cardiovascular-agents and carbazeran

Compounds with phosphodiesterase inhibitory activity stimulate myocardial contractility by increasing the intracellular cyclic AMP concentrations. They can also increase Ca2+ entry and inhibit Ca2+ sequestration by the sarcoplasmic reticulum. Xanthines produce bronchodilation with associated venous and arteriolar dilation. However, their use is limited by their positive chronotropic effect and other side effects at high plasma levels. New phosphodiesterase inhibitors have been perfected: they are more specific with little chronotropic effect. Increasing the sensitivity of the myofilaments to Ca2+, and other unclear mechanisms may be involved in the inotropic action of these drugs. These new promising active compounds are described and discussed. They augment cardiac performance and improve regional distribution of blood flow and symptoms. However, their influence on the long-term outcome of severe heart failure has yet to be determined.

Topics: Aminopyridines; Amrinone; Calcium; Carbamates; Cardiotonic Agents; Cardiovascular Agents; Enoximone; Heart Failure; Hemodynamics; Humans; Imidazoles; Milrinone; Myocardial Contraction; Phosphodiesterase Inhibitors; Pyridones; Quinazolines; Stimulation, Chemical; Time Factors; Xanthines

The animal and human pharmacology of several new drugs (prazosin, trimazosin, pirbuterol, and carbazeran) useful in the treatment of congestive heart failure (CHF) is delineated in relation to the pharmacology of other agents employed for CHF management. Prazosin and trimazosin are selective alpha 1-blockers that cause a balanced increase in cardiac output (CO) and reduction in left ventricular filling pressure (LVFP); the reduction in diastolic blood pressure with these drugs is significantly related to increase in treadmill exercise, fall in LVFP, and increase in CO. Pirbuterol is a relatively selective beta 2-agonist with somewhat greater effects on CO than on LVFP. Early promise in CHF therapy is being shown by a novel series of cyclic adenosine monophosphate (cAMP) phosphodiesterase inhibitors with combined direct inotropic and vasodilator effects. Double-blind long-term studies demonstrate persistent efficacy of prazosin and trimazosin in CHF as measured by improvement in New York Heart Association functional class, treadmill exercise performance, and noninvasive measures of cardiac function; these data are supported by studies in which repeat cardiac catheterization has been performed after several months of therapy. Double-blind studies of other CHF drugs are in progress.

Topics: Animals; Asthma; Carbamates; Cardiotonic Agents; Cardiovascular Agents; Clinical Trials as Topic; Drug Evaluation; Drug Evaluation, Preclinical; Ethanolamines; Heart Failure; Hemodynamics; Humans; Hypertension; Piperazines; Prazosin; Quinazolines; Vasodilator Agents

The animal and human pharmacology of several new drugs (prazosin, trimazosin, pirbuterol, and carbazeran) useful in the treatment of congestive heart failure (CHF) is delineated in relation to the pharmacology of other agents employed for CHF management. Prazosin and trimazosin are selective alpha 1-blockers that cause a balanced increase in cardiac output (CO) and reduction in left ventricular filling pressure (LVFP); the reduction in diastolic blood pressure with these drugs is significantly related to increase in treadmill exercise, fall in LVFP, and increase in CO. Pirbuterol is a relatively selective beta 2-agonist with somewhat greater effects on CO than on LVFP. Early promise in CHF therapy is being shown by a novel series of cyclic adenosine monophosphate (cAMP) phosphodiesterase inhibitors with combined direct inotropic and vasodilator effects. Double-blind long-term studies demonstrate persistent efficacy of prazosin and trimazosin in CHF as measured by improvement in New York Heart Association functional class, treadmill exercise performance, and noninvasive measures of cardiac function; these data are supported by studies in which repeat cardiac catheterization has been performed after several months of therapy. Double-blind studies of other CHF drugs are in progress.

Topics: Animals; Asthma; Carbamates; Cardiotonic Agents; Cardiovascular Agents; Clinical Trials as Topic; Drug Evaluation; Drug Evaluation, Preclinical; Ethanolamines; Heart Failure; Hemodynamics; Humans; Hypertension; Piperazines; Prazosin; Quinazolines; Vasodilator Agents

1. The chronotropic and inotropic effects of amrinone, carbazeran and 3-isobutyl-1-methyl xanthine (IBMX) were examined in isolated preparations of papillary muscle and right atria from rabbit heart. The effects of the drugs on cardiac phosphodiesterase and cyclic nucleotide content were also examined. 2. Amrinone (2.4 x 10(-4)M-2 x 10(-3) M), carbazeran (9.1 x 10(-6) M-1.2 x 10(-3) M), and IBMX (1.8 x 10(-5) M-4.5 x 10(-4) M) produced concentration-dependent positive inotropic responses of papillary muscle preparations, the rank order of potency being carbazeran = IBMX greater than amrinone. Sub-threshold positive inotropic concentrations of all three compounds potentiated the positive inotropic effects of isoprenaline; leftward shifts in the concentration-effect curves were 5 fold (IBMX), 11 fold (amrinone) and 46 fold (carbazeran). 3. Amrinone and IBMX produced concentration-dependent positive chronotropic responses in isolated right atria and showed a similar rate selectivity to isoprenaline, but carbazeran elicited a decrease in beating frequency. None of these drugs potentiated the positive chronotropic effects of isoprenaline. 4. Concentrations of amrinone, carbazeran and IBMX that produced similar positive inotropic responses were associated with different increases in papillary muscle cyclic AMP and cyclic GMP concentrations. 5. All three compounds inhibited right atrial and ventricular phosphodiesterase, with amrinone being the least potent. There was, however, a marked difference between the IC50 and EC50 values for phosphodiesterase inhibition and positive inotropy. In contrast the positive chronotropic effects of amrinone and IBMX were observed in the same concentration ranges that produced phosphodiestrease inhibition. 6. The results indicate that amrinone possesses a similar rate/force selectivity to isoprenaline and IBMX. In contrast, carbazeran exerts both positive inotropic and negative chronotropic effects. Phosphodiesterase inhibition and elevation of intracellular cyclic AMP concentration may be involved, at least in part, in the cardiac effects of these drugs.

Topics: 1-Methyl-3-isobutylxanthine; Amrinone; Animals; Carbamates; Cardiovascular Agents; Cyclic AMP; Cyclic GMP; Electric Stimulation; Heart; Heart Rate; In Vitro Techniques; Isoproterenol; Male; Myocardial Contraction; Papillary Muscles; Phosphodiesterase Inhibitors; Rabbits; Theophylline