Sildenafil reduces cardiovascular remodeling associated with hypertensive cardiomyopathy in NOS inhibitor-treated rats.

Many of the physiological responses to nitric oxide (NO) are mediated by cyclic 5'-guanosine monophosphate (cGMP), the intracellular levels of which are regulated by phosphodiesterase type 5 (PDE5). In situations of reduced NO formation, the inhibition of PDE5 by selective inhibitors such as sildenafil could be beneficial in restoring physiological functions by enhancing the intracellular levels of cGMP. In this study, we evaluated the effects of sildenafil on the hemodynamic and histological alterations induced by the chronic treatment of rats with N(omega)-nitro-L-arginine-methyl ester (L-NAME). After 8 weeks of concomitant treatment with sildenafil and L-NAME, arterial blood pressure was significantly lower (P<0.05) than in L-NAME-treated rats. The fall in blood pressure was associated with a slight reduction in the total peripheral vascular resistance (P<0.05). Sildenafil partially prevented the decrease in cardiac output seen in L-NAME-treated rats. Morphologically, sildenafil reduced the total area of the myocardial lesions and attenuated the cardiomyocyte and vascular smooth muscle remodeling seen with L-NAME. These results show that sildenafil prevented the deleterious hemodynamic and morphological alterations associated with L-NAME-induced hypertension. This beneficial effect was probably mediated by an increase in cardiac and vascular cGMP levels as reflected in circulating plasma cGMP levels.

Enhanced airways responsiveness in rats depleted of sensory neuropeptides by neonatal capsaicin treatment.

This study aimed to investigate the in vivo and in vitro reactivity of airway smooth muscle in rats depleted of sensory neuropeptides by treatment with capsaicin at neonatal stage. Wistar rats were neonatally injected with either capsaicin (50 mg/kg, s.c., 2nd day of life) or its vehicle (10% ethanol and 10% Tween 80, in 0.9% w/v NaCl solution) and used at adult ages (60-70 days later). Analysis of the lungs showed a higher number of infiltrating neutrophils, eosinophils and mononuclear cells into the peribronchiolar regions of capsaicin-pretreated rats compared to vehicle group. This was associated with a higher contraction index of bronchiolar wall in the capsaicin group. The in vitro tracheal reactivity in response to methacholine (full muscarinic agonist) and pilocarpine (partial muscarinic agonist) was also significantly higher in capsaicin-pretreated rats compared to vehicle group. In conclusion, the neuropeptide depletion by capsaicin neonatal treatment lead to marked contraction of the rat airways at adult age, suggesting a protective role for C fibers in the lungs.

Upregulation of muscarinic receptors by long-term nitric oxide inhibition in the rat ileum.

1. The aim of the present study was to examine the effects of long-term nitric oxide (NO) blockade on contractions of the rat ileum induced by muscarinic agonists. 2. Male Wistar rats received the NO synthesis inhibitor NG-nitro-l-arginine methyl ester (l-NAME; 20 mg/rat per day) in drinking water for 7, 15, 30 and 60 days. Concentration-responses curves to methacholine and carbachol were obtained and pEC50 values were calculated. Saturation binding assays were performed in membranes prepared from rat ileum after 60 days of l-NAME treatment and the dissociation constant (KD) and maximal number of binding sites (Bmax) were determined by Scatchard analysis. 3. The NO synthase activity of the ileum was markedly reduced in all l-NAME-treated groups. At 60 days after l-NAME treatment, a significant increase in the potency of methacholine (fourfold) and carbachol (threefold) was observed. In binding studies, we found a significant increase in Bmax for [3H]-quinuclidinyl benzilate of approximately 57% in the l-NAME treated group without any significant change in KD values. The contractile response to methacholine was not modified by the soluble guanylate cyclase inhibitor 1H-[1,2,4]oxadiazolo-[4,3-a]quinoxalin-1-one (3 micro mol/L). No morphological alterations in the rat ileum were observed in l-NAME-treated rats. 4. Our findings suggest that treatment with l-NAME for 60 days induces a marked increase in the potency of methacholine and carbachol, as well as an increase in receptor number in the rat ileum.

Attenuation of hypertension, cardiomyocyte hypertrophy, and myocardial fibrosis by beta-adrenoceptor blockers in rats under long-term blockade of nitric oxide synthesis.

The effects of propranolol and atenolol were investigated on arterial hypertension, cardiomyocyte hypertrophy, and ventricular ischaemic lesions induced by an 8-week treatment with the nitric oxide synthase inhibitor N(omega)-nitro-L-arginine methyl ester (L-NAME; 20 mg/rat per day) in Wistar rats. Propranolol and atenolol (30 mg/rat per day each) were given in the drinking water concomitantly to L-NAME. Treatment with L-NAME induced marked arterial hypertension and cardiomyocyte hypertrophy, both of which were significantly reduced by propranolol and atenolol. A marked repairing fibrosis was also observed in L-NAME-treated rats and this was significantly attenuated in animals receiving the beta-blockers. In L-NAME group, 33% mortality was observed, whereas all the animals from the other groups survived. Our study demonstrates that propranolol and atenolol reduce arterial hypertension, cardiomyocyte hypertrophy and myocardial fibrosis induced by L-NAME, suggesting that beta-blockers are of beneficial value in treatment of vascular and cardiac alterations caused by chronic nitric oxide deficiency.