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1. To 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 micrograms/heart) and D-NAME (45 micrograms/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 found.

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Abstract-Cardiac tissue is densely innervated by sensory neurons that are believed to play important modulatory roles in cardiac functions. In this study, pretreatment of neonate rats 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 ␤-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 (PϽ0.05) 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 right 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 factor. Key Words: capsaicin Ⅲ receptors, muscarinic Ⅲ receptors, adrenergic, beta Ⅲ neuropeptides Ⅲ peptides S ensory fibers have been associated with the control of smooth muscle tone, autonomic ganglia transmission, immunologic processes, tissue growth, 1 and heart functions. 2-5 A number of substances, including the peptides substance P and calcitonin gene-related peptide (CGRP), are released by the sensory nerve endings. 1,6 Capsaicin (8-methyl-N-vanillyl-6-nonenamide) is a highly selective neurotoxin that, on systemic administration, causes CGRP and substance P depletion from sensory neurons 7-9 and thus has largely been used to study the involvement of sensory fibers in different pathophysiological functions. 10 In the heart, capsaicin increases contractile force and spontaneous heart rate 3 as well as evokes coronary vasodilation through CGRP release. 11,12 Previous studies reported the presence of CGRP in the heart, predominantly in the right atria, followed by the left atria and right and left ventricles, 3,13 where it causes concentration-dependent and long-lasting positive inotropic and chronotropic effects in several species, 9,14 -17 including humans. 18 Although CGRP has also been described as a potent hypertrophic factor for cardiomyocytes, 19 no study has been performed to investigate the effect of CGRP depletion on cardiomyocyte size. The existence of interactions of sympathetic and parasympathetic nerves with sensory fibers in in vitro 20,21 and in vivo 22...

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