Endothelium-dependent relaxation competes with alpha 1- and alpha 2-adrenergic constriction in the canine epicardial coronary microcirculation.
Authors: Jones C J , DeFily D V , Patterson J L , Chilian W M 
Published: June 2012

BACKGROUND

The purpose of this study was to determine whether endothelium-dependent relaxation competes with alpha 1- and alpha 2-adrenergic coronary microvascular constriction in the beating heart in vivo.

METHODS AND RESULTS

Coronary microvascular diameters were measured using stroboscopic epi-illumination and intravital microscopy during fluorescein microangiography in open-chested dogs (n = 20). Both alpha 1- and alpha 2-adrenergic receptors were selectively activated by intracoronary infusions of norepinephrine (0.05 and 0.2 microgram.kg-1 x min-1) in the presence of the alpha 2-adrenergic antagonist rauwolscine (0.2 mg/kg) or the alpha 1-adrenergic antagonist prazosin (0.75 mg/kg) during beta-adrenergic blockade (1 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 NG-nitro-L-arginine (L-NA, 30 mg/kg) or NG-nitro-L-arginine methyl ester (L-NAME, 30 mg/kg). Under baseline conditions, alpha 1-adrenergic activation constricted small arteries (vessels with diameters between 100 and 300 microns) (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 microns). In contrast, alpha 2-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 microgram-1 x kg-1 x min-1 intracoronary infusion; 10 +/- 1% increase in diameter under baseline conditions, p < 0.05) was abolished by either analogue. Both alpha 1- and alpha 2-adrenergic coronary microvascular constriction were markedly potentiated after L-NA or L-NAME. alpha 1-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, alpha 2-adrenergic constriction was unmasked in small arteries (8 +/- 1% 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 microgram.kg-1 x 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 alpha 1- and alpha 2-adrenergic activation).

CONCLUSIONS

These data confirm that alpha-adrenergic receptors are widespread in the coronary microcirculation, with the baseline functional responses to alpha 1-adrenergic activation predominating in small arteries and those to alpha 2-adrenergic activation predominating in arterioles. Furthermore, coronary microvascular constriction caused by both alpha 1- and alpha 2-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.