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

Department of Physiology and Cell Biology, University of Nevada, Reno, Nevada

Submitted 18 November 2006 ; accepted in final form 2 February 2007

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 N-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 (E_m) and a shift to the left of the E_m-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 (Ca_v) currents in isolated coronary myocytes, and this effect was reversed by chelerythrine (1 µM) or Gö-6976 (200 nM). SNP (500 nM) reduced Ca_v currents 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 Ca_v activity and classical PKC activity. Both E_m-dependent and -independent processes contribute to contraction. Our results suggest that one E_m-independent process is direct enhancement of Ca_v current by PKC.

vascular smooth muscle; endothelium; nitric oxide; protein kinase C; calcium channels; patch clamp; membrane potential

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