The effects of beta-adrenoreceptor antagonists on the force responses of the electrically driven rat right ventricle strip to isoprenaline.

1. The force of the electrically driven rat right ventricle strip is increased by isoprenaline but not by procaterol, a beta 2-adrenoceptor agonist. The effects of some beta-adrenoreceptor antagonists on the responses of the strip to isoprenaline have been determined. 2. Metoprolol (a beta 1-adrenoreceptor-selective antagonist) at 3 x 10(-8)-3 x 10(-7) moll-1 and ICI 118,551 (a potent beta 2-adrenoreceptor-selective antagonist) at 10(-7)-10(-6) moll-1 had no effect on maximum responses to isoprenaline and caused parallel rightward shifts of the isoprenaline response curves. The pA2 values for metoprolol and ICI 118,551 were 7.86 and 7.40, respectively. Thus the isoprenaline responses of the rat right ventricle strip are due to stimulation of beta 1-adrenoreceptors. 3. Metoprolol at 10(-6) moll-1 acted as a dual antagonist of the responses of the ventricle strip to isoprenaline causing parallel rightward shifts of the concentration-response curves which was due to beta 1-adrenoreceptor antagonism and a depression of the maximum response to isoprenaline which was probably due to membrane stabilizing activity. 4. Low concentrations of (+/-)-pindolol (10(-8) moll-1), (+)-pindolol (10(-7) moll-1), (-)-pindolol (10(-8) moll-1) and mepindolol (10(-10) moll-1) had no effect on isoprenaline maximum responses and caused parallel rightward shifts of isoprenaline response curves. Both (+/-)- and (-)-pindolol at 10(-7) moll-1, mepindolol at 10(-9)-10(-7) moll-1 and bopindolol at 10(-9)-10(-7) moll-1 reduced the isoprenaline maximum responses and caused non-parallel rightward shifts of the isoprenaline response curves. 5. BAAM (an irreversible beta-adrenoreceptor antagonist) treatment (3 x 10(-6) moll-1) for 30 min followed by 60 min washout reduced the isoprenaline maximum responses and caused a non-parallel rightward shift of the isoprenaline response curve. The kA (dissociation constant) for isoprenaline was 1.10 x 10(-6) moll-1. Calculation of receptor occupancy demonstrated that in order to produce a maximal response of the rat right ventricle strip, isoprenaline had to occupy 73% of the beta 1-adrenoreceptors. 6. The use of the rat right ventricle strip, a tissue with a small beta 1-adrenoreceptor reserve for isoprenaline, allows a definitive characterization of reversible (e.g. metoprolol) and irreversible (e.g. BAAM) beta 1-adrenoreceptor antagonists. It is suggested that (+/-)- and (-)-pindolol, mepindolol and bopindolol may be slowly dissociating beta 1-adrenoreceptor antagonists.