Role of nitric oxide/cyclic GMP in myocardial adenosine A1 receptor-inotropic response.
In this study we have determined the different signalling pathways involved in adenosine A(1)-receptor (A(1)-receptor)-dependent inhibition of contractility in rat isolated atria. N-cyclopentyladenosine (CPA) stimulation of A(1)-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 A(1)-receptor-dependent increase in cyclic GMP and activation of NOS. These results suggest that CPA activation of A(1)-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.
Sterin-Borda
Leonor
L
Cátedras de Farmacología, Facultad de Odontología, Universidad de Buenos Aires, Argentina. leo@farmaco.odon.uba.ar
Gómez
Ricardo M
RM
Borda
Enri
E
D000241:Adenosine / Q000031:analogs & derivatives / Q000378:metabolism / Q000494:pharmacology; D000818:Animals; D006152:Cyclic GMP / Q000502:physiology*; D003864:Depression, Chemical; D008297:Male; D009200:Myocardial Contraction / Q000187:drug effects / Q000502:physiology*; D009206:Myocardium / Q000378:metabolism*; D009569:Nitric Oxide / Q000502:physiology*; D019001:Nitric Oxide Synthase / Q000096:biosynthesis; D010716:Phosphatidylinositols / Q000096:biosynthesis; D051381:Rats; D017208:Rats, Wistar; D018047:Receptors, Purinergic P1 / Q000502:physiology*; D015398:Signal Transduction / Q000187:drug effects / Q000502:physiology
D010716:Phosphatidylinositols; D018047:Receptors, Purinergic P1; D009569:Nitric Oxide; D019001:Nitric Oxide Synthase; D006152:Cyclic GMP; D000241:Adenosine