Endothelium-dependent hyperpolarization and relaxation resistance to N(G)-nitro-L-arginine and indomethacin in coronary circulation
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1Grantham Hospital, Department of Surgery, The University of Hong Kong, Aberdeen, Hong Kong SAR, China.
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.
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