RESUMEN
Tetrahydropalmatine (THP) is an active natural alkaloid isolated from Corydalis yanhusuo W.T. Wang which has been widely used for treating pain and cardiovascular disease in traditional Chinese medicine. Previous studies suggested THP have various pharmacological effects in neural and cardio tissue while the vascular reactivity of THP was not fully established. The present study found that THP relaxed rat aorta which contracted by phenylephrine (Phe), KCl, and U46619. The vascular relaxation effect of THP was partially attenuated by PI3K inhibitor wortmannin, Akt inhibitor IV, endothelial nitric oxide synthetase (eNOS) inhibitor L-NAME, guanylate cyclase inhibitors and the mechanical removal of endothelium. Also, the eNOS substrate L-arginine reversed the inhibition effect of L-NAME on THP-induced vascular relaxation. THP also induced intracellular NO production in human umbilical vein endothelial cells. However, Pre-incubation with ß-adrenergic receptor blocker propranolol, angiotensin II receptor 1 (AT1) inhibitor losartan, angiotensin II receptor 2 (AT1) inhibitor PD123319 or angiotensin converting enzyme inhibitor enalapril enhanced the vascular relaxation effect of THP. THP did not affect the angiotensin II induced vascular contraction. Cyclooxygenase-2 (COX2) inhibitor indomethacin did not affect the vascular relaxation effect of THP. Furthermore, pre-treatment THP attenuated KCl and Phe induced rat aorta contraction in standard Krebs solution. In Ca2+ free Krebs solution, THP inhibited the Ca2+ induced vascular contraction under KCl or Phe stress and reduced KCl stressed Ca2+ influx in rat vascular smooth muscle cells. THP also inhibited intracellular Ca2+ release induced vascular contraction by blocking Ryr or IP3 receptors. In addition, the voltage-dependent K+ channel (Kv) blocker 4-aminopyridine, ATP-sensitive K+ channel (KATP) blocker glibenclamide and inward rectifying K+ channel blocker BaCl2 attenuated THP induced vascular relaxation regardless of the Ca2+-activated K+ channel (KCa) blocker tetraethylammonium. Thus, we could conclude that THP relaxed rat aorta in an endothelium-dependent and independent manner. The underlying mechanism of THP relaxing rat aorta involved PI3K/Akt/eNOS/NO/cGMP signaling path-way, Ca2+ channels and K+ channels rather than COX2, ß-adrenergic receptor and renin-angiotensin system (RAS). These findings indicated that THP might be a potent treatment of diseases with vascular dysfunction like hypertension.
RESUMEN
OBJECTIVE: To evaluate the efficacy and safety of Xinmailong Injection (XI) in treatment of chronic heart failure (CHF) patients with qi-yang deficiency and blood stasis resistance syndrome (QY-DBSRS). METHODS: Totally 238 CHF patients with QYDBSRS were assigned to the treatment group (118 cases) and the control group (120 cases) by randomized, double-blind, placebo parallel controlled method. Patients in the treatment group received routine therapy and XI (100 mg/2 mL, by dripping at 5 mg/kg, twice per day for 5 consecutive days), while those in the control group received routine therapy and XI mimetic agent (100 mg/2 mL, by dripping at 5 mg/kg, twice per day for 5 consecutive days). The heart function classification of New York Heart Association (NYHA), 6-min walking distance, left ventricular ejection fraction (LVEF), scores for Chinese medical symptoms were observed before and after treatment, and safety assessed. RESULTS: Totally 235 patients actually entered full analysis set (FAS), including 120 cases in the control group and 115 cases in the treatment group. The total effective rate of heart function, 6-min walking distance and increased post-pre-treatment distance in the experimental group were superior to those of the control group with statistical difference (all P < 0.05). Compared with the control group, increased value of post-pre-treatment LVEF, the total effective rate of Chinese medical syndrome efficacy, scores for Chinese medical symptoms and decreased post-pre-treatment value of Chinese medical syndrome scores were obviously improved (all P < 0.05). There was no significant difference in the incidence of adverse events between the two groups (P > 0.05). CONCLUSIONS: XI could improve the heart function of CHF patients, improve Chinese medical symptoms, elevate exercise tolerance, and improve LVEF. It had no obvious toxic and side effects.