ROLE OF NITRIC-OXIDE IN THE CORONARY MICROVASCULAR RESPONSES TO ADENOSINE AND INCREASED METABOLIC DEMAND

Background The purpose of this study was to test the hypothesis that e ndothelium-derived nitric oxide (NO) participates in coronary microvas cular responses to adenosine and pacing-induced increases in metabolic demand by maintaining an optimal distribution of coronary resistance. Methods and Results Coronary microvascular diameters were measured by stroboscopic epi-illumination and intravital microscopy in open-chest dogs (n=20). Epicardial coronary blood velocity (CBV) was measured by Doppler flowmetry. Responses to adenosine (1 and 10 mu g . kg(-1) . m in(-1) IC) and left atrial pacing (180 beats per minute) were recorded before and after inhibition of NO synthesis by N-G-nitro-L-arginine m ethyl ester (L-NAME, 30 mu g . kg(-1) . min(-1) IC). At baseline, aden osine dilated arterioles (<100 mu m) (11+/-4% and 25+/-3% diameter cha nges, P<.05) more than small arteries (>100 mu m) (-4+/-6% and 7+/-3%, P<.05 for the higher dose) and increased CBV (43+/-31% and 118+/-25%, P<.05). Left atrial pacing dilated arterioles (12+/-2%, P<.05) and sm all arteries (8+/-3%, P<.05) and also increased CBV (68+/-9%, P<.05). L-NAME abolished CBV increases caused by acetylcholine (10 and 100 ng . kg(-1) . min(-1) IC; 53+/-33% and 168+/-82% versus -12+/-15% and -1/-14%, P<.05) but not papaverine. Small arteries were constricted by L -NAME (-8+/-2%, P<.05), arterioles were dilated (10+/-4%, P<.05), and CBV was unchanged. After L-NAME, adenosine failed to dilate arterioles further (3+/-3% and 2+/-2%; P<.05 versus prior responses), and CBV ch anges were attenuated (14+/-16% and 8+/-13%; P<.05 versus prior respon ses). Pacing also failed to dilate arterioles (-4+/-2%, P<.05 versus p rior response), resulting in an attenuated CBV change (34+/-13%, P<.05 versus prior response). The possibility that adenosine stimulates NO release in canine coronary arterioles was investigated in isolated art erioles (diameters, 81+/-4 mu m; n=8). Adenosine caused dose-dependent dilation to maximal diameter, which was unaffected by inhibition of N O synthesis by L-NAME. Conclusions Inhibition of NO synthesis attenuat es coronary dilation during adenosine infusions and during pacing-indu ced increases in metabolic demand. Inhibition of NO synthesis may shif t the major site of coronary resistance into small arteries through au toregulatory adjustments in arterioles. These data therefore suggest t hat NO, by dilating predominantly small coronary arteries, promotes me tabolic coronary dilation by preserving the tone and vasodilator reser ve of arterioles.