Cardioselectivity, kinetics, hemodynamics, and metabolic effects of xamoterol.

Xamoterol is a new orally active partial beta-adrenoceptor agonist. Its kinetics, hemodynamic and metabolic effects, and cardioselectivity were investigated in eight normal subjects. Plasma xamoterol concentrations after 100 micrograms/kg iv declined biexponentially over 8 hr and t 1/2 beta averaged 2.6 hr. Resting heart rate (HR) increased slightly in the supine position but was unchanged on sitting. Systolic blood pressure (SBP) rose by 5 to 10 mm Hg and cardiac index (CI) rose 15% to 20%. Both parameters were above control values 6 hr after dosing, when plasma xamoterol concentrations had fallen to about 10 ng/ml. There were no changes in diastolic or mean arterial pressure (MAP). During graded exercise the effects of xamoterol on HR and SBP were the reverse of those at rest, with lowering of exercise HR and SBP at higher work loads. CI during exercise was not altered by xamoterol. Doses of xamoterol were calculated from the kinetic data to give plasma concentrations of 100, 200, 400, and 800 ng/ml. HR and blood pressure effects at each xamoterol level were compared before and after inhibition of cardiovascular reflexes with prazosin, atropine, and clonidine. Hemodynamic effects of xamoterol and isoproterenol were compared. Before autonomic block xamoterol increased HR by 10 bpm and MAP by 7 mm Hg at the highest dose. After autonomic block there was a 200% to 300% rise in HR at each dose and MAP still rose. The rise in MAP after block could be entirely accounted for by a 23% increase in CI because total peripheral resistance did not change. The effects of isoproterenol after autonomic block were a rise in HR and a fall in MAP. Metabolic responses to xamoterol were measured at the four dose levels. There was a dose-related increase in nonesterified fatty acids and a fall in plasma lactate levels but no changes in plasma renin activity or blood glucose. Results suggest that xamoterol is a cardioselective partial beta-adrenoceptor agonist in man.