The Endothelium-dependent, Substance P Relaxation of Porcine Coronary Arteries Resistant to Nitric Oxide Synthesis Inhibition is Partially Mediated by 4-Aminopyridine-sensitive Voltage-dependent K+Channels

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Abstract
We examined the role of K+ channels in the endothelium-dependent relaxation which is resistant to nitric oxide (NO) synthase inhibition in porcine coronary artery. In the presence of 0.2 mM NG-nitro-L-arginine (L-NNA), a potent inhibitor of NO synthase, 10 nM substance P (SP) added to 9,11-dideoxy-11α,9α-epoxymethano-prostaglandin F2α (U46619) contractures elicited a relaxation. The L-NNA-resistant relaxation induced by SP was strongly inhibited by 5 mM tetrabutylammonium chloride (TBA), a non-specific inhibitor of K+ channels. Interestingly, 4-aminopyridine (4-AP, 1 mM), a relatively specific inhibitor of voltage-sensitive K+ channels, shortened the duration of SP response, but it had no effect on the peak of SP response. Although 4-AP has also been shown to inhibit Ca2+-activated K+ channels, the shortening effect of 4-AP in SP response was observed in the presence of 1 μM apamin, an inhibitor of small conductance Ca2+-activated K+ channels, or 100 nM charybdotoxin, and inhibitor of large conductance Ca2+-activated K+ channels. Moreover, although SP stimulates both L-NNA-resistant relaxation and endothelium-derived NO-dependent relaxation (EDNO) in porcine coronary arteries, a low concentration of 4-AP (1 mM) affected only the L-NNA-resistant response, but not the EDNO response. These are the first results to show that the L-NNA-resistant relaxation induced by SP, probably, endothelium-derived hyperpolarizing factor(s) (EDHF) response, is dependent on voltage-dependent K+ channels in porcine coronary artery.