Coronary Reactive Hyperemic Responses Research Articles

Adenosine A 2A Receptor and Vascular Response: Role of Soluble Epoxide Hydrolase, Adenosine A 1 Receptor and Angiotensin‐II

Previously, we reported that the coronary reactive hyperemic response (CRH) was reduced in adenosine A2A receptor-null (A2AAR-/-) mice, and reversed by soluble epoxide hydrolase (sEH) inhibitor. However, this is unknown in aortic vascular response; therefore, we hypothesized that A2AAR-gene deletion in mice (A2AAR-/-) affects adenosine-induced vascular response by increasing sEH and adenosine A1 receptor (A1AR) activities. A2AAR-/- mice showed an increase in sEH, AI AR and CYP450-4A protein expression but decrease in CYP450-2C compared to C57Bl/6 mice. NECA (adenosine-analog) and CCPA (adenosine A1 receptor-agonist)-induced dose-dependent vascular response was tested with t-AUCB (sEH-inhibitor) and angiotensin-II (Ang-II) in A2AAR-/- vs. C57Bl/6 mice. In A2AAR-/-, NECA and CCPA-induced increase in dose-dependent vasoconstriction compared to C57Bl/6 mice. However, NECA and CCPA-induced dose-dependent vascular contraction in A2AAR-/- was reduced by t-AUCB with NECA. Similarly, dose-dependent vascular contraction in A2AAR-/- was reduced by t-AUCB with CCPA. In addition, Ang-II enhanced NECA and CCPA-induced dose-dependent vascular contraction in A2AAR-/- with NECA. Similarly, the dose-dependent vascular contraction in A2AAR-/- was also enhanced by Ang-II with CCPA. Furthermore, t-AUCB reduced Ang-II-enhanced NECA and CCPA-induced dose-dependent vascular contraction in A2AAR-/-mice. Our data suggest that the dose-dependent vascular contraction in A2AAR-/- mice depends on increase in sEH, A1AR and CYP4A protein expression.

Adenosine A2A receptor and vascular response: role of soluble epoxide hydrolase, adenosine A1 receptor and angiotensin-II.

Previously, we have reported that the coronary reactive hyperemic response was reduced in adenosine A2A receptor-null (A2AAR-/-) mice, and it was reversed by the soluble epoxide hydrolase (sEH) inhibitor. However, it is unknown in aortic vascular response, therefore, we hypothesized that A2AAR-gene deletion in mice (A2AAR-/-) affects adenosine-induced vascular response by increase in sEH and adenosine A1 receptor (A1AR) activities. A2AAR-/- mice showed an increase in sEH, AI AR and CYP450-4A protein expression but decrease in CYP450-2C compared to C57Bl/6 mice. NECA (adenosine-analog) and CCPA (adenosine A1 receptor-agonist)-induced dose-dependent vascular response was tested with t-AUCB (sEH-inhibitor) and angiotensin-II (Ang-II) in A2AAR-/- vs. C57Bl/6 mice. In A2AAR-/-, NECA and CCPA-induced increase in dose-dependent vasoconstriction compared to C57Bl/6 mice. However, NECA and CCPA-induced dose-dependent vascular contraction in A2AAR-/- was reduced by t-AUCB with NECA. Similarly, dose-dependent vascular contraction in A2AAR-/- was reduced by t-AUCB with CCPA. In addition, Ang-II enhanced NECA and CCPA-induced dose-dependent vascular contraction in A2AAR-/- with NECA. Similarly, the dose-dependent vascular contraction in A2AAR-/- was also enhanced by Ang-II with CCPA. Further, t-AUCB reduced Ang-II-enhanced NECA and CCPA-induced dose-dependent vascular contraction in A2AAR-/- mice. Our data suggest that the dose-dependent vascular contraction in A2AAR-/- mice depends on increase in sEH, A1AR and CYP4A protein expression.

A kinetic model of coronary reactive hyperemic response to transient ischemia

A kinetic model is proposed to delineate the factors that determine the coronary reactive hyperemic response (RHR) to transient ischemia. The model comprises of myocardial-interstitial (M) and vascular (V) compartments. Vasodilator metabolites (VM) are produced in the M compartment during the interval of coronary occlusion. The rate of VM production is dependent on the flow rate during the ischemic period, the ratio of excess flow above the control level (R) to the loss of flow during occlusion period (D), the amount of oxygen stored and the degree of vasodilation in the V compartment prior to occlusion. Following a complete release of occlusion, VM are transported from the M to V compartment and are washed out or degraded with time. The time course of RHR is determined by the coronary patency which is proportional to VM concentration in the V compartment. Based on a set of numerical constants, the model is tested by simulating RHR to the various occlusion manoeuvres: a pair of 10 sec occlusions separated by brief release, a 15 sec release followed by a second brief occlusion, a brief release of an occlusion followed by restricted inflow and a period of restricted inflow after occlusion. The simulated results fit the experimental R/D and RH durations data of canine hearts. Factors that determine the impairment of RH capacity in coronary stenosis are suggested in terms of the model scheme.

A kinetic model of coronary reactive hyperemic response to transient ischemia

A kinetic model of coronary reactive hyperemic response to transient ischemia

Endothelial control of vascular and myocardial function in heart failure.

The effect of vascular endothelium, endocardium, and coronary endothelium on vascular tone and myocardial contraction-relaxation sequence in heart failure is discussed. Vascular endothelium affects underlying vascular smooth muscle through paracrine secretion of relaxing and constricting factors. In heart failure, systemic vasoconstriction results not only from neuroendocrine activation, but also from disturbed local endothelial control of vascular tone because of impaired endothelial-dependent vasodilation and because of increased plasma concentration of endothelin. Experimental evidence obtained in isolated cardiac muscle strips established the influence of endocardial endothelium on the duration of myocardial contraction and on the onset of myocardial relaxation. By analogy to vascular endothelium, both diffusible agents that abbreviate (endothelial-derived relaxation factor-like substance) and those that prolong (endocardin) myocardial contraction have been shown to be released from the endocardium. Similar agents are released from the coronary endothelium and, because of the close proximity of capillaries and myocytes, could exert a major effect on myocardial performance. Endothelial dysfunction and concomitant lack of release of myocardial relaxant factors could explain left ventricular relaxation abnormalities observed in the cardiac allograft or in arterial hypertension. Since endothelial-derived relaxation factor or nitric oxide mediates the coronary reactive hyperemic response, a negative inotropic action of nitric oxide could contribute to left ventricular failure when left ventricular wall stress is elevated, as occurs after myocardial infarction in the noninfarcted zone and during left ventricular volume or pressure overload in the absence of adequate hypertrophy.

NG-nitro-L-arginine attenuates flow debt repayment in the reactive hyperemic response of the open-chest dog coronary artery: contribution of endothelium-derived relaxing factor.

To test the hypothesis that the endothelium-derived relaxing factor (EDRF) contributes to coronary vasodilation induced by myocardial ischemia, we examined the effect of NG-nitro-L-arginine (a potent and selective inhibitor of EDRF release) on the coronary reactive hyperemic response in the open-chest dogs. Intracoronary infusion of NG-nitro-L-arginine at a coronary plasma concentration of 5 x 10(-5) M had no effect on hemodynamics and myocardial oxygen metabolism, but attenuated repayment of the flow debt by an average of 20.4% and 20.0% following coronary occlusion for 10 sec and 20 sec, respectively. Concomitant infusion of NG-nitro-L-arginine at the same concentration and 8-phenyltheophylline (a potent adenosine receptor blocker) at a coronary plasma concentration of 10(-5) M further attenuated flow debt repayment following 10 sec and 20 sec of coronary occlusion by 47.7 and 59.4%, respectively. These results indicate that EDRF plays a significant role in the coronary reactive hyperemic response and may cause vasodilation independently of adenosine-mediated vasodilation following coronary occlusion.

The Effects of Cardiopulmonary Bypass and Cold Cardioplegia on Coronary Flow Velocity and the Reactive Hyperemic Response in Patients and Dogs

In normal coronary arteries, reactive hyperemic responses to a 20-second occlusion, an index of coronary reserve, usually demonstrate a peak-to-resting flow velocity ratio of 4:1 or more. Most intraoperative studies that have assessed reactive hyperemic responses in bypassed vessels have reported peak-to-resting flow velocity ratios of 2:1 or less following a 20-second occlusion. These decreased reactive hyperemic responses could be due to coronary vasodilatation after cardiopulmonary bypass or to an inadequate physiological result of the surgical procedure. In 14 patients with angiographically normal coronary arteries, the peak-to-resting flow velocity ratio following a 20-second coronary occlusion decreased significantly ( p < 0.05) from 4.4 ± 0.2 (mean ± standard error) before bypass to 3.0 ± 0.3 after bypass. In a similar dog model, the peak-to-resting flow velocity ratio decreased by 36 to 52% during the first hour following one hour of cardiopulmonary bypass and cardioplegia. During the same period, left ventricular perfusion increased 21 to 30%, mean arterial pressure and coronary vascular resistance decreased, and myocardial oxygen consumption was unchanged. In a second group of dogs studied for the effects of duration (200 to 240 minutes) of anesthesia and thoracotomy alone, peak-to-resting flow velocity ratio was significantly lower. These clinical and experimental studies suggest that major coronary vasodilatation occurs early following cardiopulmonary bypass and cold cardioplegia, and may contribute to the blunted coronary reactive hyperemic responses reported during this time. Consequently, an intraoperative peak-to-resting flow velocity ratio of 3:1 for bypassed coronary arteries may represent an excellent physiological result.

Thyroxine-induced left ventricular hypertrophy in the rat. Anatomical and physiological evidence for angiogenesis.

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)

Transluminal, subselective measurement of coronary artery blood flow velocity and vasodilator reserve in man.

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.

Effects of long-term cardiac hypertrophy on coronary vasodilator reserve in SHR rats

The effects of long-term left ventricular (LV) hypertrophy on coronary vascular reserve have not been extensively investigated. To test the hypothesis that the duration of LV hypertrophy may modulate coronary vascular reserve, a newly developed pulsed Doppler flowmeter was used to compare the characteristics of coronary reactive hyperemia in Wistar Kyoto (WKY) and spontaneously hypertensive (SHR) rats. The data suggest that coronary reactive hyperemic responses in the rat are markedly different from those in larger animals and humans, e.g., peak/rest blood flow velocity ratio and the repayment/debt area ratio were 30 to 50% of those observed in larger laboratory animals. Because minimal coronary vascular resistance is similar in the rat and larger animals, the relatively high myocardial oxygen consumption at rest and consequent high myocardial blood flow at rest probably account for the alteration of coronary reactive hyperemia in the rat. In SHR rats, the characteristics of coronary reactive hyperemia decreased during developing (3-month-old) and peak (7-month-old) LV hypertrophy compared with those in their age-matched WKY controls. However, in 12-month-old SHR rats with stable LV hypertrophy, the coronary reactive hyperemic response was similar to that of 12-month-old WKY rats. Mean arterial pressures were significantly elevated in each of the 3 SHR groups. These data suggest a significant decrement in coronary vascular reserve during actively developing and peak LV hypertrophy, but the decrement disappears during stabilized hypertrophy. These studies suggest that the duration of LV hypertrophy may modulate the interaction between pathologic increases in cardiac mass and growth of the coronary vasculature.

Subendocardial underperfusion during acute aorticopulmonary shunting in anesthetized dogs

Changes in regional coronary hemodynamics during A-P shunting were studied in open-chest anesthetized dogs. During direct A-P shunting coronary driving pressure fell which resulted in decreased coronary flow to the subendocardial region of the left ventricle and abnormal coronary reactive hyperemic responses. When aortic diastolic pressure was augmented during indirect A-P shungting, underperfusion of the subendocardial region was corrected and the coronary hyperemic responses returned to normal. Since shunt flows were equal in both groups, the magnitude of the shunt was not a factor in reducing coronary flow. The present study indicates that acute A-P shunts may cause underperfusion of the left ventricular subendocardium. Thus, under these conditions, the left ventricle is stressed by a combination of an increased workload in the face of reduced subendocardial coronary flow.

Experimental subendocardial ischemia in dogs with normal coronary arteries.

Subendocardial ischemia without anatomic coronary artery obstruction may result from a discrepancy between metabolic needs and available blood supply. We studied this in open-chest anesthetized dogs and measured pressures in aorta and left ventricle (LV), phasic left coronary arterial blood flow (CBF) by electromagnetic flowmeter, total CBF and LV subendocardial (endo) and subepicardial (epi) flow with radioactive microspheres 8-10µ, in diameter. Since LV Subendocardial flow is mainly or entirely diastolic, it should depend on coronary driving pressure and duration of diastole (i.e., the area between aortic and left ventricular diastolic pressures). This diastolic pressure time index (DPTI) was varied by opening arteriovenous fistulas to lower aortic diastolic pressure, constricting the ascending aorta to raise LV diastolic pressure and pacing to shorten diastole. Myocardial oxygen needs were estimated from the tension time index (TTI). Normal endo-epi flow ratios per gram (1:1) fell to 0.1:1 with these procedures and paralleled a fall in diastolic flow fraction (often nearly zero) and postischemic coronary reactive hyperemic responses. These changes occurred despite normal or raised mean CBF and 300-500% increase in systolic CBF. The altered flow ratios were best predicted by relating them to the ratio of DPTI (supply) to TTI (demand).