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

1 Cimetidine and ranitidine can inhibit various cholinergic sites, which can account for some of their clinically documented adverse effects; ranitidine can also inhibit adrenergic transmission, closely resembling the action of guanethidine. The effects of cimetidine on adrenergic transmission in the rat isolated anococcygeus muscle (Acm) were therefore investigated. 2 The contractile (motor) responses of the Acm to electrical field stimulation (EFS; 20-30V, 10 s, 1 ms pulse width, every 2 min) at varying frequencies (Hz: 5, 10, 20) and to 3 mu M noradrenaline (NA) were inhibited in a concentration-dependent manner by cimetidine (mM: 1, 2, 4, 8). Inhibition of the EFS-induced responses was inversely related to the stimulation frequency. 3 Cimetidine (mM: 2, 4, 8) produced a concentration-dependent and non-parallel shift of the NA cumulative log concentration-response curves (CRCs; curves 2, 3, 4) to the right of the control curve (curve 1); at the highest concentration (8 mM) used, cimetidine produced a 4.3-fold shift of curve 4 accompanied by a decline of 9.4 +/- 1.5% in the maximal response to NA (compared to essentially no change in maximal responses for the corresponding 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 (postjunctionally mediated) responses: 8 mM cimetidine inhibited the responses to EFS by about 97%, whereas the responses to NA were inhibited by only 41 +/- 5%. Therefore, in addition to the partial blockade of postjunctional alpha-adrenoceptor sites, cimetidine can also cause a relatively marked, prejunctional inhibition of the contractile responses of the Acm to EFS. 5 Desipramine (0.5 mu M) did not affect the inhibition by cimetidine (8 rm?) of the contractile responses of the Acm to EFS, indicating that cimetidine is not dependent on its uptake into the adrenergic nerve terminals to mediate its inhibitory action. 6 Cimetidine (8 mM) decreased the peak tension by 61% and markedly reduced the sustained tone of the Acm raised by guanethidine (100 mu M); the peak contractile 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 These results provide strong evidence to show that cimetidine can markedly 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.