Role of beta 2-receptor stimulation in the peripheral vascular actions of the antihypertensive dilevalol.
Dilevalol (SCH 19927) is a potent, long-acting, nonselective beta-blocker with marked vasodilator actions. Unlike classical beta-blockers, dilevalol promptly lowers blood pressure and vascular resistance in animal models of hypertension. The present studies address the peripheral vascular effects of dilevalol and explore the role of beta-receptor agonism in the acute vasodilator and antihypertensive effects of the compound. In the denervated dog hindlimb preparation, dilevalol (0.1, 0.3, 1.0 and 3.0 micrograms, i.a.) significantly increased femoral blood flow by 12 +/- 6, 27 +/- 6, 84 +/- 31 and 132 +/- 41 ml/min, respectively. In contrast, celiprolol, a beta-blocker with purported vasodilator activity, caused a significant increase in flow of 31 +/- 9 ml/min at a dose of 30 micrograms i.a. Systematic pretreatment with the selective beta 2-antagonist ICI 118,551 virtually abolished dilevalol's vasodilator effect in the dog hindlimb. In conscious spontaneously hypertensive rats, 3 mg/kg i.v. dilevalol reduced blood pressure by 58 +/- 8 mmHg (P less than 0.05) and vascular resistance by 171 +/- 27 dyne.sec.cm-5/100 g (P less than 0.05) but did not change cardiac output significantly. Pretreatment of spontaneously hypertensive rats with ICI 118,551 significantly reduced both dilevalol's antihypertensive and resistance-lowering effects. Oral doses of 10 and 25 mg/kg dilevalol lowered blood pressure by 19 +/- 3 (P less than 0.05) and 37 +/- 5 mmHg (P less than 0.05) in spontaneously hypertensive rats with chronically implanted Doppler flow probes. The lower dilevalol dose reduced mesenteric vascular resistance 38 +/- 6% (P less than 0.05) while the higher dose significantly lowered vascular resistance in the hindlimb, mesenteric and renal vascular beds of spontaneously hypertensive rats by 18 +/- 8, 33 +/- 2 and 43 +/- 4%, respectively. Propranolol lowered neither blood pressure nor regional vascular resistances at the above doses in spontaneously hypertensive rats. Thus, dilevalol promotes a generalized fall in vascular resistance. Furthermore, the present studies illustrate that beta 2-receptor stimulation plays an obligatory role in both the vasodilatory and antihypertensive actions of dilevalol.
Watkins
R W
RW
Department of Pharmacology, Schering-Plough Research Division, Bloomfield, NJ 07003.
Sybertz
E J
EJ
Cook
J
J
Pula
K
K
Cedeno
K
K
Tedesco
R P
RP
McLeod
R
R
D000318:Adrenergic beta-Agonists / Q000494:pharmacology*; D000758:Anesthesia; D000818:Animals; D002302:Cardiac Output / Q000187:drug effects; D003714:Denervation; D004285:Dogs; D005260:Female; D006339:Heart Rate / Q000187:drug effects; D006439:Hemodynamics / Q000187:drug effects; D006614:Hindlimb / Q000294:innervation / Q000502:physiology; D007741:Labetalol / Q000494:pharmacology*; D008297:Male; D011412:Propanolamines / Q000494:pharmacology; D051381:Rats; D011918:Rats, Inbred SHR; D012039:Regional Blood Flow / Q000187:drug effects*; D012079:Renal Circulation / Q000187:drug effects; D012212:Rheology; D013152:Splanchnic Circulation / Q000187:drug effects; D014655:Vascular Resistance / Q000187:drug effects
D000318:Adrenergic beta-Agonists; D011412:Propanolamines; C026777:ICI 118551; D007741:Labetalol