Increase In Coronary Blood Flow Research Articles

Effect of Nifedipine on C-Reactive Protein Levels in the Coronary Sinus and on Coronary Blood Flow In Response to Acetylcholine in Patients With Stable Angina Pectoris Having Percutaneous Coronary Intervention

The effects of nifedipine on inflammation and endothelial function in the coronary circulation were studied in patients who had angina pectoris (n = 17). Long-term treatment with nifedipine (nifedipine CR, 20 mg/day for 4 months) decreased levels of C-reactive protein in the coronary sinus (from 0.35 +/- 0.09 mg/dl to 0.07 +/- 0.01 mg/dl, mean +/- SEM, p <0.05) and enhanced acetylcholine-induced increases in coronary blood flow. Thus, nifedipine is effective in decreasing inflammation and incresing endothelial function in the coronary circulation.

Increased Ambulatory Pulse Pressure Is a Strong Risk Factor for Coronary Endothelial Vasomotor Dysfunction

This study was aimed to determine the relationship between pulse pressure (PP) and coronary vasomotor dysfunction, a predictor of coronary events. Pulse pressure is a strong risk factor for coronary artery disease (CAD). However, the mechanisms by which an increase in PP affects the pathogenesis of CAD are unclear. Ambulatory blood pressure (BP) monitoring for 24 h was performed in 103 consecutive patients with normal coronary angiograms (51 hypertensive and 52 normotensive; age 42 to 70 years). The relationship between changes in coronary arterial diameter and blood flow during an intracoronary infusion of acetylcholine (ACh) (5, 10, 50 microg/min), and BP parameters, and other traditional risk factors was evaluated using univariate and multivariate linear regression analyses. With multivariate analyses, the 24-h PP showed an inverse correlation with the epicardial coronary dilator response to ACh independently of other covariates including age, smoking, and 24-h systolic BP in normotensive as well as hypertensive patients. Furthermore, multivariate analysis showed that the 24-h PP was inversely and independently correlated with the increase in coronary blood flow in response to ACh. The dilator response of epicardial coronary arteries to nitrate was not significantly correlated with 24-h PP. Increased 24-h PP is independently associated with endothelial vasomotor dysfunction in conduit and resistance coronary arteries irrespective of the presence of hypertension. Increased ambulatory PP may have an intimate relation to coronary endothelial vasomotor dysfunction.

Coronary blood flow

Arterial oxygen extraction is 70–80%, compared with 25% for the rest of the body. Therefore, increased oxygen consumption must principally be met by an increase in coronary blood flow, which may increase fivefold during exercise. Supply usually closely matches any change in demand. However, an increase in coronary blood flow can independently increase myocardial oxygen consumption (Gregg effect). 2 Thismaybeexplainedbyfullcoronary arteries splinting the heart and increasing the end-diastolic fibre length and contractility.

Poly(ADP-ribose) polymerase inhibition attenuates biventricular reperfusion injury after orthotopic heart transplantation☆

Poly (ADP-ribose) polymerase (PARP) activation plays a key role in free radical induced injury in ischemia/reperfusion. We investigated the effects of INO-1001 a novel PARP inhibitor on postischemic myocardial and endothelial function. In dogs, 12 orthotopic heart transplantations were performed after 4 h ischemic preservation. At the beginning of reperfusion either saline vehicle (control, n=6), or INO-1001 (1 mg/kg, n=6) was applied. Before explantation and after 120 min of reperfusion we measured biventricular pressure-volume relationships by a combined conductance catheter and the adaptation potential of the right ventricle to acute afterload increase by pulmonary banding. Coronary blood flow (CBF), vasoreactivity, PARP-activation and ATP-content were also determined. INO-1001 led to significantly better recovery of contractility (91+/-3 vs. 44+/-7%, P<0.05) and CBF (44+/-4 vs. 29+/-3 ml/min, P<0.05) and higher increase in CBF after acetylcholine (61+/-10 vs. 27+/-8%, P<0.05). In addition, the inotropic adaptation potential of the right ventricle to an increased afterload was better preserved after INO-1001. ATP content was significantly higher in the INO-1001 group (11.0+/-2.1 vs. 4.5+/-1.1 micromol/g drw). Immunohistology revealed PARP activation in the control group which was abolished by INO-1001 treatment. PARP inhibition reduces myocardial and endothelial reperfusion injury after orthotopic heart transplantation.

Normovolemic hemodilution and the heart

At the level of the heart, oxygen extraction is already nearly maximal under resting conditions. 3 Therefore, maintenance of myocardial oxygen delivery during isovolemic hemodilution depends essentially on the increase in coronary blood flow. This is achieved by a reduction in coronary vascular resistance related to the decreased blood viscosity but also to specific coronary vasodilation as demonstrated by analysis of vascular hindrance (vascular resistance/blood viscosity). 3 In addition, isovolemic hemodilution is associated with an increased cardiac work resulting in an augmentation of myocardial oxygen demand. Indeed, heart rate, 4 but also possibly myocardial contractility, 5 has been shown to increase during isovolemic hemodilution. When the hematocrit is reduced to 10 to 12%, myocardial oxygen consumption more than doubles. 6 In these conditions, coronary vasodilatation is near maximal. Below a hematocrit of 10%, coronary blood flow can no longer match the increased myocardial oxygen demand and ischemia develops, ultimately resulting in cardiac failure. This is in accordance with experimental data showing a decrease in systemic oxygen uptake at hematocrit values close to 10%. 7 As maximal coronary blood flow is not influenced by hemodilution, the coronary reserve (the ratio between maximal coronary blood flow and resting coronary blood flow) is significantly reduced during isovolemic anemia. Geha 8 demonstrated in intact dogs a 50% reduction in the coronary flow reserve when hematocrit is decreased from 43 to 20%. This indicates the vulnerability of the heart during anemia, especially if coronary artery disease (decreased maximal coronary blood flow) or higher work demands on the myocardium should co-exist. The lowest tolerable hematocrit in coronary artery disease patients is not known but experimental data in animals with extrinsically applied coronary stenosis have demonstrated a significant increase in the value of the hematocrit associated with the development of cardiac failure. 9 Based on a theoretical analysis, Kettler 10 estimated that coronary artery disease patients may tolerate some degree of hemodilution intraoperatively but will require a higher hematocrit in the early postoperative period to meet the increased tissue, and especially cardiac, oxygen demand. This has been confirmed by the study of Nelson et al., 11 showing that a postoperative hematocrit below 28% was associated with increased myocardial ischemic episodes and morbid cardiac events. Cardiovascular disease patients with a lower preoperative hematocrit have an increased risk of death when compared to non-cardiovascular disease patients with the same preoperative hematocrit. 12

Role of β 2 Adrenergic Receptors in Human Atherosclerotic Coronary Arteries

Adrenergic regulation of coronary vasomotion is balanced between alpha1-adrenergic-mediated (alpha1-AR) constriction and beta2-adrenergic-mediated (beta2-AR) relaxation. This study aimed at assessing the role of beta2-ARs in normal, mildly atherosclerotic, and stenotic human coronary arteries. During intracoronary (IC) infusion of increasing doses of the beta2-AR agonist salbutamol (0.15, 0.3, and 0.6 mug/min) and the endothelial vasodilator acetylcholine (1, 3, and 10 microg/min), we measured (1) changes in lumen diameter (LD) by quantitative coronary angiography in 34 normal, 55 mildly atherosclerotic, and 42 stenotic coronary artery segments and (2) changes in average peak velocity (APV) and coronary blood flow (CBF) with the use of Doppler flow wire in 11 normal, 10 mildly atherosclerotic, and 11 stenotic coronary arteries. In 6 of 11 stenotic coronary arteries, the protocol was repeated after an IC bolus (12 microg/kg) of the alpha-adrenergic blocker phentolamine. In 6 of 11 normal coronary arteries, the protocol was repeated after an IC infusion (60 micromol/min) of N(G)-monomethyl-L-arginine (L-NMMA), a nitric oxide inhibitor. Neither salbutamol IC infusion nor acetylcholine significantly changed heart rate or blood pressure, whereas L-NMMA slightly increased blood pressure. In normal coronary arteries, salbutamol increased LD (LD max %: 11+/-2, P<0.05), APV (APV max %: 53+/-17, P<0.05), and CBF (CBF max %: 57+/-17, P<0.05), whereas L-NMMA caused a blunted APV (APV max %: 27+/-6, P<0.05) and CBF (CBF max %: 29+/-6, P<0.05) response to salbutamol. In mildly atherosclerotic coronary arteries, the salbutamol increase in LD (LD max %: 10+/-2, P<0.05), APV (APV max %: 33+/-12, P<0.05), and CBF (CBF max %: 37+/-12, P<0.05) was preserved. In stenotic coronary arteries, salbutamol induced a paradoxical reduction in LD (LD max %: -6+/-2, P<0.05), APV (APV max %: -15+/-9, P<0.05), and CBF (CBF max %: -15+/-6, P<0.05), which was no longer observed after phentolamine. Acetylcholine increased LD (LD max %: 14+/-3, P<0.05), APV (APV max %: 61+/-20, P<0.05), and CBF (CBF max %: 67+/-19, P<0.05) in normal coronary arteries. In mildly atherosclerotic coronary arteries, acetylcholine induced a significant reduction in LD (LD max %: -15+/-2, P<0.05) and no changes in APV (APV max %: -6+/-13, P=NS) and CBF (CBF max %: -10+/-13, P=NS). In stenotic coronary arteries, acetylcholine significantly reduced LD (LD max %: -15+/-3, P<0.05), APV (APV max %: -15+/-9, P<0.05), and CBF (CBF max %: -15+/-6, P<0.05). In severely atherosclerotic coronary arteries, beta2-adrenergic vasodilatation is impaired, and this might contribute to alter the vasomotor balance, further precipitating myocardial ischemia during sympathetic activation.

Brachial Artery Flow-Mediated Vasodilation Is Correlated with Coronary Vasomotor and Fibrinolytic Responses Induced by Bradykinin

Endothelium plays a key role in the regulation of not only vascular tone but also thrombosis and fibrinolysis. Brachial flow-mediated vasodilation (FMD) provides a noninvasive method of assessing coronary endothelial dysfunction. However, no data are available on the relationship between brachial FMD and coronary fibrinolytic activity. Thus, we examined the relationship between brachial FMD and coronary vasomotor and fibrinolytic function. Brachial FMD by reactive hyperemia was defined as a change in diameter relative to the baseline as measured using high-resolution ultrasound. Coronary blood flow (CBF) responses to bradykinin (BK) were analyzed using Doppler flow velocity measurement. Coronary release of tissue-type plasminogen activator (tPA) antigen was determined as the transcardiac tPA gradient x [CBF x (100 - hematocrity 100)]. In 77 patients with normal coronary arteries, BK caused dose-dependent increases in CBF, transcardiac tPA gradient, and coronary tPA release. Among them, brachial FMD, the BK-induced CBF increase, and the coronary tPA release induced by BK in 14 diabetic subjects were lower than those in 63 non-diabetic subjects (p < 0.05, respectively). Brachial FMD correlated with the CBF increase, transcardiac tPA gradient (0.2 microg/min: r = 0.25; 0.6 microg/min: r = 0.43; 2.0 microg/min: r = 0.34; p < 0.05, respectively), and coronary tPA release (0.2 microg/min: r = 0.24; 0.6 microg/min: r = 0.44; 2.0 microg/min: r = 0.32; p < 0.05, respectively) in response to BK. Brachial FMD correlated significantly with coronary endothelial function and fibrinolytic activity in response to BK. Type 2 diabetes impaired coronary and brachial endothelium-dependent vasodilation and coronary fibrinolytic activity.

Changes of Coronary Blood Flow in Vasospastic Angina under Cold Stimulation by Transthoracic Doppler Echocardiography

This study was done to evaluate changes of microvascular function under cold stimulation by measuring coronary flow velocities (CFVs) in vasospastic angina (VA) patients using transthoracic Doppler echocardiography (TTDE). 14 patients with VA and 15 healthy controls were included. CFVs were measured at the distal left anterior descending coronary artery by TTDE at baseline and under cold stimulation. Hyperemia was induced by intravenous adenosine infusion (140 µg/kg/min). At baseline, CFVs and coronary flow reserve (CFR) were not different between controls and VA patients. Under cold stimulation, the degree of increment of CFV with adenosine was lower in VA patients than in controls. Comparing baseline with cold stimulation, coronary flow reserve (CFR) increased (3.1±0.7 to 3.8±1.0, p=0.06) in controls. In contrast, in VA patients, CFR was decreased (2.8±0.9 to 2.6±0.7, p=0.05) and coronary vascular resistance index markedly increased (0.35 to 0.43, p=0.01). Throughout the study, no patient experienced chest pain or ECG changes. In VA patients, CFR was preserved at baseline, but coronary blood flow increase in response to cold stimulation was blunted and CFR was decreased. These findings suggest that endothelial dependent vasodilation is impaired at the coronary microvascular and the epicardial artery level in VA under cold stimulation.

Selective blockade of serotonin 5-HT2A receptor increases coronary blood flow via augmented cardiac nitric oxide release through 5-HT1B receptor in hypoperfused canine hearts

Serotonin (5-hydroxytryptamine [5-HT]), which induces vasoconstriction via 5-HT2A receptors in smooth muscle cells and vasodilation through activating nitric oxide (NO) synthase (NOS) via 5-HT1B receptors in endothelial cells, possesses divergent effects on regulating vascular tone. These facts lead us to consider that sarpogrelate, a 5-HT2A receptor blocker, may increase coronary blood flow (CBF) via either attenuation of vasoconstriction through 5-HT2A receptor blockade or augmentation of vasodilation by relative stimulation of NOS through 5-HT1B receptor and we tested this hypothesis in ischemic canine hearts. In open chest dogs, coronary perfusion pressure was reduced so that CBF was decreased to 33% of the baseline and kept constant. Thereafter, sarpogrelate was infused selectively into the left anterior descending artery with and without either an inhibitor of NOS (NG-nitro- l-arginine methyl ester ( l-NAME)) or a 5-HT1B receptor antagonist (GR55562). An intracoronary administration of sarpogrelate increased CBF (34.0 ± 4.0 to 44.5 ± 4.4 ml/100 g/min, P < 0.05), along with the cardiac NOx release (3.2 ± 0.6 to 6.8 ± 1.2 nmol/ml, P < 0.05). The increases in both CBF and NOx by sarpogrelate were completely blunted by the co-administration of either l-NAME or GR55562. Interestingly, sarpogrelate increased the cardiac serotonin release (–4.8 ± 3.2 vs. 22.1 ± 1.5 ng/ml, P < 0.05, respectively) in the hypoperfused heart. Immunohistochemical analysis showed that sarpogrelate induced serotonin production in ischemic cardiac myocytes. These results suggest that sarpogrelate increases CBF via augmented cardiac NO production through 5-HT1B receptor activation along with the blockade of 5-HT2A receptors. The increase in cardiac release of serotonin may increase NO production in the ischemic heart.

Fréquence cardiaque et ischémie myocardique expérimentale

Every increase in heart rate represents a poor prognostic factor in cardiology, and multiple arguments have now led to the belief that reducing heart rate is a major therapeutic challenge. A comparison of the pharmacological effects of If current inhibitors such as zatebradine, and more recently ivabradine (Procoralan®) and β-blockers, have demonstrated experimentally that reductions in heart rate and myocardial contractile force contribute equally to the reduction in myocardial oxygen consumption in the normal heart. Conversely, at a similar level of reduction in heart rate, the lack of a concomitant negative inotropic effect with ivabradine affords longer diastolic perfusion times than β-blockers. In other words, a negative inotropic effect is deleterious when an increase in coronary blood flow is required. Hence, if the anti-ischaemic effects afforded by an If current inhibitor and a β-blocker are roughly comparable, the former are clearly of higher benefit than β-blockers in the treatment of myocardial dysfunction accompanying cardiac ischaemia-reperfusion, especially myocardial stunning.

In vitro and in vivo studies of F 0F 1ATP synthase regulation by inhibitor protein IF 1 in goat heart

A method has been developed to allow the level of F 0F 1ATP synthase capacity and the quantity of IF 1 bound to this enzyme be measured in single biopsy samples of goat heart. ATP synthase capacity was determined from the maximal mitochondrial ATP hydrolysis rate and IF 1 content was determined by detergent extraction followed by blue native gel electrophoresis, two-dimensional SDS-PAGE and immunoblotting with anti-IF 1 antibodies. Anaesthetized open-chest goats were subjected to ischemic preconditioning and/or sudden increases of coronary blood flow (CBF) (reactive hyperemia). When hyperemia was induced before ischemic preconditioning, a steep increase in synthase capacity, followed by a deep decrease, was observed. In contrast, hyperemia did not affect synthase capacity when applied after ischemic preconditioning. Similar effects could be produced in vitro by treatment of heart biopsy samples with anoxia (down-regulation of the ATP synthase) or high-salt or high-pH buffers (up-regulation). We show that both in vitro and in vivo the same close inverse correlation exists between enzyme activity and IF 1 content, demonstrating that under all conditions tested the only significant modulator of the enzyme activity was IF 1. In addition, both in vivo and in vitro, 1.3–1.4 mol of IF 1 was predicted to fully inactivate 1 mol of synthase, thus excluding the existence of significant numbers of non-inhibitory binding sites for IF 1 in the F 0 sector.

Effects of levosimendan on coronary vasomotor regulation and myocardial oxygen extraction

Introduction: Levosimendan (Abbott Laboratories, Abbott Park, IL) is a calcium sensitizer that has beneficial effects in patients with decompensated heart failure (HF). This agent binds to troponin C and exerts both inotropic and vasodilatory effects. In vitro studies showed levosimendan dilates harvested porcine coronary arteries. Aim: The purpose of this study is to assess the coronary hemodynamic effects of levosimendan in humans and to measure changes in myocardial oxygen extraction. Methods: Patients referred for cardiac catheterization at the University of California-San Francisco were enrolled. Patients with the following were excluded: baseline SBP ≤ 95 mmHg, on vasopressors, had received nitroglycerin or calcium blockers within 24 hours, severe renal or hepatic impairment, hypokalemia, long QT, or a contraindication to heparin. After diagnostic catheterization and full heparinization, a 0.014-inch Doppler flow wire was positioned in the proximal portion of an unobstructed coronary artery to measure average peak velocity (APV). Right heart catheterization and simultaneous blood gas sampling from the coronary sinus and aorta were performed at baseline and 30-minutes after beginning the IV infusion of levosimendan (24 mcg/kg bolus over 10-minutes). Quantitative coronary angiography was performed at baseline, 15-min, and 30-min. CBF=(coronary artery area)(APV)(0.6). Coronary resistance=(mean arterial - right atrial pressure)/CBF. Results: Ten patients were enrolled. The mean age was 60±14 years (range 42–86). Two were female. Six had coronary disease, 4 had HF, and 2 had diabetes. Mean LVEF was 46±18% (range 21–71%). Thirty minutes after beginning levosimendan, pulmonary capillary wedge decreased 37% (p=0.009), cardiac output increased 9% (p=0.04), and systemic vascular resistance decreased 18% (p<0.001). Coronary artery diameter increased 9% at 15-min (p=0.001) and 12% at 30-min (p=0.01). Coronary artery APV did not change. CBF increased 40% at 15-min (p=0.04) and 45% at 30-min (p=0.02). Coronary resistance decreased 27% at 15-min (p=0.0006) and 36% at 30-min (p=0.03). Myocardial oxygen extraction decreased 9% at 30-min (p=0.04). Conclusions: Levosimendan acutely dilated epicardial coronary arteries. There was no vasodilatory effect on the resistance arteries. Coronary blood flow increased, while coronary resistance decreased at 15- and 30-minutes. This increase in coronary blood flow was not associated with myocardial ischemia as levosimendan resulted in a significant decrease in myocardial oxygen extraction.

Effectiveness of enhanced external counterpulsation in patients with left main disease and angina

Enhanced external counterpulsation (EECP) is a noninvasive device that uses three pairs of sequentially inflated pneumatic cuffs applied to the lower extremities and synchronized with the heart beat to provide diastolic augmentation, increase coronary blood pressure and flow, venous return and cardiac output, and decrease afterload. This study examines the safety and effectiveness of EECP therapy in patients with significant left main coronary artery disease (LMD). In all, 2,861 patients enrolled in the International EECP Patient Registry (IEPR) were divided into three groups, those without LMD (n = 2,377), those with LMD and prior CABG (n = 431), and those with unbypassed LMD (n = 53). Patients with LMD, with or without prior CABG, were significantly more likely to have triple-vessel disease (98.1 and 88.7%, respectively) than patients without LMD (41.9%). Post-EECP, 74% without LMD, 75% with LMD with prior CABG, and 65% with unbypassed LMD improved their Canadian Cardiovascular Society (CCS) angina by at least one class (p = NS). There were no differences in the mean decrease in weekly angina episodes (7.1 vs. 8.0 vs. 7.6) and in the mean frequency of weekly nitroglycerin use (6.6 vs. 8.1 vs. 8.9). At 6-month follow-up, the CCS class improved further in all three groups, and there was a further reduction in mean weekly angina episodes (4.7 vs. 4.6 vs. 5.3) and nitroglycerin use (6.5 vs. 6.8 vs. 8.2). Kaplan-Meier life table analysis 8 months after starting EECP demonstrated a major cardiovascular event rate of 11.2% in patients without LMD, 15.6% in LMD with CABG, and 24.3% in LMD without prior CABG. Late mortality in unbypassed LMD was 13.2% (confidence interval [CI] 3.3-23.1) versus 4.8% (CI 2.7-7.1) in LMD with CABG, and 2.8% (CI 2.1-3.5) without LMD (p = 0.0039 by log-rank test). Enhanced external counterpulsation is equally effective in relieving angina in patients with or without LMD. However, the significantly increased late mortality in patients with LMD without prior CABG suggests that early revascularization should be considered in these patients.

Role of mitochondrial aldehyde dehydrogenase in nitroglycerin-induced vasodilation of coronary and systemic vessels: an intact canine model.

It has recently been shown that mitochondrial aldehyde dehydrogenase 2 (mtALDH) catalyzes the formation of 1,2-glyceryl dinitrate and nitrite from nitroglycerin (glyceryl trinitrate [GTN]) within mitochondria, leading to production of cGMP and vasorelaxation. However, whether this mechanism operates in the systemic and coronary beds that subserve the antianginal action of GTN is not known. In this study, we address this question in an intact canine model. Fourteen healthy mongrel dogs (weight, 20 to 25 kg) were studied. Coronary blood flow and hemodynamics were continuously monitored by a pulse Doppler flow probe implanted around the left circumflex coronary artery and with catheters in left ventricle and aorta, respectively. Each dog was given a 1-mL bolus injection of GTN, sodium nitroprusside (SNP), or adenosine through a catheter in the left atrium before and 30 minutes after infusion of cyanamide (17 mg/kg), an inhibitor of mtALDH. Cyanamide significantly inhibited both the classic dehydrogenase and GTN reductase activities of mtALDH in situ and attenuated the coronary blood flow increase and declines in blood pressure and left ventricular end-diastolic pressure produced by GTN in vivo. In contrast, mtALDH inhibition had no effect on the coronary and systemic effects of SNP and adenosine. Our data suggest that mtALDH contributes to GTN biotransformation in vivo and thus at least partly underlies the antianginal mechanism of drug action. Our findings also highlight the differences in biometabolism of clinically relevant nitrosovasodilators.

Matching coronary blood flow to myocardial oxygen consumption.

At rest the myocardium extracts approximately 75% of the oxygen delivered by coronary blood flow. Thus there is little extraction reserve when myocardial oxygen consumption is augmented severalfold during exercise. There are local metabolic feedback and sympathetic feedforward control mechanisms that match coronary blood flow to myocardial oxygen consumption. Despite intensive research the local feedback control mechanism remains unknown. Physiological local metabolic control is not due to adenosine, ATP-dependent K(+) channels, nitric oxide, prostaglandins, or inhibition of endothelin. Adenosine and ATP-dependent K(+) channels are involved in pathophysiological ischemic or hypoxic coronary dilation and myocardial protection during ischemia. Sympathetic beta-adrenoceptor-mediated feedforward arteriolar vasodilation contributes approximately 25% of the increase in coronary blood flow during exercise. Sympathetic alpha-adrenoceptor-mediated vasoconstriction in medium and large coronary arteries during exercise helps maintain blood flow to the vulnerable subendocardium when cardiac contractility, heart rate, and myocardial oxygen consumption are high. In conclusion, several potential mediators of local metabolic control of the coronary circulation have been evaluated without success. More research is needed.

Pathophysiological plasma ET-1 levels antagonize beta-adrenergic dilation of coronary resistance vessels in conscious dogs.

On the basis of in vitro experiments showing that endothelin (ET)-1 interferes with smooth muscle ATP-sensitive K(+) (K(ATP)) channel opening, which is pivotal in beta-adrenergic coronary dilation, we hypothesized that pathophysiological plasma ET-1 levels impair beta-adrenergic dilation of resistance coronary vessels. In conscious instrumented dogs, graded intravenous doses of dobutamine caused the expected inotropic responses. As myocardial O(2) consumption (MVo(2)) increased, the disproportionate rise in coronary sinus (CS) Po(2) indicates that increases in coronary blood flow (CBF) exceeded metabolic requirements, consistent with beta-adrenergic dilation. ET-1 intravenous infusions, to reach pathophysiological plasma levels, reduced slopes of the Po(2)-MVo(2) and CBF-MVo(2) relations. In contrast, the first derivative of left ventricular pressure over time responses to dobutamine were not impaired during ET-1 delivery. Clazosentan, an ET(A) receptor blocker, prevented reduction of the slope of Po(2)-MVo(2) and CBF-MVo(2) relations. After ganglionic blockade to exclude reflex influences, ET-1 still reduced slopes of Po(2)-MVo(2) and CBF-MVo(2) relations. To assess effects of ET-1 on endothelium-dependent and -independent coronary vascular responses, intracoronary ACh and nitroglycerin were given to directly target coronary vessels. CBF responses to ACh and nitroglycerin were maintained during ET-1 delivery. In contrast, responses to intracoronary K(ATP) channel-dependent dilators adenosine and lemakalim were impaired by ET-1. In conclusion, pathophysiological levels of ET-1 impaired beta-adrenergic dilation of resistance coronary vessels through an ET(A) receptor-dependent process. In contrast, left ventricular inotropic responses to dobutamine were not impaired during ET-1 delivery. Our data suggest that ET-1 may interfere with smooth muscle K(ATP) channels to impair beta-adrenergic coronary dilation.

Raloxifene Improves Coronary Perfusion, Cardiac Contractility, and Myocardial Metabolism in the Ischemic Heart: Role of Phosphatidylinositol 3-Kinase/Akt Pathway

The purpose of this study is to examine whether raloxifene, one of the selective estrogen receptor modulators, could improve myocardial ischemia and to assess the mechanisms involved. In open-chest beagle dogs anesthetized by intravenous infusion of sodium pentobarbital, the left anterior descending coronary artery (LAD) was perfused from the left carotid artery through an extracorporeal bypass tube. Raloxifene was infused into the LAD through the bypass tube under either ischemic or non-ischemic conditions. In the non-ischemic heart, raloxifene had no effect on coronary blood flow, fractional shortening, and myocardial metabolism. However, raloxifene caused an acute increase in both coronary blood flow and fractional shortening, and also improved myocardial anaerobic metabolism in the ischemic heart. These effects were partially attenuated by pretreatment with either L-NAME or wortmannin and were completely abolished by ICI182780 (an estrogen receptor antagonist) or L-NAME plus charybdotoxin (a blocker of Ca-activated K channels). Raloxifene also increased both Akt activity and the NO level, with these changes being completely abrogated by pretreatment with wortmannin. These results demonstrated that raloxifene improves coronary perfusion, cardiac contractility, and myocardial metabolism by release of NO and opening of Ca-activated K channels in the ischemic heart, and that NO production is mediated by the phosphatidylinositol 3-kinase/Akt pathway.

Beta-adrenoceptor blocker carvedilol provides cardioprotection via an adenosine-dependent mechanism in ischemic canine hearts.

Carvedilol is a beta-adrenoceptor blocker with a vasodilatory action that is more effective for the treatment of congestive heart failure than other beta-blockers. Recently, carvedilol has been reported to reduce oxidative stress, which may consequently reduce the deactivation of adenosine-producing enzymes and increase cardiac adenosine levels. Therefore, carvedilol may also have a protective effect on ischemia and reperfusion injury, because adenosine mediates cardioprotection in ischemic hearts. In anesthetized dogs, the left anterior descending coronary artery was occluded for 90 minutes, followed by reperfusion for 6 hours. Carvedilol reduced the infarct size (15.0+/-2.8% versus 40.9+/-4.2% in controls), and this effect was completely reversed by the nonselective adenosine receptor antagonist 8-sulfophenyltheophylline (45.2+/-5.4%) or by an inhibitor of ecto-5'-nucleotidase (44.4+/-3.6%). There were no differences of either area at risk or collateral flow among the various groups. When the coronary perfusion pressure was reduced in other dogs so that coronary blood flow was decreased to 50% of the nonischemic level, carvedilol increased coronary blood flow (49.4+/-5.6 to 73.5+/-7.5 mL x 100 g(-1) x min(-1); P<0.05) and adenosine release (112.3+/-22.2 to 240.6+/-57.1 nmol/L; P<0.05) during coronary hypoperfusion. This increase of coronary blood flow was attenuated by either 8-sulfophenyltheophylline or superoxide dismutase. In human umbilical vein endothelial cells cultured with or without xanthine and xanthine oxidase, carvedilol caused an increase of ecto-5'-nucleotidase activity. Carvedilol shows a cardioprotective effect against ischemia and/or reperfusion injury via adenosine-dependent mechanisms.

Effects of combined use of sildenafil citrate (Viagra) and 17$beta;-estradiol on ovine coronary and uterine hemodynamics*1

Objective This study was undertaken to determine whether Viagra (Pfizer, New York, NY), a type 5 phosphodiesterase (PDE-5) inhibitor, increases baseline coronary and uterine blood flow or potentiates estrogen-induced increases in blood flow. Study design Seven nonpregnant ovariectomized ewes were chronically instrumented to measure blood pressure, heart rate, cardiac output, and coronary and uterine blood flow. Estradiol-17β (E2, 0.3 μg/kg) (Sigma Chemical Co, St Louis, Mo) and Viagra (50 mg) were intravenously administered separately or together and hemodynamic responses monitored. Results Viagra alone rapidly decreased mean arterial pressure and cardiac output while increasing heart rate and uterine blood flow. Viagra tended to decrease coronary blood flow but not significantly. E2 by itself increased coronary and uterine blood flow over a 2-hour time course, whereas mean arterial pressure, cardiac output, and heart rate remained unchanged. Administration of E2 to animals pretreated with Viagra reversed Viagra-related decrease in cardiac output and coronary blood flow, resulting in a time-related increase in both parameters over baseline values. Viagra significantly augmented estradiol-related increases in uterine blood flow. Conclusion In our surgically menopausal ovine model, Viagra alone has a tendency to decrease baseline coronary blood flow, but the reduction does not reach statistical significance. The presence of estradiol reverses this Viagra-related negative trend and results in a net increase in coronary blood flow and cardiac output. Furthermore, Viagra significantly augments baseline and estrogen-induced increases in uterine blood flow suggesting the presence of PDE-5 in the ovine uterine vasculature.

Effects of combined use of sildenafil citrate (Viagra) and 17β-estradiol on ovine coronary and uterine hemodynamics

Objective This study was undertaken to determine whether Viagra (Pfizer, New York, NY), a type 5 phosphodiesterase (PDE-5) inhibitor, increases baseline coronary and uterine blood flow or potentiates estrogen-induced increases in blood flow. Study design Seven nonpregnant ovariectomized ewes were chronically instrumented to measure blood pressure, heart rate, cardiac output, and coronary and uterine blood flow. Estradiol-17β (E2, 0.3 μg/kg) (Sigma Chemical Co, St Louis, Mo) and Viagra (50 mg) were intravenously administered separately or together and hemodynamic responses monitored. Results Viagra alone rapidly decreased mean arterial pressure and cardiac output while increasing heart rate and uterine blood flow. Viagra tended to decrease coronary blood flow but not significantly. E2 by itself increased coronary and uterine blood flow over a 2-hour time course, whereas mean arterial pressure, cardiac output, and heart rate remained unchanged. Administration of E2 to animals pretreated with Viagra reversed Viagra-related decrease in cardiac output and coronary blood flow, resulting in a time-related increase in both parameters over baseline values. Viagra significantly augmented estradiol-related increases in uterine blood flow. Conclusion In our surgically menopausal ovine model, Viagra alone has a tendency to decrease baseline coronary blood flow, but the reduction does not reach statistical significance. The presence of estradiol reverses this Viagra-related negative trend and results in a net increase in coronary blood flow and cardiac output. Furthermore, Viagra significantly augments baseline and estrogen-induced increases in uterine blood flow suggesting the presence of PDE-5 in the ovine uterine vasculature.