الفهرس 
AcknowledgementOnly 14 pages are availabe for public view
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Abstract
The present study is the first to report on the combined effect of nicotine, the most biologically active component of cigarette smoke, and CSA, the immunosuppressant drug, on kidney function and renovascular responsiveness to p-adrenoceptor activation. Experiments were then extended to elucidate the roles of endothelial and smooth muscle signaling pathways in the nicotine/CSA renovascular interactions. Further, the question whether the rat gender influences the detrimental renal effect caused by the two intervening drugs and the potential modulatory role of estrogen in the interaction was also investigated. Changes in renovascular responsiveness to p-adrenoceptor activation were measured by determining the renal vasodilatory response to the p-adrenoceptor agonist isoprenaline in phenylephrine-preconstricted isolated perfused kidneys. A summary of the main results and conclusions of the study is outlined below.
l. The infusion of nicotine into phenylephrine-preconstricted kidneys of male rats produced significant and concentration-dependent decreases in the renal perfusion pressure. The NOS-derived NO appears to play a considerable role in the renal vasodepressor effect of nicotine because the level of NO metabolites in the renal effluent was increased after the infusion of nicotine and pharmacological inhibition of NOS or guanylate cyclase with L-NNA and methylene blue, respectively, abolished nicotine vasodilation.
2. Subsequent studies in male preparations identified vascular endothelium and nitrergic neurons as two potential sources of NO generated by nicotine. The involvement of the endothelium was verified by the observation that chemical denudation of the endothelium by CHAPS entirely abolished nicotine vasodilation. On the other hand, findings in support of the contribution of neuronal NO pools in nicotine vasodilation are: (i) nicotine increased the renal norepinephrine overflow, a measure of renal sympathetic activity, and (ii) the vasodepressor effect of nicotine was reduced after the blockade of nicotinic receptors (hexamethonium) or p-adrenoceptor (propranolol) or the inhibition of neuronal norepinephrine release (guanethidine). These findings implicated, at least partly, sympathetically-mediated facilitation of neuronal NO release along with endothelial NO in nicotine vasodilation.
3. In addition to NOS activation, K+ channel hyperpolarization also contributes to the vasodilatory effect of nicotine because the latter was diminished in male perfused kidneys depolarized with a high concentration of KCI. Studies that involved the use of selective blockers of K+ channels revealed a differential activation by nicotine of KATP and Kir channels.
4. The renal vasodilatory effect of nicotine is largely dependent on the animal gender and hormonal status. Nicotine (5x 10-4 M) produced greater vasodilation in proestrus female than in male perfused kidneys. Because NOS inhibition abolished the nicotine response in the two genders and also eliminated the gender-related difference in nicotine vasodilation, it is concluded that the presence of a higher NOS activity in female preparations might account for the sexual dimorphism in the renal response to