Comparative chronotropic activity of beta-adrenoceptive antagonists

Area of Science:

• Pharmacology
• Cardiovascular Physiology

Background:

• Catecholamine depletion impacts resting heart rate and beta-adrenoceptor sensitivity.
• Beta-adrenoceptive antagonists can possess intrinsic agonist activity.

Purpose of the Study:

• To characterize the chronotropic dose-response curves of beta-adrenoceptive antagonists in catecholamine-depleted rats.
• To compare the agonist activity and beta-adrenoceptor blocking potency of various antagonists.

Main Methods:

• Constructed non-cumulative chronotropic dose-response curves in rats pre-treated with syrosingopine.
• Administered beta-adrenoceptive antagonists and isoprenaline to assess heart rate responses.
• Estimated beta-adrenoceptor blocking activity in anesthetized cats.

Main Results:

• Catecholamine depletion reduced resting heart rate and isoprenaline's chronotropic threshold.
• Eight antagonists showed dose-dependent chronotropic responses, but with lower maximum effects than isoprenaline.
• Agonist activity order: dichloroisoprenaline > LB 46 > practolol > INPEA > oxprenolol > pronethalol > alprenolol > I.C.I. 45,763.
• Beta-adrenoceptor blocking activity order differed: LB 46 > oxprenolol > alprenolol > propranolol > I.C.I. 45,763 > practolol > dichloroisoprenaline > sotalol > INPEA > pronethalol.
• Propranolol shifted agonist dose-response curves rightward, indicating competitive antagonism.

Conclusions:

• Beta-adrenoceptive antagonists display varied intrinsic agonist activities.
• The order of agonist activity does not correlate with beta-adrenoceptor blocking potency.
• Chemical structure and physico-chemical properties do not fully explain observed differences in agonist activities.