| Autor: |
Grimm, Ulrike, Fuder, Hermann, Moser, Ulrich, Bäumert, Hans, Mutschler, Ernst, Lambrecht, Günter |
| Zdroj: |
Naunyn-Schmiedeberg's Archives of Pharmacology; 1994, Vol. 349 Issue 1, p1-10, 10p |
| Abstrakt: |
The aim of the present study was to characterize the prejunctional modulation of evoked release of endogenous noradrenaline in rabbit vas deferens by the use of muscarinic receptor agonists and subtype-prefering antagonists. Vasa deferentia of the rabbit were stimulated electrically by trains of 120 pulses delivered at 4 Hz or trains of 30 pulses at 1 Hz. The inhibition by muscarinic agonists of the stimulation-evoked overflow of endogenous noradrenaline in the absence and presence of antagonists was used to determine affinity constants for antagonists. These values were compared with those observed at putative M receptors inhibiting neurogenic twitch contractions in the rabbit vas deferens and with affinity data obtained at M(m)-M(m) receptors in functional studies and binding experiments. The evoked overflow of noradrenaline from sympathetic nerves was enhanced by the Al receptor antagonist 8-cyclopentyl-1,3-dipropylxanthine (DPCPX), the P purinoceptor antagonist pyridoxalphosphate-6-azophenyl-2′,4′-disulfonic acid (PPADS) and indomethacin, indicating a tonic inhibition by endogenous A and P purinoceptor agonists and prostanoids, respectively. The stimulation-evoked overflow at 4 Hz was not sensitive to inhibition by the muscarinic agonists methacholine or 4-(4-chlorophenylcarbamoyloxy)-2-butynyltrimethylammonium iodide (4-Cl-McN-A-343). In contrast, at a stimulation frequency of 1 Hz the evoked noradrenaline release was decreased by muscarinic agonists (EC): arecaidine propargyl ester (0.062 μM), 4-Cl-McN-A-343 (0.32 μM), 4-(4-fluorophenylcarbamoyloxy)-2-butynylN-methyl-pyrrolidinium tosylate (4-F-PyMcN; 0.48 μM) and methacholine (0.86 μM). The affinity constants of most of the muscarinic antagonists [atropine: pK = 9.47; (R)-trihexyphenidyl: pK = 9.18; pirenzepine: pA = 7.68; methoctramine: pK = 6.90] are consistent with estimates of these antagonists at M(m) receptors determined in various functional and binding studies. The high antagonistic potency of pirenzepine and (R)-trihexyphenidyl and the agonistic activity of 4-F-PyMcN argue for the involvement of M, and against that of M and M receptors in the inhibition of evoked noradrenaline overflow. However, the high apparent pK of 8.30 for himbacine is not in accordance with an M receptor; by contrast, it would be compatible with the presence of M or M receptors. The potencies of the tested muscarinic agonists and antagonists largely agree with those obtained for the inhibition of neurogenic twitch responses (0.05 Hz) in the rabbit vas deferens. In conclusion, the rabbit vas deferens is endowed with prejunctional muscarinic receptors mediating heteroinhibition of noradrenaline release that are probably of the same subtype as the putative M receptors inhibiting neurogenic twitch contractions, and are not of the M, M or m subtype. [ABSTRACT FROM AUTHOR] |
| Databáze: |
Complementary Index |
| Externí odkaz: |
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