Preclinical pharmacologic properties of dilevalol, an antihypertensive agent possessing selective beta 2 agonist-mediated vasodilation and beta antagonism.
Dilevalol is a vasodilator with selective partial beta 2 agonism and nonselective beta-antagonist activity. In contrast to its potent beta 2-agonist activity, dilevalol is essentially devoid of beta 1-agonist action, and is therefore distinct from pindolol and celiprolol. Dilevalol inhibits beta 1- and beta 2-adrenergic receptors nonselectively in dogs, rats and in isolated tissues, including human myocardium, and its beta-antagonist potency is similar to that of propranolol. In contrast to its beta-antagonist activity, it exerts minimal if any alpha-adrenergic blockade. Dilevalol is 300- to 1,000-fold more potent at beta- than at alpha 1-adrenergic receptors, including those on human myocardium and mammary arteries. At antihypertensive and vasodilator doses in rats and dogs, dilevalol does not inhibit alpha 1-adrenergic receptors. Oral doses of 2.5 to 50 mg/kg of dilevalol reduce blood pressure in spontaneously hypertensive rats. Heart rate is not significantly affected. Tolerance does not develop to the antihypertensive response. In contrast, beta blockers such as propranolol do not reduce blood pressure in this model. Antihypertensive activity is also observed in dogs with renal hypertension. The hemodynamic profile of dilevalol is consistent with its vasodilator properties. In spontaneously hypertensive rats, antihypertensive doses of dilevalol reduce peripheral resistance without affecting cardiac output. Dilevalol also improves the compliance and distensibility of the large arteries. The vasodilator and antihypertensive responses to dilevalol are mediated by a partial agonist action at vascular beta 2 receptors, because they are inhibited by the nonselective beta blocker propranolol as well as the beta 2-selective antagonist ICI 118,551.
Sybertz
E J
EJ
Department of Pharmacology, Schering Corporation, Bloomfield, New Jersey 07003.
Watkins
R W
RW
D000318:Adrenergic beta-Agonists / Q000494:pharmacology; D000818:Animals; D006329:Heart Conduction System / Q000187:drug effects; D006439:Hemodynamics / Q000187:drug effects*; D006801:Humans; D066298:In Vitro Techniques; D007741:Labetalol / Q000494:pharmacology*; D011943:Receptors, Adrenergic, beta / Q000187:drug effects; D013237:Stereoisomerism; D014665:Vasodilator Agents / Q000494:pharmacology
D000318:Adrenergic beta-Agonists; D011943:Receptors, Adrenergic, beta; D014665:Vasodilator Agents; D007741:Labetalol