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H K Hammond

Publications and source records attributed to H K Hammond.

At least 37 records · Page 2Linked to original sources
PubMed1994

Diverse G protein and beta-adrenergic receptor mRNA expression in normal and failing porcine hearts.

Right atrial and left ventricular homogenates have similar protein composition and beta-adrenergic receptor (beta-AR) numbers, but the right atrium has > 58% less adenylyl cyclase activity than the left ventricle. Associated with distinctive patterns of adenylyl cyclase activities are differences in G protein regulation between the two chambers. Compared with the left ventricle, the right atrium has 74% less Gs alpha mRNA (P < 0.0001) and 83% less G alpha i-2 mRNA (P < 0.002). When hearts are rapidly paced to produce heart failure, the left ventricle shows significant reductions in mRNA expression for both Gs alpha and G alpha i-2. However, the right atrium shows increased Gs alpha and G alpha i-2 mRNA expression. Despite divergent mRNA expression, Gs alpha and G alpha i-2 protein expression is down-regulated in both chambers in heart failure. In contrast, both chambers have similar beta 1- and beta 2-adrenergic receptor mRNA contents, and there is a selective reduction of beta 1-adrenergic receptor protein and mRNA in response to heart failure. Thus G protein and beta-AR mRNA regulation is regionally diverse in the heart. Physiological and anatomic differences between the right atrium and the left ventricle may dictate distinct patterns of adrenergic signaling and adaptations to stress.

Adenylyl Cyclases↗
PubMed1994

Force-frequency relations during heart failure in pigs.

In isolated cardiac muscle from patients with severe heart failure (HF) the force-frequency relation (FFR) is often negative, but the characteristics of the FFR under basal conditions and its responsiveness to adrenergic stimulation have not been studied in the intact, failing heart. Severe HF was produced in pigs (n = 6) by continuous rapid left ventricular (LV) pacing (225 beats/min). In the conscious resting state, high-fidelity LV pressure and its maximum first derivative (LV dP/dtmax) were obtained over a range of atrial pacing rates (100-225 beats/min) before (control) and after HF. Before HF, the relationship between increased heart rate and LV dP/dtmax (a measure of the FFR) was flat, but during dobutamine infusion the FFR showed a significant positive slope (P < 0.003). After HF, the basal FFR was depressed, but the slope of the FFR was not increased by dobutamine. After HF, responses of dP/dtmax to slowing of HR by a specific sinus node inhibitor confirmed the absence of a negative basal FFR. In conclusion, the basal LV FFR in conscious pigs with severe HF was not negative. Unlike the normal heart, in HF beta-adrenergic receptor stimulation did not amplify the FFR, a phenomenon that could play an important role in the impaired response to exercise in patients with HF.

Animals↗
PubMed1993

Downregulation of cardiac guanosine 5'-triphosphate-binding proteins in right atrium and left ventricle in pacing-induced congestive heart failure.

The extent to which congestive heart failure (CHF) is dependent upon increased levels of the cardiac inhibitory GTP-binding protein (Gi), and the impact of CHF on the cardiac stimulatory GTP-binding protein (Gs) and mechanisms by which Gs may change remain unexplored. We have addressed these unsettled issues using pacing-induced CHF in pigs to examine physiological, biochemical, and molecular features of the right atrium (RA) and left ventricle (LV). CHF was associated with an 85 +/- 20% decrease in LV segment shortening (P < 0.001) and a 3.5-fold increase (P = 0.006) in the ED50 for isoproterenol-stimulated heart rate responsiveness. Myocardial beta-adrenergic receptor number was decreased 54% in RA (P = 0.004) and 57% in LV (P < 0.001), and multiple measures of adenylyl cyclase activity were depressed 49 +/- 8% in RA (P < 0.005), and 44 +/- 9% in LV (P < 0.001). Quantitative immunoblotting established that Gi and Gs were decreased in RA (Gi: 59% reduction; P < 0.0001; Gs: 28% reduction; P < 0.007) and LV (Gi: 35% reduction; P < 0.008; Gs: 28% reduction; P < 0.01) after onset of CHF. Reduced levels of Gi and Gs were confirmed by ADP ribosylation studies, and diminished function of Gs was established in reconstitution studies. Steady state levels for Gs alpha mRNA were increased in RA and unchanged in LV, and significantly more GS alpha was found in the supernatant (presumably cytosolic) fraction in RA and LV membrane homogenates after CHF, suggesting that increased Gs degradation, rather than decreased Gs synthesis, is the mechanism by which Gs is downregulated. We conclude that cardiac Gi content poorly predicts adrenergic responsiveness or contractile function, that decreased Gs is caused by increased degradation rather than decreased synthesis, and that alterations in beta-adrenergic receptors, adenylyl cyclase, and GTP-binding proteins are uniform in RA and LV in this model of congestive heart failure.

Adenylyl Cyclases↗
PubMed1993

Regional myocardial downregulation of the inhibitory guanosine triphosphate-binding protein (Gi alpha 2) and beta-adrenergic receptors in a porcine model of chronic episodic myocardial ischemia.

Regional myocardial ischemia is associated with increased levels of adenosine and norepinephrine, factors that may alter activation of the beta-adrenergic receptor (beta AR)-G protein-adenylyl cyclase pathway in the heart. We have used the ameroid constrictor model to determine whether alterations in myocardial signal transduction through the beta AR-G protein-adenylyl cyclase pathway occur in the setting of chronic episodes of reversible ischemia. Pigs were instrumented with ameroid occluders placed around the left circumflex coronary artery. 5 wk later, after ameroid closure, flow and function were normal in the ischemic bed, but flow (P = 0.001) and function (P < 0.03) were abnormal when metabolic demands were increased. The ischemic bed showed a reduction in myocardial beta AR number (P < 0.005). Despite regional downregulation of myocardial beta AR number, adenylyl cyclase activity was similar in the ischemic and control beds. Quantitative immunoblotting showed that the cardiac inhibitory GTP-binding protein, Gi alpha 2, was decreased in the ischemic bed (P = 0.02). In contrast, the cardiac stimulatory GTP-binding protein, Gs alpha, was increased in endocardial sections from the ischemic bed (P = < 0.05). Decreased Gi alpha 2 content was associated with decreased inhibition of adenylyl cyclase. Reduced Gi alpha 2 content, in conjunction with increased Gs alpha content in the endocardium, may provide a means by which adrenergic activation is maintained in the setting of chronic episodic myocardial ischemia.

Adenylyl Cyclases↗
PubMed1992

A substantial proportion of cardiac Gs is not associated with the plasma membrane.

The precise interactions between the subunits of Gs (alpha s, beta, gamma) and the plasma membrane remain to be established. If alpha s is associated loosely with the inner membrane, is labile during activation, or is always present to some extent in the cytoplasm, then it should fractionate to the supernatant of a high-speed centrifugation. We identified abundant alpha s (52-66% of total cellular) in the supernatant fraction of right atrial and left ventricular membrane preparations of porcine heart as shown by two distinct measures of alpha s (immunoblotting and ADP ribosylation by cholera toxin). However, functional assays utilizing reconstitution of cardiac alpha s with cyc- S49 membranes revealed that the supernatant fraction contained approximately 16% of total cellular alpha s activity. The alpha s present in the supernatant fraction did not result from contamination by sarcolemmal membrane fragments. We conclude that traditional methods for quantifying alpha s which utilize only detergent extracts from high-speed pellets do not account for a sizable proportion of total cellular alpha s, but that the majority of this population of cardiac alpha s may not be functional, at least with respect to adenylyl cyclase activation.

Adenosine Diphosphate Ribose↗
PubMed1992

Heart size and maximal cardiac output are limited by the pericardium.

We tested the hypothesis that the pericardium, by restricting heart size, limits maximal cardiac output and oxygen consumption. We studied 15 pigs. Five underwent maximal treadmill running before and 14-21 days after thoracotomy and pericardiectomy; these pigs also received sequential volume infusions to determine end-diastolic pressure-dimension relationships. Five underwent maximal treadmill running before and 14-21 days after thoracotomy (pericardium undisturbed) to determine the effect of thoracotomy on exercise performance. Finally, five underwent thoracotomy, instrumentation, loose closure of the pericardium, and sequential volume infusions to determine the effect of thoracotomy without pericardiectomy on end-diastolic pressure-dimension relationships. Pericardiectomy caused similar increases in maximal cardiac output (29% increase; P = 0.007) and maximal oxygen consumption (31% increase; P = 0.02). These results were associated with increased left ventricular end-diastolic dimension (10% increase; P = 0.01) and an estimated 33% increase in end-diastolic volume. In addition, left ventricular mass was increased by pericardiectomy (18% increase; P < 0.04). Thus the pericardium, by limiting utilization of the Starling mechanism, limits maximal cardiac output, and the limit to cardiorespiratory performance lies not in oxygen utilization, but in oxygen delivery. Furthermore, removal of pericardium is associated with myocardial hypertrophy.

Animals↗
PubMed1992

Myocardial beta-adrenergic receptor expression and signal transduction after chronic volume-overload hypertrophy and circulatory congestion.

BACKGROUND: The volume-overload, high-output state induced by aortocaval fistula is unique because it is not generally associated with marked abnormalities of contractile function. Thus, changes in beta-adrenergic receptor (beta AR) expression should reflect more directly the influence of neurohumoral adrenergic tone, clarifying the manner in which peripheral (neurohumoral) versus primary myocardial factors are operative in decreased beta AR-dependent signal transduction. METHODS AND RESULTS: We examined the beta-adrenergic receptor-responsive adenylyl cyclase pathway in hearts from pigs subjected to volume-overload hypertrophy with circulatory congestion. Nine pigs underwent initial pharmacological and hemodynamic studies, and, 5 weeks after aortocaval fistula placement, when signs of circulatory congestion were evident, these measurements were repeated. Biochemical analyses of plasma and myocardium from these animals and seven normal animals were compared. Experimental animals showed signs of circulatory congestion (tachypnea, weight gain, pulmonary rales) within 3-4 weeks of fistula placement. Necropsy showed ascites and biventricular cardiac hypertrophy, but no fibrosis or inflammation was present on histological inspection. Heart rate responsiveness to beta AR stimulation was blunted, with ED50, for isoproterenol increased 133% (p less than 0.001) after development of circulatory congestion. Biochemical analyses of the beta AR-responsive adenylyl cyclase pathway showed uniform decreases in beta AR number in right atrium, right ventricle, and left ventricle (36-41% decreases, p less than 0.005). Downregulation was selective for beta 1-receptors, and remaining receptors in the right and left ventricles showed low-affinity agonist binding, suggesting an uncoupling from Gs. All measures of adenylyl cyclase activity were diminished significantly in membrane homogenates from the right atrium (mean reduction, 50 +/- 10%) and left ventricle (mean reduction, 44 +/- 8%) after volume overload. Finally, we found that amounts of cardiac Gs, as measured in reconstitution assays, were decreased in both the right atrium (p less than 0.02) and the left ventricle (p less than 0.01) of volume-overloaded animals but that levels of pertussis toxin substrate were unchanged. CONCLUSIONS: Biochemical findings occurred in the absence of myocardial inflammation or fibrosis and without pharmacological interventions, suggesting that circulatory congestion, with attendant elevation in plasma norepinephrine, may be a sufficient stimulus to induce such changes. The data are compatible with a catecholamine-driven beta AR pathway desensitization. Thus, a primary defect in intrinsic contractile function is not a necessary component for abnormalities of the myocardial beta AR-responsive adenylyl cyclase pathway.

Adenylyl Cyclases↗
PubMed1992

Myocardial adrenergic denervation supersensitivity depends on a postreceptor mechanism not linked with increased cAMP production.

BACKGROUND: Two major hypotheses have been proposed to explain catecholamine supersensitivity after myocardial denervation, but neither sufficiently explains certain features of the phenomenon. In addition, a nonsurgical method for long-term myocardial adrenergic denervation is desirable but has not been accomplished or described with respect to catecholamine supersensitivity. METHODS AND RESULTS: We have accomplished chronic myocardial adrenergic denervation by using 6-hydroxydopamine (6-OHDA). Sixteen weeks after 6-OHDA administration to newborn pigs, we found substantial myocardial adrenergic denervation associated with beta-adrenergic receptor (beta AR) downregulation. Despite decreased beta AR number, the dose of isoproterenol yielding 50% maximal heart rate change (ED50) was decreased, and heart rates during exercise showed increased responsiveness despite decreased circulating catecholamines. Thus, stimulation of fewer receptors yielded an increased response, implying improved signal transduction efficiency. Competitive binding studies with isoproterenol showed an increased proportion of beta AR with high-affinity binding in myocardial membranes from 6-OHDA pigs, suggesting that interaction between beta AR and cardiac G, may contribute to improved signal transduction efficiency. However, measures of adenylyl cyclase activity indicated marked reduction in beta AR-dependent and G2-dependent cAMP production in myocardial membranes from denervated animals despite a normal amount of cardiac Gs and decreased Gi. CONCLUSIONS: We have demonstrated that substantial, long-term myocardial adrenergic denervation is possible using 6-OHDA. Denervation supersensitivity in this model does not depend on enhanced cAMP stimulation but rather depends on postreceptor elements in the beta AR-responsive pathway that may be independent of Gs-activated adenylyl cyclase activity. In this model of adrenergic denervation supersensitivity, beta-receptors, through Gs, may be linked to an alternative effector that drives heart rate responsiveness.

Adenylyl Cyclases↗
PubMed1992

The role of the pericardium in conditioning the effects of physical training.

More work needs to be done on the extent to which the pericardium can modulate the cardiovascular response to exercise and the mechanisms whereby this modulation is brought about. Studies are needed to differentiate the effects of the pericardium on the cardiovascular exercise response, comparing trained with untrained subjects. Evidence is accumulating that exercise training in patients with heart failure improves not only the performance of exercising muscles, but also has some beneficial effects on central hemodynamics. The extent to which these beneficial effects can be attributed to conditioning the pericardium remains speculative.

Adaptation, Physiological↗
PubMed1988

Noncoordinate regulation of cardiac Gs protein and beta-adrenergic receptors by a physiological stimulus, chronic dynamic exercise.

We used a physiological stimulus, chronic dynamic exercise, in pigs to examine resultant changes in chronotropic responsiveness to catecholamine and biochemical features of cardiac beta-adrenergic receptors and the stimulatory guanine nucleotide-binding protein, GS. Long-term treadmill running resulted in a substantial (44%) down-regulation of right atrial beta-adrenergic receptors, but the dose of isoproterenol yielding a 50% maximal increase in heart rate was decreased by 57% (from 0.07 +/- 0.03 to 0.03 +/- 0.01 microgram/kg; P less than 0.02) despite this decrease in receptor number. This disparity between receptor number and physiological responsiveness suggested altered signal transduction. We therefore quantitated GS in myocardial membranes obtained before and after chronic exercise in a competitive ELISA based on an antipeptide antibody developed to the alpha S portion of GS. We found a 42% increase in the amounts of GS in right atrial membranes (from 11.4 +/- 0.8 to 16.2 +/- 2.0 pmol/mg; P less than 0.05) and a 76% increase in the amounts of GS in left ventricular membranes (from 15.6 +/- 2.6 to 27.4 +/- 5.2 pmol/mg; P = 0.02) after chronic running. These data suggest that in the heart physiological perturbations can result in changes in the levels of GS, that GS and beta-adrenergic receptor number are not coordinately regulated, and that GS may contribute to altered adrenergic responsiveness independently of changes in beta-adrenergic receptor number.

Animals↗
PubMed1987

Increased myocardial beta-receptors and adrenergic responses in hyperthyroid pigs.

Controversy exists presently as to whether thyroid hormone potentiates the action of catecholamines on the heart. Therefore, the relationships between adrenergic sensitivity, myocardial beta-receptor number, and the cardiovascular responses associated with excess thyroid hormone were investigated in pigs (Sus scrofa). A hyperthyroid state was induced by the administration of triiodothyronine (T3; 1 mg/kg iv). After 7 days there was a significant increase in resting heart rate, systolic blood pressure, rate-pressure product, and O2 consumption in the hyperthyroid state. At this time echocardiography showed a substantial increase in myocardial cross-sectional size. Pharmacological tests showed an increased intrinsic heart rate (127 +/- 29 to 205 +/- 25 beats/min; P less than 0.001) and an increased chronotropic sensitivity to isoproterenol. The concentration of isoproterenol required for a 50% of maximal response (ED50) was reduced by 33 +/- 30% (2.1 +/- 1.0 to 1.2 +/- 0.3 micrograms/l; P less than 0.025). The slope of the line relating isoproterenol concentration and change in heart rate was increased by 29 +/- 33% (61 +/- 10 to 78 +/- 10; P less than 0.025). Radioligand studies demonstrated an increase in the number of beta-receptors in right atrial membranes from hyperthyroid animals (41 +/- 7 vs. 75 +/- 18 fmol/mg; P less than 0.02). The apparent dissociation constant (KD) of the receptor for l-isoproterenol was similar in membranes from euthyroid and hyperthyroid animals (157 +/- 57 vs. 219 +/- 59 nM, respectively; P = NS). This study demonstrates that hyperthyroidism is associated with an increased chronotropic sensitivity to isoproterenol, consequent to an up-regulation of beta-adrenergic receptors in the right atrium.

Animals↗
PubMed1987

Association of decreased myocardial beta-receptors and chronotropic response to isoproterenol and exercise in pigs following chronic dynamic exercise.

The effects of chronic dynamic exercise on myocardial beta-adrenergic and muscarinic cholinergic receptors and chronotropic sensitivity to isoproterenol were studied in 5 Yucatan miniswine. Right atrial and left ventricular biopsies, heart rate responses to isoproterenol, and maximal exercise treadmill testing were obtained before and after 10-19 weeks of treadmill running. Radioligand studies using 125I-iodocyanopindolol (ICYP) and 3H-quinuclidinyl benzilate (QNB) were used to determine the number of beta-adrenergic and muscarinic cholinergic receptors. Maximal oxygen consumption increased from 52 +/- 5 to 65 +/- 7 ml/kg/min (mean +/- SD; p less than 0.02), maximal workload from 530 +/- 111 to 1,074 +/- 179 KPM/min (p less than 0.01), resting heart rate decreased from 91 +/- 13 to 62 +/- 4 beats/min (p less than 0.01), heart rate at 75% of pretraining maximal workload decreased from 253 +/- 15 to 196 +/- 12 beats/min (p less than 0.01), and maximal exercise heart rate decreased from 273 +/- 6 to 254 +/- 9 beats/min (p less than 0.01). Decreased heart rate responsiveness to adrenergic stimulation was observed following chronic exercise. Maximal isoproterenol-stimulated heart rate decreased from 225 +/- 13 to 185 +/- 28 beats/min (p less than 0.05) and the slope of the isoproterenol dose-response relation decreased from 63 +/- 16 to 40 +/- 16 (p less than 0.05). Radioligand studies revealed a decrease in beta-receptor number in the right atrium following chronic exercise (61 +/- 9 vs. 34 +/- 8 fmol/mg; p less than 0.02), but receptor number in membranes from the left ventricle did not change (60 +/- 9 vs. 62 +/- 4 fmol/mg).(ABSTRACT TRUNCATED AT 250 WORDS)

Adaptation, Physiological↗
PubMed1985

Noninvasive testing in the evaluation of myocardial ischemia: agreement among tests.

The purpose of this study was to investigate the relations among four exercise-induced phenomena--angina, ST segment depression, decrease in ejection fraction and thallium perfusion defects--and to determine their impact on aerobic capacity. One hundred fifty-six men (mean age 52 +/- 8 years) with documented coronary heart disease were studied with radionuclide ventriculography during supine bicycle exercise, thallium scintigraphy and treadmill testing with computerized electrocardiography and maximal oxygen uptake. Of 624 administered tests, 243 results (39%) were considered to indicate ischemia. The average number of abnormal tests was 1.6 per patient and, when considered as continuous variables, their results correlated poorly. Correlations did not improve when adjusting for heart rate achieved or by eliminating patients with coronary artery bypass surgery or myocardial infarction. Statistical methods of comparing degree of interest agreement yielded surprisingly weak relations among the four tests of ischemia. Treadmill performance was markedly impaired by angina, but much less impaired by other indicators of ischemia. It is concluded that the usual test responses implying ischemia have weak agreement when uniformly applied to patients with known coronary artery disease.

Adult↗
PubMed1985

Use of clinical data in predicting improvement in exercise capacity after cardiac rehabilitation.

Fifty-nine men with coronary heart disease underwent 1 year of supervised aerobic exercise. They performed exercise tests for maximal oxygen uptake, ST segment analysis, thallium scintigraphy and radionuclide ventriculography before and after the year of exercise. A computerized data base that included clinical descriptors and exercise test results was retrospectively reviewed to determine whether initial features could predict the patient's response to the exercise intervention. Poor correlations were found between the initial measurements and change in maximal oxygen consumption and other indexes of training effect. Patients who initially were in the poorest state of fitness showed the most improvement with training. None of the initial features from the history and physical examination, treadmill study or radionuclide studies was a good predictor of a beneficial result from the exercise program. The usual measurements of work intensity during training were poor predictors of outcome. A significant decrease in the amount of ischemia measured by thallium perfusion scintigraphy was demonstrated after training.

Adult↗
PubMed1985

The physiologic sequelae of chronic dynamic exercise.

The physiologic results of acute dynamic exercise include complex neurologic, hormonal, pulmonary, and cardiovascular adjustments that provide an integrated response perfectly matching oxygen supply with oxygen demands. Long-term repeated bouts of dynamic exercise of sufficient intensity and duration yield predictable changes in anatomy and physiology. These changes affect active skeletal muscle and the heart. Changes in skeletal muscle include an increased capillary blood volume, increased mitochondrial density, increased oxidative pathway enzymes, and more efficient regulation of blood flow. These adaptations result in an increased oxidative capacity and more favorable fuel utilization. Oxygen extraction increases, accounting for up to 50 per cent of the increased maximal oxygen consumption, and endurance improves. Following chronic dynamic exercise the heart beats slower and has a larger stroke volume at rest and throughout a broad range of work intensities. The maximal cardiac output increases substantially, accounting for up to 50 per cent of the increased maximal oxygen consumption. The metabolic and biochemical changes found in skeletal muscle are not found in cardiac muscle. Changes found in isolated cardiac muscle do not always correlate with heart performance. The separation of central and peripheral factors in assessing heart performance is difficult because preload and afterload are major determinants of heart function and are altered by chronic dynamic exercise. Ischemia is a major stimulus for the development of coronary collateral vessel development in animals. Because dynamic exercise does not induce ischemia in normal humans, collateral vessel development may only occur in those with coronary heart disease. However, there is no convincing evidence that chronic dynamic exercise results in physiologically important coronary collateral vasculature in patients with angina. Improved work capacity is predictable following chronic dynamic exercise in patients with coronary heart disease. Although the rate pressure product that produces angina does not change following training, heart rates are lower at matched absolute workloads and the maximal consumption of oxygen increases. Changes in heart function are largely secondary to peripheral changes in these patients.

Animals↗
PubMed1983

Radionuclide imaging correlatives of heart rate impairment during maximal exercise testing.

A lower than normal heart rate response to maximal dynamic exercise, known as chronotropic incompetence or heart rate impairment, has been demonstrated to have a poor prognosis. In order to better describe patients with this finding, 156 men with coronary heart disease were evaluated. All patients were studied with maximal exercise testing, including measurements of oxygen consumption, exercise electrocardiograms, thallium scintigraphy and radionuclide ventriculography. Chronotropic incompetence was defined as a maximal heart rate 1 standard error of the estimate below the regression line of age versus maximal heart rate on two separate exercise tests. In patients so defined, mean maximal oxygen consumption was significantly lowered and angina was the major reason for stopping exercise on the treadmill. Patients with chronotropic incompetence not limited by angina had more evidence of myocardial scar and dysfunction and had a greater prevalence of three vessel coronary disease than did patients with a normal heart rate response. Radionuclide testing results suggest that among patients with chronotropic incompetence, those with angina have a better prognosis than those who do not have angina but who may have myocardial dysfunction.

Adult↗