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 microM 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 (nM: 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%.(ABSTRACT TRUNCATED AT 250 WORDS)
Gwee
M C
MC
Department of Pharmacology, Faculty of Medicine, National University of Singapore, Kent Ridge.
Cheah
L S
LS
Shoon
M L
ML
D000818:Animals; D002927:Cimetidine / Q000494:pharmacology*; D003891:Desipramine / Q000494:pharmacology; D004558:Electric Stimulation; D006145:Guanethidine / Q000494:pharmacology; D066298:In Vitro Techniques; D008297:Male; D009119:Muscle Contraction / Q000187:drug effects; D009132:Muscles / Q000187:drug effects / Q000294:innervation*; D009469:Neuromuscular Junction / Q000187:drug effects*; D011899:Ranitidine / Q000494:pharmacology; D051381:Rats; D017207:Rats, Sprague-Dawley; D013564:Sympathetic Nervous System / Q000187:drug effects*; D009435:Synaptic Transmission / Q000187:drug effects*; D014439:Tyramine / Q000494:pharmacology
D002927:Cimetidine; D011899:Ranitidine; D003891:Desipramine; D014439:Tyramine; D006145:Guanethidine