Propranolol induces contractions of canine small and large coronary arteries.

Using isolated canine small (right coronary branch, left coronary branch; o. d. 0.4-0.8 mm) and large (left coronary, circumflex; o. d. 1-2 mm) coronary arteries, the beta-adrenergic antagonist dl-propranolol (5 X 10(-7) to 5 X 10(-5) m/l) was found to produce concentration-dependent contractions. Interestingly, most of these contractile events take place with concentrations of propranolol (0.1-1 microgram/ml) found in the blood of patients who are taking this drug for various therapeutic reasons. These propranolol-induced contractions were enhanced in Krebs-Ringer solution containing slightly elevated (weak contractile) concentrations of potassium (15 mmol/l). Experiments with specific pharmacologic antagonists indicated that propranolol-induced contractions on canine coronary arteries can not be mediated by release (or inhibition) of catecholamines, histamine, serotonin or acetylcholine. Propranolol contractions could be released by low concentrations of potassium ions (4 mmol/l), suggesting that the beta receptor antagonist might inactive coronary arterial membrane Na+, K+-ATPase. Other experiments demonstrated that propranolol can enhance coronary arterial membrane permeability to calcium ions; these observations suggest that propranolol might sensitize coronary vascular smooth muscle cells to calcium ions. Removal of calcium ions from the Krebs-Ringer solution or addition of the calcium entry blocker, verapamil, prevented completely the propranolol-induced contractions. Catecholamines (i.e., epinephrine, norepinephrine, isoproterenol), which normally induce relaxation on these isolated coronary arteries, always induced contraction after use of dl-propranolol. Overall, these experiments suggest that the so-called "beta-blocker poisoning" sometimes noted with propranolol in patients might be brought about by four actions of this drug acting in concert: 1. direct coronary arterial vasospasm; 2. an unmasking of normally silent alpha-adrenergic receptors, thus allowing circulating and released catecholamines to induce potent coronary constriction; 3. attenuation of membrane Na+, K+-ATPase activity, and 4. an enhancement of coronary vascular smooth muscle membrane permeability to calcium ions.