Leigh D. Segel

Alcohol and the heart.

Acute alcohol ingestion can lead to alterations of either mechanical function or electrophysiologic properties of the heart, whereas chronic consumption can lead to progressive cardiac dysfunction and congestive cardiomyopathy. On the other hand, alcohol appears to have a protective effect for coronary artery disease when consumed in low amounts, although prophylactic use of alcohol is not recommended.

Alcohol-induced cardiac hemodynamic and Ca2+ flux dysfunctions are reversible☆

Abstract Cardiac hemodynamic function and calcium accumulation by cardiac sarcoplasmic reticulum membrane vesicles were studied in control rats, in rats that had consumed alcohol as 39% of their daily calories for 10 months, and in alcoholic rats after a period of withdrawal from alcohol to determine if alcohol-induced alterations were reversible. Cardiac pump function was assessed with an isolated working whole heart preparation. Alcoholic rat hearts exhibited decreased response of left ventricular peak systolic pressure, d P d t max , peak aortic flow, and − d P d t max to challenge with the sympathomimetic agent, dobutamine (0.1 μ m ). After alcohol was withdrawn from the diet for 4 to 6 months, cardiac hemodynamic response to dobutamine was not significantly different from controls. In alcoholic rats, Ca 2+ binding and uptake were significantly lower than in controls. Four to six months following withdrawal of alcohol, Ca 2+ binding and uptake had returned to control values. The data indicate that chronic alcohol consumption results in cardiac impairment characterized by inability of the heart to fully respond to β-adrenergic stimulation. This adrenergic subsensitivity may be caused, at least in part, by defect(s) in relaxation and excitation-contraction coupling mediated by intracellular Ca 2+ fluxes. These defects were reversible since cardiac pump function and calcium accumulation returned to normal after withdrawing alcohol.

Selective overexpression of inflammatory molecules in hearts from brain-dead rats.

BACKGROUND Inflammatory processes that occur before, during, and after surgery may contribute to damage of transplanted hearts and their ability to withstand acute and chronic rejection. METHODS We determined the expression of mRNA for 10 inflammatory indicator molecules in hearts from brain-dead animals in which stable circulation was maintained. To produce brain death in male rats (n = 11), we inflated an intracranial balloon with saline (245 microl +/- 27 microl) to produce apnea and areflexia. Mean arterial pressure was maintained at 80 +/- 2 mm Hg for 6 hours. Controls (n = 11) received a burr hole but no balloon (mean arterial pressure, 94 +/- 1 mm Hg). We measured expression of each indicator molecule mRNA relative to expression of glyceraldehyde-3-phosphate dehydrogenase mRNA using reverse-transcriptase polymerase chain reaction. RESULTS Relative expression of intercellular adhesion molecule-1, vascular adhesion molecule-1, interleukin-1beta, and interleukin-6 mRNAs differed significantly (2.4 -4.6 times higher) between brain-dead and control hearts (p < 0.05; group t-test). CONCLUSION Increases in the inflammatory cytokine, interleukin-1beta, whose mRNA also increased, may mediate the overexpression of the adhesion molecule and interleukin-6 mRNAs. The data suggest that endothelial cells become inflamed during brain death, even when the circulation is stable, which may lead to leukocyte-endothelial interactions during brain death or after graft transplantation.

Attenuation of vasopressin-mediated coronary constriction and myocardial depression in the hypoxic heart.

To investigate the ability of arginine vasopressin (AVP) to compete with metabolic vasodilatory factors in the coronary circulation, we examined the coronary vascular and myocardial effects of AVP in isolated working rat hearts during normoxic and hypoxic perfusion. In normoxic hearts, AVP treatment (777 +/- 67 pg/ml) reduced coronary flow by 38.4 +/- 2.6%. Myocardial function was also significantly decreased by AVP whereas efficiency significantly increased. In contrast, the same dose of AVP administered to hypoxic hearts resulted in substantially smaller effects on coronary flow (-11.5 +/- 2.8%), myocardial function, and efficiency. In hearts treated first with AVP and then with hypoxia, the greater degree of coronary vasodilation compared with that observed in hearts treated with hypoxia alone also indicated an antagonizing effect of hypoxia on AVP-mediated coronary constriction. It was also noted that the hypoxia treatment alone resulted in reductions of O2 supply and consumption identical to those produced by AVP treatment during normoxia. However, hypoxia was associated with a significantly greater effect on myocardial function and, in contrast to the effect of AVP, a marked reduction in efficiency. The rate of lactate release was greater during hypoxia alone (2.07 +/- 0.08 mumol/min) than with AVP treatment during normoxia (0.76 +/- 0.05 mumol/min). These results indicate that the effect of AVP on the coronary vessels, as well as its effect on the myocardium, is significantly attenuated during hypoxia. In addition, AVP-constricted vessels appear to retain considerable vasodilatory reserve despite evidence of ischemic conditions. Thus, although the effects of AVP resemble ischemia, the increased efficiency and the relatively small effect of AVP on contractile function, as well as the preserved vasodilatory reserve, suggest otherwise. A physiological explanation for these observations is proposed wherein the constricting effects of AVP modulate the effects of autoregulatory factors such that blood flow requirements are minimized while allowing preservation of adequate blood flow for vital tissue function.

Isolated Hearts from Obese Rats Show Impaired Function during Hypoxia

Summary Cardiac hemodynamic function of genetically obese male Zucker rats and lean male littermates was studied using an isolated ejecting whole heart preparation. Minimal differences in function were observed between hearts from 9-week-old lean and obese rats. In contrast, hearts from 19-week-old obese rats exhibited depressed ventricular function curves accom-panied by decreased stroke work, maximum power, and efficiency in hypoxia, and reduced response to dobutamine in hypoxia compared with controls. These findings suggest that chronic severe obesity in the Zucker rat is associated with the development of diminished cardiac resistance to hypoxic stress.

Sodium pentobarbital effects on cardiac function and response to dobutamine

Summary: This study was undertaken to determine if sodium pentobarbital had persistent effects on isolated working rat heart function that altered the response of the heart to subsequently administered dobutamine. The effects of in vitro sodium pentobarbital treatment were studied using isolated working hearts from rats that were killed after pentobarbital anesthesia or by cervical fracture. Hemodynamic and contractile functions of the isolated hearts were significantly depressed in the presence of 0.4 mM sodium pentobarbital in vitro. After the pentobarbital was washed out of the preparation, all indices of cardiac function recovered fully except for −dP/dtmax, which remained depressed by ˜7%. The subsequent inotropic response of the hearts to 5 × 10−8 M dobutamine was minimally affected by the prior exposure to pentobarbital in vitro. The data confirmed that hearts from rats killed by cervical fracture exhibited a smaller inotropic response to dobutamine than hearts from pentobarbital-anesthetized rats. In addition, hearts excised from ventilated animals had significantly higher left ventricular peak systolic pressure, peak aortic flow rate, and peak power than hearts from nonventilated animals, indicating the importance of ventilating the animal during cardiac excision in order to obtain optimum isolated heart function.

Alcoholic cardiomyopathy in rats: Inotropic responses to phenylephrine, glucagon, ouabain, and dobutamine

The inotropic responses of chronic alcoholic and control rat hearts to phenylephrine, glucagon, ouabain, and dobutamine were studied to determine if the reported beta-adrenergic subsensitivity of alcoholic rat hearts was a specific defect. Male Long-Evans rats were maintained on nutritionally-complete liquid diets for 10 to 12 months; alcoholic rats received 38% of their calories from ethanol. Dry heart weight/body weight ratios indicated an average 15% hypertrophy of the alcoholic rat hearts. The function of isolated working hearts from these animals was studied at a constant heart rate and afterload. Ventricular function curves indicated significantly lower basal function of alcoholic rat hearts, as evident from their lower peak left ventricular relaxation rate, lower isovolumic relaxation rate, and lower peak power compared to controls. The alcoholic rat hearts had significantly lower inotropic (stroke work and peak power) responses to phenylephrine, glucagon, and dobutamine compared to controls, whereas the response of the alcoholics to ouabain was not significantly different from that of controls. Oxygen supply-to-utilization ratios decreased similarly in alcoholics and controls during treatment with the inotropic agents, as a result of increases in myocardial oxygen consumption and effects on coronary flow that were similar in both groups of animals. Thus the differences in inotropic responses observed with the alcoholic rat hearts were not primarily the result of compromised oxygen supply. Rather, the decreased stroke work response of the alcoholic hearts which occurred despite an increase in oxygen consumption suggested that the alcoholic rat hearts did not utilize oxygen as efficiently as did control hearts to perform external work. This was reflected in the significant differences between alcoholics and controls in the response of calculated external work efficiency to phenylephrine, glucagon, and dobutamine. Thus, alcohol-induced cardiac hypertrophy was associated with depressed basal left ventricular contractile function and decreased responsiveness to alpha 1-adrenergic, beta 1-adrenergic, and glucagon stimulation, but the responsiveness to ouabain was not significantly affected. These characteristics are similar to those of hearts hypertrophied by other causes.

A comparison of two anesthetic techniques for the study of rat skeletal muscle high-energy phosphates in vivo using 31P-NMR

31P-Nuclear magnetic resonance (NMR) spectroscopy was used to evaluate in vivo rat quadriceps ATP, phosphocreatine (PCr), inorganic phosphate (Pi) and tissue pH during anesthesia with ketamine/xylazine (K/X) or isoflurane (IS). A surface coil was used to receive signals from the quadriceps muscle of rats positioned in a wide-bore horizontal magnet. The PCr/beta-ATP ratios determined from the NMR spectra were 4.34 +/- 0.19 (K/X) and 4.40 +/- 0.28 (IS). Tissue pH was 7.09 +/- 0.05 (K/X) and 7.13 +/- 0.07 (IS). Metabolic stability of quadriceps PCr and ATP was demonstrated during both K/X and IS anesthesia, but the K/X-anesthetized animals had longer sleep time, lower food consumption, and lower body weight post-anesthesia than the IS-anesthetized animals. The PCr/beta-ATP ratio in quadriceps of repetitively IS-anesthetized rats did not fluctuate diurnally. In addition, the animals recovered rapidly and continued to gain weight following the multiple brief IS anesthetic procedures. These data indicate that serial in vivo investigations of high-energy-phosphate metabolism in small animals can be accomplished using 31P-NMR spectroscopy and IS anesthesia, which has several advantages over K/X anesthesia for these types of studies.

Computer-assisted simulations of phosphofructokinase-1 kinetics using simplified velocity equations

Equations useful for simulating the kinetic behavior of phosphofructokinase are presented. The equations, which are based on the concerted transition (symmetry) model for allosteric enzymes, account for substrate inhibition by MgATP, cooperative binding by F‐6‐P, activation by F‐2, 6‐P2, and deinhibition by AMP. Velocity calculations can be performed using either a spreadsheet program (e.g., MS Excel) or a web‐based program (e.g., Authorware). Both approaches are illustrated.