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Biomedical subjects

M J Sole

Publications and source records attributed to M J Sole.

At least 55 records · Page 3Linked to original sources
PubMed1989

Lung is an important source of atrial natriuretic factor in experimental cardiomyopathy.

The regulation of water and electrolyte homeostasis is multifactorial and includes the heart and kidneys as important regulatory centers. Within the heart, a recently discovered hormone, atrial natriuretic factor (ANF), has been implicated in the maintenance of water and salt balance. Primarily found in mammalian atria, ANF has been detected in low amounts in several tissues, including lungs. A disorder of the ANF system has been demonstrated in genetically cardiomyopathic hamsters, a model for human congestive cardiomyopathy. Atrial ANF gene expression and storage are decreased during development of this disease, while paradoxically, circulating levels of ANF are increased. We have hypothesized that an extracardiac source may contribute to ANF production in these pathological conditions. In this paper we provide evidence that ANF synthesis is stimulated in the lungs of hamsters during development of cardiomyopathy as revealed by increased ANF mRNA and peptide levels. Furthermore, we show that ANF synthesized in lungs is secreted and has identical chromatographic and biological properties to circulating ANF. The increased production of ANF in lungs may be physiologically important in preventing pulmonary edema. Alternatively, during cardiac dysfunction, lungs may play a compensatory role by increasing their contribution to plasma ANF levels.

Animals↗
PubMed1989

Effect of blood transfusion, dopamine, or normal saline on neurogenic shock secondary to acutely raised intracranial pressure.

An experimental model to simulate acutely raised intracranial pressure due to a rapidly expanding intracranial space-occupying lesion was used to produce neurogenic shock. Forty-one rats in neurogenic shock (defined as a mean systemic arterial pressure (SAP) of less than 60 mm Hg) were subjected to various treatments to increase the mean SAP to a level of more than 80 mm Hg. The control group with neurogenic shock received no treatment, and the six treatment groups received infusions of: whole blood, packed cells, plasma, normal saline, dopamine, or a combination of dopamine and saline. Detrimental effects were observed after transfusion of packed cells or whole blood, which caused further deterioration of mean SAP. Although dopamine or the combination of dopamine and saline were both effective (p = 0.0001) for reversing hypotension, the combination was the most effective. If this rat paradigm correlates with human disease, these results indicate that, in the absence of hypovolemia, neurogenic shock due to acute intracranial hypertension should be treated with a combined transfusion of dopamine and normal saline, but not blood since the latter could have a detrimental effect.

Animals↗
PubMed1989

The actions and role of calcium entry blockers in hypertension: cardiac considerations.

The calcium antagonists, although initially restricted to the treatment of angina pectoris, are now finding widespread application as safe and effective therapy for hypertension. These drugs reduce systemic vascular resistance and thus address the usual primary physiologic defect in high blood pressure. Reduction of blood pressure with these agents appears to lead to the concomitant reduction of hypertension-induced ventricular hypertrophy and improvement of ventricular function. Unlike other vasodilators, calcium antagonists do not secondarily lead to sodium retention or stimulation of the renin-angiotensin-aldosterone and sympathoadrenal systems. They are effective in the treatment of angina pectoris and may inhibit the onset or progression of atherosclerosis. As calcium antagonists primarily block voltage-operated, as opposed to receptor-operated, sarcolemmal calcium channels, they may be rationally and effectively combined with agents such as converting enzyme inhibitors and adrenergic antagonists. Calcium antagonists have important interactions with drugs relevant to the treatment of cardiac disease. The combination of verapamil and beta blockers or disopyramide and diltiazem with amiodarone should be avoided; caution is advised in the concomitant use of calcium antagonists and digoxin or the major antiarrhythmic agents.

Calcium Channel Blockers↗
PubMed1988

Catecholamines, calcium and cardiomyopathy.

The cardiomyopathic Syrian hamster has a genetically transmitted form of dilated cardiomyopathy and is an important paradigm of myocardial disease, particularly for studies addressing the earliest stages of myocardial dysfunction. This model exhibits an increase in cardiac sympathetic tone in the presence of an altered expression of sarcolemmal calcium channels or of alpha 1 receptors, and a defective handling of calcium by both cardiomyocytes and vascular smooth muscle cells. Increased expression of the oncogene c-myc is evident in cardiomyocytes before any overt evidence of heart disease. Alterations in a nuclear phosphoprotein, which appears to be important in the regulation of gene expression, have also been identified. The disease becomes phenotypically manifest by the development of microvascular spasm, reperfusion injury and myocyte loss. Myocyte loss, in turn, burdens the remaining cells with an increasing load, increasing sympathetic stimulation, myocyte hypertrophy and further cell loss--a continuing vicious spiral that culminates in the development of myocardial failure. All of the features of hamster cardiomyopathy may be prevented by the administration of verapamil or prazosin to juvenile hamsters before the phenotypic onset of their heart disease. This understanding has led to the study of new imaging agents that promise the detection of such forms of cardiomyopathy in their earliest stages and a means by which the effects of therapy can be assessed. If such mechanisms are applicable to human cardiomyopathy, early treatment of patients with adrenergic antagonists or calcium antagonists should be beneficial.

Animals↗
PubMed1988

Renal prostaglandin E2 and other vasoactive modulators in refractory hepatic ascites: response to peritoneovenous shunting.

To assess the role of renal prostaglandin E2 in the pathogenesis of refractory ascites, in relation to renal sodium handling and circulating levels of vasoconstrictive substances, we studied 12 cirrhotic patients with refractory ascites before and after peritoneovenous shunting. Baseline values for urinary prostaglandin E2 excretion, sodium excretion, and creatinine clearance, as well as serum aldosterone, plasma renin activity, and plasma free norepinephrine, were obtained preoperatively with patients on a sodium- and fluid-restricted diet. Diuretics were also withheld. Similar parameters were measured immediately postoperatively during four consecutive 2-h intervals, then again at 2 wk and 3 mo. In patients with refractory ascites, mean baseline urinary prostaglandin E2 excretion was significantly elevated (2.5 +/- 0.8 pmol/min), compared with that in both normal controls and cirrhotics without ascites (1.3 +/- 0.3 pmol/min). A significant natriuresis occurred immediately postoperatively and persisted at 2 wk and 3 mo. Concomitantly, the elevated levels of preoperative vasoconstrictor substances gradually normalized by 2 wk. Urinary prostaglandin E2 excretion, however, rose transiently in the immediate postoperative period and then fell gradually to within the normal range by 3 mo. Enhanced renal prostaglandin E2 synthesis, therefore, does not play a role in the sustained improvement in sodium homeostasis after peritoneovenous shunting in patients with refractory ascites.

Adult↗
PubMed1988

Increased intracranial pressure elicits hypertension, increased sympathetic activity, electrocardiographic abnormalities and myocardial damage in rats.

Intracranial pressure was increased in 59 rats by inflating a subdural balloon to a total mass volume of 0.3 ml. The increase in intracranial pressure ranged from 75 to greater than 500 mm Hg. With few exceptions, mean arterial pressure increased to as high as 227 mm Hg during the increase in intracranial pressure. Significant increases in plasma catecholamines, major electrocardiographic changes and a considerably shortened survival time were observed only in the rats that demonstrated an increase in mean arterial pressure greater than 50 mm Hg. A perfusion study with liquid silicone rubber (Microfil) revealed dilated irregular myocardial vessels with areas of focal constriction consistent with microvascular spasm. Histologic examination of the myocardium revealed widespread patches of contraction band necrosis and occasional contraction bands in the smooth muscle media of large coronary arteries. These observations suggest that myocardial damage after suddenly increased intracranial pressure resulted both from exposure to toxic levels of catecholamines and from myocardial reperfusion. Extension of these studies to humans suggests that a detailed assessment of myocardial function should be performed in victims of severe brain injury. Myocardial dysfunction may be a major determinant of the patient's prognosis or may render the heart unsuitable for transplantation.

Animals↗
PubMed1988

Cardiovascular effects of smoking in patients with ischemic heart disease.

The cardiovascular effects of smoking, including the occurrence of ventricular arrhythmias, were examined in 52 patients with ischemic heart disease. The study was a randomized, crossover comparison between smoking six cigarettes and nonsmoking with observer-blinded primary outcome measurements. Continuous Holter ECG recording for four hours showed no significant differences in the proportion of patients experiencing ventricular ectopy or the total number and complexity of ventricular premature beats during smoking vs nonsmoking. Aside from the first cigarette, smoking did not significantly alter blood pressure or heart rate. Mean (+/- SEM) plasma epinephrine (pg/ml) increased (p = 0.02) from baseline (52 +/- 4) to a maximum of 64 +/- 6 at 240 minutes with younger subjects exhibiting a more marked rise (p = 0.02) than subjects over 55 years of age. Plasma norepinephrine was unchanged by smoking. A power calculation confirmed the conclusion that the resumption of smoking after overnight abstention does not acutely increase the occurrence of ventricular ectopic activity in patients with ischemic heart disease.

Adult↗
PubMed1988

Detection of cardiomyopathy in an animal model using quantitative autoradiography.

A fatty acid analog (15-p-iodophenyl)-3,3 dimethyl-pentadecanoic acid (DMIPP) was studied in cardiomyopathic (CM) and normal age-matched Syrian hamsters. Dual tracer quantitative wholebody autoradiography (QARG) with DMIPP and 2-[14C(U)]-2-deoxy-2-fluoro-D-glucose (FDG) or with FDG and 201Tl enabled comparison of the uptake of a fatty acid and a glucose analog with the blood flow. These comparisons were carried out at the onset and mid-stage of the disease before congestive failure developed. Groups of CM and normal animals were treated with verapamil from the age of 26 days, before the onset of the disease for 41 days. In CM hearts, areas of decreased DMIPP uptake were seen. These areas were much larger than the decrease in uptake of FDG or 201Tl. In early CM only minimal changes in FDG or 201Tl uptake were observed as compared to controls. Treatment of CM-prone animals with verapamil prevented any changes in DMIPP, FDG, or 201Tl uptake. DMIPP seems to be a more sensitive indicator of early cardiomyopathic changes as compared to 201Tl or FDG. The trial of DMIPP and SPECT in the diagnosis of human disease, as well as for monitoring the effects of drugs which may prevent it seems to be warranted.

Animals↗
PubMed1987

Effect of 5-hydroxytryptamine blockade with ketanserin on myocardial uptake of epinephrine and norepinephrine in patients with congestive heart failure.

Serotonin (5-hydroxytryptamine) has multiple cardiovascular actions. The presence of serotonin in the heart suggests it may be an endogenous source of inotropic support during physiologic or pathologic stress. Serotonin may increase cardiac contractility by augmenting release of norepinephrine at sympathetic nerve endings. Norepinephrine release is markedly elevated in patients with heart failure. To explore the role of serotonin in enhancing norepinephrine release in patients with heart failure, ketanserin, a specific serotonin antagonist, was used as a physiologic tool to examine the effect on transmyocardial norepinephrine flux. Ketanserin (10 mg bolus, 4 mg/hr infusion for +/- 40 min) was administered intravenously to nine patients with congestive heart failure (NYHA III or IV) secondary to congestive cardiomyopathy (N = 7), or ischemic heart disease (N = 2). Plasma catecholamines (norepinephrine, epinephrine, dopamine) were measured in the aorta (Ao) and the coronary sinus (CS) of patients at rest and during supine leg exercise before and after administration of ketanserin. Baseline norepinephrine levels were markedly elevated at rest and during exercise in all patients. Norepinephrine levels were significantly higher in the CS than in the Ao (rest, CS 1185 +/- 235, Ao 878 +/- 381 pg/mL, P less than .05; exercise, CS 2239 +/- 697, Ao 1453 +/- 697 pg/mL, P less than .05). Baseline epinephrine levels were within normal limits. In contrast to norepinephrine levels, epinephrine levels were consistently higher in the Ao than in the CS, indicating unimpaired extraction or uptake across the heart. The relationship between norepinephrine and epinephrine concentration in the Ao and CS suggested a net overflow of norepinephrine in the CS.(ABSTRACT TRUNCATED AT 250 WORDS)

Adult↗
PubMed1987

Two different forms of beta myosin heavy chain are expressed in human striated muscle.

We have found evidence for two beta-like myosin heavy chains in humans, one cardiac and one skeletal. The cDNA sequences of the cardiac beta myosin heavy chain cDNA clone pHMC3 and the skeletal beta-like myosin heavy chain cDNA clone pSMHCZ, were compared to each other. It was found that the 3' untranslated regions as well as 482 nucleotides specifying the carboxyl coding region, were 100% homologous. Further examination revealed that the skeletal clone pSMHCZ diverges from the human cardiac beta myosin heavy chain cDNA clone pHMC3 at the 5' end. We present evidence in this report which indicates that the cardiac beta myosin heavy chain mRNA is expressed in skeletal muscle tissues. The human cardiac beta myosin heavy chain cDNA clone, pHMC3, which codes for a portion of the light meromyosin section of the myosin heavy chain, was used as a probe for S1 nuclease mapping studies with RNA derived from cardiac tissue, smooth muscle and skeletal muscle tissues consisting of fast-twitch, slow-twitch and mixed fast- and slow-twitch muscle fibres. Two probes were used to examine the expression of the mRNA. One probe (406 nucleotides) constitutes the 3' untranslated region and a portion of the coding region of the beta cardiac myosin heavy chain cDNA clone, which is 100% homologous to pSMHCZ, the skeletal cDNA clone. The other constitutes the majority of the coding region (1017 nucleotides) of the cardiac clone pHMC3 in which the first 216 nucleotides from the labelled end are 100% homologous to the skeletal clone pSMHCZ. In the soleus muscle, which is rich in slow-twitch type I muscle fibres, the expression of the cardiac beta myosin heavy chain mRNA was very prominent. In gastrocnemius muscle, a mixed fibre muscle, the expression of this mRNA was detected to a lesser degree than that for the soleus muscle. In vastus lateralis and vastus medialis, which consist of predominantly type II, fast-twitch fibres, there were trace amounts of the cardiac beta myosin heavy chain mRNA. When expression of this mRNA was tested in smooth muscle tissue none could be detected.

Base Sequence↗
PubMed1987

Construction of cosmid genomic libraries for the normal and myopathic Syrian hamsters.

Cosmid genomic libraries from both normal and myopathic Syrian hamsters have been constructed. MboI was used to generate 35- to 50-kilobase DNA fragments which were isolated from a 5-25% NaCl gradient. The 35- to 50-kilobase DNA fragments were ligated to the cosmid vector pCV108 and packaged into Escherichia coli DK1. Approximately 3 X 10(5) - 4 X 10(5) clones were obtained per microgram of ligated DNA. Thirteen clones have been isolated from 2 X 10(5) colonies using a cardiac myosin heavy chain clone as a probe. Restriction maps of two of these clones are presented here.

Animals↗
PubMed1987

Acute hemodynamic and neurohumoral effects of pindolol: a beta-adrenoceptor antagonist with high intrinsic sympathomimetic activity in patients with dilated cardiomyopathy.

It has been claimed that beta-adrenoceptor antagonists produce clinical improvement and increase longevity in patients with idiopathic dilated cardiomyopathy. Dilated heart is critically dependent upon adrenergic support to maintain forward output. Acute withdrawal of such support, even with small doses of beta-blockers, may worsen myocardial function sufficiently to limit their widespread use. Pindolol (P), a potent beta-adrenoceptor antagonist, possesses high intrinsic sympathomimetic activity. Administration of P to patients with dilated cardiomyopathy may protect against the effects of high circulating catecholamines and at the same time partially maintain intrinsic left ventricular function. We examined the acute hemodynamic effects of P (2.5 mg orally) in seven patients with dilated cardiomyopathy (average ejection fraction, 23%) and resting tachycardia (average, 111 beats/min). As compared to baseline values, P produced a highly significant fall in heart rate (rest, 19%, p less than 0.001; exercise, 24%, p less than 0.01), cardiac output (rest, 20%, p less than 0.01; exercise, 25%, p less than 0.001), and systemic arterial pressure (exercise only, 13%, p less than 0.05). Calculated systemic vascular resistance increased significantly at rest (17%, p less than 0.05). Pulmonary artery pressures did not change. Compared to normal subjects, baseline norepinephrine levels were markedly elevated in patients with dilated cardiomyopathy at rest and during exercise. Pindolol produced a further significant increase in norepinephrine levels. Two of seven patients became appreciably short of breath after P. Despite its substantial intrinsic sympathomimetic activity, pindolol, like other beta-adrenoreceptor antagonists, produces significant hemodynamic impairment in patients with congestive cardiomyopathy. An exaggerated norepinephrine response after the drug may, by increasing peripheral vascular resistance, lead to further deterioration in left ventricular performance.

Adult↗
PubMed1987

Hemodynamic and neurohumoral effects of ketanserin, a 5-HT2 receptor antagonist in patients with congestive heart failure.

Ketanserin, a recently developed 5-HT2 receptor antagonist, competitively and selectively blocks the vasoconstrictor activity of 5-hydroxytryptamine (serotonin). We explored a possible contribution of serotonin to augmented vascular tone in patients with severe heart failure, using intravenous and oral formulations of ketanserin. When administered intravenously (10 mg bolus, 4 mg/hr infusion for +/- 40 min) to 10 patients with congestive heart failure (NYHA III or IV) secondary to congestive cardiomyopathy (n = 8) or ischemic heart disease (n = 2), the drug produced a significant increase in cardiac output (rest 24%, p less than 0.001; exercise 19%, p less than 0.01) which was accompanied by a fall in systemic arterial pressure (rest 7%, p less than 0.001; exercise 10%, p less than 0.05) and pulmonary wedge (rest 17%, p less than 0.05; exercise 23%, p less than 0.001) pressure. Calculated systemic vascular resistance (SVR, rest 27%, p less than 0.001; exercise 23%, p less than 0.05) decreased significantly. No significant hemodynamic changes were observed when 40 mg of ketanserin was administered orally to the same group of patients. Plasma catecholamines (norepinephrine, NEP:epinephrine, EP:dopamine) were measured before and after ketanserin at rest and during exercise. Baseline NEP levels were markedly elevated at rest and during exercise in all patients (rest: 878 +/- 381 ng/mL, exercise: 1453 +/- 697 ng/mL). Baseline EP levels were within normal limits. Ketanserin did not produce any change in catecholamine concentration.(ABSTRACT TRUNCATED AT 250 WORDS)

Administration, Oral↗
PubMed1986

Assessment of mechanistic proposals for the binding of agonists to cardiac muscarinic receptors.

N-[3H]Methylscopolamine has been used to characterize muscarinic receptors in crude homogenates prepared from hearts of Syrian golden hamsters. The Hill coefficient is one for specific binding of the radioligand itself and for its inhibition by muscarinic antagonists; markedly lower values are obtained for its inhibition by muscarinic agonists. The binding patterns of agonists have been analyzed in terms of a mixture of sites differing in affinity for the drug and reveal the following. All agonists discern at least two classes of receptor in atrial and ventricular homogenates. The number of classes and the relative size of each differ for different agonists in the same region and for the same agonist in different regions. Atrial and ventricular affinities are in good agreement for some agonists but differ for others. Guanylyl imidodiphosphate (GMP-PNP) is without effect on the specific binding of the radioligand but alters the binding of carbachol via an apparent redistribution of receptors from one class to another; the apparent affinity at either class remains unchanged. Carbachol reveals two classes of sites in ventricular preparations, and the nucleotide mediates an interconversion from higher to lower affinity; three classes are revealed in atrial preparations, and the nucleotide eliminates the sites of highest affinity with a concomitant increase in the number of sites of lowest affinity. Taken together, the data are incompatible with the notion of different, noninterconverting sites; rather, there appear to be several possible states of affinity such that the equilibrium distribution of receptors among the various states is determined by the tissue, by the agonist, and by neurohumoral modulators such as guanylyl nucleotides. The effects of agonists and GMP-PNP cannot be rationalized in terms of a ternary complex model in which the low Hill coefficients arise from a spontaneous equilibrium between receptor (R) and G protein (G) and in which agonists bind preferentially to the RG complex.

Animals↗
PubMed1986

Assessment of a ternary model for the binding of agonists to neurohumoral receptors.

A frequently cited variant of the "mobile receptor" hypothesis has been examined for its ability to describe the binding of agonists at neurohumoral receptors that operate via a guanylyl nucleotide binding protein. The model involves a reversible association between the receptor (R) and the G protein (G). Agonists (A) bind with different affinity to R and to the RG complex; similarly, G differentiates between R and the AR complex. Theoretical binding curves calculated according to the model have been analyzed in terms of the Hill equation and as a mixture of independent and noninteracting sites. The model is shown to be compatible in some respects with reported data on the binding of agonists to the beta-adrenergic receptor but not to the muscarinic cholinergic or D2 dopaminergic receptors. It is difficult to reconcile with the reported effects of guanylyl nucleotides, magnesium, and N-ethylmaleimide on the binding of agonists at any neurohumoral receptor.

Animals↗
PubMed1986

Serotonin in the human infant carotid body.

By immunocytochemistry serotonin was localized in the chief cells of the carotid body in human infants. Radioenzymatic measurement of the serotonin concentration revealed that it represents a significant proportion of the total amine content of the carotid body.

Carotid Body↗