Histamine receptors in the human heart.
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Coronary Vessels↗
Biomedical subjects
D C Harrison
Publications and source records attributed to D C Harrison.
Tocainide for drug-resistant ventricular arrhythmias: efficacy, side effects, and lidocaine responsiveness for predicting tocainide success.
Tocainide therapy has been evaluated in 38 patients with ventricular arrhythmias. Thirty-one had recurrent sustained ventricular tachycardia and/or fibrillation and 29 required prior cardioversions. These arrhythmias could not be managed with quinidine, procainamide, disopyramide, or propranolol. Tocainide doses averaged 1,500 mg/day (range 600 to 2,400) and the majority of patients had plasma concentrations from 6 to 12 micrograms/ml. Twenty-two patients (61%) had their arrhythmias controlled with tocainide and 16 (39%) did not. Tocainide dose and plasma concentrations were similar for responders and nonresponders. Lidocaine was effective in 26 patients and 16 (63%) of these had their arrhythmias controlled with tocainide. Of 12 patients in whom lidocaine was known to be ineffective or who had not been previously treated, only two (17%) had arrhythmias controlled with tocainide (P < 0.02). Side effects occurred in approximately two thirds of patients but required discontinuation of long-term tocainide in only three patients.
Aged↗
Encainide: a new and potent antiarrhythmic agent.
Encainide is a potent Class I antiarrhythmic drug that prolongs conduction in the His-Purkinje system. It produces only minimal hemodynamic changes in the normal or depressed left ventricle. Studies to date demonstrate excellent effectiveness against ventricular arrhythmia, and in comparative studies with quinidine, encainide was superior in reducing the frequency and complexity of ventricular premature beats in patients late after myocardial infarction.
Anilides↗
Coronary hemodynamic effects of ergonovine maleate in human subjects.
The coronary hemodynamic effects of ergonovine maleate were examined in 15 patients with a chest pain syndrome not thought to be variant angina. Ergonovine was given intravenously in sequential doses of 0.05, 0.1 and 0.25 mg while measurements were made of systemic hemodynamic variables, coronary sinus blood flow and coronary arteriovenous oxygen difference at intervals during the protocol. Coronary arterial diameters were measured from the 35 mm cineangiogram. Despite an increase in myocardial metabolic demand, as estimated with the heart-rate-blood pressure product, there was no apparent increase in coronary vascular resistance. In addition, there was a significant widening of the coronary arteriovenous oxygen difference in five of the seven patients in whom it could be measured. However, neither chest pain nor ischemic electrocardiographic changes were evoked. Although ergonovine also produced a diminution in epicardial coronary arterial diameters, this effect was not sufficient to explain the absence of appropriate coronary vasodilation. These results suggest that ergonovine may limit the normal vasodilatory response of the arteriolar bed to increases in myocardial metabolic demand.
Adult↗
Influence of prolonged recumbency on drug disposition.
The disposition of lidocaine and penicillin was studied in normal subjects before and after 7 days of total recumbency. Penicillin (1,000,000 U) and lidocaine (100 mg) were administered intravenously. Lidocaine protein binding was also followed. Total body clearance, elimination half-life, and volume of distribution were calculated. There were no statistically significant differences in these disposition parameters before and after 7 days of recumbency. The binding of lidocaine also was not changed after bed rest. We conclude that the physiologic changes that occur during prolonged bed rest do not affect distribution or elimination of lidocaine or penicillin.
Bed Rest↗
[Sustained and beneficial hemodynamic effects of prazosin in cardiac insufficiency].
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Blood Pressure↗
Atenolol: once-daily cardioselective beta blockade for angina pectoris.
The physiology, pharmacokinetics and efficacy of atenolol, a cardioselective beta-adrenergic blocking agent, were evaluated in 10 patients with stable angina pectoris in a single-blind, dose-ranging study. After a 1-month control placebo period, atenolol was administered once daily at dosages of 25, 50, 100 and 200 mg for 2-week periods. All patients had fewer anginal attacks and consumed fewer nitroglycerin tablets than mg for 2-week periods. All patients had fewer anginal attacks and consumed fewer nitroglycerin tablets than during the placebo period. Twenty-four-hour ambulatory ECG recordings showed a decrease in mean hourly heart rate throughout the dosing period, with preservation of diurnal variation. Maximal, symptom-limited, treadmill exercise tests performed 3 hours after drug ingestion showed significantly increased exercise time and decreased double products for all doses, but especially with 100-mg and 200-mg doses. Exercise time 24 hours after drug ingestion continued to show a decrease in maximum heart rate and double product, with 100-mg and 200-mg doses again being most effective. Atenolol serum levels correlated with percent reduction in exercise heart rate and increased exercise time. Serum levels rose linearly, with an average elimination half-life of about 10 hours after chronic oral dosing. Thus, atenolol was an effective antianginal agent and suppressed resting and exercise-stressed heart rate for 24 hours after ingestion when given in a 100-mg or 200-mg dose once daily.
Adult↗
A new method for evaluating antiarrhythmic drug efficacy.
To develop standards for distinguishing antiarrhythmic drug effect from spontaneous variability of premature ventricular complexes (PVCs), 21 males (mean age 56 +/- 8 years) with chronic ischemic heart disease and PVCs underwent symptom-limited treadmill exercise testing and 24-hour ambulatory monitoring before and after 2 weeks of placebo medication. Linear regression analysis was used to describe the relationship between baseline and placebo PVC frequency for various indexes of ventricular ectopic activity and to establish 95% and 99% one-tailed confidence intervals for this relationship within the group of 21 patients. The lower limit of baseline PVC frequency for which the procedure could distinguish a placebo from a true drug response, termed the "sensitivity threshold," was an average frequency of 2.2 PVCs/hour for ambulatory electrocardiographic monitoring and 1.2 PVCs/min for treadmill exercise testing. All patients exceeded the sensitivity threshold on baseline ambulatory ECGs, but only 38% of patients did so on baseline treadmill exercise tests. To establish antiarrhythmic efficacy with 95% confidence, the minimal percent reduction of PVCs between baseline and placebo visits was 68% for treadmill exercise testing and 65% for ambulatory electrocardiography. Although these standards were developed in patients with chronic ischemic heart disease, the model can be used to establish antiarrhythmic drug efficacy in any patient group.
Ambulatory Care↗
Studies with isolated human coronary arteries. Some general observations, potential mediators of spasm, role of calcium antagonists.
We studied the basic mechanisms involved in human coronary artery smooth-muscle contraction in an attempt to gain insight into the pathophysiology and pathopharmacology of coronary spasm. coronary arteries were obtained from recipient hearts of patients receiving cardiac transplantation at Stanford University. Coronary ring segments were studied in an organ bath using standard Tyrode's solution. Observation included characterizations of spontaneous contractile activity, factors affecting basal tone, type of agonist-induced contractile respnse, receptor distribution, activity of cardioactive drugs, and species differences. Agents mediating contraction included histamine, acetylcholine, norepinephrine, potassium, and prostaglandins. Because of recent clinical interest in calcium antagonists, diltiazem was studied extensively. Diltiazem demonstrated noncompetitive antagonism to the effects of several agonists and competitive antagonism to calcium. The exact cause and mechanism of coronary spasm is still unknown, but we have identified new areas for future investigation.
Acetylcholine↗
Non-invasive quantification of experimental canine myocardial infarct size using two-dimensional echocardiography.
In order to study whether wall motion abnormalities detected by two-dimensional (2D) echocardiography can be quantified and correlated with infarct size, we compared wall motion abnormalities viewed by 2D echocardiography in experimental canine infarction with post-mortem infarct size. Nineteen mongrel dogs underwent left anterior descending coronary artery snare occlusion. They were sacrificed 6 h later. Infarct sizing was done by technetium 99-m stannous pyrophosphate scintigraphy of the excised, sliced left ventricles. Fourteen dogs had both 2D echo wall motion abnormalities and infarctions. Four dogs failed to develop infarction and had no or minimal wall motion abnormalities. Inter-observer variation in 2D echocardiographic measurements was small. Wall motion abnormalities correlated with infarct size both in the 14-dog subgroup with infarction (r = 0.75, P less than 0.003) and all the 18 dogs that completed the protocol (r = 0.87, P less than 0.001). Thus, wall motion abnormalities in experimental canine myocardial infraction can be roughly quantified by 2D echocardiography and correlated with post-mortem infarct size measured by scintigraphy.
Animals↗
Role of concentration-dependent plasma protein binding in disopyramide disposition.
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Blood Proteins↗
Echocardiographic diagnosis of pericardial disease.
Echocardiograms were performed in 11 patients with constrictive pericarditis or effusive-constrictive pericarditis confirmed by cardiac catheterization and pericardiectomy. Three echocardiographic patterns of pericardial disease were noted and were related to three types of pericardial pathology. Parallel moving echoes separated by a clear space were reflected from chronically fibrosed and thickened pericardium without associated pericardial exudate. Effusive-constrictive pericarditis or subacute wet pericarditis was characterized on the echocardiogram by a posterior echo-free space representing the liquid pericardial effusion and multiple ultrasonic lines from the thickened visceral pericardium. Subacute dry pericarditis was associated with numerous ultrasonic signals filling the space between the visceral pericardium and the relatively flat parietal pericardium. These ultrasonic signals were reflected from coagulated pericardial exudate which was adherent both to the parietal pericardium and the visceral pericardium. Parallel moving echoes or dense bands of echoes were reflected from either or both thickened visceral and parietal pericardium.
Chronic Disease↗
Altered adrenergic activity in coronary arterial spasm: insight into mechanism based on study of coronary hemodynamics and the electrocardiogram.
To elucidate the pathophysiologic mechanism of coronary arterial spasm, the hypothesis was examined that underlying alterations in sympathetic activity may account for this syndrome in some patients. Observations were directed to alterations in coronary arterial hemodynamics and the electrocardiogram. Spasm of the left anterior descending coronary artery produced a mean increase in coronary vascular resistance of 107 percent (P less than 0.05) in four patients in whom coronary sinus blood flow was measured with the thermodilution technique. The alpha adrenergic blocking agent phentolamine, given intravenously, acutely reversed coronary spasm and its clinical manifestations in eight patients and reduced coronary resistance. In four patients, administration of the long-acting oral alpha blocking agent phenoxybenzamine (20 to 80 mg/day) caused disappearance of symptoms during a follow-up period of 3 to 12 months. Transient prolongation of the corrected Q-T interval preceded spontaneous or ergonovine maleate-provoked coronary spasm in 11 patients with variant angina pectoris, whereas no significant change in the Q-T interval followed ergonovine administration in 27 control patients with atypical chest pain who did not have coronary spasm. T wave inversions in the resting electrocardiogram were normalized by isoproterenol infusion in one patient and by long-term phenoxybenzamine treatment in four patients with variant angina pectoris. These Q-T and T wave changes are analogous to those described with unilateral or asymmetric stellate ganglion stimulation in animals. These observations suggest that alterations in the sympathetic nervous system that are consistent with asymmetric stellate ganglion activity and transient alpha adrenergic receptor stimulation can presage the development of coronary arterial spasm in some patients with variant angina pectoris.
Adult↗
Canine electrophysiology of encainide, a new antiarrhythmic drug.
Encainide, a new benzanilide derivative with high potency and a good therapeutic/toxic ratio, was evaluated with the use of standard His bundle recording techniques to determine its effects on the cardiac conduction system in closed chest animals. Twenty mongrel dogs weighing 18 to 29 kg were anesthetized with 4 percent chloralose and classified into groups: group 1, a control group and groups 2, 3, and 4, which were given 0.3, 0.9 and 2.7 mg/kg body weight, respectively, of encainide in an intravenous infusion over a 15 minute period. Plasma concentration, blood pressure, surface electrocardiogram and atrial and His bundle electrograms were recorded before, during and after drug infusion for a total of 120 minutes. Heart rate, A-H and H-V intervals, the QRS complex and Q-Tc interval were measured every 5 minutes during sinus rhythm and with constant atrial pacing. In addition, sinus nodal recovery time and atrial, atrioventricular (A-V) nodal and left ventricular refractory periods were measured before and immediately after infusion and every 30 minutes for 2 hours. Peak plasma concentration averaged 450 ng/ml in group 2, 1,300 ng/ml in group 3 and 4,000 ng/ml in group 4. Blood pressure was not altered at any dose level throughout the study. The QRS complex and H-V interval were significantly prolonged (P less than 0.005) at doses of 0.9 mg/kg and greater. These effects correlated well with plasma concentration. There was no significant change in heart rate, corrected sinus nodal recovery time, A-H interval, Q-Tc interval atrial, A-V nodal or left ventricular refractory period. It is concluded that, unlike other antiarrhythmic agents, encainide prolongs His-Purkinje system conduction without significantly affecting conduction or refractoriness of other parts of the cardiac conduction system in animals.
Anilides↗
Surgery for life-threatening ventricular tachyarrhythmias.
Among 203 left ventricular aneurysmectomies performed since 1970, the operative mortality rate was 18.7 percent. In 49 patients (24 percent), left ventricular aneurysmectomy was performed for refractory life-threatening ventricular arrhythmias. Eight additional patients had coronary bypass grafting without ventricular aneurysmectomy. One of these patients had bypass grafting followed later by ventricular aneurysmectomy. All 56 patients had underlying coronary artery disease. The operative mortality rate was 19.6 percent. In patients with a recent myocardial infarction, the rate was 60 percent, whereas it was 11 percent in patients with a remote myocardial infarction. Other high risk variables in these patients included coronary bypass grafting without myocardial resection, and an elevated left ventricular end-diastolic pressure. The late mortality rate was 17.9 percent, but only one of these deaths was sudden and unexpected. The 35 long-term survivors have been followed up for a mean of 40.7 months (range 7 to 92 months). Of these, 20 remain on antiarrhythmic medications for palpitation or documented ventricular premature complexes, whereas 15 are free of detectable rhythm disturbances and do not require antiarrhythmic agents. Only 4 of 35 (11 percent) have had recurrent documented ventricular tachycardia. Left ventricular aneurysmectomy may be performed for refractory ventricular tachyarrhythmias with an acceptable operative mortality, particularly if the patient has survived longer than 6 weeks after myocardial infarction. Although epicardial mapping techniques may be useful in localizing the reentrant pathway of the ventricular tachycardia, ventricular aneurysmectomy without mapping techniques produces a satisfactory clinical result in the vast majority of long-term survivors.
Adult↗
Two dimensional echocardiographic quantification of infarct size alteration by pharmacologic agents.
In 27 closed chest dogs left ventricular wall motion abnormalities assessed quantitatively with two dimensional echocardiography were used as a measure of myocardial infarct size, and the change in extent of segmental wall motion abnormalities due to drug intervention early after infarction was evaluated. The extent of wall motion abnormalities was measured with echocardiography before and at 20 and 40 minutes and 5 1/2 hours after coronary occlusion. Three subgroups of dogs received, respectively, an infusion of nitroglycerin, phenylephrine or saline solution. Infarct size was measured with technetium pyrophosphate scintigraphy of the excised left ventricle. The infarct size correlated well with the extent of wall motion abnormalities before death. Wall motion was initially similar among the three groups but was significantly improved after treatment with nitroglycerin (P less than 0.025), remained stable with continued saline infusion and worsened significantly (P less than 0.05) after treatment with phenylephrine. Two dimensional echocardiography can be used to quantify experimental canine myocardial infarction and assess the effect of nitroglycerin.
Animals↗
Clinical electrophysiologic effects of encainide, a newly developed antiarrhythmic agent.
Encainide is a newly developed antiarrhythmic agent. With the use of intracardiac electrophysiologic techniques, its effects on the cardiac conduction system were examined in 10 patients with coronary artery disease. Five patients received 0.6 and five received 0.9 mg/kg body weight of encainide intravenously over 15 minutes. Plasma concentration, heart rate, blood pressure and conduction intervals (A-H, H-V, QRS and Q-T) were measured before, during and after encainide infusion. In addition, sinus nodal recovery time, Wenckebach cycle length, and atrial, atrioventricular (A-V) nodal and right ventricular refractory periods were measured before and after encainide infusion. The average peak plasma concentration was 0.49 +/- 0.35 microgram/ml (mean +/- standard error of the mean). Encainide significantly prologned H-V and QRS intervals in all patients by an average of 31 +/- 7 and 18 +/- 9 percent (standard deviation) (P less than 0.001), respectively. A minimal increase in the Q-T interval was also observed after encainide infusion (2 +/- 9 percent, P less than 0.01), but no significant changes were noted in heart rate, blood pressure, A-H interval, corrected sinus noal recovery time, Wenckebach cycle length or refractory periods of the atrium, A-V node or right ventricle. It is concluded that encainide significantly prolongs conduction in the His-Purkinje system without affecting conduction or refractoriness of other parts of the cardiac conduction system in man.
Aged↗
Cardiac damage produced by direct current countershock applied to the heart.
This study examined the pathophysiology of the myocaridal damage produced by direct current shock over a dose range of 10 to 90 watt-seconds, applied directly to the heart in 26 dosgs. The extent of injury produced was assessed with creatine kinase depletion and light and electron microscopy, and was correlated with in vivo imaging and tissue distributions of the isotopes technetium-99m pyrophosphate and thallium-201. Changes in intramyocardial temperature and regional myocardial blood flow were also measured. Uptake of technetium-99m pyrophosphate occurred exponentially with graded increases in shocks, and this agent was more sensitive than thallium-201 in detecting injury both on imaging and at tissue level. The threshold for significant injury was approximately 30 watt-seconds, and on electron microscopy a characteristic feature was marked dehiscence of the intercalated disks between the damaged myocytes. The use of different-size paddles did not appear to affect the total number of cells damaged. However, with large paddles the injury was more superficial and spread over a wider area. With short time intervals between successive shocks, a greater amount of injury occurred, in part because of a compounding of the thermal component of the damage. Hypothermia can reduce the degree of injury.
Animals↗