Participation of Nitric Oxide and Cyclic GMP in the Supersensitivity of Acute Diabetic Rat Myocardium by Cholinergic Stimuli

Abstract

The purpose of this study was to explore the pharmacological and biochemical 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 carbachol showed a negative inotropic response on both normal and diabetic isolated atria, but the latter showed a supersensitive response. No changes were found in muscarinic acethylcholine receptor (mAChR) expression. 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 production 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 diabetic atria, nitric oxide synthase and guanylate cyclase inhibitors shifted 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 state, associated with increased production of nitric oxide and cyclic GMP (cGMP). This, in turn, could increase the biological mechanical activity of the mAChR agonist, inducing in this way a higher pharmacological response, without changes in mAChR expression.