Cardiac versus Coronary Vasodilator Actions of Isobutylmethylxanthine in Dogs: Comparison with Theophylline

Abstract

Abstract-Cardiacand coronary vasodilator effects of isobutylmethylxanthine (I BMX) and theophylline were compared in isolated, blood-perfused papillary muscle, sino-atrial (SA) node and atrioventricular (AV) node preparations of dogs. I BMX (1 nmol-1 /mol) and theophylline (30 nmol-10 /tmol) were injected intra arterially.In paced papillary muscle preparations, both agents increased the force of contraction.In spontaneously beating papillary muscle preparations, both agents increased the rate of ventricular automaticity.In SA node preparations, both agents increased sinus rate. In AV node preparations, both agents decreased AV conduction time only when they were injected into the artery supplying the AV node.In all preparations, both agents increased coronary blood flow. However, both agents were not homogeneously effective on these cardiovascular variables, but showed selectivity in the following order: Ventricular muscle contraction coronary blood flow>SA nodal automaticity -*.AV nodal conduction>ventricular automaticity.These results indicate that IBMX and theophylline have almost an identical profile in their cardiac and coronary vasodilator effects.The two agents were different in that IBMX was 40-50 times as potent as theophylline in producing these effects.Thus, both agents appeared to express their cardiovascular profiles mainly through inhibition of cyclic AMP phosphodiesterase, although theophylline has been claimed to have additional actions.Recently, an intensive search has been carried out to find new non-sympathomimetic and non-glycoside positive inotropic agents (simply called novel positive inotropic agents hereafter) which can replace digitalis. As a result, nearly a dozen agents have been developed such as amrinone (1, 2), AR-L 115

T-1583 and forskolin are similar in their cardiac effects and dissimilar in their vascular effects

“…These changes in cardiac variables roughly coincide with those produced by the classical PDE inhibitors, IBMX and theophylline [9], and new positive inotropic agents with a PDE inhibitory action such as amrinone [6], milrinone [6], sulmazole [7], enoximone [8], and piroximone [8].…”

“…However, a surprising finding was that forskolin was far more coronary vasodilatory than positive inotropic, although similar findings have already been obtained in Langendorff preparations of guinea pig hearts [24]. In the previous experiments [9] the classical PDE inhibitors, theophylline and IBMX, were nearly as potent in producing coronary vasodilation as in causing positive inotropy. At present no information is available about whether turnover rates of cyclic AMP are different between ventricular myocardium and vascular smooth muscle of the coronary arterial bed, whether cyclic AMP PDE activities are different between two tissues, or whether activities of the two PDE inhibitors are different between the two tissues.…”

“…As a result, it has been clearly revealed that all these agents have such a degree of force-rate separation that sinus rate increases by a little more than 10% at the doses that produce a 50% increase in the force of contraction of ventricular myocardium. Recently, it has been shown that the classical PDE inhibitors, theophylline and 3-isobutyl-l-methylxanthine (IBMX), have also nearly the same degree of force-rate separation as these new positive inotropic agents [9].…”

“…As a result, it has been clearly revealed that all these agents have such a degree of force-rate separation that sinus rate increases by a little more than 10% at the doses that produce a 50% increase in the force of contraction of ventricular myocardium. Recently, it has been shown that the classical PDE inhibitors, theophylline and 3-isobutyl-l-methylxanthine (IBMX), have also nearly the same degree of force-rate separation as these new positive inotropic agents [9].Selective ~l-adrenoceptor agonists such as prenalterol [10] and denopamine [11] constitute another group of new positive inotropic agents as sympathomimetics [2]. This group of agents has been introduced because of less likelihood of arrhythmogenicity and positive chronotropy [12].…”

Cardiovascular and Adenylate Cyclase Stimulating Effects of Colforsin Daropate, a Water-Soluble Forskolin Derivative, Compared With Those of Isoproterenol, Dopamine and Dobutamine.

“…A similar cardiovascular profile to that of toborinone has been reported for classical phosphodiesterase inhibitors, including IBMX and theophyline. 15 Thus, the most marked difference between colforsin daropate and the catecholamines or phosphodiesterase inhibitors is its potent coronary vasodilator action, although all these drugs should increase intracellular cyclic AMP. It can be speculated that there might be a difference in the distribution of the adrenoceptorcoupled adenylate cyclase activation system, the density of adenylate cyclase that colforsin daropate would directly and/or indirectly stimulate and the concentration of cyclic AMP-hydrolyzing phosphodiesterases.…”