Effects of 8‐bromoguanosine 3′:5′‐cyclic monophosphate on phenylephrine‐induced phosphatidylinositol hydrolysis and contraction in rat caudal artery

1 The effects of 8‐bromoguanosine 3′:5′‐cyclic monophosphate (8‐bromo‐cyclic GMP) on phenylephrine‐induced contractions and phosphatidylinositol (PI) hydrolysis were investigated in rat isolated caudal artery. The effects of the nucleotide were compared to those of felodipine, a dihydropyridine Ca 2+ channel antagonist and ryanodine, a putative depletor of intracellular Ca 2+ stores. The purpose of this investigation was to examine the regulatory effects of cyclic GMP on receptor‐mediated signal transduction in vascular smooth muscle. 2 Phenylephrine induced a concentration‐dependent increase in PI hydrolysis that reached a maximum at 10 μ M phenylephrine. Pre‐incubation with felodipine (10 nM) significantly reduced PI turnover, but did not affect basal hydrolysis. Similarly, removal of extracellular Ca 2+ (2 mM ethylene glycol‐bis(β‐amino‐ethyl ether) N, N, N′ , N′‐tetraacetic acid (EGTA)) blocked phenylephrine‐induced PI hydrolysis, but did not affect basal turnover. In contrast, 8‐bromo‐cyclic GMP (10 μ M ) did not affect phenylephrine‐induced PI hydrolysis, nor did it affect basal turnover. 3 Phenylephrine induced concentration‐dependent contractions that were inhibited by each of 8‐bromo‐cyclic GMP (10 μ M ), felodipine (1 nM and 10 nM) and ryanodine (3 μ M and 10 μ M ). In addition, removal of Ca 2+ from the physiological salt solution (2 mM EGTA) completely abolished contractions elicited by phenylephrine. 4 Phenylephrine‐induced contractions were not further affected by felodipine and 8‐bromo‐cyclic GMP applied concomitantly than by equivalent concentrations of felodipine alone. However, ryanodine and 8‐bromo‐cyclic GMP applied together significantly inhibited phenylephrine‐induced contractions in comparison to ryanodine alone. 5 These results suggest that phospholipase C‐activated PI hydrolysis in the rat caudal artery is dependent on extracellular Ca 2+ , mediated, in part, through dihydropyridine‐sensitive Ca 2+ channels. Inhibition of contraction by felodipine may be brought about through indirect inhibition of IP 3 production and subsequent attenuation of intracellular Ca 2+ release. 8‐Bromo‐cyclic GMP does not inhibit PI hydrolysis; it may regulate vascular smooth muscle contraction by inhibition of Ca 2+ release from IP 3 ‐mediated intracellular stores, but it is unlikely that 8‐bromo‐cyclic GMP affects ryanodine‐sensitive stores.