Modulation of coronary blood flow and cardiac function by alpha 1-adrenergic receptors was examined in dogs during strenuous exercise. Fifteen dogs were chronically instrumented to measure left circumflex blood flow, heart rate, regional left ventricular function (systolic shortening, and rate of shortening), and global left ventricular function (left ventricular pressure, and dP/dt). The specific postsynaptic alpha 1-receptor blocker prazosin (0.5 mg) and nonselective alpha-receptor blocker phentolamine (1.0 mg) were injected through an indwelling circumflex artery catheter to produce local adrenergic blockade of the posterior left ventricular region during exercise. Exercise significantly increased heart rate, left ventricular systolic pressure, dP/dt, segment shortening and rate of shortening, and coronary blood flow. Both prazosin and phentolamine caused similar additional increases in dP/dt by 21 +/- 4%, in rate of shortening in the posterior region by 37 +/- 6%, and in myocardial O2 consumption by 26 +/- 11%, which were associated with a 21 +/- 3% increase in coronary flow during exercise but no change in O2 extraction. Similar results were obtained when dogs were beta-blocked with either atenolol (1.0 mg ic) or propranolol (1.0 mg ic) prior to exercise. These data suggest that an alpha 1-vasoconstriction modulates O2 delivery to myocardial tissue and limits both coronary vasodilation and cardiac function during exercise.

This is the first investigation of right ventricular (RV) myocardial oxygen supply/demand balance in a conscious animal. A novel technique developed in our laboratory was used to collect right coronary (RC) venous blood samples from seven instrumented, conscious dogs at rest and during graded treadmill exercise. Contributions of the RV oxygen extraction reserve and the RC flow reserve to exercise-induced increases in RV oxygen demand were measured. Strenuous exercise caused a 269% increase in RV oxygen consumption. Expanded arteriovenous oxygen content difference (A-V(Delta)O2) provided 58% of this increase in oxygen demand, and increased RC blood flow (RCBF) provided 42%. At less strenuous exercise, expanded A-V(Delta)O2 provided 60-80% of the required oxygen, and increases in RCBF were small and driven by increased aortic pressure. RC resistance fell only at strenuous exercise after the extraction reserve had been mobilized. Thus RC resistance was unaffected by large decreases in RC venous PO2 until an apparent threshold at 20 mmHg was reached. Comparisons of RV findings with published left ventricular data from exercising dogs demonstrated that increased O2 demand of the left ventricle is met primarily by increasing coronary flow, whereas increased O2 extraction makes a greater contribution to RV O2 supply.

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Modulation of myocardial contractile function and perfusion by alpha 1-adrenergic receptors were examined in anesthetized dogs during left stellate ganglion stimulation. In 11 dogs, stellate stimulation significantly increased heart rate, mean arterial pressure, left ventricular systolic pressure, maximal rate of left ventricular pressure generation, segmental shortening and rate of shortening in anterior and posterior ventricular regions, and myocardial oxygen extraction. Myocardial lactate extraction decreased. The selective alpha 1-adrenergic antagonist prazosin (0.5 mg) injected into the circumflex artery during stellate stimulation caused significant additional increases in maximal rate of left ventricular pressure generation by 19 +/- 5% and in rate of shortening in posterior subendocardium by 20 +/- 6%. No changes were observed in posterior subepicardial or anterior subendocardial segmental contractile function. Myocardial oxygen and lactate extractions returned to their control values following prazosin injection. Regional left ventricular perfusion was measured using tracer microspheres in five additional dogs. Stellate stimulation increased subepicardial and subendocardial perfusion by 30%. Prazosin increased both subepicardial and subendocardial perfusion by an additional 36%. Stellate stimulation increased norepinephrine concentration in the coronary sinus, but no further increase was noted after blockage of alpha 1-receptors by prazosin. Thus, during sympathetic stimulation, an alpha 1-vasoconstriction existed uniformly across the left ventricular wall. However, blockade of this vasoconstriction was associated with an increase in contractile function only in the deeper muscle layers.

This study was performed to examine whether an alpha 1-constrictor tone, which limits coronary functional hyperemia during exercise, imposes a significant limitation on global cardiac performance as determined by cardiac output (CO). Seven dogs were chronically instrumented to measure left ventricular pressure (LVP), maximum rate of rise of LVP (dP/dtmax), heart rate (HR), mean aortic pressure (AoP), circumflex blood flow velocity (CFV), and CO at rest and during submaximal exercise. Either the selective alpha 1-adrenergic antagonist prazo (0.5 mg) or the vasodilator adenosine was administered into the circumflex artery during exercise at 6.4 kilometers per hour (kph)/16% treadmill incline. Exercise caused significant increase in mean AoP, HR, LVP, dP/dtmax, CFV, stroke volume (SV), and CO, whereas systemic vascular resistance (SVR) was significantly reduced. After intracoronary alpha 1-blockade with prazosin, CFV, dP/dtmax, SV, and CO increased further (17 +/- 2, 19 +/- 3, 16 +/- 2, and 17 +/- 2%, respectively) without changing mean AoP, HR, or SVR. Comparable increases were observed when CFV was increased by a similar degree using the direct vasodilator adenosine. These results indicate that increasing coronary flow by removing a coronary alpha 1-constrictor tone with prazosin or by direct vasodilation with adenosine during submaximal exercise leads to an increase in myocardial oxygen supply and, as a result, cardiac pump performance (SV and CO).

This study tested the hypothesis that an alpha-adrenergic coronary constrictor tone increases with the intensity of exercise and imposes a limitation on transmural myocardial blood flow and contractile function during strenuous levels of exercise. Nine (9) dogs were chronically instrumented to measure left circumflex blood flow (CBF), global myocardial contractile function (dP/dtmax), and regional myocardial contractile function (maximal rate of segmental shortening, dL/dtmax). The dogs were subjected to a graded sub-maximal exercise test with increasing workloads encompassing 4.8 kph and 6.4 kph, 0, 4, 8, 12, and 16% incline. On separate days, either vehicle (sterile water) or the specific alpha 1-adrenergic receptor antagonist prazosin (1 microgram.kg-1.min-1) was infused into the circumflex artery during exercise. Removal of an alpha 1-receptor mediated coronary constrictor tone resulted in a 15 +/- 7%, 24 +/- 9%, and 35 +/- 10% greater increase in CBF compared with vehicle at the three most strenuous levels of exercise, respectively. Regional left ventricular blood flow was measured using labeled microspheres in four (4) additional dogs. Endocardial and epicardial blood flow increased equally by 16% during exercise after prazosin, such that the endocardial/epicardial flow ratio did not change. The augmentation in CBF after alpha 1-blockade was associated with significant increases in both regional and global left ventricular contractile function. These studies indicate that a uniformly distributed transmural coronary alpha 1-constrictor tone increases in magnitude with increasing levels of exercise intensity and, as a result, imposes a significant limitation on myocardial function.

Right coronary (RC) autoregulation and right ventricular (RV) function were assessed in conscious dogs, chronically instrumented to measure RC flow and RC pressure (RCP) as a hydraulic occluder on the RC was inflated. Dogs were then anesthetized, and RC autoregulation and RV function were again assessed. In the conscious state, moderate RC autoregulation was present with closed loop gains (Gc) of 0.59–0.27 as RCP was reduced from 100 to 40 mmHg. In the anesthetized state, Gc was not significantly less than in the conscious state at RCP >50 mmHg. The range and potency of RV autoregulation were greater in both groups than for previously reported findings in anesthetized dogs with RC perfused by an extracorporeal system. RV contractile function was well maintained in conscious and anesthetized dogs at RCP >45 mmHg. We conclude the following: 1) modest RC autoregulation is present in the conscious dog, 2) anesthesia limits the range but not the degree of RC autoregulation, 3) extracorporeal perfusion systems appear to depress RC autoregulation, and 4) RV contractile function remains constant in both conscious and anesthetized dogs until RCP falls below 50 mmHg.

The role of coronary vascular adrenergic receptors in changing coronary flow was studied in dogs instrumented to measure left circumflex artery blood flow (CBF), mean coronary artery blood pressure (CBP), and heart rate (HR). Norepinephrine (NE), isoproterenol (IP), and phenylephrine (PH) were injected into the left circumflex artery before and after selective intracoronary alpha- and beta 1- or combined beta 1- and beta 2-receptor blockade. NE, IP, and PH did not alter CBP (112 +/- 6 mmHg). In addition, IP and PH did not affect HR (103 +/- 4 beats/min). NE increased HR to 150 +/- 6 beats/min, which was eliminated by blocking beta 1-receptors with atenolol and by removing the left stellate ganglion. IP increased CBF from 65 +/- 9 to 115 +/- 16 ml/min (mediated by both beta 1- and beta 2-receptors). PH caused an alpha-receptor-mediated coronary vasoconstriction (42 +/- 5 ml/min), which was potentiated by beta 1- and beta 2-receptor blockade. NE caused a biphasic flow response. CBF initially increased to 117 +/- 14 ml/min (mediated predominantly by beta 1-receptors) followed by a prolonged decrease to 54 +/- 7 ml/min (mediated by alpha-receptors). Removing the left stellate ganglion did not affect the CBF response to NE. These data indicate that PH directly stimulates coronary alpha-receptors and IP stimulates myocardial beta 1- and coronary beta 2-receptors. NE also stimulates myocardial cells causing a reflex that increases HR and indirectly increases CBF. The vasoconstriction to NE and PH was not evident after pentobarbital anesthesia, whereas the coronary vasodilation and increase in HR to NE was still present.