Effect of MCI-154, a cardiotonic agent, on regional contractile function and myocardial oxygen consumption in the presence and absence of coronary artery stenosis in dogs

The effects of MCI-154 (6-[4-(4'-pyridyl)aminophenyl]-4,5-dihydro-3(2H)- pyridazinone hydrochloride.3H2O), a cardiotonic agent with calcium sensitizing actions, on regional contractile function and myocardial oxygen consumption (MVO2) were studied in the dog hearts with and without partial occlusion of the left anterior descending coronary artery and compared with those of dobutamine. Segment shortening by sonomicrometry, regional myocardial blood flow by microspheres and the oxygen content of coronary venous blood drawn from the ischemic left anterior descending coronary artery area were simultaneously measured. The ischemic zone segment shortening and left ventricular (LV) dP/dtmax were decreased after partial occlusion. The infusion of MCI-154 starting 20 min after ischemia improved the depressed segment shortening and LV dP/dtmax without increasing the ischemic zone MVO2 and regional myocardial blood flow. In the nonischemic hearts, MCI-154 did not increase MVO2 and coronary blood flow despite the augmentation of myocardial contractility. MCI-154 decreased LV end-diastolic pressure and systemic blood pressure. On the other hand, dobutamine failed to increase the ischemic zone segment shortening, but the drug increased MVO2, coronary blood flow and LV dP/dtmax in both ischemic and nonischemic hearts. These results indicate that MCI-154 alleviates the ischemic contractile failure without increasing myocardial oxygen demand. Thus, MCI-154 may be useful in the management of heart failure with reduced coronary reserve.     

Experimental hypothermia: effects of core cooling and rewarming on hemodynamics, coronary blood flow, and myocardial metabolism in dogs

Conflicting results have been reported as to the extent that cardiovascular function can be reestablished after rewarming from hypothermia. We measured hemodynamic function, myocardial metabolism and tissue water content in dogs core-cooled to 25 degrees C and later rewarmed. At 25 degrees C left ventricular (LV) systolic pressure (LVSP) was 54% +/- 4%, maximum rate of LV pressure rise (LV dP/dtmax) 44% +/- 5%, aortic pressure (AOP) 50% +/- 6%, heart rate (HR) 40% +/- 0%, cardiac output (CO) 37% +/- 5%, myocardial blood flow (MBF) 34% +/- 5%, and myocardial oxygen consumption (MVO2) 8% +/- 1%, compared to precooling. Stroke volume (SV) and LV end-diastolic pressure (LVEDP) were unchanged. As normothermia (37 degrees C) was reestablished, the depression of cardiac function and myocardial metabolism remained the same as that at 25 degrees C: LVSP 71% +/- 6%, LV dP/dtmax 73% +/- 7%, SV 60% +/- 9%, AOP 70% +/- 6%, CO 57% +/- 9%, MBF 53% +/- 8%, and MVO2 44% +/- 8% HR, in contrast, recovered to precooling values. The arterial concentrations of glucose and free fatty acids (FFA) did not change significantly during the experimental period, whereas an increase in lactate of nonmyocardial origin appeared after rewarming. Increased myocardial contents of creatine phosphate and water were found during both hypothermia and rewarming. The present study demonstrates a persistent depression of cardiac function after hypothermia and rewarming in spite of adequate energy stores. Thus, a direct influence on myocardial contractile function by the cooling and rewarming process is suggested.     

Increase in myocardial interstitial adenosine and net lactate production in brain-dead pigs: an in vivo microdialysis study

BACKGROUND: Brain death-related cardiovascular dysfunction has been documented; however, its mechanisms remain poorly understood. We investigated changes in myocardial function and metabolism in brain-dead and control pigs. METHODS: Heart rate, systolic (SAP) and mean (MAP) arterial pressure, left ventricular (LV) dP/dtmax, rate-pressure product, cardiac output (CO), left anterior descending coronary artery blood flow, lactate metabolism, and interstitial myocardial purine metabolite concentrations, monitored by cardiac microdialysis, were studied. A volume expansion protocol was performed at the end of the study. RESULTS: After brain death, a transient increase in heart rate (from 90 [67-120] to 158 [120-200] beats/min) (median, with range in brackets), MAP (82 [74-103] to 117 [85-142] mmHg), LV dP/dtmax (1750 [1100-2100] to 5150 [4000-62,000] mmHg x sec(-1), rate-pressure product (9100 [7700-9700] beats mmHg/min to 22,750 [20,000-26,000] beats mmHg/min), CO (2.2 [2.0-4.0] to 3.3 [3.0-6.0] L/min), and a limited increase in left anterior descending coronary artery blood flow (40 [30-60] to 72 [50-85] ml/min) were observed. Net myocardial lactate production occurred (27 [4-40] to -22 [-28, -11] mg/L, P<0.05) and persisted for 2 hr. A 6-7-fold increase in adenosine dialysate concentration was observed after brain death induction (2.9 [1.0-5.8] to 15.8 [7.0-50.7] micromol/L), followed by a slow decline. Volume expansion significantly increased MAP, CO, and LV dP/dtmax in control animals, but decreased LV dP/dtmax and slightly increased CO in brain-dead animals. A significant increase in adenosine concentration was observed in both groups, with higher levels (P<0.05) in brain-dead animals. CONCLUSIONS: Brain death increased oxygen demand in the presence of a limited increase in coronary blood flow, resulting in net myocardial lactate production and increased interstitial adenosine concentration consistent with an imbalance between myocardial oxygen demand and supply. This may have contributed to the early impairment of cardiac function in brain-dead animals revealed by rapid volume infusion.     

An improved isolated, left ventricular ejecting, murine heart model. Functional and metabolic evaluation

An improved, isolated, left ventricular-ejecting, murine heart model is described and evaluated. Special attention was paid to the design and impedance characteristics of the artificial aortic outflow tract and perfusate composition, which contained glucose (10 mM plus insulin) and pyruvate (1.5 mM) as substrates. Temperature of the isolated perfused hearts was maintained at 38.5 degrees C. During antegrade perfusion (preload 10 mm Hg, afterload 50 mm Hg, 2.5 mM Ca2+) proper design of the aortic outflow tract provided baseline values for cardiac output (CO), left ventricular developed pressure (LVDP) and the maximum first derivative of left ventricular pressure (LV dP/dtmax) of 11.1+/-1.7 ml min-1, 83+/-5 mm Hg and 6283+/-552 mm Hg s-1, respectively, resembling findings in the intact mouse. During 100 min normoxic antegrade perfusion CO declined non-significantly by less than 10%. Varying pre- and afterloads resulted in typical Frank-Starling relationships with maximal CO values of 18.6+/-1.8 ml min-1 at pre- and afterload pressures of 25 and 50 mm Hg, respectively. Left ventricular function curves were constructed at free [Ca2+] of 1.5 and 2.5 mM in the perfusion medium. Significantly higher values for CO, LVDP and LV dP/dtmax and LV dP/dtmin were obtained at 2.5 mM Ca2+ at all loading conditions investigated. Phosphocreatine and creatine levels remained stable throughout the perfusion period. Despite a small but significant decline in tissue ATP content, the sum of adenine nucleotides did not change during the normoxic perfusion period. The tissue content of glycogen increased significantly.     

Effects of a new cardiotonic phosphodiesterase III inhibitor, olprinone, on cardiohemodynamics and plasma hormones in conscious pigs with heart failure

We examined the effects of a novel phosphodiesterase III inhibitor, olprinone, on the cardiohemodynamics and plasma hormones in conscious pigs with pacing-induced heart failure. After pacing for 5-10 days, cardiac output (CO) decreased from 2.25 +/- 0.17 to 1.67 +/- 0.13 L/min (n = 8, p < 0.01) and stroke volume (SV) decreased from 20.1 +/- 2.1 to 12.0 +/- 1.6 ml (n = 8, p < 0.01), whereas left arterial pressure (LAP) increased from 2.8 +/- 1.2 to 16.7 -/+ 0.9 mm Hg (n = 7, p < 0.001) and systemic vascular resistance (SVR) increased from 38.7 +/- 3.5 to 49.8 +/- 4.2 mm Hg/L/min (n = 8, p < 0.01). Sequential intravenous infusions of 0.03, 0.3, and 3.0 microg/kg/min of olprinone at 30-min intervals to eight pigs caused dose-dependent increases in the decreased CO, SV, and maximal rate of rise in left ventricular pressure (LV dP/dt(max)) and decreased the elevated LAP and SVR. Olprinone at 3.0 microg/kg/min maximally increased CO, SV, and LV dP/dt(max) by 40.0 +/- 10.8% (p < 0.05 vs. vehicle), 25.6 +/- 6.9% (p < 0.05), and 43.9 +/- 11.2% (p < 0.01), respectively, and brought about a slight increase in heart rate and decreases in LAP and SVR, by 35.9 +/- 7.3% (p < 0.001) and 27.9 +/- 4.8% (p < 0.01), respectively. Olprinone did not affect the rate-pressure product. In addition, olprinone produced significant decreases in the plasma levels of atrial natriuretic peptide and cyclic guanosine monophosphate, with no changes in the plasma levels of cyclic adenosine monophosphate and catecholamines or plasma renin activity. These findings indicate that the short-term intravenous infusions of olprinone ameliorated the decreased left ventricular function without affecting myocardial oxygen consumption or the sympathetic nervous system in conscious pigs with heart failure.     

Effect of exercise on left ventricular mechanical efficiency in conscious dogs

BACKGROUND: We studied the effect of exercise (7.2 to 8.0 km/h) on the efficiency of the conversion of metabolic energy to external work or stroke work (SW) by the left ventricle (LV). METHODS AND RESULTS: Energy use was calculated from LV myocardial oxygen consumption per beat (MVO2). LV volume was calculated from orthogonal dimensions and coronary flow measured with ultrasonic flow probes. The total mechanical energy of the LV was calculated as the pressure-volume area (PVA). At rest, the MVO2-PVA point fell on the MVO2-PVA relation determined by steady-state changes in arterial pressure produced by graded infusions of phenylephrine. Exercise increased the slope (Ees) of LV end-systolic pressure-volume (PV) relation by 29%. During exercise, the MVO2-PVA point shifted to the right only slightly above the control MVO2-PVA relation by 0.007 +/- 0.005 mL O2.beat-1.100 g LV-1. Despite the increase in ventricular contractility with exercise, the PVA/MVO2 ratio was unchanged because of the marked increase in PVA. During exercise, the transmission of total mechanical energy to external work (SW/PVA) increased from 65 +/- 5% to 72 +/- 4% (P < .01) as the ratio of the arterial end-systolic elastance to Ees decreased from 1.1 +/- 0.2 to 0.8 +/- 0.1 (P < .05). Thus, LV mechanical efficiency (SW/MVO2 = SW/PVA.PVA/MVO2) improved from 12.9 +/- 1.5% to 14.3 +/- 1.1% (P < .05) during exercise. CONCLUSIONS: Exercise increases the efficiency of conversion of metabolic energy to external work by the LV due to alteration in LV arterial coupling resulting in increased production of mechanical energy and enhanced transmission of mechanical energy to external work, which more than offsets any increased metabolic cost of the enhanced contractility.     

Mechanisms of platelet-induced angiospastic reactions: potentiation of calcium sensitivity

BACKGROUND: Zatebradine is a new specific bradycardiac agent that selectively slows the depolarization in the pacemaker cells of the sinoatrial node. The purpose of our investigation was to determine whether the tachycardia induced by dobutamine can be attenuated by the administration of zatebradine. The results were compared with those produced by propranolol, which is used in the treatment of sinus tachycardia. METHODS: Twelve pigs were anesthetized with sodium pentobarbital, intubated, and ventilated. After baseline hemodynamic measurements were obtained, dobutamine was administered until the heart rate reached 25% above baseline. Animals were randomized to one of two groups. Group I received zatebradine, 0.5 mg/kg i.v., and Group II received propranolol, 0.5 mg/kg i.v. RESULTS: Dobutamine 10 micrograms.kg-1.min-1 increased the heart rate (FIR) by 25%, and increased mean arterial blood pressure (MAP) left ventricular (LV) dp/dt, and cardiac output (CO) (P < 0.05). Zatebradine decreased the HR to baseline (P < 0.05) without affecting left ventricular systolic pressure (LVSP), left ventricular end diastolic pressure (LVEDP), LV dP/dt, or CO. Stroke volume (SV) increased significantly (P < 0.05). Propranolol also reduced HR to baseline, but decreased LV dP/dt, LVSP, CO, and SV (P < 0.05). CONCLUSION: Zatebradine effectively attenuates the tachycardia caused by dobutamine in anesthetized pigs, without reducing cardiac performance.     

Natural killer cell cytotoxicity and paternal lymphocyte immunization in women with recurrent spontaneous abortions

Although cardiac function is depressed during endotoxic shock, it remains controversial whether the ventricular contractility and structure are altered during sepsis. To resolve this issue, rats were subjected to polymicrobial sepsis by cecal ligation and puncture (CLP). At 2, 5, and 10 h after CLP (i.e., the early, hyperdynamic stage of sepsis) or 20 h after CLP (the late, hypodynamic stage of sepsis, based on the depressed tissue perfusion), in vivo left ventricular contractility parameters such as maximal rate of the left ventricular pressure increase (+dP/dtmax) and decrease (-dP/dtmax), maximal rate of "pressure-normalized" change in ventricular pressure (dP/dtmax/P), and ventricular peak systemic pressure were determined using a Digi-Med Heart Performance Analyzer. In additional groups of animals, ultrastructure of the cardiac muscle in the left ventricle was examined at 5, 10, or 20 h after CLP, using a transmission electron microscope. The results indicate that +dP/dtmax and dP/dtmax/P increased significantly at 2-10 h after CLP. The values of -dP/dtmax and ventricular peak systemic pressure increased significantly at 2 and 5 h after the onset of sepsis, respectively. These in vivo ventricular contractility parameters, however, were not significantly different from shams at 20 h after CLP. Ultrastructural examination showed that enlarged T-tubules were prominent during the hyperdynamic stage of sepsis, which was correlated with the increased cardiac contractility. Although focal and moderate hypertrophy as well as expanded intermyocyte junctions could be observed occasionally, myocardial cells did not appear to be compromised at 20 h after CLP. Thus, the transition from the hyperdynamic to hypodynamic circulation during sepsis does not appear to be due to any depression in myocardial function because cardiac contractility and structure are not compromised even during the late, hypodynamic stage of sepsis. However, further investigation is required to determine whether cardiac function is depressed at the terminal stage of polymicrobial sepsis.     

Left ventricular dysfunction following rewarming from experimental hypothermia

This study was aimed at elucidating whether ventricular hypothermia-induced dysfunction persisting after rewarming the unsupported in situ dog heart could be characterized as a systolic, diastolic, or combined disturbance. Core temperature of 8 mongrel dogs was gradually lowered to 25 degreesC and returned to 37 degreesC over a period of 328 min. Systolic function was described by maximum rate of increase in left ventricular (LV) pressure (dP/dtmax), relative segment shortening (SS%), stroke volume (SV), and the load-independent contractility index, preload recruitable stroke work (PRSW). Diastolic function was described by the isovolumic relaxation constant (tau) and the LV wall stiffness constant (Kp). Compared with prehypothermic control, a significant decrease in LV functional variables was measured at 25 degreesC: dP/dtmax 2,180 +/- 158 vs. 760 +/- 78 mmHg/s, SS% 20.1 +/- 1.2 vs. 13.3 +/- 1.0%, SV 11.7 +/- 0.7 vs. 8.5 +/- 0.7 ml, PRSW 90.5 +/- 7.7 vs. 29.1 +/- 5.9 J/m. 10(-2), Kp 0.78 +/- 0.10 vs. 0.28 +/- 0.03 mm-1, and tau 78.5 +/- 3.7 vs. 25.8 +/- 1.6 ms. After rewarming, the significant depression of LV systolic variables observed at 25 degreesC persisted: dP/dtmax 1,241 +/- 108 mmHg/s, SS% 10.2 +/- 0.8 J, SV 7.3 +/- 0.4 ml, and PRSW 52.1 +/- 3.6 m. 10(-2), whereas the diastolic values of Kp and tau returned to control. Thus hypothermia induced a significant depression of both systolic and diastolic LV variables. After rewarming, diastolic LV function was restored, in contrast to the persistently depressed LV systolic function. These observations indicate that cooling induces more long-lasting effects on the excitation-contraction coupling and the actin-myosin interaction than on sarcoplasmic reticulum Ca2+ trapping dysfunction or interstitial fluid content, making posthypothermic LV dysfunction a systolic perturbation.     

Mitochondrial dysfunction in neurodegenerative disorders

Left ventricular hypertrophy with adequate wall thickness, preserved adult phenotype and extracellular matrix may be useful in the prevention of heart failure. Because activation of subtype 1 of angiotensin II (AT1) receptors is thought to be involved in the hypertrophic response of cardiomyocytes, we tested the potential of systemic AT1 blockade to modify the development of left ventricular hypertrophy due to pressure overload. Sham-operated rats and rats with ascending aorta constriction were treated with losartan (30 mg/kg/day) for 8 weeks. Left ventricular geometry, dynamics of isovolumic contractions, hydroxyproline concentration as well as myosin isozymes (marker of fetal phenotype) were assessed. Rats with aortic constriction exhibited a marked increase in left ventricular weight and the diastolic pressure-volume relationship was shifted to smaller volumes. An enlarged ventricular pressure-volume area and increased (p < 0.05) peak values of +dP/dtmax and- dP/dtmax demonstrated an enhanced overall ventricular performance. Signs of congestive heart failure were not apparent. In contrast, parameters of myocardial function (normalized length-stress area, +d delta /dtmax and -d delta /dtmax) were depressed (p < 0.05), indicating an impaired myocardial contractility. The hydroxyproline concentration remained unaltered. However, the proportion of beta-myosin heavy chains (MHC) was increased (p < 0.05). Administration of losartan decreased (p < 0.05) blood pressure and body weight in sham operated and pressure overloaded rats. By contrast, neither the concentric left ventricular hypertrophy or depressed myocardial function nor the increased beta-MHC expression were significantly altered. Thus, activation of AT1 receptors appears not to be involved in the initial expression of the fetal phenotype of pressure overloaded heart which may be responsible for the progressive functional deterioration of the hypertrophied ventricle.     

Effects of magnesium sulphate on the cardiovascular system, coronary circulation and myocardial metabolism in anaesthetized dogs

We have studied the effects of i.v. bolus doses of magnesium sulphate (MgSO4) 60, 90 and 120 mg kg-1 on haemodynamic state, the coronary circulation and myocardial metabolism in nine dogs anaesthetized with pentobarbitone and fentanyl. MgSO4 produced dose-dependent decreases in arterial pressure, heart rate, left ventricular dP/dtmax and left ventricular minute work index (LVMWI) and an increase in the time constant of left ventricular isovolumic relaxation. Stroke volume increased, systemic vascular resistance decreased and cardiac output did not change significantly. MgSO4 produced decreases in coronary perfusion pressure, coronary vascular resistance and myocardial oxygen consumption (MVO2). Coronary sinus blood flow, lactate extraction ratio and the ratio of LVMWI to myocardial MVO2, that is an index of cardiac efficiency, did not change significantly. This study indicated that the depressant effect of MgSO4 on cardiac function was offset by lowering of peripheral vascular resistance, so that cardiac pump function remained effective, and the almost constant coronary sinus blood flow resulted from the decrease in coronary vascular resistance even at higher doses.     

Effects of enoximone and R 80122, a new selective phosphodiesterase III inhibitor, on hemodynamics and myocardial energetics in patients with ischemic heart disease

The present study was designed to compare the effects of enoximone and R 80122, a highly selective phosphodiesterase (PDE) III inhibitor, on left ventricular hemodynamics and myocardial blood flow and metabolism in patients with coronary artery disease. Twenty male, anesthetized patients, ASA physical status III, were studied before they underwent coronary artery bypass grafting (CABG) surgery. They were allocated randomly to receive either 0.3 mg/kg R 80122 (Group 1) or 1 mg/kg enoximone (Group 2) intravenously (IV). All patients were taking maintenance doses of either beta-receptor antagonists or calcium-channel-blocking drugs and nitrates. After receiving flunitrazepam, 2 mg orally, anesthesia was induced with fentanyl, midazolam, and pancuronium IV. Following control measurements after the induction of anesthesia, the PDE III inhibitor was infused over 2 min and measurements were repeated 5, 30, and 60 min after drug administration. There were no external stimuli to the patients during any of the measurement periods. R 80122 and enoximone decreased mean arterial pressure (MAP) by 20% and systemic vascular resistance (SVR) by 36% and 38%, respectively, while cardiac index (CI) increased by 27% and 30%, respectively. There were increases in heart rate (HR) by 10% and 19%, respectively, and in contractility (dp/dtmax) by 18% and 38%, respectively. Coronary perfusion pressure (CPP) decreased by 23% and 22%, respectively, and coronary vascular resistance (CVR) by 38% and 21%, respectively. Myocardial blood flow (MBF) and myocardial oxygen uptake (MVO2) increased in both groups, the increase in MBF being statistically significant (+34%) only in Group 1, whereas the changes in myocardial metabolism were not significant in either group.(ABSTRACT TRUNCATED AT 250 WORDS)     

Desflurane, sevoflurane, and isoflurane impair canine left ventricular-arterial coupling and mechanical efficiency

BACKGROUND: The effects of desflurane, sevoflurane, and isoflurane on left ventricular-arterial coupling and mechanical efficiency were examined and compared in acutely instrumented dogs. METHODS: Twenty-four open-chest, barbiturate-anesthetized dogs were instrumented for measurement of aortic and left ventricular (LV) pressure (micromanometer-tipped catheter), dP/dtmax, and LV volume (conductance catheter). Myocardial contractility was assessed with the end-systolic pressure-volume relation (Ees) and preload recruitable stroke work (Msw) generated from a series of LV pressure-volume diagrams. Left ventricular-arterial coupling and mechanical efficiency were determined by the ratio of Ees to effective arterial elastance (Ea; the ratio of end-systolic arterial pressure to stroke volume) and the ratio of stroke work (SW) to pressure-volume area (PVA), respectively. RESULTS: Desflurane, sevoflurane, and isoflurane reduced heart rate, mean arterial pressure, and left ventricular systolic pressure. All three anesthetics caused similar decreases in myocardial contractility and left ventricular afterload, as indicated by reductions in Ees, Msw, and dP/dtmax and Ea, respectively. Despite causing simultaneous declines in Ees and Ea, desflurane decreased Ees/Ea (1.02 +/- 0.16 during control to 0.62 +/- 0.14 at 1.2 minimum alveolar concentration) and SW/PVA (0.51 +/- 0.04 during control to 0.43 +/- 0.05 at 1.2 minimum alveolar concentration). Similar results were observed with sevoflurane and isoflurane. CONCLUSIONS: The present findings indicate that volatile anesthetics preserve optimum left ventricular-arterial coupling and efficiency at low anesthetic concentrations (< 0.9 minimum alveolar concentration); however, mechanical matching of energy transfer from the left ventricle to the arterial circulation degenerates at higher end-tidal concentrations. These detrimental alterations in left ventricular-arterial coupling produced by desflurane, sevoflurane, and isoflurane contribute to reductions in overall cardiac performance observed with these agents in vivo.     

Tachycardia alone fails to change the myocardial pharmacokinetics and dynamics of lidocaine, thiopental, and verapamil after intravenous bolus administration in sheep

Previous reports have suggested that tachycardia alone can increase the rate of myocardial uptake of some drugs. As part of a systematic study of the determinants of the myocardial uptake and effects of drugs in critical illness, the effect of tachycardia induced by intracardiac pacing on the myocardial disposition and effects of lidocaine, verapamil, and thiopental were studied in chronically instrumented sheep. For each drug, seven sheep received either 100 mg of lidocaine, 10 mg of verapamil, or 750 mg of thiopental over 2 min in unpaced and paced (140 beats/min) states on separate occasions and in random order. Arterial and coronary sinus (effluent from the heart) blood samples were taken at regular intervals for 30 min, and the maximum rate of change of left ventricular pressure (LV dP/dtmax) was measured as an index of myocardial contractility. There were no differences between unpaced and paced studies in the time courses of arterial and coronary sinus concentrations, or the time-courses of myocardial contractility and blood flow, after bolus iv injections of these drugs. Tachycardia alone does not appear to influence the myocardial kinetics or dynamics of lipophilic drugs that can rapidly diffuse into the heart.     

Effects of the calcium channel antagonist mibefradil on haemodynamic and morphological parameters in myocardial infarction-induced cardiac failure in rats

OBJECTIVE: Calcium channel antagonists (CCA) have been proposed for the prevention of cardiac events after myocardial infarction (MI). Mibefradil is a CCA featuring a selective blockade of T-type Ca2(+)-channels. The aim of the study was to characterize the effects of mibefradil on haemodynamic and morphological parameters in a model of postMI chronic heart failure and to establish the "therapeutic window" for the start of therapy. METHODS: MI was induced by permanent ligation of the left coronary artery in male normotensive Wistar rats. Animals were assigned to placebo- or mibefradil-treated (10 mg/kg/day p.o.) groups as follows: (1) sham operation; (2) MI placebo treatment; (3) 7 days preMI start of treatment; (4) 3 h postMI start of treatment; (5) 24 h postMI start of treatment; (6) 3 days postMI start of treatment; (7) 7 days postMI start of treatment. Treatment was continued for 6 weeks postMI. At this time point, mean arterial blood pressure (MAP), heart rate, left ventricular enddiastolic pressure (LVEDP) and contraction force (dP/dtmax) were measured in conscious rats at baseline and after methoxamine (MEX; 0.5-1.0 mg/h i.v.) stimulation to increase afterload. The hearts were subjected to histological determination of infarct size (IS), infarct length (IL), noninfarcted length (NL), left ventricular circumference (LVC), inner LV-diameter (LVD) and septal thickness (ST). RESULTS: Six weeks after MI, MAP was lowered, LVEDP increased and dP/dtmax reduced. Mibefradil treatment increased basal MAP in groups 3-5 compared to the placebo-treated MI group. Under mibefradil, LVEDP was reduced at baseline in groups 3-6 and, after MEX, in all groups. dP/dtmax was increased in groups 3-4 at baseline and after MEX. In the placebo-treated MI group, the infarcted area was 39% of the LV and heart weight, LVD and LVC were increased. Heart weights of mibefradil-treated rats (groups 3-6) did not differ from those of the placebo-treated group. Early onset of treatment with mibefradil reduced IS and IL and increased NL in groups 3-4. LVD and LVC were decreased in group 3 only. ST was increased in groups 3-5. CONCLUSION: Chronic treatment with mibefradil exerts beneficial actions on cardiac structure and performance in postMI cardiac failure in rats, especially when the onset of treatment is either prior to or within hours after the acute ischemic event.     

The distributional clines in P susceptibility causing by the P family transposable element in Drosophila melanogaster population of China

BACKGROUND: Recombinant human growth hormone (rhGH) has shown beneficial effects on cardiac function after myocardial infarction (MI) in rats. High-dose angiotensin II (AT1) receptor blockade in normal rats inhibited the hypertrophic effect of growth hormone (GH), therefore we investigated whether GH effects after MI would be enhanced by giving it in sequence after remodeling had been inhibited by prior AT1 blockade (losartan, L). METHODS AND RESULTS: Rats given losartan for 10 weeks after MI followed by rhGH for 2 weeks (2 mg/kg twice a day, GH plus losartan) were compared with rats given losartan for 10 weeks followed by placebo for 2 weeks (placebo plus losartan group) and with untreated controls (n = 17-20/group). Average MI sizes and left ventricular (LV) end diastolic (ED) dimensions (echocardiography) did not differ between groups. In GH and losartan, body weight (BW) was increased but left ventricular weight (LVW)/BW was reduced, and the LV fractional shortening and LV dP/dtmax (catheter tip micromanometer) were increased compared with the control group (20.3 vs 15.4% and 5579 vs 4699 mmHg/s, respectively, P < .05). The cardiac index also was significantly increased. In the placebo plus losartan group, the LVW/BW was also reduced and the cardiac index increased versus controls. Stroke volume was increased in GH plus losartan group compared with both placebo plus losartan and controls, and the systemic vascular resistance was significantly decreased only in the GH plus losartan group. The ED posterior wall thickness (noninfarcted wall) was increased in GH plus losartan compared with both control and placebo plus losartan. Left ventricular end diastolic pressure reduction was not significant in GH plus losartan group versus controls but was reduced in placebo plus losartan group, whereas LV relaxation (tau) was improved in both groups versus control rats. Thus, persistent remodeling effects caused by prior AT1 blockade undoubtedly contributed to some responses, but short-term GH given in sequence after chronic AT1 blockade had favorable actions on the failing heart and peripheral circulation by increasing LV wall thickness with partial reversal of unfavorable remodeling, lowering of vascular resistance, improvement of LV contractility, and enhanced LV systolic function and cardiac index relatively late after experimental MI.     

Cardiovascular effects of the K-ATP channel blocker U-37883A and structurally related morpholinoguanidines

The cardiovascular effects of the K-ATP channel blocker U-37883A and 5 related morpholinoguanidines were determined in 6 experimental preparations. In anesthetized dogs, U-37883A (0.5-8.0 mg/kg i.v.) increased mean arterial pressure (MAP; +18%) and left ventricular (LV) effective refractory period (ERP; +35%), and decreased LV contractility (-41%). Higher doses of U-37883A (16-32 mg/kg) fatally reduced MAP (-84%), heart rate (HR; -57%) and LV contractility (-72%). In anesthetized rats, U-37883A (1.0-50 mg/kg i.v.) also maximally reduced MAP, HR and LV contractility by 68, 77 and 48%, respectively. U-37883A and its analogs were diuretic in conscious rats (1.5-15 mg/kg i.v.) and blocked pinacidil in rabbit mesenteric artery (EC50 = 0.5-50 microM). In rabbit papillary muscle, 50 microM U-37883A significantly reduced force of contraction (-33%) and prolonged conduction time (+244%). Milder papillary effects were seen with the N'-OH analog U-45194A, which did not depress LV contractility in intact rats. In conscious dogs, oral U-45194A (50 mg/kg) was diuretic but reduced LV stroke volume and increased peripheral vascular resistance. These studies characterize U-37883A's systemic cardiovascular and direct myocardial effects, and identify U-45194A as a less cardiac depressant analog having U-37883A-like diuretic and functional K-ATP channel blocking activities.     

Systemic and coronary hemodynamic effects of repetitive cocaine administration in conscious dogs

The cardiovascular actions of cocaine are complex, and previous studies suggest that tachyphylaxis to the positive chronotropic and pressor effects of cocaine may develop after repetitive administration. We examined changes in systemic and coronary hemodynamics when single or multiple doses of intravenous (i.v.) cocaine were administered to conscious dogs. Dogs were chronically instrumented for measurement of aortic blood pressure (BP) and left ventricular pressure (LVP), LV dP/dtmax and dP/dt50, subendocardial segment length (%SS), diastolic coronary blood flow (CBF) velocity, and cardiac output (CO). Myocardial oxygen consumption was estimated by the pressure-work index (PWI). In one series of experiments, a single dose of cocaine (0.1, 0.2, 0.4, 0.8, or 1.6 mg/kg) was administered on 5 consecutive days in random fashion and peak changes in systemic and coronary hemodynamics were recorded. These doses were then randomly repeated in a second group of experiments with a 1-h interval between doses on the same day. Peak and steady-state changes in cardiovascular variables were recorded within and between each dose, respectively. In other experiments, higher doses of cocaine (0.8 or 1.6 mg/kg; separate groups) were administered four times at 1-h intervals in the same dogs and peak and steady-state changes in hemodynamics were determined. Cocaine caused dose-related increases in heart rate (HR), mean arterial pressure (MAP), LV systolic pressure (LVSP) and end-diastolic pressure (LVEDP), PWI, CO, and diastolic coronary vascular resistance and decreases in %SS when administered on different days. Cocaine also caused significant increases in baseline HR, MAP, LVSP, and PWI between doses given on the same day at 1-h intervals, but the absolute value of the peak response to cocaine of these hemodynamic parameters was independent of dosing regimen. These results were confirmed when we administered four doses of 0.8 mg/kg cocaine at 1-h intervals. The results indicate that baseline changes in systemic hemodynamic variables are a predominant feature of repetitive administration of lower doses of cocaine (< or = 0.8 mg/kg), but administration of higher doses of cocaine (> or = 8 mg/kg) at 1-h intervals caused tachyphylaxis to the hypertensive actions and myocardial oxygen consumption effects of cocaine.     

Beneficial effect of raxofelast, an hydrophilic vitamin E analogue, in the rat heart after ischemia and reperfusion injury

Several studies report that among the antioxidant agents used to reduce injury after myocardial ischemia/reperfusion, analogues of vitamin E (VE) seem to have a significant efficacy. Raxofelast is a potent antioxidant agent under investigation, structurally related to VE, having an excellent bioavailability and favourable physicochemical properties. We assessed raxofelast in a rat model of myocardial damage induced by 1 h of left coronary artery occlusion followed by 6 h of reperfusion. Myocardial ischemia/reperfusion produced: wide tissue necrosis (50.3+/-10.3%); membrane peroxidation, evaluated by assessing cardiac malondialdehyde (MAL) (87.8+/-15.8 nmol/g tissuev 9.53+/-2.4 nmol/g tissue) and plasma conjugated dienes (CD) (8.73+/-1.86 DeltaABS/mlv 1.61+/-0.45 DeltaABS/ml); endogenous antioxidant wasting [cardiac VE=23.5+/-10.2 nmol/g tissuev 61.4+/-13.4 nmol/g tissue, cardiac reduced glutatione (GSH)=2.15+/-1.23 micromol/g proteinv 7.34+/-0.92 micromol/g protein and cardiac superoxide dismutase (SOD)=8.9+/-4.1 U/mg proteinv 17. 5+/-4.2 U/mg protein]; depressed mean arterial blood pressure (MAP) (61.4+/-5.8 mmHgv 85.3+/-6.2 mmHg); heart rate (HR) (275+/-35 beats/minv 368+/-34 beats/min) and left-ventricular derivative developed force (LV dP/dtmax) (1050+/-187 mmHg/sv 2520+/-194 mmHg/s); and cardiac neutrophil accumulation, evaluated by assessing cardiac myeloperoxidase (MPO) (9.23+/-2.1 U/g tissuev 0.92+/-0.12 U/g tissue). Administration of raxofelast (25, 50 and 100 mg/kg i.p. 5 min after occlusion) limited myocardial necrosis (22.3+/-14.8%P<0. 005, following the highest dose), reduced lipid peroxidation (MAL=43. 5+/-14.7 nmol/g tissueP<0.001 and CD=4.01+/-2.21 DeltaABS/mlP<0.001, following the highest dose), restored the endogenous antioxidants VE (52.8+/-14.2 nmol/g tissueP<0.001, following the highest dose), SOD (14.2+/-2.7 U/mg proteinP<0.001, following the highest dose) and GSH (4.92+/-1.33 micromol/g proteinP<0.005, following the highest dose), improved hemodynamic parameters (MAP=68.1+/-5.3 mmHgP<0.05, HR=317+/-27 beats/minP<0.05, LV dP/dtmax=1427+/-143 mmHg/sP<0.05, following the highest dose) and reduced myocardial neutrophil infiltration (MPO=5.1+/-1.5 U/g tissueP<0.001, following the highest dose). These data suggest that raxofelast could be considered a useful drug to reduce myocardial infarction.     

Comparative effects of chronic angiotensin-converting enzyme inhibition and angiotensin II type 1 receptor blockade on cardiac remodeling after myocardial infarction in the rat

BACKGROUND: After myocardial infarction, the noninfarcted left ventricle develops reactive hypertrophy associated with a depressed coronary flow reserve, myocardial interstitial fibrosis, and reduced capillary density. The present study investigated the comparative cardiac effects of chronic angiotensin-converting enzyme (ACE) inhibition and selective angiotensin II type 1 receptor (AT1) blockade in the rat model of myocardial infarction and failure. METHODS AND RESULTS: Seven days after coronary ligation (MI), rats were randomized to enalapril (n = 8; 500 micrograms.kg-1.d-1), losartan (n = 9; 3 mg.kg-1.d-1), or placebo (n = 8) and treated for 6 weeks. Sham-operated rats (n = 10) served as controls. Coronary blood flow was measured with radiolabeled microspheres during baseline and maximal coronary dilation induced by dipyridamole (2 mg.kg-1.min-1 over 10 minutes). Right and left ventricular (LV) weight was increased in infarcted rats compared with sham-operated animals and enalapril- and losartan-treated MI rats. Minimal LV and right ventricular coronary vascular resistance was increased in MI rats but normalized with enalapril and losartan (LV:sham, 8.9; MI-placebo, 12.7; MI-enalapril, 9.2; MI-losartan, 8.8 mm Hg.mL-1.min-1.g-1, all P < .05 versus MI-placebo). Interstitial fibrosis determined from perfusion-fixed hearts was increased in infarcted rats but reduced by both enalapril and losartan. Myocardial capillary density improved with enalapril and losartan. In separate groups treated as above, plasma and tissue ACE activity was determined and demonstrated significantly higher ACE activity in noninfarcted LV tissue of MI-placebo rats compared with sham (0.64 vs 0.27 nmol.mg protein-1.min-1, P < .05). Enalapril and losartan reduced LV ACE activity (0.39 and 0.29 nmol.mg protein-1.min-1, P < .05 versus MI-placebo). CONCLUSIONS: The present study demonstrates that both chronic ACE inhibition and AT1 receptor blockade (1) reduces cardiac hypertrophy, (2) restores minimal coronary vascular resistance in postinfarction reactive hypertrophy, and (3) attenuates the development of myocardial interstitial fibrosis in the noninfarcted LV. These results suggest that inhibition of generation of angiotensin II and AT1 receptor blockade are equally effective in preventing important features of ventricular remodeling after myocardial infarction.