Myocardial Mechanical Function Research Articles

Vascular dysfunction and myocardial contractility in the JCR:LA-corpulent rat.

The JCR:LA-corpulent rat is a unique animal model of human vascular disease that exhibits a profound insulin resistance, vasculopathy, and cardiovascular dysfunction. We tested the hypothesis that the defects affect endothelial and smooth muscle function of the coronary microvasculature as well as cardiac contractility. Coronary, myocardial and aortic function were assessed in obese (homozygous for the cp gene, cp/cp) and lean (heterozygous or homozygous normal, +/?) littermates aged 7 and 18 weeks. Coronary endothelial relaxation was examined in isolated perfused hearts by determining the effect of bradykinin (0. 1-1000 nmol l(-1)) on coronary perfusion pressure (CPP), myocardial mechanical function was evaluated in terms of left-ventricular developed pressure (LVDevP), and aortic relaxation with the endothelium-dependent agonist, A 23187 (1-1000 nmol l(-1)). In rats aged 7 weeks, bradykinin reduced CPP from 133+/-1 mmHg to 43+/-1 mmHg (-67%) in lean rats, but only to 64+/-3 mmHg (-52%) in corpulent rats (n=6, P<0.05). Similar differences were found in rats aged 18 weeks (n=8). Inhibition of NO synthase with N(G)-nitro-L-arginine (L-NNA; 0.2 mmol l(-1)) impaired, and tetrahydrobiopterin (0.1 mmol l(-1)), a NO synthase cofactor, restored relaxation in cp/cp rats. Spermine/NO equally reduced CPP in both groups (-58%). Mechanical function was similar in lean and corpulent rats, aortic endothelial relaxation was attenuated by approximately 30% and aortic smooth muscle function was normal (7 weeks) or improved (18 weeks) in the cp/cp genotype. These results suggest that (i) there is a specific impairment of NO-mediated relaxation of the coronary resistance vessels in the JCR:LA-corpulent rat that is not associated with impaired baseline myocardial contractility, and (ii) exogenous tetrahydrobiopterin reversed the relaxation defects that are part of the vascular complications typical for the insulin resistance syndrome.

RSR13, a Synthetic Allosteric Modifier of Hemoglobin, Improves Myocardial Recovery Following Hypothermic Cardiopulmonary Bypass

Background —During hypothermic blood cardioplegia, oxygen delivery to myocytes is minimal with ineffective anaerobic metabolism predominating. RSR13, 2-[4-[[(3,5-dimethylanilino) carbonyl]methyl]phenoxy]-2-methylpropionic acid, a synthetic allosteric modifier of hemoglobin (Hb), increases release of oxygen from Hb, increasing oxygen availability to hypoxic tissues, and reverses the hypothermia-dependent increase in Hb oxygen affinity. We studied recovery of myocardial mechanical and metabolic function and examined myocardial morphology after cardioplegia, comparing RSR13 (1.75 mmol/L)-supplemented blood (RSR13-BC) to standard blood cardioplegia (BC). Methods and Results —Twelve dogs underwent 15 minutes of 37°C global ischemia on cardiopulmonary bypass, followed by 75 minutes of hypothermic cardioplegia (13°C) with either BC (n=6) or RSR13-BC (n=6). There were no differences in baseline function between groups. Cardiac function was assessed after 30 minutes of 37°C reperfusion (BC versus RSR13-BC, respectively) by measuring: % return to normal sinus rhythm (0/100%), % of baseline+dP/dt (33.7±1.7/76.3±1.9), % of baseline−dP/dt (26.6±2.0/81.1±1.6), stroke volume (3.5±0.5/7.1±0.9 mL), cardiac output (340±20/880±40.3 mL/min), and LVEDP (11.3±2.2/0.3±2.9 mm Hg). Postischemic oxidative and metabolic parameters including myocardial lactate, pyruvate, ATP content, and percent water content also were determined. Histological analysis demonstrated preservation of endothelial and myocyte morphology in hearts receiving RSR13-BC compared with BC. Conclusions —These results indicate that in the setting of hypothermic cardiopulmonary bypass, RSR13 improves recovery of myocardial mechanical and metabolic function compared with standard hypothermic BC. Findings from this study suggest that RSR13-BC, by decreasing hemoglobin oxygen affinity, improves oxidative metabolism and preserves cellular morphology, resulting in significantly improved contractile recovery on reperfusion.

RSR13, a synthetic allosteric modifier of hemoglobin, improves myocardial recovery following hypothermic cardiopulmonary bypass.

During hypothermic blood cardioplegia, oxygen delivery to myocytes is minimal with ineffective anaerobic metabolism predominating. RSR13, 2-[4-[[(3,5-dimethylanilino) carbonyl]methyl]phenoxy]-2-methylpropionic acid, a synthetic allosteric modifier of hemoglobin (Hb), increases release of oxygen from Hb, increasing oxygen availability to hypoxic tissues, and reverses the hypothermia-dependent increase in Hb oxygen affinity. We studied recovery of myocardial mechanical and metabolic function and examined myocardial morphology after cardioplegia, comparing RSR13 (1.75 mmol/L)-supplemented blood (RSR13-BC) to standard blood cardioplegia (BC). Twelve dogs underwent 15 minutes of 37 degrees C global ischemia on cardiopulmonary bypass, followed by 75 minutes of hypothermic cardioplegia (13 degrees C) with either BC (n=6) or RSR13-BC (n=6). There were no differences in baseline function between groups. Cardiac function was assessed after 30 minutes of 37 degrees C reperfusion (BC versus RSR13-BC, respectively) by measuring: % return to normal sinus rhythm (0/100%), % of baseline+dP/dt (33.7+/-1.7/76.3+/-1.9), % of baseline-dP/dt (26.6+/-2.0/81.1+/-1.6), stroke volume (3.5+/-0.5/7.1+/-0.9 mL), cardiac output (340+/-20/880+/-40.3 mL/min), and LVEDP (11.3+/-2.2/0. 3+/-2.9 mm Hg). Postischemic oxidative and metabolic parameters including myocardial lactate, pyruvate, ATP content, and percent water content also were determined. Histological analysis demonstrated preservation of endothelial and myocyte morphology in hearts receiving RSR13-BC compared with BC. These results indicate that in the setting of hypothermic cardiopulmonary bypass, RSR13 improves recovery of myocardial mechanical and metabolic function compared with standard hypothermic BC. Findings from this study suggest that RSR13-BC, by decreasing hemoglobin oxygen affinity, improves oxidative metabolism and preserves cellular morphology, resulting in significantly improved contractile recovery on reperfusion.

Peroxynitrite contributes to spontaneous loss of cardiac efficiency in isolated working rat hearts.

We examined the mechanism of the time- and protein synthesis-dependent decline in cardiac mechanical function in isolated working rat hearts. Hearts were perfused with Krebs-Henseleit buffer for 120 min in the presence or absence of the protein synthesis inhibitor cycloheximide (CX; 10 microM). Cardiac work remained stable for 60 min and then spontaneously decreased during 60-120 min of perfusion. This was accompanied by an increase in myocardial inducible nitric oxide synthase (iNOS) and xanthine oxidase (XO) activities and enhanced dityrosine formation in the perfusate, an indicator of peroxynitrite generation. CX markedly attenuated the loss in contractile function and prevented the increase in iNOS and XO activities and dityrosine level. Despite the decline in cardiac work in control hearts, the coupling between tricarboxylic acid (TCA) cycle activity and oxygen consumption remained constant in both groups. ATP, creatine phosphate, and glycogen levels were not different between control and CX groups and did not differ over 120 min of perfusion. We concluded that the delayed and spontaneous loss in myocardial mechanical function in isolated working rat hearts is 1) attenuated by CX treatment, 2) accompanied by a concomitant increase in both iNOS and XO activities and peroxynitrite generation in the heart, and 3) not dependent on a direct impairment in myocardial ATP production, myocardial oxygen consumption, or TCA cycle acetyl-CoA production but may be due to an inefficiency of the heart to utilize ATP for contractile work.

Dietary Magnesium Supplementation Attenuates Ethanol‐Induced Myocardial Dysfunction

Hypomagnesemia is positively correlated with a number of cardiovascular abnormalities and recent evidence suggests that magnesium supplementation prevents ethanol-induced development of hypertension. The purpose of our study was to assess whether dietary magnesium supplementation effectively reverses or attenuates chronic ethanol-induced cardiac dysfunction, both at the tissue and the cellular level. Therefore, the influence of dietary magnesium supplementation during chronic ethanol ingestion on the mechanical properties of cardiac muscle was studied using isolated papillary muscles and ventricular myocytes from rat heart. In addition, the acute effects of ethanol on cardiac muscle from animals chronically exposed to ethanol in the absence and presence of dietary magnesium supplementation were also examined. Chronic ethanol exposure caused significant cardiac, hepatic, and renal enlargement, increased systolic blood pressure, and produced hypomagnesemia. After chronic ethanol exposure, the baseline force generating capacity of papillary muscles was markedly depressed and was associated with a significant slowing in the maximum velocities of contraction and relaxation. By contrast, in isolated myocytes, long-term ethanol exposure increased the extent of cell shortening associated with a significant reduction in the duration of relengthening and an increase in both the maximum velocities of shortening and relengthening. Dietary magnesium supplementation among animals chronically ingesting ethanol effectively normalized heart size, systolic blood pressure, and reduced plasma ethanol concentration. Magnesium supplementation also attenuated chronic ethanol-induced depression of contractile force and increased the extent of cell shortening. As expected, acute ethanol exposure caused a dose-dependent inhibition of both isometric force and isotonic shortening associated with a decrease in the intracellular calcium transient. However, the extent of the acute ethanol-induced reduction in isometric force and isotonic shortening was always slightly greater among preparations from animals chronically exposed to ethanol. Dietary magnesium supplementation normalized the acute inhibitory action of ethanol on isometric force, isotonic shortening, and the intracellular calcium transient. Our results suggest that dietary magnesium supplementation may attenuate chronic ethanol-induced alterations in baseline myocardial mechanical function and normalize the cardiac response to acute ethanol exposure.

K(ATP)-channel activation: effects on myocardial recovery from ischaemia and role in the cardioprotective response to adenosine A1-receptor stimulation.

1. Optimization of myocardial energy substrate metabolism improves the recovery of mechanical function of the post-ischaemic heart. This study investigated the role of K(ATP)-channels in the regulation of the metabolic and mechanical function of the aerobic and post-ischaemic heart by measuring the effects of the selective K(ATP)-channel activator, cromakalim, and the effects of the K(ATP)-channel antagonist, glibenclamide, in rat fatty acid perfused, working hearts in vitro. The role of K(ATP) channels in the cardioprotective actions of the adenosine A1-receptor agonist, N6-cyclohexyladenosine (CHA) was also investigated. 2. Myocardial glucose metabolism, mechanical function and efficiency were measured simultaneously in hearts perfused with modified Krebs-Henseleit solution containing 2.5 mM Ca2+, 11 mM glucose, 1.2 mM palmitate and 100 mu l(-1) insulin, and paced at 300 beats min(-1). Rates of glycolysis and glucose oxidation were measured from the quantitative production of 3H20 and 14CO2, respectively, from [5-3H/ U-14C]-glucose. 3. In hearts perfused under aerobic conditions, cromakalim (10 microM), CHA (0.5 microM) or glibenclamide (30 microM) had no effect on mechanical function. Cromakalim did not affect glycolysis or glucose oxidation, whereas glibenclamide significantly increased rates of glycolysis and proton production. CHA significantly reduced rates of glycolysis and proton production but had no effect on glucose oxidation. Glibenclamide did not alter CHA-induced inhibition of glycolysis and proton production. 4. In hearts reperfused for 30 min following 30 min of ischaemia, left ventricular minute work (LV work) recovered to 24% of aerobic baseline values. Cromakalim (10 microM), administered 5 min before ischaemia, had no significant effect on mechanical recovery or glucose metabolism. CHA (0.5 microM) significantly increased the recovery of LV work to 67% of aerobic baseline values and also significantly inhibited rates of glycolysis and proton production. Glibenclamide (30 microM) significantly depressed the recovery of mechanical function to < 1% of aerobic baseline values and stimulated glycolysis and proton production. 5. Despite the deleterious actions of glibenclamide per se in post-ischaemic hearts, the beneficial effects of CHA (0.5 microM) on the recovery of mechanical function and proton production were not affected by glibenclamide. 6. The data indicate that the cardioprotective mechanism of adenosine A1-receptor stimulation does not involve the activation of K(ATP)-channels. Furthermore, in rat fatty acid perfused, working hearts, stimulation of K(ATP)-channels is not cardioprotective and has no significant effects on myocardial glucose metabolism.

Transient Ischemia Does Not Limit Subsequent Ischemic Regional Dysfunction in Humans: A Transesophageal Echocardiographic Study During Minimally Invasive Coronary Artery Bypass Surgery

Objectives. This study sought to assess the effects of sequential coronary artery occlusion during minimally invasive coronary artery bypass graft surgery (CABG) on hemodynamic variables and left ventricular systolic function by means of transesophageal echocardiography (TEE).Background. Clinical and experimental studies suggest a protective effect of ischemic preconditioning in patients with acute coronary syndromes. However, the effect of repetitive myocardial ischemia on myocardial mechanical function in humans is not completely understood.Methods. Seventeen patients with left anterior descending coronary artery (LAD) stenosis ≥70% and normal rest left ventricular systolic function referred for minimally invasive CABG underwent intraoperative TEE for assessment of regional left ventricular wall motion and measurement of hemodynamic variables at baseline (baseline 1), during a 5-min coronary occlusion (occlusion 1), after a 5-min reperfusion period (baseline 2) and a during a second coronary occlusion during bypass anastomosis (occlusion 2).Results. Left ventricular wall motion score (LVWMS) increased significantly from baseline (16.0) to occlusion 1 (21.4 ± 3.1 [mean ± SD], p < 0.05) and occlusion 2 (21.8 ± 3.1, p < 0.05). No difference in LVWMS was noted between occlusions 1 and 2. Pulmonary artery systolic pressure increased significantly from baseline (25 ± 6 mm Hg) to occlusion 1 (32 ± 7 mm Hg, p < 0.05) and occlusion 2 (33 ± 6 mm Hg, p < 0.05). Pulmonary artery diastolic pressure also increased significantly from baseline (12 ± 4 mm Hg) to occlusion 1 (16 ± 4 mm Hg, p < 0.05) and occlusion 2 (16 ± 4 mm Hg, p < 0.05). No significant differences in pulmonary artery pressures were noted between occlusions 1 and 2.Conclusions. Ischemic dysfunction was precipitated by the 5-min LAD occlusion, as shown by the increase in LVWMS and pulmonary artery pressure. However, a 5-min coronary occlusion and the resulting ischemia do not alter regional left ventricular systolic function during subsequent ischemia in humans.

Stimulation of Carbohydrate Metabolism Reduces Hypothermia-induced Calcium Load in Fatty Acid-perfused Rat Hearts

In the present study we examined the impact of glycolysis and glucose oxidation on myocardial calcium control and mechanical function, of fatty acid-perfused rat hearts subjected to hypothermia and rewarming. One group (control) was given glucose (11.1 mm) and palmitate (1.2 mM) as energy substrates. In a second group glycolysis was inhibited by iodoacetate (IAA, 100μm) and replacement of glucose with pyruvate (5 mM), whereas in the third group glucose oxidation was stimulated by administration of dichloroacetate (DCA, 1 mM) and insulin (500μU/ml). All groups showed a rise in myocardial calcium ([Ca]total) in response to hypothermia (10°C). However, [Ca]totalwas significantly lower both in IAA- and DCA-treated hearts, as compared to controls (2.20±0.22 and 2.94±0.20v3.83±0.29 nmol/mg dry wt.,P<0.025). The reduced calcium load in the treated hearts was correlated with higher levels of high energy phosphates. Following rewarming, control and DCA-treated hearts still showed elevated [Ca]total, whereas IAA-treated hearts [Ca]totalwas not different from the pre-hypothermic value. All groups showed a reduction in cardiac output following rewarming. Furthermore, the control group, in contrast to both IAA- and DCA-treated hearts, showed a significant reduction in systolic pressure. These results show that hypothermia-induced calcium uptake in glucose and fatty acid-perfused rat hearts was reduced by two different metabolic approaches: (1) inhibition of glycolysis by IAA while simultaneously by-passing the glycolytic pathway by exogenous pyruvate; and (2) stimulation of glucose oxidation by DCA. Thus, glycolytic ATP is not an essential regulator of sarcolemmal calcium transport under the present experimental conditions. Instead, we suggest that a change in oxidative substrate utilization in favour of carbohydrates may improve myocardial calcium homeostasis during hypothermia and rewarming.

Differential effects of chronic calcium channel blocker treatment on the inotropic response of diabetic rat myocardium to acute ethanol exposure

Cardiomyopathy is a consistent feature of diabetic myocardium as well as in prolonged alcohol consumption. Diabetes-induced myocardial dysfunction has been attributed, in part, to calcium overload within individual myocytes. The present study compares the effectiveness of the calcium channel blocker nifedipine (dihydropyridine-type) with verapamil (phenylalkylamine-type) in reversing myocardial dysfunction and diminishing the negative inotropic effect of ethanol on diabetic rat myocardium. Wistar rats were made diabetic with streptozotocin (55 mg/kg, IV) and isolated electrically stimulated papillary muscles were studied under isometric conditions in the absence and presence of clinically relevant concentrations of ethanol (80–240 mg/d1, i.e., 17.4–52.1 mM). Subgroups of diabetic and normal animals received daily injections of verapamil or nifedipine 2 weeks after induction of diabetes for 8 weeks Untreated diabetic animals exhibited hyperglycemia, hyperlipidemia, reduced growth, cardiomegaly, and hepatomegaly. Compared to verapamil chronic nifedipine treatment normalized or reversed the effects of diabetes on myocardial mechanical function. The negative inotropic effect of ethanol was attenuated only in muscles from verapamil-treated diabetic animals. Thus, chronic nifedipine treatment may be more effective than verapamil in reducing hyperglycemia, attenuating both cardiac and liver enlargement, and restoring myocardial mechanical function, in experimental diabetes However, chronic verapamil therapy is more effective in diminishing the negative inotropic effect of ethanol on diabetic myocardium. These findings may have clinical significance among diabetic patients who consume alcoholic beverages while receiving long-term calcium blocker therapy.

Rapid increase in inducible nitric oxide synthase gene expression in the heart during endotoxemia

Inducible, Ca 2+-independent nitric oxide (NO) synthase activity in the heart is elevated during endotoxemia and the resulting excess release of NO depresses cardiac contractile function. We show here that this is due to an extremely rapid induction of inducible NO synthase gene expression. Following injection of endotoxin (bacterial lipopolysaccharide) in rats we detected increased inducible NO synthase mRNA levels in the left ventricular wall within 30 min which then peaked at 3 h. This was followed by an increase in myocardial inducible NO synthase enzyme activity and plasma levels of NO metabolites, nitrate and nitrite, which peaked at 6 and 12 h, respectively. The extremely rapid induction of inducible NO synthase may serve to protect the heart against microbial infection and concomitantly alter myocardial mechanical function.

Influence of calcium channel blocker treatment on the mechanical properties of diabetic rat myocardium

The objective of this investigation was to determine whether calcium channel blocker (CCB) treatment effectively restores normal baseline mechanical function in diabetic myocardium and to evaluate its effect on the interval-strength relationship. Wistar rats were made diabetic with streptozotocin (55 mg/kg, IV). Left-ventricular papillary muscles from normal and diabetic (10 weeks) rats were superfused with Tyrode's solution at 30 degrees C. A subgroup of diabetic and normal animals received daily injections of verapamil or nifedipine (10 mg/kg, IP; 8 weeks) to compare the effectiveness of a phenylalkylamine to a dihydropyridine in reversing diabetes-induced contractile dysfunction in vitro. Muscles were electrically stimulated at 0.5 Hz with suprathreshold stimuli, and the following parameters were measured: peak tension developed, time to-peak tension, time-to-90% relaxation, and the maximum velocities of tension development and decay. Experimental diabetes was characterized by: severe hyperglycemia, hepatomegaly, reduced body weight gain, cardiomegaly, and increased plasma phospholipid levels. In addition, baseline values of peak tension developed, time to-peak tension, and time-to-90% relaxation were significantly greater in muscles from diabetic animals. Chronic nifedipine treatment reduced hyperglycemia and plasma phospholipid levels, normalized body weight gain, and reduced both heart and liver sizes in diabetic animals. Nifedipine treatment completely reversed diabetes-induced prolongation in both time-to-peak tension and time-to-90% relaxation. In diabetic myocardium, a slightly positive component was present in the interval-strength relationship between 0.01 and 1 Hz, resulting in a rightward shift in the entire curve across a wide range of stimulation frequencies (0.01-5 Hz). This positive component was absent in muscles from diabetic animals treated with both CCBs, and verapamil produced a leftward shift in the frequency response curve. The results of this study suggest that chronic nifedipine treatment may be more effective than verapamil in restoring normal baseline myocardial mechanical function, reducing hyperglycemia and hyperlipidemia, as well as attenuating both cardiac and liver enlargement in experimental diabetes. In contrast, verapamil treatment tended to normalize more effectively the inotropic response to changes in stimulation frequency in diabetic myocardium.

Experimental hypothermia and rewarming: changes in mechanical function and metabolism of rat hearts.

Rewarming from accidental hypothermia is associated with fatal circulatory derangements. To investigate potential pathophysiological mechanisms involved, we examined heart function and metabolism in a rat model rewarmed after 4 h at 15-13 degrees C. Hypothermia resulted in a significant reduction of left ventricular (LV) systolic pressure, cardiac output, and heart rate, whereas stroke volume increased. The maximum rate of LV pressure rise decreased to 191 +/- 28 mmHg/s from a control value of 9,060 +/- 500 mmHg/s. Myocardial tissue content of ATP, ADP, and glycogen was significantly reduced, whereas lactate content remained unchanged. After rewarming, heart rate returned to control value, whereas LV systolic pressure, cardiac output, and stroke volume all remained significantly depressed. The posthypothermic maximum rate of LV pressure rise was 5,966 +/- 1.643 mmHg/s. The posthypothermic myocardial lactate content was significantly increased (to 13.3 +/- 3.2 nmol/mg from control value of 5.7 +/- 1.9 nmol/mg), and ATP and glycogen remained significantly lowered. Creatine phosphate or energy charge did not change significantly during the experiment. The finding of deteriorated myocardial mechanical function and a shift in energy metabolism shows that the heart could be an important target during hypothermia and rewarming in vivo, thus contributing to the development of a posthypothermic circulatory collapse.

Mechanical and Biochemical Cardiac Disturbances Induced by Bolus Administration of Iodinated Contrast Media and Noniodinated Solutions

Bolus injection of iodinated contrast media has been observed to alter myocardial mechanical function, but the consequences on cellular metabolism are poorly documented. Modifications of metabolic parameters (intracellular pH as well as adenosine triphosphate [ATP], phosphocreatine, and inorganic phosphate contents) and of mechanical function (coronary flow, heart rate, and left ventricular developed pressure) were simultaneously recorded on isolated rat hearts perfused over 2 minutes with a high osmolality contrast medium (HOCM) and two low osmolality contrast media (LOCM). In addition, the effects of test solutions mimicking the ionicity and the osmolality of LOCM were evaluated. Isovolumic rat hearts were submitted to a 2-minute perfusion with oxygenated Radioselectan, Hexabrix, and Omnipaque (320 mgI/mL) at 37 degrees C. Metabolic parameters were obtained by P-31 nuclear magnetic resonance spectroscopy at 4.7 Tesla. Noniodinated ionic and nonionic solutions also were tested for comparison. HOCM irreversibly impairs the metabolic and mechanical functions, whereas ionic and nonionic LOCM and test solutions induce transient cardiac failure but no permanent alteration of the metabolic or mechanical parameters. In this protocol, HOCM causes irreversible degradation of the biochemical status and definitive heart failure, whereas ionic and nonionic LOCM only induce transient changes of myocardial function. Treatments with the LOCM do not induce any modification of the ATP and PCr content, and, at the end of the reperfusion period, the mechanical function is equivalent to that of control hearts. Depending on the ionic content of the solutions (iodinated or not), the evolution of the ventricular developed pressure after injection differs from one group of hearts to another. From these experiments, it is concluded that ionic imbalance and viscosity of the solutions, rather than iodine content or hyperosmolality, should be considered the causes of heart failure.

Chronic stunning: the new switch in thought.

One picture may be worth a thousand words, as they say, but I was asked to write the thousand words and not to provide the picture. My major point can in fact be made in even fewer words. Despite the unanimous acceptance of the standard definition of stunning (1), it appears that this includes vastly different experimental and clinical conditions. Regarding the definition-according to Bolli (1), it is a state in which myocardial blood flow is fully restored following prior ischemia and during which time myocardial mechanical function is depressed. A further feature is that there is no evidence of myocardial necrosis.

The effect of ischemic preconditioning on nucleotide metabolism and function of rat heart after prolonged cold storage.

Experimental data suggests that brief periods of myocardial ischemia followed by reperfusion induced by coronary artery occlusion or global ischemia enhances myocardial tolerance to subsequent, more prolonged ischemic episodes (Ischemic Preconditioning)1. However, the effect of ischemic preconditioning on the contractility and metabolism of the heart subjected to prolonged cold storage induced by a single use of cold cardioplegia as in clinical heart transplantation has not been determined. In this study we evaluated the effect of 5 min ischemia and 10 min reperfusion on the recovery of myocardial mechanical function and metabolism following 6 hours of 4°C preservation using an isolated rat heart preparation.

31P nuclear magnetic resonance study of the effects of the calcium ion channel antagonist fantofarone on the rat heart

The biochemical and mechanical effects of a new calcium ion channel antagonist, fantofarone ((2-isopropyl-1-((4-(3-( N-methyl- N-(3,4-dimethoxy- β-phenethyl)-amino)propyloxy)benzenesulfonyl))-indolizine), on isovolumic perfused rat heart have been assessed by using 31P nuclear magnetic resonance (NMR) spectroscopy together with simultaneous monitoring of myocardial mechanical function. Cytosolic pH and phosphocreatine, adenosine triphosphate and inorganic phosphate contents were monitored by using 31P NMR. Heart rate, coronary flow and left ventricular developed pressure were measured routinely to assess mechanical function. Perfusion with 10 nM, 100 nM or 1 μM fantofarone for a period of 48 min did not cause any measurable metabolic changes. However, coronary vasodilatation and a partial positive inotropic effect were noted. A 15-min pretreatment with 100 nM did not protect against the deleterious effects of an 18-min period of normothermic, zero-flow ischemia. In contrast, a 20-min pretreatment period with 1 μM fantofarone significantly improved the recovery of mechanical performance, metabolic activity and pH after the same 18 min of ischemia. While only a slight protection of the ATP pool was noted during the ischemic period, a major beneficial effects were observed during the reperfusion period, such that reflow was characterized by high recoveries of left ventricular pressure and rate pressure product (70–80%), low end diastolic pressure (<10 mm Hg), significant recovery of ATP content (to 55%), a complete repletion of the phosphocreatine pool and a fast return of cytosolic pH to normal value.

Limitation of stunning in dog myocardium by nucleoside and nucleotide mixture, OG-VI.

OG-VI is a nucleoside-nucleotide solution composed of 30 mM inosine, 30 mM cytidine, 30 mM sodium 5'-guanylate, 22.5 mM uridine, and 7.4 mM thymidine. It is expected to enhance the efficacy of intravenous hyperalimentation in surgically stressed patients. One of the main causes of ischemic myocardial damage is loss of adenine nucleotides from heart cells. The aim of the present study, therefore, was to examine the effect of OG-VI on myocardial mechanical function and energy metabolism in stunned myocardium. Pentobarbital-anesthetized dogs were subjected to 20 min ligation of the left anterior descending (LAD) coronary artery, followed by reperfusion for 30 min. OG-VI at 0.1 or 0.2 ml/kg/min or saline was infused from the left femoral vein throughout the experiment. The tissue levels of high-energy phosphates in the hearts were determined after 30 min reperfusion. LAD flow, first derivative of left ventricular pressure (LVdp/dt), and segment function were increased by OG-VI in a dose-dependent manner. OG-VI infusion resulted in a significant improvement in LVdP/dt and segment shortening in the ischemic/reperfused myocardium compared with saline infusion. The levels of segment shortening with saline, 0.1, and 0.2 ml/kg/min OG-VI after reperfusion for 30 min were -0.3, 75, and 82% of the preligation levels, respectively. The tissue level of adenosine triphosphate (ATP) after reperfusion in OG-VI-infused animals was significantly higher than that in saline-infused animals. OG-VI has a positive inotropic action, and its infusion results in a marked cardioprotective effect in stunned myocardium associated with the restoration of tissue ATP level.

Ruthenium red, ribose, and adenine enhance recovery of reperfused rat heart.

Postischemic cardiac failure may be associated with inadequate storage of myocardial adenosine triphosphate (ATP). ATP precursors were administered to resuscitate the postischemic myocardium. Hearts isolated from male Wistar adult rats were perfused with Krebs-Henseleit buffer (pH, 7.40), subjected to 30 minutes of global ischemia at 36 degrees C, followed by 30 minutes of retrograde reperfusion with the postischemic intervention of ruthenium red (1 microM), ribose (1 mM), and adenine (1 mM). Multiple analysis of variance was used to compare means between groups (eight rats in each group). In comparison with the nonischemic group, the postischemic nontreated group had a decrease in the maximum rate of left ventricular pressure rise (+dP/dt, P < 0.0005) and level of myocardial ATP (P < 0.0005) but an increase in level of mitochondrial Ca2+ (P < 0.005). In comparison with the nontreated group, ribose and adenine had no effect on all the above-mentioned parameters, and ruthenium red elevated maximum left ventricular +dP/dt (P < 0.05) and reduced mitochondrial Ca2+ (P < 0.05) with no change in ATP (P > 0.05). However, ruthenium red with ribose and adenine achieved a significant increase in maximum left ventricular +dP/dt (P < 0.0005), ATP levels (P < 0.005), and a decrease in levels of mitochondrial Ca2+ (P < 0.005). Acute postischemic cardiac failure may be related to Ca2+ overload in mitochondria. Ruthenium red may reduce mitochondrial Ca2+ overload. Ruthenium red, ribose, and adenine in combination may be capable of enhancing the recovery of myocardial high-energy phosphates and mechanical function in the postischemic myocardium.

Endothelin release during ischaemia and reperfusion of isolated perfused rat hearts

The hypothesis tested was that release of endogenous endothelin plays a role in events associated with or leading to myocardial ischaemia and/or post-ischaemic reperfusion damage. Release of endogenous endothelin into the coronary perfusate of isolated perfused rat hearts during ischaemia and reperfusion was measured with a sensitive radioimmunoassay using a polyclonal antibody with 100% cross-reactivity for all three endothelin isomers. Basal endothelin release was 0.69 ± 0.02 pg/min/g wet heart weight ( n = 35) and was constant up to 180 min. During low-flow hypoxic ischaemia for 180 min ( PO 2 ≈ 250 mmHg) and in the presence of 1% foetal calf serum, the release rate was reduced to below 10% of controls ( P < 0.01) and increased four-fold on reperfusion ( P < 0.05). The influence of endothelin on vascular and myocardial reperfusion damage was studied with exogenous endothelin-2. After 1 h of low-flow ischaemia, endothelin-2 increased the coronary perfusion pressure to a similar extent as in non-ischaemic hearts, but with a 30-times higher potency. The threshold dose for the constrictive effect was ≈100 to 300 pg per heart, about ten times more than was recovered in the coronary effluent upon reperfusion. The influence of endothelin on myocardial reperfusion mechanical function (stunning) was assessed with 100 ng endothelin-2, a dose some 3500-fold higher than the amount released during 30 min reperfusion. This dose, given at the onset of reperfusion, improved post-ischaemic aortic output recovery during the first 20 min of reperfusion, but worsened it thereafter (up to 40 min). These data indicate that, in the isolated perfused rat heart model, (1) endothelin is released in measurable amounts into the coronary circulation, (2) the release is much reduced during ischaemia and increased on early reperfusion following prolonged ischaemia, (3) based on the amounts released and the post-ischaemic sensitization of the coronary vasculature to endothelin, the peptide could contribute to reperfusion vascular damage, and (4) endothelin is unlikely to influence stunning owing to the extremely high dose necessary to alter reperfusion mechanical function.

Enhancement of low coronary reflow improves postischemic myocardial function

The effect of reperfusion coronary vasodilatation on postischemic myocardial mechanical function has been investigated in the isolated working rat heart. After a working period to assess control function, all the hearts were subjected to a single infusion (10 ml) of St. Thomas' Hospital cardioplegic solution No. 1 at 4 degrees C and were kept immersed in the same solution for 4 hours at 4 degrees C. Then hearts (six in each group) were initially reperfused at 37 degrees C for 10 minutes, either with ordinary reperfusate (Krebs-Henseleit bicarbonate buffer) or with reperfusate containing additional coronary dilator. After this period, all hearts were subjected to a further 5 minutes of ordinary reperfusate before being put back into the working mode to assess functional recovery. Mean reperfusion coronary flows and the steady coronary flow measured after 10 minutes of reperfusion in ml/min +/- SEM were--Krebs (control): 17.4 +/- 0.39 and 13.4 +/- 0.40; adenosine (3.75 mumol/L): 19.9 +/- 0.6 and 16.7 +/- 0.8; papaverine (0.05 mmol/L): 21.8 +/- 2.3 and 17.3 +/- 1.8; dipyridamole (2 mmol/L): 20.7 +/- 1.7 and 17.9 +/- 1.0; nitroglycerin (15 mg/L): 20.5 +/- 0.45 and 19.9 +/- 1.4; diltiazem (0.05 mmol/L): 19.6 +/- 2.98 and 17.7 +/- 1.8; calcitonin gene-related peptide (0.03 mmol/L): 20.8 +/- 0.69 and 18.0 +/- 1.3; 5-hydroxytryptamine (0.01 mmol/L): 19.2 +/- 0.53 and 16.9 +/- 0.80. Mean postischemic recovery of cardiac output, peak aortic pressure, and differentiation of pressure were expressed as percent of preischemic control +/- SEM were--Krebs: 54.1 +/- 2.8, 69.1 +/- 2.8, and 53.9 +/- 3.0; adenosine: 78.0 +/- 5.6, 89.5 +/- 2.9, and 69.1 +/- 1.9; papaverine: 81.8 +/- 3.9, 91.8 +/- 3.1, and 71.0 +/- 4.1; dipyrdamole: 67.3 +/- 3.3, 84.3 +/- 2.3, and 75.0 +/- 2.7; nitroglycerin: 83.1 +/- 4.8, 79.7 +/- 2.7, and 69.0 +/- 0.5; diltiazem: 76.5 +/- 3.7, 85.9 +/- 2.9, and 73.3 +/- 1.7; calcitonin gene-related peptide: 79.5 +/- 3.6, 90.0 +/- 4.9, and 75.4 +/- 3.9; 5-hydroxytryptamine: 71.6 +/- 3.2, 85.5 +/- 3.5, and 67.9 +/- 4.8. There was a positive correlation between mean reperfusion coronary flow, steady coronary flow, and postischemic recovery of cardiac output, peak aortic pressure, and differentiation of pressure. Mean reperfusion coronary flow, steady coronary flow, and postischemic recovery of cardiac output, peak aortic pressure, and differentiation of pressure were significantly greater in groups reperfused with vasodilators (p < 0.05) compared with control values.(ABSTRACT TRUNCATED AT 400 WORDS)