Activation of Ca_v1.2 and BK_Ca is involved in the downregulation of caffeine-induced contraction in mice mesenteric arteries.

AIMS:Caffeine is a methylxanthine with multiple actions in vascular smooth muscle cells (VSMCs), including the increase in the intracellular Ca²⁺ (_iCa²⁺) concentration by the activation of ryanodine receptors (RyRs). The present study aimed at investigating the participation of Ca²⁺-influx through different Ca²⁺-channels on the transient contraction (TC) induced by caffeine in mice mesenteric arteries. MAIN METHODS:Second-order of mesenteric arteries was isolated from male Swiss mice. Vessels without functional endothelium were stimulated with caffeine (10 mM). The caffeine-induced TC was evaluated after the incubation of artery rings for 30 min with the following drugs: nifedipine (10 μM), a Ca_v1.2 blocker; 2-aminoethoxydiphenyl borate (2-APB; 10 μM) and ruthenium red (RuR; 10 μM), transient receptor potential (TRPs) channels blockers; capsazepine (10 μM) and HC067047 (10 μM), TRPV1 and TRPV4 antagonists, respectively; paxilline (1 μM), a selective BK_Ca blocker; and SKF-96365 (30 μM), an Orai blocker. Ca²⁺-fluorescence measurements were also performed on the investigated arteries. KEY FINDINGS:The TC induced by caffeine was partially dependent on Ca²⁺-influx. However, the blockage of Ca_v1.2 increased the TC while reduced the _iCa²⁺ signal. Similar results were observed after the blockage of TRPs or BK_Ca. Therefore, caffeine promoted Ca²⁺-influx via TRPs and Ca_v1.2, and hyperpolarization through the activation of BK_Ca, inducing negative feedback of TC. SIGNIFICANCE:Our results indicate an alternative mechanism for the control of VSMCs contraction in resistance arteries. The evidence of the negative feedback of contraction via TRP-Ca_v1.2-BK_Ca provides a new perspective for understanding the mechanism involved in the vascular responses triggered by caffeine.

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