Modulation of the smooth muscle contractions of the rat vas deferens by TRPM8 channel agonist menthol

TRPM8 is nonselective, Ca2- permeable cationic channel, which is activated by innocuous cold and by chemical drugs imitators of cooling, menthol, icilin and cucalyptol. TRPM8 expression was detected in the smooth muscle cells of the rat vas deference with preferential localization of the TRPM8 protein to the membrane of sarcoplasmic reticulum (SR). In the present work we have studied the effects of TRPM8 channel agonist, menthol, on the contractions of the smooth muscle strips of the epididimal and prostatic portions of the rat vas deferens evoked by potassium rich (KCl) Krebs solution and by muscarinic or adrenergic agonists carbachol (CCh) or noradrenalin (Nor). Menthol (0.1-1 mmol/l) per se virtually unaffected the basal tone, but inhibited in a dose-dependent manner KCl-, CCh- and Nor-evoked contractions of both parts of the vas deference by 30-50%. Blockade of the Ca2+ -ATPase of the SR with cyclopiazonic acid (CPA, 10 micromol/l) enhanced inhibitory action of menthol on KCl-induced contractions, but slightly decreased inhibition by menthol of agonist-induced ones. Nonspecific TRPM8 blocker, capsazepine (10 micromol/l), did not eliminate, but augmented inhibitory action of menthol on all types of contractions. Our data propose that menthol inhibits contractions via two mechanisms: partial blockade of Ca2+ entry via the voltage-gated, L-type calcium channels and a decrease of the calcium storage capacity of the SR. The latter mechanism at least in part is mediated by the SR-resident TRPM8 channel, which by activation of menthol leads to the enhancement of passive leak of Ca2+ from the SR and reduction in the amount of the releasable calcium during activation of contractions.