Endothelium-dependent hyperpolarization and relaxation resistance to N(G)-nitro-L-arginine and indomethacin in coronary circulation.
OBJECTIVE
It is controversial whether endothelium-dependent relaxation resistance to inhibitors of nitric oxide (NO) and prostacyclin synthases is completely attributed to endothelium-derived hyperpolarizing factor (EDHF). This study examined NO release and K+ channels involved in endothelium-dependent relaxation and hyperpolarization resistance to N(G)-nitro-L-arginine (L-NNA) and indomethacin in coronary arteries with emphasis on the microarteries.


METHODS
NO release, isometric force, and membrane potential of porcine coronary arteries were measured using a NO-specific electrode, wire myograph, and microelectrode, respectively.


RESULTS
In large arteries pretreated with indomethacin, bradykinin (BK) evoked a rise in [NO] from 5.5+/-2.4 nM to 105.0+/-19.6 nM and hyperpolarization. L-NNA treatment significantly reduced the BK-stimulated rise in [NO] to 32.1+/-11.3 nM but did not affect the hyperpolarization. In the presence of indomethacin and L-NNA, U46619 contracted and depolarized (from -51+/-3 mV to -30+/-4 mV) vascular smooth muscle in microarteries. The addition of BK produced dose-dependent relaxation (maximal: 70.2+/-5.7%) and repolarization (membrane potential: -50+/-4 mV). Oxyhemoglobin eliminated indomethacin and L-NNA-resistance rise in [NO] but not relaxation (42.3+/-4.4%) and repolarization (-40+/-2 mV) by BK. Tetraethylammonium, charybdotoxin, and iberiotoxin partially decreased the BK-induced responses. Apamin alone did not affect the relaxation by BK; however, in combination with charybdotoxin it almost completely abolished the BK-induced relaxation and hyperpolarization.


CONCLUSIONS
In porcine coronary arteries, both EDHF and NO contribute to BK-induced relaxation resistance to indomethacin and L-NNA. Large conductance Ca2+-activated K+ channels (BK(Ca)) may play an important role in mediating the BK-induced responses and small conductance Ca2+-activated K+ channels might function as 'backup' mechanisms when BK(Ca) is curtailed.
Ge
Z D
ZD
Grantham Hospital, Department of Surgery, The University of Hong Kong, Aberdeen, Hong Kong SAR, China.
Zhang
X H
XH
Fung
P C
PC
He
G W
GW
D000818:Animals; D001030:Apamin / Q000494:pharmacology; D001920:Bradykinin / Q000494:pharmacology; D018999:Charybdotoxin / Q000494:pharmacology; D003331:Coronary Vessels; D004305:Dose-Response Relationship, Drug; D004730:Endothelium, Vascular / Q000187:drug effects*; D066298:In Vitro Techniques; D007213:Indomethacin / Q000494:pharmacology; D007537:Isometric Contraction / Q000187:drug effects; D008564:Membrane Potentials / Q000187:drug effects; D009131:Muscle, Smooth, Vascular / Q000187:drug effects; D009569:Nitric Oxide / Q000378:metabolism*; D019001:Nitric Oxide Synthase / Q000037:antagonists & inhibitors*; D019335:Nitroarginine / Q000494:pharmacology*; D015221:Potassium Channels / Q000378:metabolism*; D013552:Swine
D015221:Potassium Channels; D018999:Charybdotoxin; D019335:Nitroarginine; D001030:Apamin; D009569:Nitric Oxide; D019001:Nitric Oxide Synthase; D001920:Bradykinin; D007213:Indomethacin