Testosterone-induced relaxation involves L-type and store-operated Ca2+ channels blockade, and PGE2 in guinea pig airway smooth muscle

Abstract

In vascular smooth muscle, it has been described that testosterone (TES) produces relaxation by blocking L-type Ca(2+) channels. Recently, we found that L-type Ca(2+) and store-operated Ca(2+) (SOC) channels are the main membranal structures that provide extracellular Ca(2+) for carbachol (CCh)-induced contraction in airway smooth muscle (ASM). We studied the possible interactions between L-type and SOC channels in TES-induced relaxation in guinea pig ASM. TES (10, 32, 100, and 178 μM) induced a complete relaxation of CCh-precontracted tracheal smooth muscle, and indomethacin partially inhibited this response. In single myocytes, the KCl-induced intracellular Ca(2+) increase ([Ca(2+)]i) was decreased by 32 and completely blocked by 100 nM TES. This androgen (32 and 100 μM) significantly diminished (~25 and 49 %, respectively) the capacitative Ca(2+) entry. Myocytes stimulated with CCh produced a transient Ca(2+) peak followed by a sustained plateau. D-600 was added during the plateau phase, and a partial diminution (~35 %) was observed. A greater decrease (~78 %) was seen when 2-aminoethyl diphenylborinate (2-APB, SOC antagonist) was used. The combination of both drugs completely abolished the Ca(2+) plateau induced by CCh. TES (100 μM) also completely abolished the CCh-induced Ca(2+) plateau. Indomethacin significantly diminished this effect of TES. PGE2 and butaprost proportionally decreased the Ca(2+) plateau as indomethacin blocked it. Sarcoplasmic reticulum refilling was partially, dependently, and significantly diminished by TES. We concluded that TES-induced relaxation involves blockade of L-type Ca(2+) channels at nanomolar and SOC channels at micromolar concentration and PGE2 seems to be also involved in this phenomenon.

Ca2+ Dynamics and Ca2+ Sensitization in the Regulation of Airway Smooth Muscle Tone

“…Therefore, Ca 2+ sensitization by RhoA/Rho-kinase processes [1,173,174,175] and Ca 2+ dynamics by ion channels including VDC and SOC [6,11,12,176] may be a therapeutic target for obstructive pulmonary diseases including asthma.…”

Nuciferine Relaxes Tracheal Rings via the Blockade of VDLCC and NSCC Channels

“…ACh, a muscarinic receptor agonist, can activate both VDLCCs and NSCCs, which induce Ca 2+ influx and cause ASM contraction [19][20][21][22]. Our results demonstrated that nuciferine also relaxed ACh-contracted ASMs in a dose-dependent manner, which suggested that nuciferine could also inhibit all NSCCs except VDLCCs.…”

“…ACh elicited a contraction in TRs by activating the muscarinic receptor and its downstream signaling pathways [19][20][21][22], which differ from the pathway activated by high K + . To further elucidate the mechanisms of nuciferine-induced relaxation, we explored the effects of nuciferine on ACh-contracted TRs.…”

“…VDLCCs play a crucial role in regulating the tone of ASMs [18][19][20]. Therefore, to explore the mechanism of nuciferine-induced relaxation in TRs, we studied the effects of nuciferine on VDLCC currents in ASMCs.…”

Cellular Na+ handling mechanisms involved in airway smooth muscle contraction (Review)

“…After its emptying, the SR Ca 2+ refilling seems to involve increases in Na + concentrations in sites nearby. This refilling is also related to smooth muscle sustained contraction (12–18). Recent findings in our laboratory, demonstrate that Na + permeates through the L-type voltage dependent Ca 2+ channels when ASM is stimulated with carbachol (19).…”