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The goal of this study was to test the hypothesis that circulating catecholamines are primarily responsible for alpha-adrenergic coronary vasoconstriction during submaximal exercise. The experimental series consisted of chronic studies in which a regional left ventricular sympathectomy was performed with phenol. Myocardial perfusion to the innervated and sympathectomized left ventricular regions was measured in these animals during (1) a control period, (2) treadmill exercise, (3) exercise during beta-adrenergic blockade, and (4) exercise during combined alpha- + beta-adrenergic blockade. We found no differences in myocardial perfusion between the innervated and sympathectomized regions or the transmural distribution of perfusion during any of these interventions. Thus, there is no evidence for neurogenic alpha-adrenergic coronary vasoconstriction. However, during exercise in the presence of alpha- and beta-blockade, coronary resistance (mmHg X min X 100 g/ml) was significantly less in both the innervated (0.65 +/- 0.07) and sympathectomized (0.68 +/- 0.07) regions than during beta-blockade, 0.90 +/- 0.17 and 0.89 +/- 0.16, respectively. This suggests that coronary alpha-adrenergic constriction was produced by circulating catecholamines. This concept of humorally mediated, alpha-adrenergic coronary vasoconstriction was strengthened by in vivo and in vitro studies that demonstrated that alpha-adrenergic supersensitivity of the coronary vasculature was not present. Myocardial beta-adrenergic supersensitivity was observed in the phenol regional sympathectomy model; however, this effect was blocked by propranolol (1 mg/kg). This indicates that alpha-adrenergic vasoconstriction in both myocardial regions during submaximal exercise is produced by circulating catecholamines. The major conclusion of this study is that, during submaximal exercise in the canine, alpha-adrenergic coronary vasoconstrictor tone is predominantly due to circulating catecholamines rather than direct neural effects.

Assessment of coronary blood flow and the vasodilator reserve capacity of individual coronary arteries in the catheterization laboratory has been hampered by methodologic limitations. We have developed and validated a small Doppler catheter that can subselectively measure phasic coronary blood flow velocity (CBFV). In seven anesthetized calves, CBFV was varied from 0.1 to 5.7 times control CBFV. Changes in mean CBFV measured intraluminally by catheter in the left anterior descending and left circumflex arteries were similar to those measured simultaneously with an epicardial Doppler probe on the surface of the same vessel (n = 85, r = .95, slope = 1.04) and to changes in coronary sinus flow (n = 69, r = .97, slope = 1.06) measured with timed venous collections. Identical maximal coronary reactive hyperemic responses with the catheter present and absent in the artery being studied demonstrated that coronary obstruction by the catheter was minimal. Safety studies in six additional calves demonstrated that the catheter caused small changes in coronary endothelial permeability. Histologic studies revealed no endothelial denudation or thrombus formation. Stable phasic recordings of coronary blood flow velocity have been obtained in 58 of 70 patients studied. One of the 70 patients studied had abrupt coronary occlusion probably related to catheter-induced vasospasm. In 10 normal patients, intracoronary meglumine diatrizoate increased CBFV to 3.5 times that at rest (range 2.8 to 5.0). CBFV rose 5.0-fold after an intravenous infusion of dipyridamole (range 3.8 to 7.0). In each patient, dipyridamole produced greater vasodilation than meglumine diatrizoate. The time- and dose-response characteristics to dipyridamole infusion were heterogeneous, underscoring the advantage of continuous on-line measurement of CBFV in the measurement of vasodilator reserve. This method of measuring CBFV and assessing vasodilator reserve in the catheterization laboratory should facilitate studies of the coronary circulation in man.

Large-conduit coronary arteries respond to vasoactive stimuli differently than smaller coronary arterioles, but the quantitative effects of many vasoactive stimuli at various levels of the microvasculature remain unknown. To determine the site of constriction or dilation to serotonin and vasopressin in the coronary microcirculation, we studied microvascular responses in the left ventricle of anesthetized cats (n = 36). To compensate for motion due to contraction of the heart, the epicardium was visualized with stroboscopic epi-illumination controlled by a computer to flash once per cardiac cycle in mid-diastole, making the vessels appear stationary. Serotonin (16 micrograms/kg/min) or vasopressin (0.5 units/min) was infused into the left atrium while maintaining aortic pressure constant with a snare on the descending aorta or inferior vena cava. Myocardial blood flow was measured with radioactive microspheres. During infusion of serotonin, aortic pressure and heart rate did not change, but myocardial perfusion increased 90 +/- 38% (mean +/- SEM) from a control value of 159 +/- 27 ml/min.100 g. Arteries and arterioles larger than 90 microns constricted in response to serotonin (control 159 +/- 12 microns; percent change -18 +/- 3; range -41 to 10%) while arterioles less than 90 microns dilated to serotonin (control 54 +/- 7 microns; percent change 22 +/- 9; range -10 to 62%). During infusion of vasopressin, aortic pressure and heart rate did not change, and myocardial perfusion decreased 16 +/- 7% (control, 147 +/- 18 ml/min.100 g).(ABSTRACT TRUNCATED AT 250 WORDS)

The goal of this study was to examine myogenic responses of isolated porcine subepicardial and subendocardial arterioles (80–100 micron in diameter) within physiological ranges of intraluminal pressure. Arterioles were located by perfusion with india ink-gelatin solution then dissected and cannulated with glass micropipettes. Intraluminal pressure was altered in 20-cmH2O steps over the range of 20–140 cmH2O. IN physiological salt solution (36–37 degrees C), the coronary arterioles developed spontaneous tone and exhibited myogenic responses. At the lower pressures (20–60 cmH2O), subendocardial arterioles responded passively (diameter decreased from a control diameter at 60 cmH2O), whereas subepicardial arterioles maintained their diameters. At higher pressures (100–140 cmH2O), both subepicardial and subendocardial arterioles demonstrated myogenic constriction, but subepicardial arterioles demonstrated greater myogenic constriction than subendocardial arterioles. This implies that myogenic autoregulation in subepicardial arterioles is better than that in the subendocardial arterioles at both low and high pressures. In the presence of nitroprusside (10(-4) M), all arterioles responded to pressure changes passively, and there were no differences between subepicardial and subendocardial vessels. The functional integrity of the endothelium was verified by relaxation to substance P (10(-7) M). This is the first in vitro study to demonstrate coronary myogenic activity and transmural differences in these arteriolar responses. Our data support the concept that myogenic mechanisms in 80 to 100-micron arterioles may actively contribute to autoregulation of coronary blood flow.

Left ventricular hypertrophy is generally viewed as a compensatory response to pressure or volume overload that results in normalization of left ventricular wall stress. For example, during systemic hypertension, the increase in arterial pressure causes an initiation of ventricular hypertrophy that stabilizes after some period. During the period of stable hypertrophy, there is no change in ventricular volume or the total mass of the myocardium [1, 2]. During this period of stable hypertrophy, resting ventricular systolic wall stress is normal because the increased wall thickness compensates for increased ventricular pressure [3, 4, 5]. With the normalized systolic wall stress, resting left ventricular oxygen consumption per unit mass of myocardium, is reported as normal. [6, 7] Since myocardial perfusion is primarily regulated by myocardial oxygen consumption, during stable left ventricular hypertrophy, myocardial perfusion, per unit mass of myocardium, is usually found to be normal with respect to that in normal, unhypertrophied hearts [7, 8, 9, 10, 11, 12, 13]. Despite normalized wall stress and normalized blood flow at rest there are many pathological manifestations of cardiac hypertrophy.

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)

To determine if mature coronary collateral vascular smooth muscle contains functioning alpha-adrenergic receptors, we studied 13 dogs, 6-10 months after circumflex ameroid occlusion. Regional myocardial blood flow was measured with radioactive microspheres in a blood-perfused heart preparation at constant aortic pressure (80 mm Hg). Normal zone resistance was calculated as aortic pressure divided by normal zone flow, and transcollateral resistance was calculated as aortic pressure minus circumflex pressure distal to the ameroid constrictor divided by coronary collateral flow. Flow and resistance were measured during adenosine vasodilation before and during graded doses of a constant infusion of the alpha-adrenergic agonist methoxamine (n = 6) or the alpha 2-adrenergic agonist clonidine (n = 7). In the hearts that received methoxamine, normal zone resistance increased from a control of 0.29 +/- 0.06 to 0.39 +/- 0.06 mm Hg X min/ml per 100 g (resistance units) during infusion of 10(-5)M methoxamine (p less than 0.05). In contrast transcollateral resistance averaged 0.24 +/- 0.02 resistance units under control conditions and did not change during methoxamine infusion. In the hearts that received clonidine, normal zone resistance averaged 0.24 +/- 0.03 resistance units and increased to 0.39 +/- 0.07 resistance units (p less than 0.05) with the highest dose of clonidine administered (10(-5) M). Transcollateral resistance averaged 0.17 +/- 0.03 resistance units during control conditions and did not change with clonidine infusion. In separate studies isometric tension development by the left anterior descending and coronary collateral vessels was examined in organ baths. The left anterior descending coronary artery demonstrated dose-dependent constriction to phenylephrine (peak response 22 +/- 5% of the response to 100 mM KCl). Clonidine produced weak constrictor responses in the left anterior descending coronary artery (5 +/- 2.5% maximal KCl response). In contrast, neither phenylephrine nor clonidine produced responses in mature collaterals. We also examined responses of mature collateral vessels to nonadrenergic agonists. In the vascular ring preparation the mature collaterals developed tension in the presence of KCl (2.3 +/- 0.9 g), prostaglandin F2 alpha (16 +/- 18% of the KCl responses), and vasopressin (90 +/- 30% of the KCl response). In adenosine-vasodilated hearts, pharmacologic doses of vasopressin caused a two-fold increase in transcollateral resistance. Thus, these studies performed on intact hearts and isolated vascular rings demonstrate that mature coronary collaterals do not contain functioning alpha-adrenergic receptors.(ABSTRACT TRUNCATED AT 400 WORDS)

We examined anatomical and physiological responses of the left coronary vascular system to thyroxine-induced myocardial hypertrophy. Wistar-Kyoto rats (1 and 5 months old) were administered thyroxine (0.25 mg/kg per day) or the saline vehicle (sham-treated controls) for 2 months. At the ages of 3 and 7 months, each group of animals was used for one of three experimental protocols: determination of numerical capillary density in perfusion-fixed hearts, measurement of coronary reactive hyperemic responses following a 20-second coronary occlusion (peak-to-resting blood flow velocity) as an index of coronary reserve, and assessment of myocardial perfusion under resting conditions and during maximum coronary dilation (dipyridamole infusion) for the calculation of minimum coronary resistance per unit weight of the left ventricle or minimum coronary resistance of the total left ventricle. In both groups of thyroxine-treated animals, the left ventricular weight-to-body weight ratio increased by 35-40%. Capillary density of the 3- and 7-month-old Wistar Kyoto controls was 4467 +/- 352 (mean +/- SEM) and 4029 +/- 143 capillaries/mm2, respectively, but was increased significantly in the thyroxine-treated animals to 6052 +/- 409 capillaries/mm2 (3-month) and 4654 +/- 201 capillaries/mm2 (7-month). In both age control groups, the peak-to-resting blood flow velocity ratio was about 2.2. This index of coronary reserve was not changed in the thyroxine-treated animals. Myocardial perfusion measurements were limited to the 7-month-old animals.(ABSTRACT TRUNCATED AT 250 WORDS)

The goal of this study was to examine changes in blood flow to the adrenal medulla during reflex stimuli that release catecholamines. Adrenal blood flow was measured with microspheres during exercise in conscious dogs and during bicuculline-induced seizures in anesthetized dogs. In awake dogs, blood flow to the adrenal cortex and adrenal medulla was 310 +/- 48 and 1,613 +/- 258 (SE) ml.min-1.100 g-1, respectively. Blood flow to the cortex and medulla was not affected by moderate exercise. Anesthesia (pentobarbital sodium) reduced blood flow to the adrenal cortex and medulla to 158 +/- 12 and 243 +/- 24 ml.min-1.100 g-1, respectively. In anesthetized dogs, seizures markedly increased blood flow to the adrenal medulla (282 +/- 68 to 1,257 +/- 128 ml.min-1.100 g-1), and this response was blocked by sectioning the greater splanchnic nerve. Vasodilator responses of the adrenal medulla to adenosine were not impaired by adrenal denervation. Blood flow to the adrenal cortex was not affected by seizures but increased in response to intravenous adenosine. These findings suggest that 1) anesthesia decreases adrenal blood flow, particularly to the adrenal medulla, and 2) reflex stimuli that release catecholamines can produce selective increases in blood flow to the adrenal medulla.

1. 1. Hibernating and active thirteen-lined ground squirrels, Spermophilus tridecimlineatus , showed no differences in serum urea levels and total osmolality. 2. 2. Erythrocytes of hibernating S. tridecimlineatus contained less than one-tenth the concentration of urea found in erythrocytes of active animals. 3. 3. Erythrocyte fragility in an isosmotic urea solution showed that erythrocytes of hibernating animals were much less permeable to urea than erythrocytes from active animals.

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)

For decades coronary macrovascular atherosclerosis has been considered the principal manifestation of coronary heart disease, with most of our effort dedicated to identifying and removal of coronary stenosis. However, growing body of literature indicates that coronary microcirculation also contributes substantially to the pathophysiology of cardiovascular disease. An understanding of mechanisms regulating microvascular function is of critical importance in understanding its role in disease, especially because these regulatory mechanisms vary substantially across species, vascular bed and due to comorbidities. Indeed, the most obvious consequence of coronary stenosis is that it may limit blood supply to the dependent myocardium to the point of causing ischaemia during exercise or even at rest. However, this flow limiting effect is not only due to the passive hydraulic effect of a narrowed conduit, but also to active responses in the coronary microcirculation triggered by the presence of an epicardial stenosis. To understand this problem it is important to review the inter-related mechanisms that regulate flow to the left ventricular wall and modulate transmural distribution of flow. These regulatory mechanisms operate hierarchically and are heterogeneously distributed along the coronary vascular tree. It is also important to discuss the effect of myocardial performance in modulating both blood flow demands and coronary resistance. Some of the interactions between coronary stenosis and microcirculation are transient, like those documented in acute coronary syndromes or during percutaneous interventions. However, microcirculatory remodeling may be triggered by a chronic coronary stenosis, leading to a sustained impairment of blood supply even after successful removal of the epicardial stenosis. A deeper understanding of these phenomena may explain paradoxical findings in patients undergoing coronary revascularization, particularly when functional tests are used in their assessment. These aspects are discussed in detail in this review.