Alterations of beta-adrenoceptor responsiveness in postischemic myocardium after 72 h of reperfusion

To determine the effect of a completely developed reperfused myocardial infarction model on beta-adrenoceptor responsiveness, we induced a 90-min regional ischemia followed by 72 h of reperfusion in dog hearts. Regional myocardial blood flow was determined after 60 min of ischemia using radioactive microspheres. beta-adrenoceptor density was reduced in the ischemic endocardium (95+/-16 fmol/mg) and epicardium (160+/-13 fmol/mg) compared to the nonischemic region (304+/-21 fmol/mg). beta-adrenoceptor density in the ischemic endocardium varied with the degree of collateral blood flow measured (r2=0.79, P<0.05); this relation was the opposite of that in the ischemic epicardium (r2=0.77, P<0.05). Higher levels of tissue catecholamines and G protein-coupled receptor kinase 2 (GRK2) were observed in the ischemic epicardium as compared to nonischemic tissue. Forskolin-induced adenylyl cyclase activities were depressed in both ischemic regions as compared to nonischemic region, correlating with a reduction in regional myocardial blood flow. Using forskolin stimulation as covariate, no difference in isoproterenol-induced adenylyl cyclase activity was identified in the different regions. It is concluded that cAMP production induced by beta-adrenoceptor activation is dependent upon adenylyl cyclase enzyme activity rather than beta-adrenoceptor density in the ischemic myocardium. However, the density of the beta-adrenoceptor in the viable ischemic regions can be modified by the presence of GRK2 and tissue catecholamines, an index of regional sympathetic efferent postganglionic nerve terminal activity.     

Assessment of the acute cardiotoxic potential of sodium nitroprusside infusions in Beagle dogs

Fourteen unanesthetized dogs were infused with nitroprusside for 30 min (10 or 100 μg/kg/min), 3 hr (25 μg/kg/min), or 6 hr (12.5 or 25.0 μg/kg/min) on two consecutive days. Two animals died following the high-dose 6-hr infusion. Minimal left papillary muscle necrosis was detected in one of the four hearts taken from the dogs infused with 12.5 μg/kg/min for 6 hr. In four anesthetized dogs the 12.5- and 25.0-μg/kg/min doses depressed blood pressure by an average of 20–27% and 45–48%, respectively. Both doses increased heart rate approximately 20%. The effect of 60-min nitroprusside infusion of 3.5–28.0 μg/kg/min on a variety of cardiovascular functions was assessed in 10 dogs. The most consistently observed changes were a dose-related decrease in blood pressure (19–50%) and an increase in coronary blood flow (30–300%). In spite of the hypotensive response, only minor changes in heart rate, cardiac output, and ventricular force of contraction occurred. The results indicate that the secondary cardiovascular actions of nitroprusside are not as prominent as with other vasodilators. Consequently nitroprusside appears to possess less acute cardiotoxic potential than other agents such as minoxidil, diazoxide, or hydralazine.     

Vasodilating β-adrenoceptor blocking drugs do not redistribute myocardial flow during acute coronary ligation in dogs

The effects of two nonselective β-adrenoceptor blocking drugs, additionally endowed with vasodilating properties with different mechanisms: labetalol which blocks α-adrenoceptors, and bucindolol which nonspecifically relaxes vascular smooth muscle, were investigated on regional myocardial blood flow (RMBF) distribution in ischemic and nonischemic areas and on ST-segment elevation in ischemic areas during intermittent coronary artery occlusion in dogs. Both labetalol and bucindolol reduced heart rate, arterial blood pressure and myocardial oxygen consumption. However, they did not affect coronary vascular resistance and did not induce any favorable coronary blood flow redistribution phenomenon either from the epicardium to the endocardium or from the nonischemic to the ischemic areas. These results indicate that the inability of labetalol and bucindolol to favorably redistribute RMBF was due to the fact that their vasodilating properties counteract one major determinant of RMBF redistribution. i.e. the β-adrenoceptor blockade-induced increase in regional coronary vascular resistance. Finally, both labetalol and bucindolol dose dependently decreased ST-segment elevation in ischemic myocardial areas.     

(S)-emopamil, a novel calcium and serotonin antagonist for the treatment of cerebrovascular disorders. 3rd communication: effect on postischemic cerebral blood flow and metabolism, and ischemic neuronal cell death

The effect of (S)-emopamil ((2S)-2-isopropyl-5-(methylphenethylamino)-2-phenylvaleronitril e hydrochloride) treatment on postischemic cerebral blood flow and metabolism was investigated in nitrous oxide anesthetized, artificially ventilated rats. Forebrain ischemia was induced and maintained for 20 min by lowering arterial blood pressure to approximately 40 mmHg and clamping both carotid arteries. Local cerebral blood flow and glucose utilization were evaluated autoradiographically in 34 cerebral regions. In the cerebral blood flow studies intravenous infusion of 0.1 mg/(kg min) (S)-emopamil was begun 5 min after the end of ischemia. Local cerebral blood flow was determined 60 min later using [14C]iodoantipyrine. When the animals were treated with saline only, postischemic blood flow of 22 affected forebrain areas fell on average to 42 +/- 13% of nonischemic control. Treatment with (S)-emopamil increased perfusion of the same areas in a region-dependent fashion by an average of 54 +/- 19%, resulting in 63 +/- 17% of control values. The rise of blood flow in structures not directly affected by ischemia amounted to 52 +/- 27% (134 +/- 23% of control). In the studies on cerebral metabolism, the experimental animals received a total of 6 mg/kg (S)-emopamil by slow intravenous infusion before and during the ischemic episode. Determination of local cerebral glucose utilization was initiated after 50 min of postischemic recirculation using [14C]deoxyglucose. In the placebo-treated experimental group average glucose utilization of 14 forebrain areas was significantly lower (74 +/- 9% of control) than in the nonischemic control group.(ABSTRACT TRUNCATED AT 250 WORDS)     

Differential effects of various inotropic agents on the intracellular NADH redox level in the in vivo dog heart

A similar inotropic response was elicited by either increasing heart rate or infusing noradrenaline or ouabain in the open-chest dog preparation. Changes in local coronary blood supply and intracellular NADH redox level produced by these inotropic interactions were examined. Contractile tension was measured using a strain gauge arch; coronary flow, using a thermistor probe; and NADH redox level, by surface fluorometry. For each inotropic agent, isometric tension increased by about 40%. However, the mean increase in coronary flow was 80 +/- 9.7% for adrenaline, 67 +/- 18% for tachycardia, and 1 +/- 10.8% for ouabain. The mean changes in intracellular NADH redox level were -17 +/- 4.4%, 49 +/- 8.4%, and -6 +/- 6.4% for noradrenaline, tachycardia, and ouabain, respectively. The time course of changes in the various parameters was different following the onset of each inotropic stimulus. Furthermore, inducing tachycardia while the heart was under the influence of the various inotropic agents caused a reduction in contractility at different rates. These results indicate a large variation in the oxygen cost of contraction produced by these inotropic interventions, and also demonstrate notable variations in the intracellular oxygen balance. The possible relation between the intracellular NADH level and the "mechanical reserve" of cardiac muscle is discussed.     

Effect of pinacidil on myocardial blood flow in the chronically pressure overloaded hypertrophied left ventricle.

This study examined the effect of pinacidil on the transmural distribution of myocardial blood flow in the chronically pressure overloaded hypertrophied left ventricle. Studies were performed in six dogs in which banding of the ascending aorta had resulted in an 88% increase in left ventricular mass, as well as in six normal control animals. Two doses of pinacidil were administered to decrease mean arterial pressure by approximately 10 mm Hg (low dose) and 20 mm Hg (high dose). Animals with hypertrophy required significantly smaller drug doses to achieve the desired reductions in arterial pressure. During control conditions mean myocardial blood flow was significantly higher in animals with hypertrophy (1.90 +/- 0.21 ml/min/g) than in normal animals (1.12 +/- 0.08 ml/min/g; p less than 0.05). Subendocardial flow (endo) exceeded subepicardial flow (epi) in normal dogs during control conditions (endo/epi = 1.41 +/- 0.13), but not in animals with hypertrophy (endo/epi = 1.06 +/- 0.06; p less than 0.05). Pinacidil caused coronary vasodilation with similar relative increases in blood flow in both normal and hypertrophied hearts, so that after pinacidil, absolute blood flow rates remained higher than normal in animals with hypertrophy. Pinacidil caused a redistribution of blood flow away from the subendocardium in normal hearts (endo/epi = 0.90 +/- 0.11 during high-dose pinacidil) and in hearts with hypertrophy (endo/epi = 0.81 +/- 0.13 during high-dose pinacidil). The endo/epi ratios during high-dose pinacidil were not significantly different between the two groups. This study demonstrates that pinacidil is a potent coronary vasodilator in both normal and hypertrophied hearts.(ABSTRACT TRUNCATED AT 250 WORDS)     

Anti-ischemic activity of the novel benzazepine calcium antagonist SQ 31,486.

We tested the benzazepine, SQ 31,486 for its ability to selectively block the voltage-dependent calcium channel and to protect the ischemic myocardium. SQ 31,486 was found to be a selective calcium antagonist in vascular tissue with an IC50 value of 1.5 microM in KCl-contracted rabbit aorta. SQ 31,486 decreased contractile function and increased coronary flow in nonischemic isolated rat hearts in a concentration-dependent manner. SQ 31,486 also significantly reduced postischemic lactate dehydrogenase (LDH) release and end-diastolic pressure (EDP) compared to vehicle. Reperfusion double product [heart rate (HR) x left ventricular developed pressure (LVDP)] was also significantly improved by SQ 31,486. Diltiazem was a less potent anti-ischemic agent and was significantly more cardiodepressant relative to its anti-ischemic efficacy than was SQ 31,486. Thus, SQ 31,486 should have a larger therapeutic index. In a model of pacing-induced myocardial ischemia in anesthetized, open chest dogs, SQ 31,486 reduced pacing-induced ST-segment elevation approximately 50% at 10, 40, and 70 min after drug administration. This protective effect occurred despite a lack of effect of SQ 31,486 on ischemic regional blood flow and peripheral hemodynamic status.     

The effect of graded doses of norepinephrine on the O2 supply/consumption balance in ischemic and nonischemic rabbit myocardium

The purpose of this study was to determine the effect of graded doses of norepinephrine on the regional O2 supply/consumption ratio in ischemic rabbit hearts. Open chested, anesthetized rabbits were used and regional flows, O2 extraction, consumption and O2 supply/consumption ratios were determined before and 1 h after occlusion of the left anterior descending coronary artery in controls and animals given 0.1, 1.0 and 10 micrograms/kg per min norepinephrine (NE). After occlusion in controls, mean myocardial blood flow decreased 40% in the occluded region. Blood flow was also depressed in the occluded region for all NE doses compared to their own preocclusion values, but was higher in these regions compared to control animals. O2 extraction was higher in the occluded region compared to the nonoccluded region for all groups; however these values were lower in the NE groups compared to controls. NE increased O2 consumption in the occluded and nonoccluded regions compared to control group values. The O2 supply/consumption ratio was depressed in the occluded region in all groups compared to the nonoccluded region, though no differences were seen between NE and control groups. Thus, increases in the blood flow to the occluded region were proportional to the increases in O2 consumption with infusion of NE, indicating that a reserve exists and can be utilized with NE.     

Comparative effects of two slow channel calcium entry blockers, FR 34235 and nifedipine, on true coronary collateral blood flow

The effect of a new dihydropyridine calcium entry blocker, FR 34235, on coronary collateral blood flow was compared with that of nifedipine in anesthetized dogs following acute ligation of the left anterior descending coronary artery. A special technique was used to separate true coronary collateral blood flow from overlap flow due to interdigitation of normally perfused tissue contained within the ischemic region. During infusion of doses of both agents, which produced nearly equivalent decreases (15-20 mm Hg) in mean arterial pressure, flow was significantly increased in normal myocardium; however, no change in collateral perfusion to ischemic myocardium was observed. When blood pressure was returned to control by an aortic cuff, blood flow to the normal region further increased. Transmural flow to the ischemic region was also significantly increased by both compounds. Nifedipine increased collateral flow primarily to the subepicardium, whereas FR 34235 increased collateral perfusion to the subepicardium, midmyocardium, and subendocardium. These results suggest that dihydropyridine calcium entry blockers may increase collateral blood flow to ischemic myocardium if drug-induced hypotension is minimized. In addition, FR 34235 has a more favorable effect on the transmural distribution of blood flow than nifedipine.     

Improvement in regional myocardial O2 supply and O2 consumption by nitroglycerin during ischemia

In eight open-chest anesthetized dogs, nitroglycerin (10 micrograms/kg per min) was infused intravenously for 2 h, beginning 10 min following ligation of the left anterior descending coronary artery. Oxygen supply, (radioactive microspheres), extraction (microspectrophotometry) and consumption were determined in subepicardial and subendocardial regions of both ischemic and non-ischemic myocardium, and compared to eight control hearts. In control, coronary occlusion reduced both subepicardial and subendocardial blood flow by 49.5% and 79.5% respectively. In the presence of nitroglycerin, depression of blood flow to the occluded regions was significantly less marked (-79.5% in control and -26.6% in the nitroglycerin group in the subendocardium). O2 extraction was significantly lowered by nitroglycerin in all areas. Regional O2 consumption was significantly lower in the control occluded than non-occluded regions; no regional O2 consumption differences were observed following nitroglycerin. In the occluded regions, nitroglycerin reduced the number of veins with very low O2 saturation. It is concluded that nitroglycerin improves the O2 supply/consumption balance in ischemia by redistribution of blood flow and possibly by alterations in local O2 consumption.     

Effects of the cardioselective KATP channel blocker HMR 1098 on cardiac function in isolated perfused working rat hearts and in anesthetized rats during ischemia and reperfusion

It has been argued that activation of KATP channels in the sarcolemmal membrane of heart muscle cells during ischemia provides an endogenous cardioprotective mechanism. In order to test whether the novel cardioselective KATP channel blocker HMR 1098 affects cardiac function during ischemia, experiments were performed in rat hearts during ischemia and reperfusion. Isolated perfused working rat hearts were subjected to 30 min of low-flow ischemia in which the coronary flow was reduced to 10% of its control value, followed by 30-min reperfusion. In the first set of experiments the hearts were electrically paced at 5 Hz throughout the entire protocol. At the end of the 30-min ischemic period the aortic flow had fallen to 44 +/- 2% (n=8) of its nonischemic value in vehicle-treated hearts, whereas in the presence of 0.3 micromol/l and 3 micromol/l HMR 1098 it had fallen to 29 +/- 7% (n=5, not significant) and 8 +/- 2% (n=12, P<0.05), respectively. Glibenclamide (3 micromol/l) reduced the aortic flow to 9.5 +/- 7% (n=4, P<0.05). In control hearts the QT interval in the electrocardiogram shortened from 63 +/- 6 ms to 36 +/- 4 ms (n=10, P<0.05) within 4-6 min of low-flow ischemia. This shortening was completely prevented by 3 micromol/l HMR 1098 (60 +/- 5 ms before ischemia, 67 +/- 6 ms during ischemia, n=9, not significant). When rat hearts were not paced, the heart rate fell spontaneously during ischemia, and HMR 1,098 (3 micromol/l) caused only a slight, statistically non-significant reduction in aortic flow during the ischemic period. In order to investigate whether HMR 1098 shows cardiodepressant effects in a more pathophysiological model, the left descending coronary artery was occluded for 30 min followed by reperfusion for 60 min in anesthetized rats. Treatment with HMR 1098 (10 mg/kg i.v.) had no statistically significant effects on mean arterial blood pressure and heart rate during the control, ischemia and reperfusion periods. At the end of the reperfusion period, aortic blood flow was slightly reduced by HMR 1098, without reaching statistical significance (two-way analysis of ANOVA, P=0.15). Myocardial infarct size as a percentage of area at risk was not affected by HMR 1098 (vehicle: 75 +/- 3%, HMR 1098: 72 +/- 2%, n=7 in each group). In conclusion, cardiodepressant effects of HMR 1098 were observed only in isolated perfused working rat hearts which were continuously paced during global low-flow ischemia. In the model of anesthetized rats subjected to regional ischemia, HMR 1098 had no significant effect on cardiac function or infarct size.     

Importance of the flow perfusion deficit in the response to captopril in experimental myocardial infarction.

Previous results on the effects of angiotensin-converting enzyme (ACE) inhibition in myocardial ischemia are conflicting. To determine whether acute ACE inhibition may influence myocardial perfusion deficit during ischemia and reduce ischemia-reperfusion injury, anesthetized open-chest dogs underwent 2-h left anterior descending coronary artery (LAD) occlusion followed by 6-h reperfusion. After 1-h coronary occlusion, each dog was randomized to receive either captopril [5 mg/kg intravenous (i.v.) bolus and 0.25/kg/h infusion for 7 h] or saline. Whereas arterial pressure was reduced (p = 0.001), captopril did not influence myocardial perfusion deficit: Blood flow in the central ischemic zone represented 17.1 +/- 2.8% of the flow in the nonischemic zone versus 20.5 +/- 3.8% before treatment (NS). The values of the control group were 17.8 +/- 2.5 and 16.7 +/- 2.4%, respectively. In addition, there was no difference in infarct size: 35.9 +/- 3.3% of the area at risk in captopril-treated dogs versus 40.0 +/- 3.6% in controls. Analysis of subgroups based on the level of the collateral flow indicated, however, that ACE inhibition had an adverse effect on infarct size in dogs with high collateral flow: 31.9 +/- 4.6% in captopril dogs versus 17.6 +/- 4.7 (p = 0.048). This effect was related to a decrease in collateral flow because animals exhibiting the highest increase in perfusion deficit presented the greatest increase in infarct size (r = -0.92, p = 0.003). Although in dogs with low collateral flow, ACE inhibition appeared to exert a slight beneficial effect on infarct size, we conclude that at least in this dog model, acute ACE inhibition could exacerbate myocardial injury.     

Collateral blood flow following acute coronary artery occlusion: comparison of a new intracellular calcium antagonist (KT-362) and diltiazem

The effects of a new intracellular calcium antagonist, KT-362 (150 and 300 micrograms/kg per min), on hemodynamics and collateral function (retrograde pressure and flow, radioactive microspheres) distal to an acute coronary artery occlusion were studied in anesthetized dogs and compared with the effects of the structurally related classical calcium channel blocker, diltiazem (15 and 30 micrograms/kg per min), and a saline-treated control group. In the saline series, there were no changes in systemic hemodynamics or coronary collateral blood flow over the 90-min ischemic period. KT-362 reduced mean aortic pressure, heart rate, and dP/dt whereas diltiazem only decreased aortic blood pressure. When blood pressure was controlled by a distal aortic cuff, heart rate was significantly reduced in both groups and dP/dt was reduced in the KT-362 series and increased in diltiazem-treated dogs. In both drug-treated groups, retrograde pressure and flow were significantly increased only when aortic pressure was controlled. Regional myocardial tissue blood flow in the nonischemic or ischemic region did not change significantly after KT-362 treatment despite its hypotensive actions, and in the presence of a constant aortic pressure, transmural collateral blood flow and the ischemic/nonischemic blood flow ratio tended to increase. In contrast, diltiazem treatment resulted in a significant decrease in the ischemic/nonischemic blood flow ratio in the absence of blood pressure control. In the presence of constant aortic pressure, blood flow to the nonischemic area was markedly increased by diltiazem whereas subendocardial blood flow was significantly increased in the ischemic area.(ABSTRACT TRUNCATED AT 250 WORDS)     

Effects of nipradilol, a new beta-adrenoceptor blocking agent with vasodilating properties, on transmural energy metabolism in the underperfused canine heart

Effects of nipradilol on hemodynamics and transmural energy metabolism of underperfused (ischemic) canine hearts were investigated. The ischemic heart was prepared by constricting a tube connecting the circumflex coronary artery with the carotid artery for 10 min so that the perfusion pressure (CPP) was reduced to 30 mmHg. The reduction in CPP resulted in decreases in coronary blood flow (CBF) by 70%, regional myocardial contractile force (MCF) by 30%, myocardial ATP contents by 32% (inner layer)-22% (outer) and creatine phosphate by 75% (inner)-60% (outer). Increases in the left ventricular end diastolic pressure (LVEDP) by 4.8 mmHg, myocardial inorganic phosphate contents by 1.9 times (inner)-1.3 (outer) and lactate by 4.3 times (inner)-2.4 (outer) were also observed. In dogs with normal hearts, an infusion of nipradilol (10 micrograms/kg/min, i.v., for 15 min) decreased CPP by 25%, CBF by 40%, cardiac effort index by 45% and MCF by 30 to 40%, and it slightly increased LVEDP without affecting myocardial high-energy phosphate and lactate levels. In ischemic hearts, nipradilol infusion starting 5 min before ischemia attenuated the ischemia-induced elevation of LVEDP to 1.8 mmHg, and the ischemia-induced changes in high-energy phosphate contents to 1/2 (inner)-1/3 (outer) and changes in lactate to 1/6 (inner)-1/10 (outer). These results indicate that nipradilol improves the ischemic derangement of both transmural energy metabolism and hemodynamics.     

Effects of felodipine, a new dihydropyridine vasodilator, on regional myocardial blood flow during acute coronary occlusion in the pig

We studied the effects of felodipine [4-(2,3-dichlorophenyl)-1,4-dihydropyridine-2,6-dimethyl 3,5-dicarboxylic 3-ethylester and 5-methylester] on the coronary vascular bed of pig hearts with an ischemic region in the left ventricle following ligation of the left anterior descending coronary artery. At an infusion rate of 0.12 nmol X kg-1 X min-1, felodipine caused a slight reduction in mean arterial blood pressure and a decrease in coronary vascular resistance in both normal myocardium and partly ischemic myocardium of the border zone. In another series of experiments, felodipine was infused at a higher rate (0.38 nmol X kg-1 X min-1). The resultant decrease in mean arterial blood pressure, which was about 30%, was counterbalanced by inflation of an aortic balloon to keep the afterload and the coronary perfusion pressure constant. In this situation, felodipine caused a pronounced increase in blood flow to all parts of the heart except the central ischemic zone, where blood flow was extremely low. We conclude that felodipine has a coronary vasodilator action which is at least of the same magnitude as its peripheral vasodilator action, and that it markedly increases coronary blood flow in the border zone of an ischemic area.     

葛根素对急性心肌缺血狗区域性心肌血流与心脏血流动力学的作用

麻醉开胸狗ⅳ葛根素(puerarin)可减慢心率(HR)、降低主动脉压(MAP),用同位素标记微球法测得的缺血区侧枝冠脉血流量并不减少。从狗的右室旁路制备的心脏血流动力学实验发现葛根素明显减低张力一时间指数(TTI)与左室压力升高速度(LV dp/dt)。当MAP调整到给药前的水平时,TTI与LV dp/dt恢复,进入缺血区的侧技血流增加,非缺血区的冠脉血流量(CBF)亦增加。葛根素减低冠脉血管阻力(CVR)的作用比减低全身血管阻力(SVR)的作用更显著。葛根素不影响心肌收缩力,但增加局部心肌缺血时的侧枝血流并减少与心肌氧消耗有关的血流动力学参数。这些结果提示葛根素有益于治疗心肌缺血。     

The role of calcitonin gene-related peptide (CGRP) in ischemic preconditioning in isolated rat hearts

Brief coronary artery occlusion can protect the heart against damage during subsequent prolonged coronary artery occlusion; ischemic preconditioning. The role of calcitonin gene-related peptide (CGRP) in ischemic preconditioning is investigated in isolated perfused rat hearts, by measuring CGRP release during ischemic preconditioning and mimicking this by exogenous CGRP infusion, either in the absence or presence of the CGRP antagonist BIBN4096BS. CGRP increased left ventricular pressure and coronary flow in a concentration dependent manner, which was effectively antagonized by BIBN4096BS. Rat hearts (n=36) were subjected to 45 min coronary artery occlusion and 180 min reperfusion, which was preceded by: (1) sham pretreatment, (2) BIBN4096BS infusion (1 microM), (3) preconditioning by 15 min coronary artery occlusion and10 min reperfusion, (4) as 3, but with BIBN4096BS, (5) 15 min CGRP infusion (5 nM) and 10 min washout, (6) as 5, but with BIBN4096BS. Cardiac protection was assessed by reactive hyperaemia, creatine kinase release, infarct size related to the area at risk (%), and left ventricular pressure recovery. Preconditioning increased CGRP release into the coronary effluent from 88+/-13 to 154+/-32 pg/min/g, and significantly protected the hearts by decreasing reactive hyperaemia (35%), reducing creatine kinase release (53%), limiting infarct size (48%), and improving left ventricular pressure recovery (36%). Exogenous CGRP induced preconditioning-like cardioprotection. BIBN completely abolished the cardioprotection induced by preconditioning as well as by exogenous CGRP. In conclusion, since cardioprotection of preconditioning-induced CGRP release can be mimicked by exogenous CGRP, and both can be blocked by a CGRP antagonist, results indicate an important role for CGRP in ischemic preconditioning.     

Role of adenosine in catecholamine-induced global coronary functional hyperemia in isolated guinea pig hearts.

This study was designed to test the hypothesis that endogenous adenosine participates in the global coronary functional hyperemia accompanying intracoronary infusions of norepinephrine (NE) and isoproterenol (ISO). Intracoronary adenosine deaminase (ADA) was employed to test the hypothesis in isolated, perfused guinea pig hearts. We measured coronary perfusate flow (CPF) at a constant coronary perfusion pressure. Heart rate (HR), left ventricular pressure, and its rate of development were also measured. Global myocardial oxygen consumption (MVO2) and oxygen extraction were calculated, and blood gases and pH were measured routinely in inflow and outflow perfusate samples. In the absence of ADA, NE and ISO increased HR 67 +/- 6 and 106 +/- 11 beats.min-1, left ventricular pressure development 519 +/- 46 and 375 +/- 35 mm Hg.s-1, MVO2 22 +/- 2 and 28 +/- 3 microliters.min-1.g-1, and CPF 1.6 +/- 0.2 and 2.2 +/- 0.2 ml.min-1.g-1, respectively. With constant infusion of ADA (4.5 U.min-1.g-1, a dose which produces no direct effects on cardiac function) for 4 min, similar increments in HR and left ventricular pressure development were achieved with both catecholamines. Corresponding changes in MVO2 (9 +/- 2 and 6 +/- 3 microliters.min-1.g-1) were significantly less than those seen in the absence of ADA. Moreover, CPF did not increase in response to NE and ISO in the presence of ADA. These findings support an important role for adenosine in catecholamine-induced global coronary functional hyperemia in isolated, perfused guinea pig hearts.     

Effects of nitroglycerin on regional O2 supply and O2 consumption in reperfused dog myocardium

This study was designed to assess whether nitroglycerin would improve the relationship between O2 supply and O2 consumption in the reperfused ischemic dog myocardium. In 16 dogs the left anterior descending coronary artery was occluded for 2 h, followed by a 4 h period of reperfusion. In 8 of the 16 dogs, an infusion of 10 micrograms/kg per min of nitroglycerin was begun 10 min prior and continued during 4 h of reperfusion. Small artery and vein O2 saturations obtained microspectrophotometrically were combined with regional blood flow measurements using radioactive microspheres to determine regional myocardial O2 consumption. In both groups, 2 h of occlusion lowered the regional flow to a similar level. In the control group, 4 h of reperfusion returned the blood flow towards normal levels, from 15 +/- 20 ml/min per 100 g (mean +/- S.D.) at the end of occlusion to 57 +/- 39 in the affected area compared to 84 +/- 32 ml/min per 100 g in the nonischemic area. In nitroglycerin treated animals, the flow increase with reperfusion was similar to the control group (12 +/- 10 to 65 +/- 33 ml/min per 100 g). O2 extraction was greater in the reperfused than in the unaffected area in both groups. However, reperfused region O2 extraction was lower in the nitroglycerin treated than control group. There was a greater number of arteries and veins with reduced O2 saturations in the control group reperfused area compared to the nonischemic area. Nitroglycerin decreased the number of low O2 saturation vessels in the reperfusion area. Reperfusion alone does not restore the ratio of O2 supply to O2 consumption to control values, while nitroglycerin significantly improves this ratio. Thus nitroglycerin appears to better match the increased flow during reperfusion with microregional O2 consumption.     

Pronounced accumulation of metoprolol in ischemic myocardium after coronary venous retroinfusion.

The myocardial availability of the beta 1-selective blocker metoprolol was compared following standard intravenous (i.v.) administration and after coronary venous retroinfusion. Thirteen open-chest farm pigs were subjected to 90-min occlusion of the left anterior descending coronary artery. In six of these pigs, metoprolol was administered as an i.v. injection while 7 pigs received the drug retrogradely into the coronary vein. The time of administration was 5 min. In both groups, metoprolol was administered after 30 min of coronary artery occlusion. Metoprolol did not influence heart rate (HR) or blood pressure (BP) whether administered i.v. or into the coronary vein. At the end of administration, plasma metoprolol was significantly higher when administered i.v. (2,955 +/- 543 nmol/L) than after coronary venous infusion (1,213 +/- 464 nmol/L; p less than 0.05). At 30 and 60 min after injection, plasma metoprolol did not differ significantly between the two groups. Myocardial tissue concentration of metoprolol in nonischemic myocardium was approximately 480 pmol/g for both groups and similar in the subendocardial, midmyocardial, and subepicardial layers of the myocardium. After i.v. administration, myocardial Metoprolol concentration in the ischemic zone was less than that in the nonischemic zone, averaging 150-300 pmol/g tissue. In contrast, coronary venous retroinfusion of metoprolol resulted in a substantial accumulation of the drug in the ischemic zone, as exemplified by a subendocardial concentration of 2,002 +/- 689; a midmyocardial concentration of 26,643 +/- 8,813 and a subepicardial concentration of 98,571 +/- 58,930 pmol/g, respectively (mean +/- SE). Coronary venous retroinfusion of metoprolol resulted in a pronounced accumulation of drug in the ischemic myocardium.(ABSTRACT TRUNCATED AT 250 WORDS)