PREJUNCTIONAL AND POSTJUNCTIONAL INHIBITION OF ADRENERGIC TRANSMISSION IN THE RAT-ISOLATED ANOCOCCYGEUS MUSCLE BY CIMETIDINE

1 Cimetidine and ranitidine can inhibit various cholinergic sites, whi ch can account for some of their clinically documented adverse effects ; ranitidine can also inhibit adrenergic transmission, closely resembl ing the action of guanethidine. The effects of cimetidine on adrenergi c transmission in the rat isolated anococcygeus muscle (Acm) were ther efore investigated. 2 The contractile (motor) responses of the Acm to electrical field stimulation (EFS; 20-30V, 10 s, 1 ms pulse width, eve ry 2 min) at varying frequencies (Hz: 5, 10, 20) and to 3 mu M noradre naline (NA) were inhibited in a concentration-dependent manner by cime tidine (mM: 1, 2, 4, 8). Inhibition of the EFS-induced responses was i nversely related to the stimulation frequency. 3 Cimetidine (mM: 2, 4, 8) produced a concentration-dependent and non-parallel shift of the N A cumulative log concentration-response curves (CRCs; curves 2, 3, 4) to the right of the control curve (curve 1); at the highest concentrat ion (8 mM) used, cimetidine produced a 4.3-fold shift of curve 4 accom panied by a decline of 9.4 +/- 1.5% in the maximal response to NA (com pared to essentially no change in maximal responses for the correspond ing CRCs in the NA control series). Cimetidine therefore inhibited the postjunctional alpha-adrenoceptor sites. 4 The contractile responses of the Acm to EFS (i.e. prejunctionally mediated responses) were more sensitive to inhibition by cimetidine than the NA-induced (postjunctio nally mediated) responses: 8 mM cimetidine inhibited the responses to EFS by about 97%, whereas the responses to NA were inhibited by only 4 1 +/- 5%. Therefore, in addition to the partial blockade of postjuncti onal alpha-adrenoceptor sites, cimetidine can also cause a relatively marked, prejunctional inhibition of the contractile responses of the A cm to EFS. 5 Desipramine (0.5 mu M) did not affect the inhibition by c imetidine (8 rm?) of the contractile responses of the Acm to EFS, indi cating that cimetidine is not dependent on its uptake into the adrener gic nerve terminals to mediate its inhibitory action. 6 Cimetidine (8 mM) decreased the peak tension by 61% and markedly reduced the sustain ed tone of the Acm raised by guanethidine (100 mu M); the peak contrac tile responses of the Acm to tyramine (20 mu M) were also decreased by 55.8 +/- 5.6% by cimetidine (8 mM). The blockade of the responses of the Acm to guanethidine and tyramine may be attributed to the blocking action of cimetidine at postjunctional alpha-adrenoceptor sites. 7 Th ese results provide strong evidence to show that cimetidine can marked ly inhibit noradrenergic transmission in the Acm by some prejunctional mechanism of action and, also, by a postjunctional mechanism causing partial blockade of alpha-adrenoceptor sites.