprilat reduced this to 49 plus/minus 4% (P < .001), but losartan had little effect (74 plus/minus 6%, P = NS). Pretreatment with Hoe 140, NitrogenG-nitro-L-arginine methyl ester, or indomethacin abolished the beneficial effect of ramiprilat. Compared with the 30-minute ischemia/120-minute reperfusion group, nonreperfused hearts with 30 minutes of ischemia had significantly smaller infarct size as a percentage of the area at risk, whereas in the 150-minute ischemia group it was significantly larger. This suggests that reperfusion caused a significant part of the myocardial injury, but it also suggests that compared with prolonged ischemia, reperfusion salvaged some of the myocardium. Ventricular arrhythmias mirrored the changes in infarct size. Thus, angiotensin-converting enzyme inhibitors protect the myocardium against ischemia/reperfusion injury and arrhythmias; these beneficial effects are mediated primarily by a kinin-prostaglandin-nitric oxide pathway, not inhibition of angiotensin II formation. (Hypertension. 1996;27:7-13.)

ISSN:0194-911X    

出版商:OVID    

年代:1996

数据来源: OVID

摘要:

Nitric oxide inhibits proliferation and migration of vascular smooth muscle cells and contractility of cardiomyocytes in vitro. In spontaneously hypertensive rats (SHR), evidence suggests intrinsic abnormalities of the L-arginine-nitric oxide axis, such as low cGMP-dependent protein kinase in the heart and abnormal L-arginine metabolism. To investigate the in vivo effect of L-arginine on cardiac hypertrophy, 30 SHR and 30 Wistar-Kyoto rats (WKY) were randomly grouped to receive L-arginine (7.5 g/L in drinking water) or vehicle for 12 weeks. L-Arginine treatment did not affect body weight or arterial pressure in either strain. In vehicle-treated animals, the heart/body weight ratio was significantly higher in SHR than in WKY (P < .01). L-Arginine treatment decreased the heart/body weight ratio in SHR (P < .05) but did not affect it in WKY. Expression of skeletal alpha-actin mRNA, known to be expressed in the hypertrophied myocardium, was attenuated in L-arginine-treated SHR compared with vehicle-treated SHR. Cardiac cGMP content and nitrate/nitrite content were less in SHR than WKY. L-Arginine treatment increased these levels only in SHR, suggesting enhanced nitric oxide production. Thus, chronic L-arginine administration attenuated cardiac hypertrophy independently of blood pressure and increased myocardial content of cGMP and nitrate/nitrite. Our results suggest that abnormality of the cardiac L-arginine-nitric oxide axis may play an important role in the pathogenesis of cardiac hypertrophy in SHR. (Hypertension. 1996;27:14-18.)

ISSN:0194-911X    

出版商:OVID    

年代:1996

数据来源: OVID

摘要:

We investigated the contribution of nitric oxide to the short-term blood pressure reduction caused by interruption of the renin-angiotensin system in angiotensin-dependent hypertension. The blood pressure of rats made hypertensive by coarctation of the aorta between the renal arteries at their origin fell after administration of the angiotensin-converting enzyme inhibitor ramiprilat (2 mg/kg IV; -75 plus/minus 5 mm Hg) or the angiotensin II antagonist losartan (30 mg/kg IV; -79 plus/minus 6 mm Hg). But the antihypertensive effect of these agents was attenuated in rats pretreated with NitrogenG-nitro-L-arginine methyl ester (10 mg/kg IV) to inhibit nitric oxide synthesis (ramiprilat, -23 plus/minus 7 mm Hg; losartan, -37 plus/minus 5 mm Hg). In rats made hypertensive by long-term infusion of angiotensin II (60 ng/min IV, 6 to 7 days), the vasodepressor response to discontinuation of the angiotensin II infusion also was attenuated by pretreatment with the nitric oxide synthesis inhibitor (-52 plus/minus 7 versus -31 plus/minus 7 mm Hg); this attenuation was not demonstrable in rats receiving sodium nitroprusside (1 micro gram [centered dot] kg-1[centered dot] min-1IV) to replace the loss of endogenous nitric oxide (-72 plus/minus 9 mm Hg). Pretreatment with NitrogenG-nitro-L-arginine methyl ester did not interfere with the vasodepressor effect of sodium nitroprusside or prazosin in rats with aortic coarctation-induced hypertension or with the blood pressure reduction caused by discontinuation of an infusion of phenylephrine in rats made hypertensive by long-term administration of this drug. These data suggest a contribution of nitric oxide to the blood pressure reduction caused by interruption of the renin-angiotensin system in models of established angiotensin-dependent hypertension. (Hypertension. 1996;27:19-24.)

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 effects of long-term antihypertensive therapy on blood pressure and vascular responses of resistance arteries during prolonged inhibition of nitric oxide synthesis. Four groups of 6-week-old Wistar-Kyoto rats were treated with either placebo as controls or Nitrogenomega-nitro-L-arginine methyl ester (L-NAME) alone or in combination with verapamil or with trandolapril. Drugs were given orally for 6 weeks or short-term in vitro to vessels obtained from untreated rats. Endothelium-dependent and -independent relaxations as well as contractions were studied in isolated perfused mesenteric and renal arteries with an arteriograph. Kidney nitric oxide synthase activity was also evaluated. Verapamil and trandolapril prevented the increase in systolic blood pressure and the blunted acetylcholine-induced relaxations that occurred with L-NAME treatment without improving the nitric oxide synthase activity. Both antihypertensive regimens also normalized sensitivity to sodium nitroprusside, which was enhanced by L-NAME. In contrast, short-term in vitro preincubation with verapamil or trandolaprilat in the presence of L-NAME did not improve the impaired relaxations to acetylcholine. Long-term but not short-term therapy with a calcium antagonist or angiotensin-converting enzyme inhibitor improved the blunted endothelium-dependent relaxations in nitric oxide-deficient hypertension. These findings strongly suggest that the role of other vasodilator systems, which normally do not regulate vascular tone, is enhanced with long-term but not short-term treatment with these drugs. These observations emphasize the potential importance of these treatments in the management of hypertension in which nitric oxide production is diminished. (Hypertension. 1996;27:25-31.)

ISSN:0194-911X    

出版商:OVID    

年代:1996

数据来源: OVID

摘要:

The endothelium plays a critical role in maintaining vascular tone by releasing vasoconstrictor and vasodilator substances. Endothelium-derived nitric oxide is a vasodilator that can be rapidly inactivated by superoxide (reaction rate constant, K = 3.6 x 109L/mol per second). The measurement of nitric oxide concentration in biological systems is a challenging analytic problem because nitric oxide is also rapidly inactivated by Iron(II), Iron(III), and Oxygen2, all of which are found in great abundance in biological systems. To date, no currently used instrumental technique has been suitable for direct in situ measurement of NO in isolated resistance arteries. We designed the present study to perform for the first time direct in situ measurements of NO in rat mesenteric resistance arteries and to delineate the effects of hypertension on the release of NO and/or its interaction with superoxide. We describe here an adaptation of the recently published design of a porphyrinic sensor for direct in vitro measurement of NO in a single cell. The most significant advantage of this modified porphyrinic microsensor is that its small size makes it ideal for NO measurement in resistance arteries with an internal diameter of 200 micro meter or less. Small segments of the third-order branch of the mesenteric artery were isolated from normotensive Wistar-Kyoto rats and stroke-prone spontaneously hypertensive rats and placed in an organ chamber filled with Hanks' balanced salt solution buffer (2 mL, 37 degrees Celsius). The tip of the porphyrinic microsensor was inserted into the lumen of an isolated vascular ring, and NO release was monitored in situ after maximal stimulation of NO synthase with the receptor-independent agonist calcium ionophore A23187 (10 micro mol/L). Maximal surface concentration of NO measured after A23187 administration was significantly smaller in 15-week-old hypertensive rats (0.28 plus/minus 0.03 micro mol/L, n = 10) than in age-matched normotensive rats (0.38 plus/minus 0.03 micro mol/L, n = 10, P < .03). However, in the presence of the superoxide scavenger superoxide dismutase (100 U/mL), the peak NO level from the hypertensive rats was 0.37 plus/minus 0.04 micro mol/L (n = 10), which was comparable to that observed for the normotensive rats in the absence and presence of superoxide dismutase. In summary, our results demonstrate that in rat mesenteric resistance arteries hypertension is associated with increased NO decomposition by superoxide, whereas NO release remains unaffected. This may be important in the pathogenesis of hypertension and its cardiovascular complications. (Hypertension. 1996;27:32-35.)

ISSN:0194-911X    

出版商:OVID    

年代:1996

数据来源: OVID

摘要:

Nitric oxide, synthesized from the semiessential amino acid L-arginine by nitric oxide synthase, is a remarkable regulatory molecule and plays an important role in physiological functions. However, the physiological role of nitric oxide in cardiovascular regulation by the central nervous system is not well understood. In this study we investigated the cardiovascular effects of nitric oxide in the lateral ventricle, nucleus tractus solitarii, area postrema, and rostral ventrolateral medulla in urethane-anesthetized male Sprague-Dawley rats. Microinjection of NitrogenG-monomethyl-L-arginine, a nitric oxide synthase inhibitor, into the cerebral ventricle of rats elicited a dose-dependent increase in blood pressure and heart rate. This suggests that nitric oxide may be involved in central cardiovascular regulation. Unilateral microinjection (60 nL) of L-arginine (1 to 100 nmol) into the nucleus tractus solitarii and rostral ventrolateral medulla produced prominent dose-related depressor and bradycardic effects and reduced renal sympathetic nerve activity. However, L-arginine had no significant cardiovascular effects in the area postrema. In addition, 4 to 6 hours after intravenous injection of bacterial endotoxin-lipopolysaccharide (10 mg/kg), there was a time-related potentiation of the L-arginine-induced depressor and bradycardic effects in the nucleus tractus solitarii. These results indicate that nitric oxide is involved in central cardiovascular regulation. The depressor effect of nitric oxide in the nucleus tractus solitarii and rostral ventrolateral medulla may be through inhibition of renal sympathetic nerve activity. (Hypertension. 1996;27:36-42.)

ISSN:0194-911X    

出版商:OVID    

年代:1996

数据来源: OVID

摘要:

Previous studies reported sex differences in production of endothelium-derived substances and suggested that these compounds may be involved in regulation of vascular tone under both normal and pathological conditions. The present study was designed to compare the effects of endothelium-dependent contractions in pulmonary artery vessels obtained from male and female rabbits. Rings of intrapulmonary arteries were suspended under isometric tension in oxygenated Krebs' buffer. In male rabbit pulmonary artery, arachidonic acid and methacholine elicited endothelium-dependent, concentration-related contractions (maximal contraction, 79 plus/minus 4% and 54 plus/minus 4% of the KCl contractions, respectively). In contrast, endothelium-dependent arachidonic acid- and methacholine-induced contractions were greater in female pulmonary arteries (maximal response, 113 plus/minus 7% and 101 plus/minus 6% of the KCl contractions, respectively). There was no difference in KCl-induced contractions in female and male pulmonary arteries (1.2 plus/minus 0.1 versus 1.3 plus/minus 0.1 g, respectively). In male rabbits, the vasoconstrictor responses to arachidonic acid and methacholine were inhibited by the cyclooxygenase inhibitor indomethacin. We have previously identified thromboxane Argon2as the endothelium-dependent contracting factor in male rabbits. However, indomethacin only partially inhibited arachidonic acid-induced contractions in female pulmonary arteries (maximal inhibition, 46% of the control response) suggesting that a noncyclooxygenase metabolite of arachidonic acid mediates contraction in female rabbits. Likewise, indomethacin only partially inhibited methacholine-induced contractions of female pulmonary arteries. The combined cyclooxygenase/lipoxygenase inhibitor BW 755C and the lipoxygenase inhibitor nordihydroguaiaretic acid completely blocked arachidonic acid-induced contractions in females. Furthermore, both basal and stimulated production of thromboxane Boron2, as measured by radioimmunoassay, were similar in female and male pulmonary arteries. When segments of pulmonary arteries obtained from female and male rabbits were incubated with14Carbon-arachidonic acid and the extracted metabolites were resolved by reverse-phase high-performance liquid chromatography, there was an enhanced production of metabolites in females. Pretreatment with indomethacin attenuated metabolism of all products in the males but enhanced production of some compounds in vessels from the females. These observations suggest that the enhanced vasoconstrictor response to arachidonic acid in female pulmonary arteries is due to a lipoxygenase metabolite of arachidonic acid. (Hypertension. 1996;27:43-48.)

ISSN:0194-911X    

出版商:OVID    

年代:1996

数据来源: OVID

摘要:

Inhibition of nitric oxide synthase by L-arginine analogues is associated with elevation of blood pressure in rats. Deoxycorticosterone acetate (DOCA)-salt hypertensive rats and DOCA-salt-treated spontaneously hypertensive rats (SHR) overexpress the endothelin-1 gene in blood vessels, and this is associated with severe vascular hypertrophy, whereas SHR do not overexpress endothelin-1 and exhibit limited vascular hypertrophy. In this study malignant hypertension was induced in SHR by chronic administration of the L-arginine analogue NitrogenG-nitro-L-arginine methyl ester (L-NAME), a potent inhibitor of nitric oxide synthase, to determine whether malignant hypertension would result in endothelin-1 gene overexpression in blood vessels and in greater severity of vascular hypertrophy, as found in malignant DOCA-salt-treated SHR. L-NAME treatment induced malignant hypertension in SHR, with a systolic blood pressure of 246 plus/minus 2 mm Hg, compared with 211 plus/minus 2 mm Hg (P < .01) in untreated SHR. Plasma renin activity was very high in L-NAME-treated SHR, and their plasma immunoreactive endothelin concentration was slightly but significantly elevated (P < .01). After 3 weeks of treatment, aortic and to a lesser degree mesenteric artery weights were significantly increased in L-NAME-treated SHR compared with untreated SHR. However, cardiac weight and the media cross-sectional area or media width-to-lumen diameter ratio of small arteries from the coronary, renal, mesenteric, or femoral vasculature were not increased in L-NAME-treated SHR in comparison with untreated SHR. The abundance of endothelin-1 mRNA measured by Northern blot analysis was significantly increased in L-NAME-treated SHR in aorta and with less magnitude in the mesenteric arterial tree. The absence of accentuation of cardiac and small artery hypertrophy in malignant hypertension in L-NAME-treated SHR, despite enhanced expression of the endothelin-1 gene in blood vessels, may suggest a direct or indirect inhibitory effect of L-NAME on cardiovascular growth, probably independent of its effects on nitric oxide synthase, counterbalanced in aorta and large mesenteric arteries by the hypertrophic effect of enhanced vascular endothelin-1 gene expression. These results also suggest a role for blood pressure and potentially for nitric oxide in the regulation of endothelin-1 gene expression in blood vessels. (Hypertension. 1996;27:49-55.)

ISSN:0194-911X    

出版商:OVID    

年代:1996

数据来源: OVID

摘要:

We propose that the dichotomy between the in vivo reduction in intravascular prostacyclin production that occurs in preeclampsia and the in vitro stimulatory effect of plasma from preeclamptic patients on endothelial cell prostacyclin production is due to differential effects of chronic versus acute exposure to the plasma. We studied the acute versus chronic effects of 2% plasma from healthy pregnant and preeclamptic subjects by measuring endothelial prostacyclin production at different time periods after exposure to plasma. To determine whether such effects were specific to prostacyclin, we also measured prostaglandin E2production. To determine whether chronic changes in prostacyclin production resulted from altered cellular responsiveness, we stimulated cells that had been exposed to plasma for 72 hours with arachidonic acid and measured prostaglandin production. Preliminary characterization of the plasma factor or factors responsible for alterations in prostaglandin production was performed. After 24 hours cells exposed to plasma from preeclamptic women produced more prostacyclin and prostaglandin E2than cells exposed to plasma from healthy pregnant women. In contrast, after 72 hours exposure to plasma from preeclamptic women resulted in less endothelial cell prostacyclin production than exposure to plasma from healthy pregnant women, but there were no such differences in prostaglandin E2production. Cells that had been exposed to plasma from preeclamptic women for 72 hours produced less prostacyclin but the same quantity of prostaglandin E2after stimulation with arachidonic acid than cells exposed to plasma from healthy pregnant women. The plasma factor or factors responsible for altered prostacyclin production were sensitive to heat, acid, and proteases. In contrast to acute exposure, chronic exposure to plasma from preeclamptic women alters endothelial cells to result in decreased prostacyclin production, an observation consistent with in vivo findings. (Hypertension. 1996;27:56-61.)

ISSN:0194-911X    

出版商:OVID    

年代:1996

数据来源: OVID

摘要:

An insertion (I)/deletion (D) polymorphism of the angiotensin I-converting enzyme (ACE) gene that has been associated with certain cardiovascular disorders accounts for nearly half the variation in serum ACE level in white subjects. Whether a similar association of serum ACE with the I/D polymorphism occurs in other racial groups is not known. We studied the I/D polymorphism of ACE in relation to serum ACE activity in 141 white and 62 black healthy, unrelated children and adolescents (mean age, 14.7 years). The mean level of ACE activity in whites homozygous for the D allele was higher than in heterozygotes (P = .002) and in homozygotes for the I allele (P = .0001), consistent with an earlier study. In blacks, on the other hand, no significant difference in serum ACE activity between genotypes was observed. An additional finding was a significantly positive relationship between serum ACE activity and diastolic pressure (P = .009). In children and adolescents, serum ACE activity is related to the ACE gene I/D polymorphism in whites but not in blacks. The results indicate a potentially important ethnic variation in genetic regulation of serum ACE activity and the relationship of the I/D polymorphism to cardiovascular disease. (Hypertension. 1996;27:62-66.)

ISSN:0194-911X    

出版商:OVID    

年代:1996

数据来源: OVID