Vasorelaxant and antihypertensive effects of formononetin through endothelium-dependent and -independent mechanisms

Abstract

Aim: To investigate the mechanisms underlying the vasorelaxant effect of formononetin, an O-methylated isoflavone, in isolated arteries, and its antihypertensive activity in vivo. Methods: Arterial rings of superior mesenteric arteries, renal arteries, cerebral basilar arteries, coronary arteries and abdominal aortas were prepared from SD rats. Isometric tension of the arterial rings was recorded using a myograph system. Arterial pressure was measured using tail-cuff method in spontaneously hypertensive rats. Results: Formononetin (1-300 μmol/L) elicited relaxation in arteries of the five regions that were pre-contracted by KCl (60 mmol/L), U46619 (1 μmol/L) or phenylephrine (10 μmol/L). The formononetin-induced relaxation was reduced by removal of endothelium or by pretreatment with L-NAME (100 μmol/L). Under conditions of endothelium denudation, formononetin (10, 30, and 100 μmol/L) inhibited the contraction induced by KCl and that induced by CaCl 2 in Ca 2+ -free depolarized medium. In the absence of extracellular Ca 2+ , formononetin (10, 30, and 100 μmol/L) depressed the constriction caused by phenylephrine (10 μmol/L), but did not inhibit the tonic contraction in response to the addition of CaCl 2 (2 mmol/L). The contraction caused by caffeine (30 mmol/L) was not inhibited by formononetin (100 μmol/L). Formononetin (10 and 100 μmol/L) reduced the change rate of Ca 2+ -fluorescence intensity in response to KCl (50 mmol/L). In spontaneously hypertensive rats, formononetin (5, 10, and 20 mg/kg) slowly lowered the systolic, diastolic and mean arterial pressure. Conclusion: Formononetin causes vasodilatation via two pathways: (1) endothelium-independent pathway, probably due to inhibition of voltage-dependent Ca 2+ channels and intracellular Ca 2+ release; and (2) endothelium-dependent pathway by releasing NO. Both the pathways may contribute to its antihypertensive effect.

Berberine inhibits enterovirus 71 replication by downregulating the MEK/ERK signaling pathway and autophagy

“…BBR has been reported to have multi pharmacological effects such as antibacterial effect [19], hypotensive effect [33], and antiviral activity [21, 22]. It has been reported that BBR could regulate signaling pathway in vitro, such as, EGFR/MEK/ERK signaling pathway [23], AMPK/mTOR signaling pathway [24].…”

Calycosin and Formononetin Induce Endothelium‐Dependent Vasodilation by the Activation of Large‐Conductance Ca2+‐Activated K+ Channels (BKCa)

“…However, here in rat mesenteric arteries we observed that calycosin-elicited relaxation is both endothelium-dependent and endothelium-independent. For formononetin, results from previous studies in rat aortic rings showed that formononetin elicited relaxation through endothelium-dependent pathway involving NO synthesis, and endothelium-independent involving iberiotoxin- (IbTX-) sensitive BK Ca channel, glibenclamide-sensitive K ATP channel, and the inhibition of VDCC [5, 6, 36]. Here in rat mesenteric arteries, we observed very similar effects of formononetin, but in our preparation the sensitivity to IbTX was only observed in endothelium-intact vessels, indicating a more important role of endothelial BK Ca channels in the mesenteric resistance arteries.…”

“…Previous studies have shown that calycosin and formononetin produced antihypertensive effects and improved endothelial and cardiovascular functions [3–6]. They have been shown to display vasoactive effects in various vascular beds [3, 5–7]. In rat aorta, calycosin induced vasodilation mainly by inhibiting voltage-dependent Ca 2+ channel (VDCC) in vascular smooth muscle [7], while formononetin caused vasodilation by releasing nitric oxide (NO) in endothelial cells, as well as by the activation of large-conductance Ca 2+ -activated K + (BK Ca ) and ATP-sensitive potassium (K ATP ) channels in aortic smooth muscle cells [6].…”

Mechanisms underlying the vasorelaxation of human internal mammary artery induced by (-)-epicatechin

“…We tested the possibility that the mechanism of action of (-)-epicatechin is linked to the inhibition of intracellular Ca 2 þ release mechanisms from the sarcoplasmic reticulum and/or the stimulation of the intracellular Ca 2 þ uptake by the sarcoplasmic reticulum via Ca 2 þ -ATPase. Because the release of intracellular Ca 2 þ is mainly regulated by inositol-trisphosphate receptor system and ryanodine receptor system (Sun et al, 2011), we have investigated the effect of (-)-epicatechin on phenylephrine-and caffeine-induced contractions in Ca 2 þ -free Krebs solution. In this condition, when extracellular Ca 2 þ is absent, contraction to phenylephrine relies on the release of intracellular Ca 2 þ stored in the sarcoplasmic reticulum via activation of the inositol-trisphosphate cascade (Ford and Broadley, 1999;Han et al, 1987).…”