The long term objective of the present proposal is to determine the mechanism by which acetylcholine (ACh) produces renal vasodilation, natriuresis, and diuresis in the dog. Previous studies have shown that renal arterial infusion of ACh in control dogs produced a sustained renal vasodilation, whereas in dogs pretreated with Indomethacin (Indo), an inhibitor of prostaglandin (PG) synthetase, ACh produced an initial vasodilation followed by a profound renal vasoconstriction. Recently, we have observed that renal arterial infusion of a low dose of atropine, a non-specific muscarinic receptor blocker, prevented the renal vasoconstriction, whereas a high dose of atropine prevented the renal vasodilation by ACh in Indo-treated dogs. These observations suggest that the renal vasodilator and vasoconstrictor effect may be mediated by two different muscarinic receptors. One of the specific aims of the present proposal is to determine the role of different muscarinic receptors in the renal vasoconstriction and vasodilation produced by ACh in Indo-treated dogs. This would be done by the renal arterial infusion of specific muscarinic receptor blockers before and during the infusion of ACh in Indo-treated dogs. Since ACh is also known to stimulate the formation of cGMP, PGI2 and cAMP in the renal vasodilatory response to ACh. This would be done by the determination of renal excretion of cGMP, PGI2, and cAMP before and during the infusion of ACh in control and Indo- treated dogs. Furthermore, the role of the EDRF-nitric oxide-cGMP system and PGI2-cAMP in the renal vasodilatory response to ACh would also be examined in control and Indo-treated dogs receiving an intrarenal infusion of N-monomethyl-L-arginine an inhibitor of nitric oxide synthesis. Information about why blockade of PG synthesis predisposes to renal vasoconstriction may increase our understanding of the nature of the impairment in renal function that occurs in certain clinical disorders when PG synthetase inhibitors are given.
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