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Schwarzinicine A inhibits transient receptor potential canonical channels and exhibits overt vasorelaxation effects.

ABSTRACT: This study investigated the vasorelaxant effects of schwarzinicine A, an alkaloid recently reported from Ficus schwarzii Koord. Regulation of calcium homeostasis in vascular smooth muscle cells (VSMC) is viewed as one of the main mechanisms for controlling blood pressure. L-type voltage-gated calcium channel (VGCC) blockers are commonly used for controlling hypertension. Recently, the transient receptor potential canonical (TRPC) channels were found in blood vessels of different animal species with evidence of their roles in the regulation of vascular contractility. In this study, we studied the mechanism of actions of schwarzinicine A focusing on its regulation of L-type VGCC and TRPC channels. Schwarzinicine A exhibited the highest vasorelaxant effect (123.1%) compared to other calcium channel blockers. It also overtly attenuated calcium-induced contractions of the rat isolated aortae in a calcium-free environment showing its mechanism to inhibit calcium influx. Fluorometric intracellular calcium recordings confirmed its inhibition of hTRPC3-, hTRPC4-, hTRPC5- and hTRPC6-mediated calcium influx into HEK cells with IC₅₀ values of 3, 17, 19 and 7 μM, respectively. The evidence gathered in this study suggests that schwarzinicine A blocks multiple TRPC channels and L-type VGCC to exert a significant vascular relaxation response.

SUBMITTER: Mak YY

PROVIDER: S-EPMC9544403 | biostudies-literature | 2022 Jul

REPOSITORIES: biostudies-literature

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Schwarzinicine A inhibits transient receptor potential canonical channels and exhibits overt vasorelaxation effects.

Mak Yin-Ying YY Loong Bi-Juin BJ Millns Paul P Bauer Claudia C CC Bon Robin S RS Mbaki Yvonne Y Lee Fong-Kai FK Lim Kuan-Hon KH Kong Cin C Then Sue-Mian SM Ting Kang-Nee KN

Phytotherapy research : PTR 20220510 7

This study investigated the vasorelaxant effects of schwarzinicine A, an alkaloid recently reported from Ficus schwarzii Koord. Regulation of calcium homeostasis in vascular smooth muscle cells (VSMC) is viewed as one of the main mechanisms for controlling blood pressure. L-type voltage-gated calcium channel (VGCC) blockers are commonly used for controlling hypertension. Recently, the transient receptor potential canonical (TRPC) channels were found in blood vessels of different animal species w ...[more]

PMID: 35537691

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Project description:Circulating hormones stimulate the phospholipase Cβ (PLC)/Ca(2+) influx pathway to regulate numerous cell functions, including vascular tone. It was proposed previously that Ca(2+)-independent phospholipase A(2) (iPLA(2))-dependent store-operated Ca(2+) influx channels mediate hormone-induced contractions in isolated arteries, because bromoenol lactone (BEL), a potent irreversible inhibitor of iPLA(2), inhibited such contractions. However, the effects of BEL on other channels implicated in mediating hormone-induced vessel contractions, specifically voltage-gated Ca(2+) (Ca(V)1.2) and transient receptor potential canonical (TRPC) channels, have not been defined clearly. Using isometric tension measurements, we found that thapsigargin-induced contractions were ∼34% of those evoked by phenylephrine or KCl. BEL completely inhibited not only thapsigargin- but also phenylephrine- and KCl-induced ring contractions, suggesting that Ca(V)1.2 and receptor-operated TRPC channels also may be sensitive to BEL. Therefore, we investigated the effects of BEL on heterologously expressed Ca(V)1.2 and TRPC channels in human embryonic kidney cells, a model system that allows probing of individual protein function without interference from other signaling elements of native cells. We found that low micromolar concentrations of BEL inhibited Ca(V)1.2, TRPC5, TRPC6, and heteromeric TRPC1-TRPC5 channels in an iPLA(2)-independent manner. BEL also attenuated PLC activity, suggesting that the compound may inhibit TRPC channel activity in part by interfering with an initial PLC-dependent step required for TRPC channel activation. Conversely, BEL did not affect endogenous voltage-gated K(+) channels in human embryonic kidney cells. Our findings support the hypothesis that iPLA(2)-dependent store-operated Ca(2+) influx channels and iPLA(2)-independent hormone-operated TRPC channels can serve as smooth muscle depolarization triggers to activate Ca(V)1.2 channels and to regulate vascular tone.

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Schwarzinicine A inhibits transient receptor potential canonical channels and exhibits overt vasorelaxation effects.

Publications

Schwarzinicine A inhibits transient receptor potential canonical channels and exhibits overt vasorelaxation effects.

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