ENDOTHELIUM-DEPENDENT RELAXATION COMPETES WITH ALPHA-1-ADRENERGIC AND ALPHA-2-ADRENERGIC CONSTRICTION IN THE CANINE EPICARDIAL CORONARY MICROCIRCULATION

Background. The purpose of this study was to determine whether endothelium-dependent relaxation competes with alpha1- and alpha2-adrenergic coronary microvascular constriction in the beating heart in vivo. Methods and Results. Coronary microvascular diameters were measured using stroboscopic epiillumination and intravital microscopy during fluorescein microangiography in open-chested dogs (n=20). Both alpha1- and alpha2-adrenergic receptors were selectively activated by intracoronary infusions of norepinephrine (0.05 and 0.2 mug . kg-1 . min-1) in the presence of the alpha2-adrenergic antagonist rauwolscine (0.2 mg/kg) or the alpha1-adrenergic antagonist prazosin (0.75 mg/kg) during beta-adrenergic blockade (I mg/kg propranolol). Microvascular diameters during selective alpha-adrenergic receptor activation were measured under baseline conditions and after inhibition of endogenous nitric oxide synthesis by an analogue Of L-arginine, either N(G)-nitro-L-arginine (L-NA, 30 mg/kg) or N(G)-nitro-L-arginine methyl ester (L-NAME, 30 mg/kg). Under baseline conditions, alpha1-adrenergic activation constricted small arteries (vessels with diameters between 100 and 300 mum) (4+/-1% and 5+/-1% decrease in diameter for the low and high doses of norepinephrine, respectively, both p<0.05) but did not change the diameter of arterioles (vessels with diameters <100 mum). In contrast, alpha2-adrenergic activation by the lower but not the higher dose of norepinephrine induced constriction of arterioles (6+/-2% and 3+/-4% decrease in diameter, p<0.05 and NS, respectively) but not small arteries. Inhibition of nitric oxide synthase activity by either L-NA or L-NAME produced constriction of small coronary arteries (9+/-2% decrease in diameter, p<0.01) and arterioles (6+/-1% decrease in diameter, p<0.05). The dilatation of small arteries and arterioles by acetylcholine (0.05 mug-1 - kg-1 . min-1 intracoronary infusion; 10+/-1% increase in diameter under baseline conditions, p<0.05) was abolished by either analogue. Both alpha1- and alpha2-adrenergic coronary microvascular constriction were markedly potentiated after L-NA or L-NAME. Alpha1-Adrenergic constriction was unmasked in arterioles (7+/-3% and 10+/-4% decrease in diameter, p <0.05), although it was not significantly increased in small arteries. Conversely, alpha2-adrenergic constriction was unmasked in small arteries (8+/-l% and 6+/-2% decrease in diameter, both p<0.05) and potentiated in arterioles (12+/-1% and 8+/-4% decrease in diameter, both p<0.05). After L-NA or L-NAME, microvessels retained the ability to dilate to sodium nitroprusside (0.1 mug - kg-1 . min-1 intracoronary infusion; 10+/-2% increase in diameter, p<0.05). alpha-Adrenergic constriction was not accentuated by increased tone alone, since it was either attenuated or converted to dilatation during a similar degree of preconstriction by the endothelium-independent vasoconstrictor angiotensin II (p<0.05 for both alpha1- and alpha2-adrenergic activation). Conclusions. These data confirm that alpha-adrenergic receptors are widespread in the coronary microcirculation, with the baseline functional responses to alpha1-adrenergic activation predominating in small arteries and those to alpha2-adrenergic activation predominating in arterioles. Furthermore, coronary microvascular constriction caused by both alpha1- and alpha2-adrenergic receptor activation is significantly modulated by endothelium-dependent relaxation, being markedly potentiated by inhibition of nitric oxide synthase activity. The data imply that alpha-adrenergic activation will assume considerable importance as a determinant of coronary microvascular resistance, in pathophysiological situations associated with coronary endothelial impairment.