INHIBITION OF MUSCARINIC STIMULATED PHOSPHOINOSITIDE HYDROLYSIS IN THE RAT PAROTID-GLAND BY CAMP

The ability of agents that increase or mimic cAMP to affect muscarinic receptor mediated phosphoinositide hydrolysis was investigated in the rat parotid gland. Forskolin (10 mu M) and isoproterenol (10 mu M) el evated cAMP in the parotid gland by 2-fold and 7-fold, respectively, a nd these agents also inhibited oxotremorine-M (3 mu M) mediated phosph oinositide hydrolysis by 14% and 26%, respectively. Forskolin (1, 4.3, 18, and 75 mu M) increased cAMP accumulation and inhibited PIP2 hydro lysis in a concentration-dependent manner. Forskolin (75 mu M) shifted the concentration-response curve for the full agonist oxotremorine-h rightward by 4.2-fold. Pre-treatment with the phosphodiesterase inhibi tor isobutylmethylxanthine (1 mM) reduced the maximum effect of oxotre morine-M by 31%. The inhibitory effect of isoproterenol and forskolin on muscarinic receptor-mediated phosphoinositide hydrolysis was unaffe cted by the removal of extracellular Ca2+. Moreover, isoproterenol and forskolin dampened sodium fluoride and oxotremorine-M mediated phosph oinositide hydrolysis to the same extent suggesting that the inhibitor y effect of cAMP is downstream from the muscarinic receptor.