ACTIONS OF C-TYPE NATRIURETIC PEPTIDE AND SODIUM-NITROPRUSSIDE ON CARBACHOL-STIMULATED INOSITOL PHOSPHATE FORMATION AND CONTRACTION IN CILIARY AND IRIS SPHINCTER SMOOTH MUSCLES

Purpose. To investigate the effects of C-type natriuretic peptide (CNP ) and sodium nitroprusside (SNP) on cyclic guanosine monophosphate (cG MP) accumulation and on carbachol (CCh)stimulated inositol 1,4,5-triph osphate (IP3) production and contraction in ciliary muscle (CM) and ir is sphincter (Sph) isolated from bovine and other mammalian species. M ethods. Ciliary muscle and sphincter isolated from cows, cats, dogs, r abbits, monkeys, and humans were used. Bovine specimens were used in t he present work. Accumulation of cGMP and cyclic adenosine monophospha te (cAMP) in tissue extracts was measured by radioimmunoassay, IP3 pro duction was measured by ion-exchange chromatography, and changes in te nsion were recorded isometrically. Results. In general, CNP and SNP ex erted differential inhibitory effects on muscarinic-receptor-induced r esponses in CM and Sph isolated from the various species. Thus in bovi ne CM, SNP stimulated cGMP formation in a time-and concentration-depen dent manner and dose dependently inhibited CCh-induced IP3 production and contraction. These effects were inhibited by LY 83583, a soluble g uanylyl cyclase inhibitor, and mimicked by 8-Br-cGMP, a cell-membrane permeable analogue of cGMP. The inhibitory effects of the soluble cGMP analogue are tissue and species specific. Sodium nitroprusside had no effect on the muscarinic responses in bovine Sph, but it attenuated C Ch-induced contractions in Sph isolated from cats, dogs, and rabbits. In bovine Sph, CNP increased cGMP accumulation in a time-and dose-depe ndent manner and dose dependently inhibited CCh-induced IP3 production and contraction. LY 83583 had no effect on the muscarinic responses. C-type natriuretic peptide attenuated CCh-induced contraction in CM is olated from monkey and human, but it had no influence on this response in CM isolated from cows, cats, and dogs. Conclusions. In bovine CM, SNP effects are probably mediated through soluble guanylyl cyclase, wh ereas in Sph the CNP effects are mediated through membrane-bound guany lyl cyclase, which is associated with the type-B natriuretic peptide r eceptor. Agents chat strongly increase intracellular cGMP levels, incl uding SNP and CNP, produce significant inhibition of CCh-induced IP3 p roduction and contraction. These effects are tissue and species specif ic. The results indicate that the cGMP signaling system, similar to th e cAMP system, has a major inhibitory influence on the muscarinic resp onses in smooth muscles of the iris-ciliary body. The agents CNP and S NP, which stimulate cGMP accumulation in the ocular smooth muscles, co uld reduce intraocular pressure, presumably by increasing uveoscleral outflow induced by relaxation of the CM. However, the relationships be tween the CNP- and SNP-induced inhibition of the muscarinic stimulatio n and the reported intraocular pressure-lowering effects of the cGMP-e levating agents remain to be determined.