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Variable potency of nitrergic‐nitrovasodilator relaxations of the mouse anococcygeus against different forms of induced tone
Author(s) -
Gibson A.,
McFadzean I.,
Tucker J.F.,
Wayman C.
Publication year - 1994
Publication title -
british journal of pharmacology
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 2.432
H-Index - 211
eISSN - 1476-5381
pISSN - 0007-1188
DOI - 10.1111/j.1476-5381.1994.tb17165.x
Subject(s) - carbachol , chemistry , potency , nifedipine , muscarinic acetylcholine receptor , endocrinology , thromboxane a2 , medicine , thromboxane , receptor , calcium , biochemistry , in vitro , platelet , organic chemistry
1 U46619 (thromboxane A 2 receptors; 0.002‐1 μ m ), carbachol (muscarinic M 3 receptors; 0.1–100μ m ), cyclopiazonic acid (CPA; Ca 2+ ‐ATPase inhibitor; 0.1–30 μ m ) and K + (5‐100mM) produced concentration‐dependent contractions of the mouse isolated anococcygeus muscle. Equi‐effective, sub‐maximal concentrations of each agent were used in further experiments (40 n m U46619; 5 μ m carbachol; 5μ m CPA; 70 m m K + ). 2 Nifedipine (1 μ m ) totally abolished contractile responses to K + ; those to U46619, carbachol and CPA were reduced by only 20–30% in the presence of nifedipine, but were greatly reduced (>90%) by a combination of nifedipine and SKF 96365 (0.1–40 μ m ). 3 In Ca 2+ ‐free medium, contractions to K + and CPA were abolished. Small residual responses remained to both carbachol and U46619; those to carbachol were transient, could not be repeated in the continued absence of Ca 2+ and were prevented by pre‐incubation with CPA, but unaffected by SKF 96365; those to U46619 were sustained, could be repeated in the absence of Ca 2+ , and were resistant to CPA and SKF 96365. 4 Tone induced by all four agents could be relaxed by sodium nitroprusside (SNP), but with a clear order of potency. SNP (pIC 40 ) was most effective against U46619 (7.92), less so against carbachol (6.80) and CPA (6.68), and least potent against K + (5.94). A similar order of potency was observed with 8Br‐cyclic GMP (50 μ m ) and nitrergic field stimulation (1–20 Hz). 5 The relaxant potency of SNP was similar in normal Krebs solution and in high K + (70 μ m ) Krebs containing 1 μ m nifedipine. 6 Inclusion of SNP (0.01‐1 μ m ) or 8Br‐cyclic GMP (50 μ m ) in the Ca 2+ ‐free medium inhibited the transient residual response to carbachol. Inclusion of similar concentrations of SNP or 8Br‐cyclic GMP, during Ca 2+ re‐loading, increased the subsequent residual contraction to carbachol in Ca 2+ ‐free medium. 7 At higher concentrations, SNP (0.1–10 μ m ) produced a partial relaxation of the sustained contraction to U46619 in Ca 2+ ‐free medium. 8 Thus, the relaxant potency of the nitrergic stimuli was dependent on the agent and mechanism used to induce tone in the preparation. Examination of the contractile/relaxant interactions suggests that altered Ca 2+ sequestration and inhibition of contractile protein function may underlie nitrergic relaxations of this tissue.