AJP - Gastrointestinal and Liver Physiology, Vol 247, Issue 4 366-G376, Copyright © 1984 by American Physiological Society
Reversible effects of phenothiazines on frog gastric stimulation
N. Raphael, E. B. Ekblad and T. E. Machen
The calmodulin inhibitors trifluoperazine (TFP), chlorpromazine (CPZ), and
promethazine (PZ) were tested for effects on stimulus-secretion coupling in
in vitro bullfrog gastric mucosa. When added to histamine-stimulated
tissues, the drugs caused H+ secretion to decrease and transepithelial
resistance to increase over a 2-h time course. The potency sequence was TFP
(IC50 = 40 microM) greater than CPZ (IC50 = 72 microM) congruent to PZ
(IC50 = 72 microM). Anesthetics and other phenothiazines with weak
anticalmodulin activity had no effect on secretory parameters. In the
presence of histamine, further addition of isobutylmethylxanthine (IBMX, a
phosphodiesterase inhibitor) plus dibutyryl cAMP (DBcAMP), IBMX alone, or
forskolin (a specific activator of adenylate cyclase) to
phenothiazine-inhibited tissues caused full resumption of secretory
activity. If TFP (50 microM) was added before stimulation with histamine,
the normal increases in tissue cAMP content (which occurs primarily in
oxyntic cells), oxyntic cell apical membrane elaboration (morphometric
analysis of electron micrographs), and H+ secretion were all blocked.
Subsequent addition of IBMX or IBMX plus DBcAMP completely reversed the TFP
effect. These results indicate that the histamine-sensitive adenylate
cyclase may be the site of TFP inhibition and Ca2+-calmodulin regulation;
since these drugs inhibited stimulation by DBcAMP plus IBMX, they may also
be exerting additional effects distal to cAMP generation.
