INOTROPIC AND METABOLIC EFFECTS OF THREE BETA-ADRENERGIC RECEPTOR BLOCKING DRUGS ON ISOLATED RABBIT LEFT ATRIA

¹ Research Laboratories, Presbyterian Medical Center, San Francisco, California

The inotropic effects of three beta-adrenergic receptor blocking agents, pronethalol, propranolol, and MJ-1999, were studied on electrically driven rabbit left atria. Pronethalol (3.76 x 10^-6 and 1.13 x 10³ M) and propranolol (1.35 x 10^-6. and 1.35 x 10^-5 M) produced a significant depression of force of contraction in atria driven at 120 beats/minute. The negative inotropic effect and subsequent asystole produced by the higher concentration of propranolol was accompanied by a depression of the electrical properties of the atria. Quinidine (1.27 x 10^-5 M) produced a negative inotropic effect similar to that seen with pronethalol (1.13 x 10^-5 M) and propranolol (1.35 x 10^-6 M).

MJ-1999, a methanesulfonanilide substituted isopropylphenylethylamine, was found to be devoid of any direct depressant effects on force of contraction, even in a concentration of 6.5 x 10^-4 M. This is more than 50 times the concentration needed to produce a 50% attenuation of the inotropic effects of isoproterenol (9.4 x 10^-8 M) on the atrial preparations. With a 3-minute pretreatment period, pronethalol and propranolol were approximately 1.5 and 11 times more potent, respectively, than MJ-1999 in blocking the inotropic effects of isoproterenol (9.4 x 10^-8 M).

At a rate of 60 beats/minute, both pronethalol (1.13 x 10^-5 M) and propranolol (1.35 x 10^-5 M) still produced significant depression of force of contraction comparable (in percent change) to that seen with a higher rate of stimulation. Only in comparing the force of contraction seen during the last 120 to 180 minutes of drug action is there evidence that the depressant effect of pronethalol is significantly less at 60 beats/minute than at 120 beats/minute.

Measurement of O₂ uptake of isolated left atria (Warburg technique) indicated that propranolol, pronethalol, MJ-1999, and quinidine had no significant effects on oxidative mebolism.

These results emphasize the separability of cardiac depressant action, beta-adrenergic blocking effects and changes in myocardial O₂ consumption in isolated rabbit left atria.