Nitric Oxide Synthase Activity in Guinea Pig Ventricular Myocytes Is Not Involved in Muscarinic Inhibition of cAMP-Regulated Ion Channels

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Abstract
It has recently been demonstrated that NO plays an obligatory role in muscarinic inhibition of β-adrenergically stimulated ion channels in cardiac sinoatrial node cells (J Gen Physiol. 1995;106:45-65). We looked for evidence that NO might play a similar role in ventricular cells by using histochemical staining for NO synthase (NOS) activity and whole-cell patch-clamp recording of cAMP-regulated Cl− currents. Myocytes isolated from guinea pig hearts stained positively for NADPH-diaphorase activity, suggesting that these cells do express NOS. Acetylcholine (ACh) inhibition of the R(−)-isoproterenol bitartrate (Iso)–activated Cl− current was also reversed by the cGMP-lowering agents LY-83583 and methylene blue, consistent with the idea that NO activation of guanylate cyclase may contribute to muscarinic responses. However, LY-83583 and methylene blue activated the Cl− current in the presence of subthreshold concentrations of Iso alone, suggesting that their effects may not be due to antagonism of an NO/cGMP-dependent response. Furthermore, ACh inhibition of Iso-activated Cl− currents could not be mimicked by the NO donors sodium nitroprusside, 3-morpholinosydnonimine, and spermine-NO. Similarly, ACh inhibition of the Iso-activated Cl− current could not be blocked by the NOS inhibitor NG-monomethyl-l-arginine. These results indicate that even though ventricular myocytes possess NOS activity, NO production does not play an important role in muscarinic inhibition of β-adrenergically regulated Cl− channels in these cells.