Biomedical subjects
R E Beamish
Publications and source records attributed to R E Beamish.
Biphasic changes in heart performance with food restriction in rats.
To examine effects of food restriction resembling very-low-calorie dieting on heart performance, normal rats were fed 25% of ad libitum food intake for 14 days. Although heart weight decreased (P < 0.05) after 5 days, left ventricular systolic pressure as well as rates of pressure development and fall were increased (P < 0.05) at 7 days and decreased (P < 0.05) after 14 days. Systolic and diastolic blood pressures were also increased from 5 to 7 days and decreased after 14 days. The increased hemodynamic performance of heart was associated with a raised plasma norepinephrine concentration, which peaked at day 7 of food restriction; epinephrine concentration was increased (P < 0.05) also at day 7. An increased catecholamine synthesis was indicated by the raised (P < 0.05) plasma dopamine beta-hydroxylase activity at 3 days, but this was decreased (P < 0. 05) at 14 days. The concentration of dopamine in the heart was increased (P < 0.05) at 2-14 days, of norepinephrine at 7-14 days, and of epinephrine at 10 and 14 days. Food restriction thus appears initially to be associated with an enhanced catecholamine influence on the heart and is followed by a depressed cardiac performance.
The Canadian Cardiovascular Society--the first and the next 50 years.
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Differential changes in sympathetic activity in left and right ventricles in congestive heart failure after myocardial infarction.
Although congestive heart failure subsequent to myocardial infarction is known to be associated with increased sympathetic activity, very little information regarding changes in the sympathetic nerves in the left and right ventricles at various stages after infarction is available. Male Sprague-Dawley rats were subjected to coronary artery ligation and studied 4 and 8 weeks later; these animals had mild and moderate stages of congestive heart failure. A sham group, without coronary ligation, was used as control. Four weeks after myocardial infarction, plasma and ventricular (left and right) epinephrine (EPI), unlike norepinephrine (NE), were markedly increased. Whereas plasma catecholamine (EPI and NE) levels were increased 8 weeks after infarction, NE concentration in the left ventricle was unchanged but EPI concentration was increased in comparison with sham control. The right ventricle showed an increased level of both NE and EPI 8 weeks after infarction. Measurement of the rate of change in the specific activity of NE (NE turnover) in the left and right ventricles 8 weeks after infarction revealed an increase in NE turnover in the left ventricle, without any changes in the right ventricle. The concentration of EPI, unlike NE, was increased in the kidney, spleen, and brain 8 weeks after coronary occlusion. These results are interpreted to mean that congestive heart failure caused by myocardial infarction is associated with differential changes in the status of sympathetic nerves in the left and right ventricles; sympathetic activity is increased only in the left ventricle, whereas the right ventricle may play an adaptive role by increasing catecholamine stores during the development of heart failure.
Differential changes in left and right ventricular adenylyl cyclase activities in congestive heart failure.
The status of beta-adrenergic receptors and adenylyl cyclase in crude membranes from both left and right ventricles was examined when the left coronary artery in rats was occluded for 4, 8, and 16 wk. The adenylyl cyclase activity in the presence of isoproterenol was decreased in the uninfarcted (viable) left ventricle and increased in the right ventricle subsequent to myocardial infarction. The density of beta1-adrenergic receptors, unlike beta2-receptors, was reduced in the left ventricle, whereas no change in the characteristics of beta1- and beta2-adrenergic receptors was seen in the right ventricle. The catalytic activity of adenylyl cyclase was depressed in the viable left ventricle but was unchanged in the right ventricle. In comparison to sham controls, the basal, as well as NaF-, forskolin-, and 5'-guanylyl imidodiphosphate [Gpp(NH)p]-stimulated adenylyl cyclase activities were decreased in the left ventricle and increased in the right ventricle of the experimental animals. Opposite alterations in the adenylyl cyclase activities in left and right ventricles from infarcted animals were also seen when two types of purified sarcolemmal preparations were employed. These changes in adenylyl cyclase activities in the left and right ventricles were dependent on the degree of heart failure. Furthermore, adenosine 3',5'-cyclic monophosphate contents were higher in the right ventricle and lower in the left ventricle from infarcted animals injected with saline, isoproterenol, or forskolin in comparison to the controls. The results suggest differential changes in the viable left and right ventricles with respect to adenylyl cyclase activities during the development of congestive heart failure due to myocardial infarction.
Mechanisms of subcellular remodelling in post-infarct heart failure.
Occlusion of a coronary artery results in myocardial ischemia and subsequent myocardial infarction. Whenever the infarct size is more than 30% of the ventricular wall, the remaining myocardium attempts to compensate for the loss of muscle mass by changing the size and shape of cardiocytes in addition to developing cardiac hypertrophy, cardiac dilatation and congestive heart failure. This remodeling of the heart is associated with changes in the extracellular matrix including collagen proteins and is most probably due to the activation of both sympathetic nervous system and renin-angiotensin system as well as increased formation of various growth factors. Alterations in contractile function of the infarcted heart are associated with remodelling of the sarcoplasmic reticulum with respect to Ca(2+)-pump and Ca(2+)-release channels as well as contractile and regulatory proteins of the myofibrils. Myocardial infarction has also been shown to result in remodelling of the sarcolemmal membrane with respect to Ca(2+)-channels, Ca(2+)-transport systems, cardiac receptors and signal transduction mechanisms. Although information regarding remodelling of mitochondria in the infarcted heart is limited, alterations in energy yielding and Ca(2+)-accumulating systems are suspected. Accordingly, it is suggested that changes in cardiac contractile dysfunction due to myocardial infarction are associated with remodeling of both extracellular matrix and subcellular organelles in the heart.
Mechanisms of alterations in cardiac membrane Ca2+ transport due to excess catecholamines.
The occurrence of excessive catecholamine release is often associated with stress due to the lifestyle of Western societies. Contrary to the general thinking that excess catecholamines produce cardiotoxicity mainly via binding to adrenoceptors, there is increasing evidence that catecholamine-induced deleterious actions may also occur through oxidative mechanisms. In this overview it is shown that a high dose of isoproterenol induces a biphasic change in cardiac Ca2+ transport in the sarcolemma and in sarcoplasmic reticulum. Both sarcolemmal and sarcoplasmic reticular Ca2+-transport activities are initially increased to maintain Ca2+ homeostasis and then are impaired, which may be associated with the occurrence of intracellular Ca2+ overload. On the other hand, mitochondrial Ca2+-transport activities exhibited a delayed increase. Pretreatment with vitamin E partially prevented the deleterious changes in cardiac membranes as well as the depressed energetic status of the heart muscle cell. It is concluded that excess catecholamines affect Ca2+-transport mechanisms primarily via oxidation reactions involving free radical-mediated damage. Thus drug approaches that reduce circulating catecholamines and/or prevent their oxidation should prove beneficial. A combination therapy involving inhibitors of catecholamine release, blockers of adrenoceptors, and antioxidants may be indicated for stress-induced heart disease.
Modification of catecholamine-induced changes in heart function by food restriction in rats.
In view of the common practice of dieting for weight reduction, the influence of severe food restriction (about 25% of ad libitum intake) on adrenergic mechanisms was studied. Cardiac norepinephrine and epinephrine concentrations as well as plasma norepinephrine levels, were increased upon feeding a restricted diet to rats for 14 days in comparison with control rats that ingested about 30 g food/ day. Bradycardia as well as characteristic electrocardiographic abnormalities, including prolongation of the QRS and QT intervals, were observed in food-restricted rats. Diet-restricted rats did not develop ventricular arrhythmias in response to epinephrine injections as readily as control rats. Depression in both + dP/dt and -dP/dt of the heart in situ as well as reductions in the inotropic responses to epinephrine were evident in diet-restricted rats. Beta-adrenergic binding studies revealed a significant decrease in receptor density, but the dissociation constant for binding was also depressed in the food-restricted rat heart. Downregulation of the beta-adrenergic receptors in the heart may explain the lack of an epinephrine-induced increase in contractile force development as well as arrhythmias in food-restricted rats. These data demonstrate that severe food restriction has marked effects on adrenergic mechanisms and heart function, and thus some caution should be exercised at early periods of this therapy for weight reduction.
The globalization of heart research. Reflections on the XVth World Congress of the International Society for Heart Research, Prague 1995.
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Cholesterol hypothesis vindicated by simvastatin study. Why did it take so long?
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Role of extracellular matrix proteins in heart function.
The cardiac interstitium is populated by nonmyocyte cell types including transcriptionally active cardiac fibroblasts and endothelial cells. Since these cells are the source of many components of the cardiac extracellular matrix, and because changes in cardiac extracellular matrix are suspected of contributing to the genesis of cardiovascular complications in disease states such as diabetes, hypertension, cardiac hypertrophy and congestive heart failure, interest in the mechanisms of activation of fibroblasts and endothelial cells has led to progress in understanding these processes. Recent work provides evidence for the role of the renin-angiotensin-aldosterone system in the pathogenesis of abnormal deposition of extracellular matrix in the cardiac interstitium during the development of inappropriate cardiac hypertrophy and failure. The cardiac extracellular matrix is also known to change in response to altered cardiac performance associated with post-natal aging, and in response to environmental stimuli including intermittent hypoxia and abnormal nutrition. It is becoming clear that the extracellular matrix mainly consists of molecules of collagen types I and III; they form fibrils and provide most of the connective material for typing together myocytes and other structures in the myocardium and thus is involved in the transmission of developed mechanical force. The data available in the literature support the view that the extracellular matrix is a dynamic entity and alterations in this structure result in the development of heart dysfunction.
Harold Nathan Segall (1897-1990).
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Characteristics and mechanisms of tachyphylaxis of cardiac contractile response to insulin.
Although insulin is known to cause internalization of its own receptors, the physiological significance of this phenomenon is not clear. In the isolated rat heart we observed that the positive inotropic effect of 25 munits/ml insulin was completely abolished if the heart was preperfused with insulin for 10 min. This tachyphylactic response to insulin began to appear 3-4 min after starting preperfusion with insulin and was partially reversible after 30 min of washing. Preperfusion with insulin did not affect the action of vanadate, which has insulin-like effect on glucose transport, or the actions of the other positive inotropic agents, isoproterenol and ouabain. The presence of propranolol in the perfusion medium, unlike atenolol, phenoxybenzamine, guanethidine, verapamil or quinidine, modified the inotropic as well as tachyphylactic responses to insulin. The positive inotropic and tachyphylactic responses to insulin were not altered in hearts from reserpine-treated animals. Perfusion of heart with glucose-free solution abolished the tachyphylaxis due to insulin. Likewise, no tachyphylactic response to insulin was evident when iodoacetate, but not sodium fluoride, was added in medium containing glucose. These results suggest that ATP formed during glycolysis may play an important role in insulin-induced tachyphylaxis with respect to cardiac contractile activity.
The new science of chaos--implications for cardiology?
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