Role of L-type calcium channels and PKC in active tone development in rabbit coronary artery

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Abstract
The present study investigated active tone development in isolated ring segments of rabbit epicardial coronary artery. Endothelium-denuded (E−) or endothelium-intact (E+) vessels treated with the NO synthase inhibitor Nω-nitro-l-arginine (100 μM) developed active tone, which was enhanced by stretch and reversed by the NO donor sodium nitroprusside (SNP; IC50= 9 nM). Nifedipine abolished active tone and the contractile response to phorbol dibutyrate (PDBu; 10 nM) with the same potency (IC50= 8 nM), whereas 300 nM PDBu responses were only partially blocked by nifedipine. The classical and novel PKC inhibitors GF-109203X (IC50= 1–2 μM) and chelerythrine (IC50= 4–5 μM) and the classical PKC inhibitor Gö-6976 (IC50= 0.3–0.4 μM) blocked both active tone and 10 nM PDBu responses with similar potency. Active tone development was associated with depolarization of membrane potential ( Em) and a shift to the left of the Em-vs.-contraction relationship determined by varying extracellular potassium. The depolarization and leftward shift were reversed by either chelerythrine (10 μM) or SNP (30 nM). PDBu (100–300 nM) increased peak L-type calcium channel (Cav) currents in isolated coronary myocytes, and this effect was reversed by chelerythrine (1 μM) or Gö-6976 (200 nM). SNP (500 nM) reduced Cavcurrents only in the presence of the PKA blocker 8-bromo-2′- O-monobutyryl-cAMPS, Rp isomer (10 μM). In conclusion, active tone development in coronary artery is suppressed by basal NO release and is dependent on both enhanced Cavactivity and classical PKC activity. Both Em-dependent and -independent processes contribute to contraction. Our results suggest that one Em-independent process is direct enhancement of Cavcurrent by PKC.

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