Antihypertensive Potential And Mechanism Of Effects Of Honokiol On SHRs

BACKGROUND AND AIM:Honokiol,is the major phenolic compound purified from the medical plant Cortex magnoliae officinalis,which has activity of calcium channel blocking,anti-inflammatory effects and antioxidative effects.The main aim of this paper is to probe the antihypertensive potential and mechanism of effects of honokiol on rats.Isolated thoracic aorta with or without the endothelium of Sprague-Dawley rat were used to verify the effect of honokiol on aortic rings.And the mechanism of the effects of honokiol involved of calcium channel,NO and PGI₂ were investigated.In Langendorff isolated hearts model,the direct effects of honokiol on cardiac function in isolated rat hearts were observed.The direct effects of honokiol on calcium transients in cardiomyocytes from neonate rats were investigated to probe the mechanism of the negative inotropic and chronotropic effects of honokiol on heart.To study the effects of chronic treatment with 200 and 400 mg/kg honokiol oral administration on spontaneously hypertensive rats,the effects of honokiol were investigated by determination of the level of blood pressure,vascular reactivity,oxidative parameters,the level of inflammation and histological change of aorta and coronary artery.METHODS:(1) Isometric tension recordings were applied to evaluate the effects of honokiol on resting,phenylephrine(PE)-preconstricting or KCl-preconstricting aortic rings with or without the endothelium.Using the corresponding agents such as L-N(ω)-nitro-arginine methyl ester(L-NAME), indomethacin and nifedipine,the underlying mechanism of vasorelaxation-induced honokiol was determined.(2) Langendorff model were established from adult male rats of and were subjected to continuous perfusion of K-H solution,honokiol,K-H solution in turn.Left ventricular developed pressure(LVDP),heart rate(HR),the maximal rate of left ventricular pressure rise and fall(+/-dp/dt max),and coronary flow rate(CFR) were measured to observe the direct effect of honokiol on isolated rat heart.(3) Recording the calcium transients of spontaneous contraction in primary culture cardiomyocytes from neonate rats.The effects of 1,3μmol/L honokiol on calcium transients were observed.And the effects of 3μmol/L honokiol on the potentiation of calcium transients induced by isoproterenol were observed. (4) The spontaneously hypertensive rats were used to investigate the effects of long-term honokiol administration on hypertension.Systolic blood pressure, heart rate and body weight were observed through 7 weeks drug administration. After the last drug administration,the vascular reactivity to acetylcholine and sodium nitroprusside were observed.The plasma level of NO₂^-/NO₃^- and TNF-αand the level of malondialdehyde in SHRs were tested.And histological change of aorta and hearts were observed too.RESULTS:(1) Honokiol exhibited negligible vasomotor actions on aortic rings with or without endothelium at resting tension.Honokiol had dose-dependent relaxation on endothelium-denuded rings stimulated by KCl or PE.Honokiol caused two-phases(fast in 2min,slow in 15min) relaxation on endothelium-intact rings stimulated by PE.These two relaxations were concentration-dependent.The fast relaxation was completely antagonized by L-NAME,but not by indomethacin.(2) The LVDP,CF,+/-dp/dt max and CFR were markedly decreased irreversibly while perfusing the isolated heart with honokiol.(3) The baseline and the peak height/baseline(%) were markedly decreased,the time to peak 50%and time to baseline 50%were markedly prolonged after honokiol were added in solution directly.And 3μmol/L honokiol inhibited the potentiation of calcium transients induced by isoproterenol significantly.(4) In all groups,HR and BW were no different compared with vehicle-treated group(P＞0.05).Long-term administration with honokiol (400mg/kg) decreased systolic blood pressure significantly(P＜0.05).In SHRs, honokiol enhanced the aortic relaxation to acetylcholine after 49 d treatment (P＜0.05),but has no significant effects on the relaxation to sodium nitroprusside(P＞0.05).Oral administration of honokiol significantly increased the plasma level of NO₂^-/NO₃^-,but decreased the plasma level of TNF-αand the level of MDA in liver compare to the control vehicle(P＜0.05). In addition,honokiol showed significant reduction in the elastin bands and media thickness in the rat aorta(P＜0.05),but has no significant effects on coronary arterial wall-thickness(P＞0.05).CONCLUSION:Honokiol has relaxing effects on vascular smooth muscle.The mechanisms involved voltage dependent calcium channel(VDCC),receptor operating calcium channel(ROCC) and NO bioavaibility.Honokiol possesses negative inotropic and chronotropic effects in hearts isolated from rats. Decreasing the intracellular calcium concentration is the one of the mechanism of the negative inotropic and chronotropic effects of honokiol on heart of rats.There results suggest that chronic treatment with honokiol experts an antihypertensive effect in SHRs,and its vscorelaxant action,and anti-oxidant, anti-inflammatory properties may contribute to reduce the elevated blood pressure.