The partial beta
adrenoceptor agonist properties of
cicloprolol,
xamoterol and
pindolol have been compared in vivo (anesthetized
catecholamine-depleted or pithed rats) and in vitro (guinea pig or rat right atria and guinea pig tracheal muscle preparations) conditions. All three compounds increased heart rate in the former preparations, and their intrinsic activities relative to
isoproterenol were 0.7, 0.65 and 0.45, respectively. The positive chronotropic effects of
cicloprolol or
xamoterol were competitively antagonized by
betaxolol or
propranolol; however, part of those induced by
pindolol were resistant to these
beta adrenoceptor antagonists. None of these compounds increased the spontaneous beating rate of isolated guinea pig atria; however,
xamoterol only increased heart rate in isolated rat atria, and its intrinsic activity with respect to
isoproterenol was 0.4.
Pindolol,
xamoterol and
cicloprolol behaved as competitive beta-1
adrenoceptor antagonists against
isoproterenol-induced
tachycardia in a pithed rat model. In order to mimic the intrinsic effects of the partial agonist drugs, control dose-response curves for
isoproterenol were determined in pithed rats in which the base-line heart rate was elevated by thoracic
spinal cord stimulation. In this in vivo preparation,
xamoterol and
pindolol were more potent beta-1
adrenoceptor antagonists than
cicloprolol; however,
cicloprolol and
xamoterol, in contrast to
pindolol, were selective for beta-1
adrenoceptors. In isolated spontaneously beating guinea pig right atria,
cicloprolol and
xamoterol were equipotent beta-1
adrenoceptor antagonists but were about 50 times less potent than
pindolol. In isolated rat atria, the beta-1
adrenoceptor antagonist potency of
xamoterol was greater (pA2 = 8.7) than in guinea pig atria (pA2 = 7.8). The potencies of
cicloprolol and
pindolol did not vary between these species. In
catecholamine-depleted rats, high i.v. doses of
cicloprolol had
vasodilator activity that was partly mediated by beta-2
adrenoceptors. In
carbachol-contracted guinea pig trachea,
cicloprolol and
xamoterol, in contrast to
pindolol, were relatively inactive against
isoproterenol-induced relaxation. In conclusion,
cicloprolol and
xamoterol, similarly to
pindolol, behave as agonists and antagonists of beta-1
adrenoceptors. However, only
cicloprolol and
xamoterol show an elevated degree of selectivity toward the beta-1
adrenoceptor subtype.