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Nitric oxide inhibition unmasks ischemic myocardium-derived vasoconstrictor signals activating endothelin type A receptor of coronary microvessels

¹Department of Cardiovascular Medicine, Tohoku University Graduate School of Medicine, and ²Department of Comprehensive Medicine, Tohoku University Hospital, Sendai, Japan

Submitted 6 July 2004 ; accepted in final form 7 February 2005

NO plays an important role in the compensatory increase in coronary flow conductance against myocardial ischemia, and NO bioavailability is impaired in various diseases. We tested the hypothesis that, when NO production is inhibited, vasoconstrictor signals from the ischemic myocardium are unmasked. We investigated the involvement of endothelin type A (ET_A) receptors in the transduction of the constrictor signal. To detect coronary vasoactive signals derived from ischemic myocardium, we used a bioassay system in which an isolated rabbit coronary microvessel (detector vessel, DV) was placed on beating myocardium perfused by the left anterior descending coronary artery (LAD) of an anesthetized open-chest dog (n = 38). The DV was pressurized to 60 cmH₂O throughout the experiment and observed with an intravital microscope equipped with a floating objective. After the intrinsic tone of the DV was established, vehicle (n = 7), N-nitro-L-arginine (L-NNA, 100 µmol/l; n = 13), L-NNA + BQ-123 (a selective ET_A receptor blocker, 1 µmol/l; n = 7), or BQ-123 alone (1 µmol/l; n = 7) was superfused onto the DV. Thereafter, the LAD of the beating heart was occluded. Coronary occlusion produced significant dilation of the DV by 10 ± 4%. When L-NNA was applied, the DV significantly constricted by 12 ± 5% in response to LAD occlusion, and BQ-123 abolished the vasoconstriction. Pretreatment with BQ-123 alone produced an enhancement of the ischemia-induced dilation. We conclude that ischemic myocardium releases transferable vasomotor signals that produce coronary microvascular constriction during the blockade of NO production and the constrictor signal is mediated by ET_A receptors.

coronary circulation; ischemia; microcirculation; vasoconstriction; cross talk

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