Is beta 1-antagonism essential for the antihypertensive action of beta-blockers?

Abstract

Both nonselective beta-blockers and beta 1-selective blockers are effective antihypertensive agents. beta 1-Blockade generally is considered to be responsible for their antihypertensive action, whereas beta 2-blockade is regarded as undesirable. These common assumptions notwithstanding, the mechanism by which beta-blockers lower blood pressure remains unknown. To examine the possibility that beta 2-blockade may contribute to the antihypertensive action of beta-blocker therapy, we studied the cardiovascular effects of compound ICI 118551, a beta 2-selective blocker. First, we showed that 50 mg t.i.d. orally is a beta 2-selective dose. In contrast to propranolol, 80 mg t.i.d., or atenolol, 100 mg once a day, 50 mg of ICI 118551 t.i.d. failed to block beta 1-mediated inotropic stimulation and stimulation of renin by isoproterenol. We then performed a double-blind, placebo-controlled trial in patients with mild essential hypertension to compare this compound with propranolol, 80 mg t.i.d., and showed that ICI 118551 significantly decreased systolic and diastolic blood pressure. This antihypertensive effect was demonstrated by direct as well as by indirect blood pressure measurements. Thus, contrary to prevailing thought, beta 2-blockade has an antihypertensive effect independent of, and distinct from, beta 1-blockade.

β 2 -Adrenoceptor Antagonist ICI 118,551 Decreases Pulmonary Vascular Tone in Mice via a G i/o Protein/Nitric Oxide-Coupled Pathway

“…In accordance with our data, 2 different studies in humans also reported that ICI did not affect systemic blood pressure. 23,24 Only Vincent et al 25 found a reduction of systemic blood pressure, however, only 1 week after the beginning of treatment and when using a much higher concentration (0.7 mg/kg for patients of 70-kg weight) compared with our study. Thus, low concentrations of ICI specifically reduce vascular tone in pulmonary vessels.…”

Agonist-induced desensitization of beta-adrenoceptor function in humans. Subtype-selective reduction in beta 1- or beta 2-adrenoceptor-mediated physiological effects by xamoterol or procaterol.

“…Procaterol treatment increased heart rate by [10][11][12][13][14][15] beats/min after 12-24 hours. During further treatment, heart rate declined slowly and reached predrug levels about 2-3 days after withdrawal of procaterol.…”

The applied pharmacology of beta-adrenoceptor antagonists (beta blockers) in relation to clinical outcomes

“…In the study by Dahlof et al [24], ICI 118551 reduced heart rate and cardiac output significantly but did not alter mean blood pressure. In a more recent study by Vincent et al [26], ICI 118551, 50 mg three times daily, was compared with propranolol 80 mg three times daily and placebo in 19 hypertensive subjects. Systolic and diastolic blood pressures were significantly reduced after 7 days treatment.…”

“…ICI 118551 causes a significant reduction in heart rate in all the studies and a fall in cardiac output in the single study where this was measured indirectly. In the negative study [26], a placebo was not used, though the subjects were known responders to other beta blockers. Thus the question as to whether selective beta 2 blockade reduces blood pressure remains controversial.…”