Role of basal nitric oxide synthesis in vasoconstrictor hyporeactivity in the perfused rat hindlimb after myocardial infarction: effect of captopril.
(65/1305)
OBJECTIVES: The contribution of vascular changes to the development of heart failure is largely unknown. In the present study, we evaluated endothelial and vascular contractile function in the rat hindlimb vascular bed after myocardial infarction (MI), including the modulatory role of basal nitric oxide (NO) production and the effects of treatment with the angiotensin converting enzyme inhibitor captopril on vascular function. METHODS: MI was induced in male Wistar rats by ligation of the left coronary artery. Acetylcholine-induced dilatations were assessed in the ex vivo perfused hindlimb at various time points. At 2 and 5 weeks post-MI, vascular contractile function in the perfused hindlimb was assessed from resistance changes induced by 35 mM and 125 mM potassium (K+) and the maximum increase in resistance (delta Rmax, 125 mM K+ and 3 mg phenylephrine). Basal NO synthesis was blocked for 2 weeks with L-nitro-arginine methylester (L-NAME) in sham and MI rats and similar contractility experiments were performed. The effect of captopril treatment from 2 to 5 weeks post-MI on vasoconstrictor responses was also tested. RESULTS: Acetylcholine-induced dilatations in the presence of 10 microM indomethacin were not different between sham and MI rats. Vasoconstrictor responses to K+ and delta Rmax were reduced at 2 weeks after MI. This reduction in vasoconstrictor ability was similar to that seen in L-NAME-treated sham rats, while chronic L-NAME treatment did not affect vasoconstrictor reactivity in MI rats. Similarly, L-NAME induced an increase in mean arterial pressure in sham rats, but not in MI rats. At 5 weeks after MI, vasoconstriction to 125 mM K+ and delta Rmax were still reduced in MI rats; this response was however partially restored after captopril treatment. CONCLUSION: The development of vascular contractile hyporeactivity in the rat hindlimb after MI may be due to reduced basal NO production. Delayed treatment with captopril improves peripheral vascular contractile function in this setting. (+info)
Comparative effects of pretreatment with captopril and losartan on cardiovascular protection in a rat model of ischemia-reperfusion.
(66/1305)
OBJECTIVES: We sought to assess the comparative effects of pretreatment with captopril and losartan on myocardial infarct size and arrhythmias in a rat model of ischemia-reperfusion. BACKGROUND: Angiotensin-converting enzyme (ACE) inhibitors and angiotensin II receptor blockers (ARBs) inhibit the renin-angiotensin system in different ways. However, the comparative effects of pretreatment with ACE inhibitors or ARBs on acute myocardial infarct size and arrhythmias are unknown. METHODS: We randomly assigned 117 female Sprague-Dawley rats into three groups: group N was the normal control; group C was given 40 mg/kg body weight per day of captopril in drinking water; and group L was given 40 mg/kg per day of losartan in drinking water. After 10 weeks of pretreatment, 25 rats in each group were subjected to 17 min of left anterior descending coronary artery occlusion and 2 h of reperfusion with hemodynamic and electrocardiographic monitoring. Fourteen rats in each group had blood samples drawn and aortic rings removed to study vascular reactivity. RESULTS: Mortality during ischemia and reperfusion was lower in combined groups L and C than in group N (4.2% vs. 19.2%, p = 0.042). Rats treated with losartan had significantly higher levels of angiotensin II in their plasma. Hemodynamic variables were not significantly different among the three groups. The thresholds of ventricular fibrillation (VF) before occlusion and after reperfusion were significantly higher in groups L and C than in group N (1.99 +/- 0.24 and 1.93 +/- 0.27 vs. 1.23 + 0.17 mA, p = 0.04; 2.13 +/- 0.25 and 1.78 +/- 0.22 vs. 0.95 +/- 0.11 mA, p = 0.001). The average episodes of ventricular tachycardia (VT) and VF per rat were significantly less in groups L and C than in group N (0.96 +/- 0.2 and 1.2 +/- 0.3 vs. 2.8 + 0.4 mA, p < 0.001). Myocardial infarct size was significantly smaller in groups L and C than in group N (34 +/- 3% and 35 +/- 3% vs. 44 +/- 3%, p = 0.031, 0.043). Endothelium-dependent vasorelaxation induced by a calcium ionophore (A23187) was increased in both groups but was only statistically significant in group C (p = 0.020). CONCLUSIONS: Losartan and captopril have similar cardiovascular protective effects in a rat model of ischemia-reperfusion. They increased the threshold of VF, decreased mortality and decreased episodes of VT and VF, as well as decreased myocardial infarct size. (+info)
Improvement in fatty acid utilization in relation to a change in left ventricular hypertrophy in spontaneously hypertensive rats.
(67/1305)
Although fatty acid metabolism is reportedly impaired in myocardial hypertrophy, it is unclear whether the antihypertensive drugs are associated with improved fatty acid metabolism. In order to evaluate the effects of antihypertensive drugs on fatty acid metabolism and myocardial perfusion, the simultaneous uptake of iodine-125(125I)-15-(p-iodophenyl)-3-(R,S)-methylpentadecanoic acid (BMIPP) and thallium-201 (Tl) were measured in 3 groups of rats: (1) spontaneously hypertensive rats (SHR) without treatment (SHR-N), (2) SHR chronically treated with captopril (SHR-C), and (3) SHR chronically treated with hydralazine (SHR-H). Captopril and hydralazine were administered to their respective groups for 3 weeks from 12 weeks of age. The hearts were removed 10 min after simultaneous intravenous injections of BMIPP and Tl and the 125I and 201Tl counts were measured to calculate the uptake ratio. The systolic blood pressure (SBP) in SHR-N was 222+/-10 mm Hg, whereas the SHR-C and SHR-H groups showed significant SBP reduction (156+/-11, and 158+/-10 mm Hg, respectively) (p<0.01 each). The heart/bodyweight ratio was significantly lower in SHR-C (2.48+/-0.09) than in SHR-N (2.74+/-0.11) (p<0.05). However, there was no significant difference in the heart/bodyweight ratio between SHR-N and SHR-H (2.65+/-0.09). The ratio of BMIPP uptake to Tl uptake (BMIPP/Tl) was significantly higher in SHR-C (0.71+/-0.13) than in SHR-N (0.50+/-0.09) (p<0.05). However, BMIPP/Tl in SHR-H (0.53+/-0.09) was similar to that in SHR-N. These results suggest that captopril improves fatty acid metabolism in the hypertrophied ventricle in SHR. The metabolic alterations may improve with left ventricular hypertrophy regression but are not effected by the reduction of blood pressure only. (+info)
ACE-inhibition promotes apoptosis after balloon injury of rat carotid arteries.
(68/1305)
OBJECTIVE: Angiotensin II stimulates vascular smooth muscle cell (VSMC) growth, and is considered to be an important mediator of intimal thickening after vascular injury. Recent evidence has indicated that VSMC apoptosis plays a major role in the response to balloon injury, and we therefore examined the effect of angiotensin converting enzyme (ACE)-inhibition on VSMC apoptosis and vascular lesion formation in the rat model of balloon injury. METHODS: Male Sprague-Dawley rats were subjected to carotid artery balloon injury and randomised to a standard diet or a diet supplemented with 1 mg/ml captopril in the drinking water. Animals were sacrificed 2 and 14 days after injury for assessment of apoptosis and proliferation by in situ terminal deoxynucleotidyl transferase-mediated dUTP-biotin nick end labelling (TUNEL) and proliferating cell nuclear antigen (PCNA) immunohistochemistry, respectively. At 14 days post injury, vessel cross-sections were subjected to microscopic morphometry and total cell numbers were determined. RESULTS: At 2 days after balloon injury, captopril-treated animals displayed a significant increase in the percentage of TUNEL-positive VSMCs in the medial area (12 +/- 4% vs. 1 +/- 1%; P < 0.05) as compared to controls. This increase in early apoptosis was associated with decreased intimal cellularity 14 days post injury (238 +/- 47 cells/cross-section vs. 449 +/- 75 cells/cross-section; P < 0.05), and a reduction of neointimal formation (0.13 +/- 0.02 mm2 vs. 0.23 +/- 0.04 mm2; P < 0.05). The fraction of PCNA-positive VSMCs per cross-section 2 or 14 days after injury was not significantly altered by captopril administration. CONCLUSION: Captopril inhibits neointimal formation in the rat model of arterial injury by mechanisms involving induction of VSMC apoptosis. (+info)
New Q waves on the presenting electrocardiogram independently predict increased cardiac mortality following a first ST-elevation myocardial infarction.
(69/1305)
AIMS: The prognostic significance of pathological Q waves appearing in the acute phase of myocardial infarction has not been determined. We investigated whether new Q waves on the presenting electrocardiogram of patients with acute ST-segment elevation were independently associated with a worse outcome after a first myocardial infarction. METHODS AND RESULTS: The presence or absence of new Q waves on the presenting electrocardiogram was assessed in 481 patients who presented within 4 h of symptom onset and were randomized to receive either captopril or placebo within 2 h of streptokinase therapy for myocardial infarction. Ventriculography was performed at 22+/-6 days and mortality status was obtained at a median follow-up of 5.6 years. New Q waves were associated with a lower ejection fraction (51+/-13% vs 61+/-12%, P<0.0001), a larger end-systolic volume index (37 ml vs 28 ml, P<0.001), and increased cardiac mortality at 30 days (7% vs 2%, P=0.01) and at follow-up (17% vs 7%, P=0.002). On multivariate analysis, age (P<0.01), new Q waves at presentation (P<0.01) and a history of angina (P=0.046) were independent predictors of cardiac mortality, whereas randomization to captopril and the time from symptom onset to streptokinase administration were not. CONCLUSION: New Q waves at presentation are independently associated with a worse outcome after a first myocardial infarction. The presence of new Q waves on the presenting electrocardiogram allows very early identification of patients at risk of increased cardiac mortality. (+info)
Inactivation of bradykinin by angiotensin-converting enzyme and by carboxypeptidase N in human plasma.
(70/1305)
Because bradykinin (BK) appears to have cardioprotective effects ranging from improved hemodynamics to antiproliferative effects, inhibition of BK-degrading enzymes should potentiate such actions. The purpose of this study was to find out which enzymes are responsible for the degradation of BK in human plasma. Human plasma from healthy donors (n = 10) was incubated with BK in the presence or absence of specific enzyme inhibitors. At high (micromolar) concentrations, BK was mostly (>90%) degraded by carboxypeptidase N (CPN)-like activity. In contrast, at low (nanomolar) substrate concentrations, at which the velocity of the catalytic reaction is equivalent to that under physiological conditions, BK was mostly (>90%) converted into an inactive metabolite, BK-(1-7), by angiotensin-converting enzyme (ACE). BK-(1-7) was further converted by ACE into BK-(1-5), with accumulation of this active peptide. A minor fraction (<10%) of the BK was converted into another active metabolite, BK-(1-8), by CPN-like activity. The present study shows that the most critical step in plasma kinin metabolism, i.e., inactivation of BK, is mediated by ACE. Thus inhibition of plasma ACE activity would be cardioprotective by elevating the concentration of BK in the circulation. (+info)
Renal angiotensin II receptors and protein kinase C in diabetic rats: effects of insulin and ACE inhibition.
(71/1305)
It has been shown that glomerular ANG II receptors are downregulated and protein kinase C (PKC) activity is enhanced in diabetes mellitus. Therefore, we investigated glomerular and preglomerular vascular ANG II receptors and PKC isoform regulation in streptozotocin (STZ)-diabetic rats treated with insulin and/or captopril. Diabetic rats were prepared by injecting STZ (60 mg/kg). Those that developed diabetes after 48 h were treated with low or high doses of insulin, or with a low dose of insulin as well as captopril, and killed 14 days later. Their glomeruli and preglomerular vessels were purified, competitive binding studies were performed by using the ANG II antagonists losartan and PD-123319, and PKC analysis was carried out by Western blotting. Competitive binding studies showed that the AT(1) receptor was the only ANG II receptor detected on both glomeruli and preglomerular vessels of all groups. Preglomerular vascular AT(1) receptor density (B(max)) was significantly upregulated in low insulin-treated STZ rats, whereas glomerular AT(1) B(max) was downregulated. Furthermore, both the captopril- and high insulin-treated groups had less glomerulosclerosis and vascular damage than the low insulin-treated group. PKCalpha, PKCdelta, PKCepsilon, and PKCmu isoforms found in preglomerular vessels were upregulated by captopril and high insulin doses, respectively, whereas no such regulation occurred in glomeruli. We conclude that in STZ-diabetic rats ANG II receptors and PKC isoforms on preglomerular vessels and glomeruli are differentially regulated by treatment with insulin and/or captopril. (+info)
Impaired endothelium-dependent regulation of ventricular relaxation in pressure-overload cardiac hypertrophy.
(72/1305)
BACKGROUND: Endothelium-derived nitric oxide (NO) selectively enhances myocardial relaxation and may benefit diastolic function. Left ventricular hypertrophy (LVH) is characterized by abnormal myocardial relaxation and endothelial dysfunction. We investigated endothelium-dependent regulation of LV relaxation in moderate pressure-overload LVH induced by aortic banding in guinea pigs. METHODS AND RESULTS: Isolated ejecting hearts of banded or sham-operated animals (shams) were studied. The specific agonists for endothelial release of NO, bradykinin (10 nmol/L), and substance P (100 nmol/L) both induced earlier onset of LV relaxation in shams (time to LV dP/dt(min) [tdP/dt(min)], -13.4+/-3.0 and -10.4+/-2.5 ms, respectively) without altering peak LV pressure or LV dP/dt(max). Neither agent altered tdP/dt(min) in banded animals. The ACE inhibitor captopril (1 micromol/L) also selectively reduced tdP/dt(min) in shams via a bradykinin/NO-dependent mechanism but had no effect in banded animals. An exogenous NO donor, sodium nitroprusside (0.1 micromol/L), selectively reduced tdP/dt(min) to a similar extent in both shams and banded animals. Endothelial-type NO synthase (eNOS) protein expression in whole LV homogenate was unaltered in banded animals. CONCLUSIONS: Endothelium-dependent enhancement of LV relaxation is impaired in moderate pressure-overload LVH, despite a preserved response to exogenous NO. This is not accounted for by altered eNOS expression. These abnormalities may contribute to diastolic dysfunction in LVH. (+info)