EFFECTS OF CGMP ON CALCIUM HANDLING IN ATP-STIMULATED RAT RESISTANCE ARTERIES

The mechanisms by which guanosine 3',5'-cyclic monophosphate (cGMP) mo dulates the contraction induced by ATP were investigated in small mese nteric resistance arteries of the rat. The nitric oxide donors 3-morph olinosydnonimine (SIN-1, 10 mu M) and sodium nitroprusside (SNP, 10 mu M) increased cGMP but not adenosine 3',5'-cyclic monophosphate (cAMP) content of the tissue. SIN-1, SNP, and 8-bromoguanosine 3',5'-cyclic monophosphate (8-BrcGMP, 100 mu M) inhibited the myosin light chain ph osphorylation and the contractile response to ATP. Both effects were c ompletely reversed by the selective inhibitor of cGMP protein kinase, Rp-8-bromoguanosine 3',5'-cyclic monophosphorothioate (30 mu M). The s ensitivity to Ca2+ of arteries permeabilized with Staphylococcus aureu s alpha-toxin (4,000 hemolytic units/ml) was not affected by 8-BrcGMP. The two nitric oxide donors and 8-BrcGMP decreased the rise in intrac ellular Ca2+ induced by ATP. The vasodilator agents abolished the cont ractile response to the exogenous calcium in vessels that were exposed to 3 mM ATP after depletion of intracellular Ca2+ stores. Thapsigargi n (1 mu M), an inhibitor of the sarcoplasmic reticulum Ca2+-adenosinet riphosphatase, reversed the inhibitory effect of the vasodilator agent s when the contraction induced by ATP was elicited in the presence of the Ca2+ entry blocker nitrendipine (1 mu M) or in Ca2+-free medium. T hese results show that cGMP inhibits ATP-induced contraction by decrea sing intracellular Ca2+ concentration in small resistance arteries. Th ey indicate that this effect results from decreased Ca2+ influx and en hanced Ca2+ sequestration through a thapsigargin-sensitive pump via ac tivation of a cGMP protein kinase.