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 α-toxin or with β-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 α₁-adrenergic agonist (phenylephrine) and by guanosine 5'-O-(3-thiotriphosphate) (GTPγS), but not that induced by inositol 1,4,5-trisphosphate (InsP₃). These Ca²⁺ channel blockers also did not block the phenylephrine- or GTPγS-induced force development at constant cytoplasmic Ca²⁺ (''Ca²⁺ sensitization''). An α₁-blocker (prazosin) inhibited both the Ca²⁺-releasing and Ca²⁺-sensitizing effects of phenylephrine, but not those of GTPγS, 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.