Enalapril Does Not Prevent The Myocardial Ischemia Caused By The Chronic Inhibition Of Nitric Oxide Synthesis

In rats, chronic administration of the nitric oxide (NO) inhibitor Nω-nitro-l-arginine methyl ester (L-NAME) causes arterial hypertension, cardiac hypertrophy and myocardial ischemic alterations such as necrosis and fibrosis. In this study, we evaluated the effect of 8 weeks of treatment with enalapril maleate on cardiac weight and on the development of the histological alterations induced by L-NAME. Enalapril significantly inhibited the development of both arterial hypertension (117.2 ± 5.8, 161.8 ± 8.8 and 122.0 ± 10.6 mm Hg, for control, L-NAME- and L-NAME + enalapril-treated animals, respectively) and left ventricular hypertrophy (1.36 ± 0.13, 1.60 ± 0.04 and 1.48 ± 0.05 mg/g, for control, L-NAME- and L-NAME + enalapril-treated animals, respectively), but had no effect on the myocardial lesions. These findings demonstrate that although the renin-angiotensin system plays a major role in the development of arterial hypertension and cardiac hypertrophy, it does not modulate the ischemia-induced myocardial alterations observed in this model. © 1995.28719396Baylis, Mitruka, Deng, Chronic blockade of nitric oxide synthesis in the rat produces systemic hypertension and glomerular damage (1992) J. Clin. Invest., 90, p. 278Brush, Cannon, III, Schenke, Bonow, Leon, Maron, Epstein, Angina due to coronary microvascular disease in hypertensive patients without left ventricular hypertrophy (1988) New Engl. J. Med., 319, p. 1302Buttrick, Malhotra, McDermott, Lam, Brodman, Isomyosin distribution on overloaded human atrial myocardium (1986) J. Am. Coll. Cardiol., 7 (2), p. 86AChilds, Adams, Mak, Regression of cardiac hypertrophy in spontaneously hypertensive rats by enalapril and the expression of contractile proteins (1990) Hypertension, 16, pp. 662-668Dunn, Oigman, Ventura, Messerli, Kobrin, Frohlich, Enalapril improves systemic and renal hemodynamics and allows regression of left ventricular mass in essential hypertension (1984) Am. J. Cardiol., 53, p. 105Factor, Bhan, Minase, Wolinsky, Sonnenblick, Hypertensive-diabetic cardiopathy in the rat (1981) Am. J. Pathol., 102, p. 219Jover, Herizi, Ventre, Dupont, Mimran, Sodium and angiotensin in hypertension induced by long-term nitric oxide blockade (1993) Hypertension, 21, p. 944Lund, Tomanek, Myocardial morphology in spontaneously hypertensive and aortic-constricted rats (1978) Am. J. Anat., 152, p. 141Moore, Al Swayeh, Chong, Evans, Mirzazadeh, Gibson, l-NG-Nitroarginine (NOARG) inhibits endothelium-dependent vasodilatation in the rabbit aorta and perfused rat mesentery (1989) Br. J. Pharmacol., 176, p. 219Moreno, Jr., Metze, Antunes, Zatz, De Nucci, Chronic nitric oxide blockade causes cardiac ischemia but not cardiac hypertrophy: an experiment of four weeks in rats (1994) Verh. Dtsch. Ger. Path., 78, p. 459Nemoto, Matsuoka, Hasegawa, Ueki, Kimura, Kawamura, Masuda, Miura, Effect of enalapril and E4177 on the heart under chronic nitric oxide suppression in in vivo rat model (1994) J. Mol. Cell. Cardiol., 26, p. 228Ribeiro, Antunes, De Nucci, Lovisolo, Zatz, Chronic inhibition of nitric oxide synthesis: a new model of arterial hypertension (1992) Hypertension, 20, p. 298Tan, Jalil, Pick, Janicki, Weber, Cardiac myocyte necrosis induced by angiotensin II (1991) Circ. Res., 69, p. 1185Ueki, Matsuoka, Hasegawa, Nemoto, Kimura, Kawamura, Masuda, Miura, Comparison the effects of long-term nitric oxide suppression on the heart between young and old rats (1994) J. Mol. Cell. Cardiol., 26, p. 228Weber, Brilla, Janicki, Signals for the remodeling of the cardiac interstitium in systemic hypertension (1991) J. Cardiovasc. Pharmacol., 17, p. 14Zatz, A low cost tail-cuff method for the estimation of mean arterial pressure in conscious rats (1990) Lab. Anim. Sci., 40, p. 19

Non-specific inhibitors of nitric oxide synthase cause myocardial necrosis in the rat

FAPESP - FUNDAÇÃO DE AMPARO À PESQUISA DO ESTADO DE SÃO PAULOCNPQ – CONSELHO NACIONAL DE DESENVOLVIMENTO CIENTÍFICO E TECNOLÓGICOTo study the effect of acute nitric oxide (NO) inhibition on the rat heart both in vitro and in vivo, male Wistar rats received a single bolus injection of saline, N-omega-nitro-L-arginine methyl ester (L-NAME; 0.5, 1.5, 5.0, 15.0 and 45.0 mg/kg) and D-NAME (45.0 mg/kg). 2. Animals were killed 72 h after the bolus injection of L-NAME and the hearts were removed and studied under light microscopy. In other groups of animals, saline, L-NAME and D-NAME were administered as above and the mean arterial blood pressure (MABP/carotid) was recorded, Furthermore, L-NAME was also administered in the drinking water (20 mg/kg per day) for 72 h and animals were then killed and their hearts evaluated as described above, Hearts of control animals were perfused in vitro and coronary flow was measured following saline, L-NAME (45 mu g/heart) and D-NAME (45 mu g/heart). 3. Areas of necrosis were observed in the left ventricle of animals that had received L-NAME at 5.0, 15.0 and 45.0 mg/kg, Also, only doses higher than 1.5 mg/kg caused an important increase in MABP. The frequency and extent of the lesions paralleled the dose of L-NAME administered and no lesions were observed in D-NAME- and saline-treated animals. 4. The oral administration of L-NAME also caused myocardial lesions similar to those described above, but the frequency and extent of these lesions were more discrete compared with those observed following 5.0 mg/kg, i.v., L-NAME. 5. Bolus injection of L-NAME into control rat hearts in vitro resulted in a small and transient fall in coronary flow (17.2 +/- 1.4 and 12.2 +/- 1.2 mL/min before and after L-NAME administration, respectively) within 30 s and this was followed 4.5 min later by a further (11.5 +/- 1.6 mL/min) decrease. The administration of D-NAME to control hearts caused no change in coronary flow. 6. In conclusion, the acute inhibition of NO biosynthesis by L-NAME causes myocardial necrosis, Both high levels of MABP and a small but significant reduction in coronary flow (associated or not) can be responsible for the lesions we found245349352FAPESP - FUNDAÇÃO DE AMPARO À PESQUISA DO ESTADO DE SÃO PAULOCNPQ – CONSELHO NACIONAL DE DESENVOLVIMENTO CIENTÍFICO E TECNOLÓGICOFAPESP - FUNDAÇÃO DE AMPARO À PESQUISA DO ESTADO DE SÃO PAULOCNPQ – CONSELHO NACIONAL DE DESENVOLVIMENTO CIENTÍFICO E TECNOLÓGICOsem informaçãosem informaçã

Modulation of coronary flow and cardiomyocyte size by sensory fibers

Cardiac tissue is densely innervated by sensory neurons that an believed to play important modulatory roles in cardiac functions. In this study, pretreatment of neonate mts with capsaicin was performed. In adult rats, cardiomyocyte size and amount of fibrous tissue in left ventricles as well as in vitro coronary flow were evaluated, The chronotropic and inotropic responses to beta-adrenoceptor agonists (norepinephrine and isoproterenol), muscarinic agonists (carbachol and pilocarpine), and calcitonin gene-related peptide (CGRP) were also investigated with the use of the isolated right atria preparation. Capsaicin pretreatment significantly (P<0.05) reduced both basal coronary flow (18% reduction) and cardiomyocyte size (34% reduction) without affecting the amount of fibrous tissues in the left ventricles. The positive inotropic and chronotropic effects in response to norepinephrine in the isolated rat heart did not significantly differ between control and capsaicin-treated rats, Similarly, the positive chronotropic effects in response to norepinephrine, isoproterenol, and CGRP as well as the negative chronotropic responses to carbachol and pilocarpine in the isolated light atria were not affected by capsaicin pretreatment, Our data are consistent with the suggestion that reductions of both basal coronary flow and cardiomyocyte size seen in hearts from capsaicin-pretreated rats may be consequences of CGRP depletion. The cardiomyocyte size reduction produced by capsaicin treatment may be related to a modulatory role of CGRP as a growth factorAmerican Heart Association3442790794Dallas, T

Effect of Ca2+ channel blockers on arterial hypertension and heart ischaemic lesions induced by chronic blockade of nitric oxide in the rat

FAPESP - FUNDAÇÃO DE AMPARO À PESQUISA DO ESTADO DE SÃO PAULOThe effects of the Ca2+ channel blockers diltiazem, nifedipine and amlodipine were investigated on both arterial hypertension and myocardial changes induced by chronic blockade of nitric oxide synthesis. Control male Wistar rats received N-omega-nitro-L-arginine methyl ester (L-NAME; 20 mg rat(-1) day(-1)) in the drinking water for 8 weeks; blood pressure and body weight were monitored weekly. The Ca2+ channel blockers were given concomitantly to L-NAME, as follows: diltiazem (13.5 mg rat(-1) day(-1)) and amlodipine (6.25 mg rat(-1) day(-1)) were administered in the drinking water whereas nifedipine (6.25 mg rat(-1) day(-1)) was given in the chow. N-omega-nitro-L-arginine methyl ester induced a time-dependent increase in blood pressure which was significantly attenuated by diltiazem (154 +/- 1.6 vs. 139 +/- 1.6 mm Hg, p < 0.05), nifedipine (166 +/- 2.7 vs. 150 +/- 2.1 mm Hg, p < 0.05) and amlodipine (208 +/- 5.8 vs. 158 +/- 1.8 mm Hg, p < 0.05) at the last week of the treatment. Rats treated with the L-NAME also developed myocardial ischaemia, as indicated by the increased percentage of fibrous tissue found in the left ventricles of these animals (10.9 +/- 0.1%, p < 0.01) when compared to control ones (6.3 +/- 0.1%), Neither diltiazem (14.9 +/- 1.2%) nor nifedipine (11.1 +/- 1.5%) prevented this effect whereas amlodipine (6.9 +/- 1.1%, p < 0.01) virtually abolished the increase in fibrous tissue induced by L-NAME. The plasma concentration of the Ca2+ channel blockers was measured by liquid chromatography coupled to mass spectrometry at two different time points (morning and afternoon). Only amlodipine treatment was able to maintain constant levels (186 +/- 46 ng ml(-1) in the morning and 110 +/- 19 ng ml(-1) in the evening) compared to nifedipine (3003 +/- 578 ng ml(-1) in the morning and 436 +/- 100 ng ml(-1) in the evening) and diltiazem (77 +/- 51 ng ml(-1) in the morning and not detectable in the evening). In conclusion, our results indicate that amlodipine (but not diltiazem and nifedipine) can efficiently control myocardial ischaemia in nitric oxide deficient rats, probably due to its intrinsically long half-lifeElsevier3732-3195200FAPESP - FUNDAÇÃO DE AMPARO À PESQUISA DO ESTADO DE SÃO PAULOFAPESP - FUNDAÇÃO DE AMPARO À PESQUISA DO ESTADO DE SÃO PAULOsem informaçãoAmsterda