Influence of intrinsic sympathomimetic activity of beta-adrenoceptor blockers on the heart rate and blood pressure responses to graded exercise

Abstract

1 The relationship between plasma concentration and effect on heart rate and blood pressure at rest and at three levels of exercise were examined for four β-adrenoceptor blocking drugs having differing pharmacological properties.

2 Four doses of each drug were administered, the highest doses producing maximum effects of the work-heart rate and work-blood pressure relationships.

3 Pindolol and oxprenolol, which have intrinsic sympathomimetic activity (ISA) differed from timolol and metoprolol (which do not) in having a smaller effect on resting heart rate at each dose.

4 During exercise the four drugs had similar maximum effects on slope of the work-heart rate relationship suggesting similar suppression of reflex enhancement of sympathetic activity during exercise by each drug. The higher heart rate after drugs with ISA at rest was therefore still present at each level of exercise, e.g. maximum reduction of heart rate at 0.5 maximum work capacity was 20.5, 20.8. 24 and 28% for pindolol, oxprenolol, metoprolol and timolol respectively (P < 0.01 for difference between drugs with and without ISA).

5 The relationship between plasma concentration and reduction of heart rate at 0.5 maximum work capacity was qualitatively similar for each drug and was adequately described by a sigmoidal relationship wtih half-maximal effects at 4.4, 22, 35 and 5 ng/ml for pindolol, oxprenolol, metoprolol and timolol respectively whilst maximal effects occurred at approximately 30, 150, 100 and 30 ng/ml.

6 The results suggest that differences with exercise heart rate due to ISA are mainly due to effects on resting heart rate. The dose-response relationship of β-adrenoceptor blockers reaches a plateau at higher doses, irrespective of whether or not they possess ISA.