ICI 147,798: a slowly dissociable beta adrenoceptor antagonist that causes insurmountable beta-1 and surmountable beta-2 adrenoceptor antagonism in isolated tissues.
ICI 147,798 has been shown to exhibit both diuretic and beta-antagonist properties in vivo. The present study investigated the nature and selectivity of the beta-antagonism in a variety of isolated tissues. ICI 147,798 produced a concentration-dependent suppression of the maximum chronotropic response of norepinephrine in guinea pig right atria (beta-1 adrenoceptor). ICI 147,798 caused a concentration-dependent shift to the right of the salbutamol concentration-response curve in the guinea pig trachea (beta-2 adrenoceptor), and Schild analysis suggested competitive inhibition. Propranolol produced parallel shifts to the right of the norepinephrine concentration-response curve in guinea pig right atria, except at relatively high concentrations. The inhibitory effects of propranolol in guinea pig right atria were reversed by greater than 95%, whereas the effects of ICI 147,798 were only slightly reversed after a 6-hr washout period. Preincubation of propranolol with ICI 147,798 in guinea pig right atria prevented completely the suppression of the norepinephrine maximum chronotropic response. Postincubation of propranolol with ICI 147,798 partially reversed the suppression of the maximum chronotropic response. ICI 147,798 had no effect on the maximum chronotropic responses of either histamine (H2-receptor) or forskolin (adenylate cyclase activation) in guinea pig right atria and had no effect on agonist responses in a variety of other receptor systems. The insurmountable beta-1 adrenoceptor antagonism was evaluated based on the assumptions of irreversible competitive antagonism, mixed competitive and noncompetitive antagonism and slowly dissociating competitive antagonism ("hemi-equilibrium" conditions). Concentration-dependent changes in norepinephrine KA values suggested the first three possibilities were unlikely.(ABSTRACT TRUNCATED AT 250 WORDS)
Keith
R A
RA
Department of Pharmacology, ICI Americas Inc., Wilmington, Delaware.
Hwang
T F
TF
Murthy
V S
VS
Kau
S T
ST
Salama
A I
AI
Giles
R E
RE
D000319:Adrenergic beta-Antagonists / Q000494:pharmacology*; D000818:Animals; D006168:Guinea Pigs; D006339:Heart Rate / Q000187:drug effects; D066298:In Vitro Techniques; D008297:Male; D009638:Norepinephrine / Q000494:pharmacology; D011433:Propranolol / Q000494:pharmacology; D011719:Pyrazines / Q000494:pharmacology*; D011817:Rabbits; D051381:Rats; D011919:Rats, Inbred Strains; D011943:Receptors, Adrenergic, beta / Q000187:drug effects*
D000319:Adrenergic beta-Antagonists; D011719:Pyrazines; D011943:Receptors, Adrenergic, beta; C053707:ICI 147798; D011433:Propranolol; D009638:Norepinephrine