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We sought to compare the sensitivity of endocardial and epicardial microvessels to several important neurohumoral substances. Porcine endocardial microvessels (86-200 microns diam) from the anterior papillary muscle and epicardial microvessels of similar size from the left anterior descending distribution were studied in a pressurized state using an in vitro microvessel-imaging apparatus. Endothelium-dependent relaxations to bradykinin, ADP, A23187, and to the endothelium-independent vasodilator nitroprusside were identical between endocardial and epicardial microvessels. In contrast, the sensitivity of endocardial microvessels to adenosine was substantially greater than that of epicardial microvessels (ED50s of -6.59 +/- 0.05 vs. -5.66 +/- 0.11, P less than 0.001, endocardial vs. epicardial, respectively), although adenosine caused 100% relaxation of both groups of vessels at the highest concentrations. Adenosine vasorelaxation was not affected by inhibition of cyclooxygenase by indomethacin (1 microM) or depletion of guanosine 3',5'-cyclic monophosphate by LY 83583 (1 microM). Forskolin dilated both endocardial and epicardial vessels completely but was more potent in endocardial vessels. These data show that endocardial and epicardial microvessels exhibit similar sensitivity to most vasodilator agents. Endocardial microvessels, however, are more sensitive to both adenosine and forskolin. The enhanced responsiveness to adenosine may be related to adenosine 3',5'-cyclic monophosphate-mediated mechanisms and may have important implications regarding regulation of myocardial perfusion in deeper subendocardial layers.

Previous in vivo studies have shown that vasopressin, which releases the endothelium-derived relaxing factor and constricts coronary smooth muscle, produces augmented constriction of coronary microvessels perfused by mature collaterals. We hypothesized that chronic perfusion through collaterals produces endothelial dysfunction in the recipient vasculature. Mature collaterals were stimulated in mongrel dogs by the ameroid constrictor technique. After 3-6 months, rings of conduit vessels (obtuse marginals) were studied in organ chambers, and coronary microvessels (100-220 microns) were studied in a pressurized, no-flow state with a microvessel imaging apparatus. Eleven dogs were used as controls. Large vessels were preconstricted with prostaglandin F2 alpha to 30-70% of the maximum potassium chloride tension, and microvessels were preconstricted to 20-60% of the baseline diameter with the thromboxane mimetic U46619. Relaxations to the receptor-mediated agents acetylcholine and ADP were markedly impaired in collateral-dependent coronary microvessels, whereas relaxations to nitroglycerin were enhanced compared with microvessels from control dogs. Relaxation to the calcium ionophore A23187, which releases the endothelium-derived relaxing factor through nonreceptor-mediated mechanisms, were similar in control and ameroid microvessels. Constriction to vasopressin was augmented in collateral-dependent microvessels compared with controls. Responses to all agonists were similar between control and collateral-dependent large vascular rings. In conclusion, chronic perfusion through collateral vessels selectively impairs receptor-mediated endothelium-dependent relaxations and augments constriction to vasopressin in the coronary microcirculation. These findings may have important implications regarding neurohumoral regulation of perfusion to collateral-dependent myocardium.

As a result of gradual coronary occlusion, coronary collaterals are stimulated to develop. This maturation process involves not only dilatation of the vessel, but the development of new vascular smooth muscle. Experiments have been performed to examine vasomotor characteristics of mature coronary collaterals from dogs 3 to 6 months following ameroid constrictor placement. Studies in Langendorff blood-perfused hearts have shown that transcollateral resistance does not change during either the administration of α1-or α2-adrenergic agonists. Isolated collateral vessels studied as rings in organ chambers do not constrict to either α1- or α2-adrenergic agonists. These studies show that mature collateral vessels are not likely to possess functioning α-adrenergic receptors. Subsequent experiments using a cover slip autoradiographic ligand-binding approach have demonstrated a population of β-adrenergic receptors on mature coronary collaterals. Studies of isolated collaterals have demonstrated β-adrenoceptor-mediated relaxation that appears due to a population of mixed β1- and β2-adrenergic receptors.

We examined the effects of ischemia with and without reperfusion on endothelium-dependent and -independent vascular relaxation in both conduit and resistance coronary arteries. Studies were performed on dogs under control conditions (n = 13) or after 1 hour of circumflex coronary artery occlusion with (n = 10) or without (n = 8) 1 hour of reperfusion. Rings of obtuse marginal branches of the left circumflex coronary artery (conduit arteries) were studied in organ chambers. Coronary microvessels (110-220-microns diameter) were studied in a pressurized state with an in vitro microvessel imaging apparatus. Relaxation was evaluated after preconstriction with prostaglandin F2 alpha and U46619 (a thromboxane A2 analogue) in conduit and resistance vessels, respectively. Conduit vessel function was not altered by ischemia with or without reperfusion. Endothelium-dependent microvascular relaxation was depressed in response to acetylcholine, ADP, and calcium ionophore A23187 after ischemia with reperfusion compared with control relaxation (ED50 as -log[M]: 6.0 +/- 0.2 [p less than 0.05], 5.1 +/- 0.4 [p less than 0.05], and 5.8 +/- 0.1 versus 6.8 +/- 0.2, 6.8 +/- 0.2, and 6.6 +/- 0.2, respectively). Ischemia without reperfusion modestly altered microvascular endothelium-dependent relaxation. Microvascular relaxation to nitroglycerin was not altered by ischemia with reperfusion. We conclude that 1) endothelium-dependent relaxation in large epicardial coronary arteries is relatively refractory to ischemia with or without reperfusion, 2) ischemia alone produces mild alterations of coronary microvascular reactivity, 3) ischemia followed by reperfusion produces a marked and selective impairment of endothelium-dependent responses in the coronary microcirculation.