Coronary microvascular responses to reductions in perfusion pressure. Evidence for persistent arteriolar vasomotor tone during coronary hypoperfusion.

The goals of this study were to test the following hypotheses: 1) Coronary autoregulatory adjustments to decreases in perfusion pressure occur primarily in coronary arterioles (less than 150 microns in diameter). 2) Small coronary arteries (greater than 150 microns in diameter) can be recruited to participate in the autoregulatory adjustments as perfusion pressure is progressively lowered. 3) Small arterioles are the location of vasodilator reserve in the coronary microcirculation during hypoperfusion. Studies were performed in anesthetized open-chest dogs in which coronary perfusion pressures were reduced to 80, 60, 40, and 30 mm Hg. During reductions in coronary perfusion pressure, measurements were made of systemic hemodynamics, myocardial blood flow (radioactive microspheres), and coronary microvascular diameters. Arterial pressure and heart rate were largely unchanged during the experimental maneuvers. Measurements of microvascular diameters in the beating heart were performed during epi-illumination via a stroboscopic light source synchronized to the cardiac cycle using fluorescence intravital microscopy. Coronary autoregulatory adjustments were evident during reductions in perfusion pressure from control (96 mm Hg) to 80 and 60 mm Hg. Blood flow was unchanged from control, and active vasodilation of coronary arterioles was observed. At 80 mm Hg, only coronary arterioles dilated (4.4 +/- 1.2%), whereas at 60 mm Hg both small arteries (4.9 +/- 2.2%) and arterioles (6.9 +/- 1.2%) demonstrated significant vasodilation (p less than 0.05). The magnitude of dilation (i.e., percent increase in diameter) was inversely related to the initial diameter; that is, the arterioles dilated to a greater extent, percentage wise, than the small arteries. At 40 mm Hg, myocardial blood flow decreased slightly from that under control conditions, but coronary arterioles dilated to a greater extent than at 60 mm Hg (8.1 +/- 1.6%); yet, microvessels were incompletely vasodilated, because adenosine produced a further increase in microvessel diameter (12.5 +/- 2.1%) (p less than 0.05). At a perfusion pressure of 30 mm Hg, arterioles demonstrated a decrease in vascular diameter (-0.2 +/- 2.1%), which was reversed by adenosine (11.1 +/- 3.1%). From these results we concluded the following: 1) Coronary autoregulatory adjustments involve primarily coronary arteriolar vessels, but small coronary arteries can be recruited to participate in the autoregulatory response. 2) The magnitude of vessel dilation appears to be inversely related to vascular diameter. 3) Coronary arterioles are not maximally vasodilated during coronary hypoperfusion, and these vessels may be the source of persistent vasomotor tone during coronary insufficiency.

Microvascular occlusions promote coronary collateral growth.

The objective of this study was to examine whether myocardial ischemia without alterations in pressure gradients between large epicardial coronary arteries was a sufficient stimulus to produce coronary collateral growth and development. To accomplish this aim, we partially embolized the circumflex coronary perfusion territory with 25-microns diameter microspheres to produce multiple microvascular occlusions, sufficient to abolish or greatly attenuate coronary vasodilator reserve. The embolization procedure was performed in two groups of dogs during aseptic surgery. After the dogs recovered for 1-3 wk (short-term embolization) or 6-8 wk (long-term embolization), indexes of vascular growth were compared with a group of control animals in which all operative procedures were performed, except embolization. Retrograde blood flow, an index of collateral blood flow and coronary vascular resistance, was determined in an isolated beating empty heart preparation during coronary vasodilation with adenosine. Circumflex retrograde blood flow from the left anterior descending artery was increased from 0.09 ml.min-1.g-1 (sham) to 0.21 and 0.17 ml.min-1.g-1 in the short-term and long-term groups, respectively (P less than 0.05). Collateral blood flow from the septal artery was also increased from 0.03 ml.min-1.g-1 (sham) to 0.08 ml.min-1.g-1 (P less than 0.05) in the short-term group. Collateral contribution from the right coronary artery was not significantly altered in either group of embolization animals. The contributions of epicardial and intramyocardial collaterals to the total retrograde flow were also determined and were found to be different among the three experimental groups.(ABSTRACT TRUNCATED AT 250 WORDS)

Effects of atherosclerosis on the coronary microcirculation.

We tested the hypothesis that atherosclerosis potentiates coronary vasoconstriction to serotonin and ergonovine. Coronary microvascular pressures and diameters were measured in the beating left ventricle in normal and atherosclerotic cynomolgus monkeys. Pressures were measured in arteries (190-350 microns diam) that were distal to atherosclerotic lesions. Microvascular pressure and simultaneous measurements of aortic pressure and myocardial blood flow were used to calculate segmental vascular resistance (large artery resistance and microvascular resistance) during serotonin, phenylephrine, and ergonovine dosages. Aortic pressure was maintained constant during all interventions. Administration of phenylephrine (50 micrograms.kg-1.min-1 iv) produced a similar increase in microvascular resistance from base line (P less than 0.05) in atherosclerotic and normal animals, 26 +/- 5 and 14 +/- 9 mmHg.min.g.ml-1, respectively. Serotonin (50 micrograms/min) did not influence coronary resistance in normal animals but produced a significant increase in both large artery (8 +/- 3 mmHg.min.g.ml-1) and microvascular resistance (21 +/- 6 mmHg.min.g.ml-1) in atherosclerotic animals (P less than 0.05). A higher dose of serotonin (200 micrograms/min) produced a modest increase in large artery resistance from base line in normal animals (3 +/- 1 mmHg.min.g.ml-1) and a greater increase in atherosclerotic animals (9 +/- 4 mmHg.min.g.ml-1) (P less than 0.05 vs. normals). Ergonovine (10 micrograms.kg-1.min-1 iv) elevated microvascular resistance in both normal and atherosclerotic animals (P less than 0.05) but increased large artery resistance only in atherosclerotic animals (10 +/- 4 mmHg.min.g.ml-1) (P less than 0.05). In summary, coronary vasoconstrictor responses to serotonin and ergonovine were potentiated by atherosclerosis. Because augmented constrictor responses to serotonin were observed in both the diseased arteries and the microcirculation of atherosclerotic animals, we speculate that the pathophysiological consequences of atherosclerosis extend into the microcirculation.

Redistribution of coronary microvascular resistance produced by dipyridamole.

This study assessed the redistribution of coronary microvascular resistance during vasodilation produced by dipyridamole. Measurements of microvascular diameter and pressure in the beating left ventricle of anesthetized cats were accomplished by means of a computer-controlled system that enabled measurements in the beating heart. Resistances of coronary arteries, microvessels, and veins were calculated from the quotients of the pressure gradient across each vascular compartment and myocardial perfusion (radioactive microspheres). Administration of dipyridamole increased coronary blood flow from 1.80 +/- 0.09 to 6.42 +/- 0.31 ml.min-1. g-1 (P less than 0.05). During control conditions, 25 +/- 8% of total resistance occurred in coronary arteries (proximal to 170 microns), 68 +/- 8% of total resistance was in coronary microvessels (between arterioles less than 170 microns in diameter and venules less than 150 microns in diameter), and 7 +/- 7% of resistance resided in veins (distal to 150 microns). There was a significant redistribution (P less than 0.05) of resistance in all vessel classes after dipyridamole: coronary arteries constituted 42 +/- 6%, microvessels contained 27 +/- 5%, and veins had 31 +/- 8% of total coronary resistance. During control conditions, vascular resistance in coronary arteries and microvessels was 17 +/- 4 and 45 +/- 6 mmHg.min.g.ml-1, respectively. During vasodilation, resistance was significantly reduced (P less than 0.05) in both the arterial and microvessel segments to 6 +/- 2 and 4 +/- 2 mmHg.min.g.ml-1, respectively. Venous resistance was not significantly affected during dipyridamole-induced vasodilation. In conclusion, there was a marked reduction of coronary vascular resistance in response to dipyridamole, with the major component accounted for by dilation of microvessels.(ABSTRACT TRUNCATED AT 250 WORDS)

Heterogeneous microvascular coronary alpha-adrenergic vasoconstriction.

We tested the hypothesis that humoral or neurogenic alpha-adrenergic activation in the coronary circulation would produce heterogeneous vascular reactions. To accomplish this, the epicardial coronary microcirculation was viewed through an intravital microscope using stroboscopic epi-illumination. Microvascular diameters were measured under control conditions during beta-adrenergic blockade (propranolol 1 mg/kg) and beta-adrenergic blockade with pacing; during coronary alpha-adrenergic activation in the presence of beta-adrenergic blockade with three doses of norepinephrine infusion (0.1, 0.5, and 1.0-2.0 micrograms/kg/min) or three frequencies of bilateral stellate nerve stimulation (2, 10, and 20 Hz); and during combined alpha- and beta-adrenergic blockade (phentolamine 2 mg/kg and propranolol 1 mg/kg). Diameters of both arterial and venous vessels were reduced during beta-adrenergic blockade but returned back to baseline with pacing. At the lowest level of norepinephrine infusion or frequency of bilateral stellate stimulation, microvessel constriction was not observed. At the higher doses of norepinephrine a -5.1 +/- 0.9% (1.0-2.0 micrograms/kg/min) and a -4.0 +/- 1.1% (0.5 micrograms/kg/min) decrease in diameter of arterial vessels greater than 100 microns in diameter were observed (p less than 0.05). At 10 Hz and 20 Hz of stellate stimulation, diameter decreased by -4.8 +/- 1.9% and -4.4 +/- 2.1%, respectively, in these relatively large vessels. Small coronary arterioles (less than 100 microns diameter) dilated significantly during the highest levels of nerve stimulation (9.2 +/- 2.5% increase in diameter) or infusion rate of norepinephrine (13.6 +/- 2.7% increase in diameter) (p less than 0.05). These constrictor and dilator responses were abolished following combined alpha- and beta-adrenergic blockade. Norepinephrine infusion resulted in a decrease in diameter of coronary veins and venules (7.2 +/- 1.3%) (p less than 0.05), whereas stellate stimulation did not significantly reduce venous and venular diameters. In summary, the coronary venous and venular vasculature responds to alpha-adrenergic activation from circulating norepinephrine but is not affected by stellate stimulation. In contrast, stellate stimulation and norepinephrine infusion elicit similar responses in the coronary arterial and arteriolar microvasculature. Constriction occurs in vessels greater than 100 microns in diameter, whereas dilation predominates in vessels less than 100 microns in diameter. Such heterogeneous arterial responses would undoubtedly result in a redistribution of coronary vascular resistance toward larger coronary arteries and arterioles.

Small vessel phenomena in the coronary microcirculation: phasic intramyocardial perfusion and coronary microvascular dynamics.

To place the characteristics of the coronary microcirculation in perspective to another muscular organ system, we have compared various parameters from exchange vessels in the heart and red skeletal muscle. The major differences between cardiac and skeletal muscle microcirculations relate to the larger density of capillaries in the heart. This increased density is responsible primarily for a greater capillary filtration coefficient-permeability-surface area product to various solutes, surface area, and decreased intercapillary distances. These features most likely represent an adaptation of the microcirculation of the heart to the very high, continual metabolic demands. Interestingly, capillary permeabilities and reflection coefficients of different solutes are in the same range (although the heart tends to have higher capillary permeabilities). Thus, the adaptation of the coronary circulation to facilitate exchange of nutrients and solutes is mediated via an increase in the numbers of exchange vessels, rather than modifications of the membrane characteristics of these exchange vessels. Within the last decade, there has been much information assimilated on the regulation of the coronary microcirculation. Most of the knowledge has been the result of many indirect approaches to studying the coronary microcirculation (indicator-dilution techniques, nuclide-labeled microspheres, plasma-lymph concentration of solutes). There are relatively few direct observations on regulation of the coronary microcirculation. This is primarily due to difficulties in techniques. Exploration of the phasic nature of intramyocardial perfusion is handicapped by the location of these intramuscular vessels. Visualization of the coronary microcirculation is hampered by movements of the heart, and such measurements are restricted to the superficial layers of the myocardium. It is worth emphasizing that direct observations of red cell velocities in epicardial capillaries, measurements of microvascular caliber, and the pressure profiles in the coronary microcirculation are restricted to the superficial, epicardial layer. It is not unreasonable to speculate that microvascular events and regulation occurring in the subepicardium may be quite different than that in the subendocardium. There are several salient points in this review that are worth emphasizing.(ABSTRACT TRUNCATED AT 400 WORDS)

Effects of epinephrine on coronary microvascular diameters.

This study was designed to examine the hypothesis that epinephrine has nonuniform effects on coronary microvascular diameters. Measurements of coronary microvascular diameter were completed in anesthetized, open-chest cat preparations in which the epicardial microcirculation was viewed through an intravital microscope using stroboscopic epi-illumination. Images of coronary microvessels were digitized and analyzed on a video monitor. With arterial pressure controlled, measurements in the absence and presence of beta-adrenergic blockade (propranolol 1 mg/kg) were obtained during epinephrine infusion (1-2 micrograms/kg/min). In the absence of beta-adrenergic blockade, epinephrine produced a 25% increase in myocardial perfusion. Under these conditions, coronary vasodilation was observed in all classes of coronary arterial and arteriolar vessels. In the presence of beta-adrenergic blockade, epinephrine produced a significant decrease in myocardial perfusion (-20%). Nonuniform effects on diameter were observed in arterial and venous segments of the coronary circulation. These data are consistent with the view that in the absence of beta-adrenergic blockade, the functional coronary hyperemia associated with epinephrine administration is produced by uniform coronary arterial and arteriolar dilation. In the presence of beta-adrenergic blockade, with metabolic effects controlled, epinephrine produced a decrease in myocardial perfusion, which is related to a nonuniform decrease in coronary microvascular diameters. Such heterogeneous effects on microvascular diameters result in a redistribution of coronary microvascular resistance.