CA2+ CHANNEL BLOCKERS DISTINGUISH BETWEEN G-PROTEIN-COUPLED PHARMACOMECHANICAL CA2+ RELEASE AND CA2+ SENSITIZATION

The effects of Ca2+ channel blockers on two modes of G protein-mediated pharmacomechanical coupling, Ca2+ release and modulation of Ca2+ sensitivity of the contractile apparatus, were investigated. Smooth muscles were permeabilized with Staphylococcal alpha-toxin or with beta-escin to avoid effects due to block of sarcolemmal Ca2+ channels, while retaining receptor/G protein coupling. In permeabilized portal vein smooth muscle, verapamil and nifedipine inhibited Ca2+ release induced by an alpha-1-adrenergic agonist (phenylephrine) and by guanosine 5'-O-(3-thiotriphosphate) (GTP-gamma-S), but not that induced by inositol 1,4,5-trisphosphate (InsP3). These Ca2+ channel blockers also did not block the phenylephrine- or GTP-gamma-S-induced force development at constant cytophasmic Ca2+ ("Ca2+ sensitization"). An alpha-1-blocker (prazosin) inhibited both the Ca2+-releasing and Ca2+-sensitizing effects of phenylephrine, but not those of GTP-gamma-S, nor did it block InsP3-induced Ca2+ release. We conclude that Ca2+ channel blockers selectively uncouple the Ca2+-releasing, but not the Ca2+-sensitizing, component of pharmacomechanical coupling. These findings raise the possibility that pharmacomechanical Ca2+ release may be modulated by dihydropyridine binding proteins at the level of G proteins/phospholipase C and also indicate a divergence of the Ca2+-releasing and Ca2+-sensitizing effects at some step prior to phospholipase C.