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Biomedical subjects

H R Adams

Publications and source records attributed to H R Adams.

At least 73 records · Page 4Linked to original sources
PubMed1986

New perspectives in cardiology: pharmacodynamic classification of antiarrhythmic drugs.

Recent advancements in cardiac pharmacology and physiology have led to the identification of many new antiarrhythmic drugs and a better understanding of basic arrhythmogenic mechanisms. These parallel developments prompted a new nomenclature system for classifying the clinically important antiarrhythmic drugs according to their predominant electrophysiologic actions in cardiac cells. Antiarrhythmic drugs are now grouped into 4 main classes: classes I through IV. Class I agents comprise the standard membrane-stabilizing drugs such as lidocaine, quinidine, and procainamide; newer class I agents include disopyramide, aprindine, tocainide, and flecainide. Class II agents decrease sympathoadrenal excitation of the heart, and the clinically relevant members of this type act through blockade of the cardiac beta 1-adrenergic receptors; propranolol is the prototype. Class III agents selectively prolong the cardiac action potential and refractory period, and bretylium and amiodarone represent this group. Class IV agents are the calcium entry blocking drugs such as verapamil. An understanding of this classification system is essential to the internist and cardiologist who are beset with an emerging array of new antiarrhythmic drugs and affiliated pharmacodynamic terminologies.

Action Potentials↗
PubMed1986

New perspectives in cardiology: recent advances in antiarrhythmic drug therapy.

During the past decade, advances in basic and applied cardiology have led to the introduction of several new antiarrhythmic drugs that have distinct clinical advantages over their older counterparts. These therapeutic advantages comprise either a more favorable pharmacokinetic disposition in the patient or new and perhaps novel mechanisms of antiarrhythmic actions. The class IV agent verapamil, for example, selectively blocks the slow inward Ca++ current in excitable tissues and this action is proving to be quite effective in controlling supraventricular tachyarrhythmias. Tocainide is a newly approved class I agent that exerts lidocaine-like effectiveness in treating serious ventricular arrhythmias. Unlike lidocaine, however, tocainide is not restricted to intensive care because it is effective after oral administration and has comparatively longer duration of antiarrhythmic action. Other recently approved or investigational agents include bretylium and amiodarone (class III), and aprindine, mexiletine, and disopyramide (class I). Along with clinical advantages, however, each drug has a characteristic pharmacologic-toxicologic profile and resulting spectrum of therapeutic application for only particular cardiac dysrhythmias. The advantages and disadvantages of each compound should be weighed equally when the new antiarrhythmic drugs are assessed as therapeutic alternatives for the older ones.

Adrenergic beta-Antagonists↗
PubMed1986

Ca++ channel-blocking drugs in shock and trauma: new approaches to old problems?

The development of drugs that inhibit Ca++ influx through voltage-regulated cell membrane channels of excitable cells represents a new pharmacodynamic addition to the therapy of cardiovascular disorders. These drugs, the Ca++ channel-blocking agents, have important therapeutic roles in the management of exertional and variant angina and also in the treatment of certain types of supraventricular tachyarrhythmias. In addition, a rapidly expanding body of evidence indicates that these compounds also may exert beneficial actions in various other cardiovascular-related disorders, including different forms of shock and trauma. Theoretically, beneficial effects of Ca++ channel blockade may be explained by either a direct reduction of pathologic Ca++ overload in injured cells or, indirectly, by vasodilation and hemodynamic improvement in tissue perfusion-oxygen demand relationships. Many questions remain unanswered, however, and recent experimental studies have questioned the routine use of these drugs in shock or trauma. Furthermore, the propensity for hypotensive and cardiodepressant actions of Ca++ channel blockade may well be enhanced in patients with preexisting or occult loss of myocardial contractile reserves. These complexities should be assessed carefully before Ca++ channel-blocking drugs are used in the treatment of shock states.

Animals↗
PubMed1985

Inotropic, chronotropic and coronary vasodilator potency of forskolin.

The cardiodynamic profile of forskolin, a direct activator of adenylate cyclase, was examined in an isovolumic left ventricular (LV) preparation of coronary-perfused guinea-pig hearts. Forskolin consistently induced concentration-dependent increases in LV systolic pressure development, increases in spontaneous beating frequency and decreases in coronary vascular resistance. However, the forskolin concentration required for one-half of the maximal effect (EC50) for coronary vasodilation (3.8 +/- 0.6 X 10(-8) M, n = 6) was 7- to 10-fold less than the EC50 for positive chronotropy (29.3 +/- 4.6 X 10(-8) M, P less than 0.01) and 17- to 20-fold less than the EC50 for positive inotropy (66.3 +/- 7.4 X 10(-8) M, P less than 0.001). The inotropic response to forskolin was not secondary to the concomitant increase in bearing frequency. Also, the coronary vasodilator response persisted in K+-depolarized non-beating hearts, and therefore did not depend on endogeneous coronary vascular autoregulation secondary to increased myocardial oxygen demand. We conclude that forskolin induces direct pharmacologic effects in ventricular muscle, pacemaker cells and the coronary vasculature, but add that the coronary vasculature is over one order of magnitude more sensitive to forskolin than is ventricular muscle. Perhaps adenylate cyclase systems in the heart exist as different subtypes with different affinity characteristics for forskolin-like drugs.

Adenylyl Cyclases↗
PubMed1985

Blink reflex in patients with hemispheric cerebrovascular accident (CVA). Blink reflex in CVA.

A blink reflex consists of an early unilateral component, R1, and a late bilateral component, R2. During an acute phase of hemispheric cerebrovascular accident, R1 and R2 were abnormal in 30 and 50 of 66 patients, respectively. Paired stimuli usually corrected R1 but not R2, which was profoundly suppressed. The discrepancy between polysynaptic R2 and oligosynaptic R1 indicates a greater disfacilitation at the level of interneurons than at the motoneuron, which serves as the final common path. Abnormality of R2 occurred bilaterally with stimulation on the affected side of face and contralaterally after stimulation on the normal side in 31 patients. This finding suggests a diffuse loss of internuncial excitability, contralateral to the hemispheric lesion. Changes of R2 implicated the brainstem pathways forming the afferent and efferent arc of the reflex in 7 and 8 patients, respectively. The remaining 4 comatose patients had no R2 irrespective of stimulus sites. Clinical localization of the hemispheric lesion showed no consistent correlation with the type of blink reflex abnormalities. The CT scans revealed widely scattered changes in 29 patients with abnormal blink reflex but with a tendency to overlap in the inferior Rolandic area. This contrasted with conspicuous sparing of the inferior post-central region in 10 patients with normal blink reflex. These findings suggest the presence of crossed facilitation to this reflex from wide areas of the cortex but most prominently from the sensory representation of the face.

Acute Disease↗
PubMed1985

Reduction of intrinsic contractile reserves of the left ventricle by Escherichia coli endotoxin shock in guinea-pigs.

To test the hypothesis that cardiodynamic responses during endotoxemia are limited by intrinsic myocardial dysfunction, we studied contractile properties of isovolumic left ventricular (LV) preparations isolated from E. coli endotoxin-shocked guinea pigs. Compared to control hearts, shock hearts developed significantly lower LV systolic pressures (54 +/- 7 v. 84 +/- 2 mmHg; P less than 0.001) and maximal rates of LV pressure rise (+dP/dtmax; 886 +/- 106 v. 1246 +/- 39 mmHg/s; P less than 0.006) and fall (-dP/dtmax; 702 +/- 98 v. 1103 +/- 26 mmHg/s; P less than 0.001). The LV mechanical disadvantage of shock hearts was not correlated with changes in beating frequency, active state duration, or tissue water content; neither was it surmounted by pyruvate nor by maximally effective increases in coronary flow, diastolic stretch, or extracellular Ca2+ concentration. These findings suggest that endotoxin pathogenesis encompasses a decrease in intrinsic contractile reserves of the left ventricle, and that the resulting changes in myocardial contractile mechanisms may underlie cardiac involvement in endotoxin shock syndromes.

Animals↗
PubMed1985

Development of myocardial dysfunction in endotoxin shock.

Isolated heart muscle preparations were used to investigate the onset and development of myocardial inotropic dysfunction during endotoxin shock in guinea pigs. Left atrial muscles were removed from separate groups of animals at increasing time intervals after administration of either 4 mg/kg purified Escherichia coli endotoxin (shock groups) or an equivalent volume of isotonic saline (control groups). Peak developed contractile tension (CT) and maximal rate of tension development (+dT/dtmax) were significantly depressed in shock tissues as early as 2 h postendotoxin (P less than 0.01), with the magnitude of the contractile deficit progressively increasing during 4, 6, and 12 h postendotoxin. Contractility remained significantly depressed (P less than 0.001) at 16 and 24 h postendotoxin but progressively recovered toward control levels during 16, 24, 48, and 72 h postendotoxin. Shock-induced myocardial dysfunction was characterized by altered contractile responsiveness to low-Ca2+ medium (0.5 mM), gentamicin (4 mM), and hypoxia; altered inotropic reactivity to these interventions followed similar temporal development as the postendotoxin changes in basal contractile parameters. Left ventricular papillary muscles obtained at 16 h postendotoxin corroborated the shock-induced contractile depression observed in atria. These studies provide evidence for early and progressive intrinsic myocardial dysfunction in endotoxin shock and demonstrate that this dysfunction can be unmasked through the study of in vitro atrial and ventricular heart muscle preparations isolated from in vivo shocked animals.

Animals↗
PubMed1985

Isolated cardiac preparations: models of intrinsic myocardial dysfunction in circulatory shock.

Isolated cardiac preparations have been adapted for modeling intrinsic myocardial responses to circulatory shock syndromes independently of immediate influence from depressive or supportive constraints operative in the intact host. Left atrial and left ventricular (LV) papillary muscles and coronary-perfused hearts were removed from guinea pigs during development of Escherichia coli endotoxin shock. Preparations were then subjected to a battery of functional analyses under conditions of constant perfusate pH, pO2, pCO2, electrolyte and substrate concentrations, osmolality, and temperature. Evidence for contractile depression intrinsic to the myocardium itself was a consistent and reproducible finding in all three tissue models. The LV mechanical disadvantage of shock hearts was not correlated with changes in cardiac cycle length (beating frequency), active state duration (contraction-relaxation intervals), or tissue water content; neither was it surmounted by maximally effective increments in coronary flow, [Ca2+]o, or diastolic fiber length. Taken in concert, studies to date suggest that gram-negative endotoxin leads in some way to a reduction of intrinsic contractile reserves of the myocardium, and we have postulated that this change underlies the circulatory shock phase of endotoxicosis. The experimental approach embodied in these models may yield unique cardiodynamic interpretations that will allow the formulation of testable hypotheses about the pathogenesis and prevention of intrinsic cardiac complications of endotoxin and related shock forms.

Animals↗
PubMed1984

New perspectives in cardiopulmonary therapeutics: receptor-selective adrenergic drugs.

Recent advances in basic biomedical research have led to the development of clinically useful drugs known as "second generation" adrenergic receptor stimulants (agonists) and blockers (antagonists). Adrenergic receptors are now differentiated into 4 distinct subtypes: alpha 1, alpha 2, beta 1, and beta 2. The new drugs are more receptor-selective and tissue-specific than older ones and, hence, have increased potential for directed therapeutic action, with relatively less side effects on nontargeted organs. The beta 2-selective agonist terbutaline, eg, causes bronchodilation with less beta 1-cardiac excitation than does the beta 1-beta 2 nonselective agonist isoproterenol. Compared with the latter, the beta 1-selective agonist dobutamine increases myocardial contractile force and cardiac output with less beta 2-mediated vasodilation and hypotension. The beta 1-selective antagonist metoprolol has advantage over the beta 1-beta 2 nonselective blocker propranolol for controlling beta 1-cardiac excitation in patients with compromised pulmonary function. Prazosin, an alpha 1-selective blocking agent, evokes peripheral vasodilation with less reflex tachycardia than does the nonselective alpha 1-alpha 2 blocker phentolamine, probably because the former spares the prejunctional alpha 2-receptors that subserve autoinhibition of norepinephrine release from the sympathetic neuron. The contemporary practice of internal medicine will no doubt include an understanding of the pharmacologic properties associated with the various adrenergic receptor subtypes.

Adrenergic alpha-Agonists↗
PubMed1984

Decreased contractility and compliance of the left ventricle as complications of thermal trauma.

To test the hypothesis that systemic complications of dermal burns encompass dysfunction of myocardial contractile mechanisms, we studied contraction-relaxation properties of isovolumic left ventricular (LV) preparations isolated from guinea pigs 24 hours after full-thickness burn to approximately 47% total body surface area. Compared to control hearts, hearts from burned subjects consistently generated significantly lower values for LV systolic pressure (94 +/- 2 vs 66 +/- 2 mm Hg; p less than 0.001) and maximal rates of LV pressure rise (+ dP/dtmax; 1296 +/-71 vs 1091 +/- 46 mm Hg X sec-1; p less than 0.05) and fall (-dP/dtmax; 1214 +/- 45 vs 856 +/- 34 mm Hg X sec-1; p less than 0.001). The LV contractile deficit of burn hearts was not correlated with changes in tissue water content, and it was not surmountable by excess glucose, insulin, increased coronary flow, or maximal preload elevation. In addition, end-diastolic pressure-volume relationships in burn hearts were shifted upward and to the left of controls in the direction of decreased compliance (p less than 0.05 to p less than 0.01). Thus, LV sequelae of thermal trauma manifest in isolated hearts as decreased contractility, slowed isovolumic relaxation, and decreased diastolic compliance; in the intact animal this combination would reduce ejection and impede filling of the ventricle, with diastolic pressures reflecting changes in compliance as well as in contractile function.

Adenosine↗
PubMed1984

Contractile function and rhythmicity of cardiac preparations from Escherichia coli endotoxin-shocked guinea pigs.

Isovolumic left ventricular (LV) preparations were isolated from guinea pigs 16-18 hr after IP injection of either saline (control groups) or 4 mg/kg of Escherichia coli endotoxin (shock groups). The tissues were then subjected to mechanical performance comparisons in a carefully regulated coronary perfusion system. Endotoxicosis consistently resulted in myocardial contractile dysfunction as evidenced by significantly low values for LV systolic pressure and maximal rates of LV pressure rise (+dP/dtmax) and fall (-dP/dtmax). There was a distinct tendency for spontaneous tachybradydysrhythmias in the shock groups, but the LV contractile deficit was not dependent upon beating frequency. Also, LV function curves (systolic pressure vs end-diastolic pressure) generated by shock hearts were shifted downward and to the right of control curves, in the direction of inotropic failure. Thus, cardiodynamic adjustments during endotoxin shock may reflect and be limited by underlying dysfunction intrinsic to the heart itself; by 16-18 hr, the resulting functional changes in LV myocardium are manifested in an isolated environment and do not depend on depressive constraints operative in the intact host.

Animals↗
PubMed1983

Pharmacologic problems in circulation research: alpha adrenergic blocking drugs.

Alpha adrenergic receptors can be differentiated into two distinct subtypes designated alpha 1 and alpha 2. Alpha 1 receptors represent the more classical alpha receptor population; they are located postjunctionally on effector cells and are blocked more potently by prazosin than yohimbine. Alpha 2 receptors are newly discovered; they are localized prejunctionally on neuron terminals and also postjunctionally on some effector cell types, and are blocked more potently by yohimbine than prazosin. Phentolamine and phenoxybenzamine block both alpha 1 and alpha 2 receptors. Alpha 2 receptors of noradrenergic neurons subserve an important autoinhibitory effect on norepinephrine release mechanisms. Norepinephrine discharged from the nerve terminal can feed back and activate prejunctional alpha 2 receptors, resulting in a diminution of subsequent neuroeffector transmission. On the other hand, nonselective alpha 1-alpha 2 blocking drugs inhibit alpha-mediated events in effector organs, but they also facilitate catecholamine release by freeing noradrenergic nerves from the alpha 2 feedback inhibition. Resulting increments in catecholamine concentrations may lead to a seemingly paradoxical sympathomimetic response owing to beta receptor activation in heart, vasculature, and perhaps other tissues. These pharmacodynamic complexities should be considered when nonselective alpha 1-alpha 2 blocking drugs are used in attempts to define cause-effect relationships in experimentally shocked animals.

Adrenergic alpha-Antagonists↗
PubMed1983

Pharmacologic problems in shock research.

Recent advances with receptor-selective agonists and antagonists have provided great impetus to the deployment of drugs as experimental tools in cardiovascular research. Often overlooked, however, is the important limitation that few exogenous chemicals actually exert only one biologic action. This discussion appraised several prototype drugs used in this field, and theorized how a lack of consideration of subsidiary pharmacologic actions may lead to over-simplified interpretations of drug-based data.

Adrenergic alpha-Antagonists↗
PubMed1982

Amrinone activates K+-depolarized atrial and ventricular myocardium of guinea pigs.

Amrinone is a new synthetic drug that increases contractile strength of mammalian heart muscle; however, its mechanism of positive inotropic action has not been determined. We now report that amrinone (0.053-5.3 mM) consistently restores typical slow response electromechanical activity fo K+-depolarized atrial and ventricular myocardial preparations from guniea pigs. This action was blocked in both tissues by D-600 (1 microM), but it was not significantly inhibited by either tetrodotoxin (23.5 microM), d,l-propranolol (1 microM), or phentolamine (10 microM). Cimetidine (3 microM) or metiamide (10 microM) slightly inhibited amrinone's effect only in the ventricle, whereas pyrilamine (10 microM) slightly inhibited amrinone's response only in the atrium. These data indicate that amrinone's positive inotropic action may involve augmented Ca++ influx via the slow inward Ca++ current, and that although this action is independent of adrenoceptor mechanisms, it seems to include a small histaminergic component.

Aminopyridines↗
PubMed1982

Contractile function of heart muscle from burned guinea pigs.

Atrial muscle isolated from burned guinea pigs was used to assess myocardial contractile changes associated with thermal injury. Muscle was obtained 16-18 hours after the animals were subjected to sham burn (controls) or to scald burn equivalent to 16% of total body surface area. Isometric contractile tension (CT) and its maximal rate of increase (+dT/dt) were not significantly altered by burn. However, the maximal rate of relaxation (-dT/dt) was uniformly less in muscle from the burned group, and this difference was significant at several time intervals after in vitro contractile responses were elicited. Similarly, -dT/dt responses to increased stimulation frequency (0.1-3.0 Hz) and to increased calcium ion concentration (1.0-10.0 mM) were generally less in the burned group, whereas corresponding CT and +dT/dt responses of the burn and controls groups were not significantly different. Present data indicate that atrial muscle removed from moderately burned guinea pigs exhibits normal contractile capabilities, but may be characterized by impaired relaxation properties.

Animals↗