Role of nitric oxide/cyclic GMP in myocardial adenosine A1 receptor‐inotropic response

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Abstract
In this study we have determined the different signalling pathways involved in adenosine A1‐receptor (A1‐receptor)‐dependent inhibition of contractility in rat isolated atria. N‐cyclopentyladenosine (CPA) stimulation of A1‐receptor exerts: negative inotropic response, inositol phosphates accumulation, stimulation of nitric oxide synthase (NOS), increased production of nitric oxide (NO) and cyclic GMP. Inhibitors of phospholipase C (PLC), protein kinase C (PKC), calcium/calmodulin, NOS and guanylate cyclase shifted the dose‐response curve of CPA on contractility to the right. Those inhibitors also attenuated the A1‐receptor‐dependent increase in cyclic GMP and activation of NOS. These results suggest that CPA activation of A1‐receptors exerts a negative inotropic effect associated with increased production of nitric oxide and cyclic GMP. The mechanism appears to occur secondarily to stimulation of phosphoinositide turnover via PLC activation. This, in turn, triggers cascade reactions involving calcium/calmodulin and PKC, leading to activation of NOS and soluble guanylate cyclase. British Journal of Pharmacology (2002) 135, 444–450; doi:10.1038/sj.bjp.0704487

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