PARTICIPATION OF NITRIC-OXIDE AND CYCLIC-GMP IN THE SUPERSENSITIVITY OF ACUTE DIABETIC RAT MYOCARDIUM BY CHOLINERGIC STIMULI

The purpose of this study was to explore the pharmacological and bioch emical mechanisms involved in diabetic cardiomyopathy, with particular interest in the abnormal function of cholinergic neurotransmission at the onset of the pathology. The muscarinic acethylcholine agonist car bachol showed a negative inotropic response on both normal and diabeti c isolated atria, but the latter showed a supersensitive response. No changes were found in muscarinic acethylcholine receptor (mAChR) expre ssion. Measurements of mAChR associated second messengers indicated no significant differences between normal and diabetic rat atria in the stimulatory effect of carbachol on protein kinase C activity and the p roduction of inositol phosphates, or in the inhibitory effect induced by carbachol on cyclic AMP (cAMP) production. On the contrary, nitric oxide (NO) synthase activity and cyclic GMP production were higher in diabetic cardiac preparations than in normal ones. Moreover, in diabet ic atria, nitric oxide synthase and guanylate cyclase inhibitors shift ed the carbachol concentration-response curve on contractility to the right, reaching values similar to those of normal atria. These results suggest an early alteration in the mACh system during the diabetic st ate, associated with increased production of nitric oxide and cyclic G MP (cGMP). This, in rum, could increase the biological mechanical acti vity of the mAChR agonist, inducing in this way a higher pharmacologic al response, without changes in mAChR expression. BIOCHEM PHARMACOL 55 ;12:1991-1999, 1998. (C) 1998 Elsevier Science Inc.