Pharmacological Actions of Sodium Ferulate in Cardiovascular System

Transcription

1 Cardiovascular Drug Reviews Vol. 23, No. 2, pp Neva Press, Branford, Connecticut Pharmacological Actions of Sodium Ferulate in Cardiovascular System Bao-Hua Wang, Jing-Ping Ou-Yang Department of Pathophysiology, School of Medicine, Wuhan University, Wuhan, P. R. China Keywords: Antioxidants Antithrombotics Atherosclerosis Cardiovascular system Chinese traditional medicine Coronary heart disease Sodium ferulate Thrombosis. ABSTRACT Sodium ferulate (SF) or 3-methoxy-4-hydroxy-cinamate sodium is an active principle from Angelica sinensis, Cimicifuga heracleifolia, Lignsticum chuangxiong, and other plants. It has been used in traditional Chinese medicine and is approved by State Drugs Administration of China as a drug for treatment of cardiovascular and cerebrovascular diseases. SF has antithrombotic, platelet aggregation inhibitory and antioxidant activities in animals and humans. For several decades SF has been widely used in China to treat cardiovascular and cerebrovascular diseases and to prevent thrombosis. Exciting clinical results have been obtained with SF in coronary heart disease, atherosclerosis, pulmonary heart disease and thrombosis. Its safety and efficacy have been demonstrated in clinical practice. This article briefly reviews basic pharmacology, pharmacokinetics, toxicology and clinical pharmacology of SF. The in vitro and in vivo data support the view that SF is a useful drug for the treatment of cardiovascular diseases. INTRODUCTION The chemical name of sodium ferulate (SF) is 3-methoxy-4-hydroxy-cinnamate sodium; it has a molecular formula of C 10 H 9 O 4 Na. The chemical structure of SF is shown in Fig. 1. SF is a Na salt of ferulic acid, which is an effective component of Chinese me- Address correspondence and reprint requests to: Bao-Hua Wang, PhD, Dept. of Pathophysiology, School of Medicine, Wuhan University, Dong-Hu Road #115, Wuhan , P. R. China. Tel: +86 (27) ; Fax: +86 (27) ; wbaohua@hotmail.com 161

2 162 B.-H. WANG AND J.-P. OU-YANG O O HC 3 O HO FIG. 1. Chemical structure of sodium ferulate (SF). Na dicinal herbs, such as Angelica sinensis, Cimicifuga heracleifolia, and Lignsticum chuangxiong. Ferulic acid is not soluble in water, while SF is stable, water soluble, and can be easily synthesized. SF is, therefore, widely used in research and clinical medicine, as well as in food and cosmetics. In vitro and in vivo studies revealed that SF possesses beneficial pharmacological effects such as inhibition of the production of inflammatory mediators, inhibition of platelet aggregation and thrombus formation, prevention of oxidation, decrease of free radicals production and acceleration of their clearance, decrease of serum lipids and inhibition of oxidation of low-density lipoproteins (LDLs) (5,13,16,17,28,29, 41,56,62). In China, SF has been used to treat patients with cardiovascular and cerebrovascular diseases for decades. Clinical studies demonstrated significant protective properties of SF in cardiovascular and cerebrovascular ischemic diseases. SF has low toxicity and is safe to use. This article briefly reviews the basic and clinical pharmacology of SF as well as in vitro and in vivo data supporting the view that SF is a cardiovascular protective agent. PHARMACOLOGY Antithrombotic and Platelet Aggregation Inhibitory Activities Platelet adhesion, aggregation and thrombosis are affected by the metabolic products of arachidonic acid (AA): thromboxane A 2 (TXA 2 ) and prostaglandin I 2 (PGI 2 ). TXA 2 is a platelet activator, while PGI 2 is a platelet inhibitor. The TXA 2 PGI 2 balance determines the aggregation of platelet and the development of thrombus. In vivo and in vitro studies had shown that SF inhibits platelet aggregation and has antithrombotic activity. At 0.3 g kg i.v. SF inhibited experimental thrombosis in rat carotidjugular extracorporeal shunt model (46). In vitro SF (0.4 mg ml) inhibited platelet aggregation induced by adenosine diphosphate (ADP) or collagen (55). At 1 mg ml SF inhibited thrombin-induced platelet aggregation and release of [ 3 H]5-HT from labelled platelets (55). In combination with aspirin SF synergistically inhibited rat platelet aggregation and release of [ 3 H]5-HT(47). In rats with experimental hypoxic pulmonary hypertension SF, 0.2 g kg (0.5 ml) s.c., inhibited platelet aggregation (36).

3 SODIUM FERULATE 163 The mechanism of SF action appears to be mediated by inhibition of cyclooxygenase and TXA 2 synthase. Inhibition TXA 2 production leads to a change in TXA 2 PGI 2 balance (38,54). By intragastric administration to rats SF (0.6 g kg) inhibited platelet aggregation induced by collagen and reduced the activity of TXA 2 (48). In rabbit platelets SF ( mmol L) inhibited generation of TXB 2 from [ 14 C]arachidonic acid in a dose-dependent manner (49). At mmol L SF suppressed generation of 6-keto PGF 1á in rabbit aorta (50). The antithrombotic activity of SF was associated with inhibition of platelet aggregation, reduction in the concentration of plasma fibrinogen, and a decrease in blood viscosity (17). Furthermore, SF has been reported to antagonize contractions of rabbit aortic strips and to increase perfusion flow in isolated perfused guinea pig hearts (17). Antioxidant Activity The hydroxyphenil moiety of SF molecule is a functional group that is likely to facilitate the clearance of free oxygen radicals and is responsible for the antioxidant activity of SF. In vitro SF inhibited lipid peroxide malondialdehyde (MDA) production from the platelets of rats (54), inhibited haemolysis induced by MDA and hydroxyl radical (OH ) (26), and in erythrocyte membranes it inhibited lipid peroxidation induced by hydrogen peroxide (H 2 O 2 ) and superoxide anions ( O 2 ) (26). In biomembranes SF inhibited lipid peroxidation reaction induced by hydroxyl radical; its effective concentrations were 39.4 mmol L for human red blood cell membranes, 1.4 mmol L for human platelet membranes and 2.8 mmol L for rat liver mitochondrial membranes (23). Furthermore, pretreatment with 5 mmol L SF for 60 minutes markedly prevented H 2 O 2 -induced apoptosis of human lymphocytes in vitro (24). SF 30 ìmol L effectively scavenged oxygen free radicals produced by phorbol myristate acetate (PMA)-stimulated polymorphonuclear leukocytes (PMN), scavenged O 2 and OH produced by cell-free oxygen free radical generating systems of xanthine-xanthine oxidase system and Fenton s reaction. SF, 30 ìmol L, prominently inhibited the chemiluminescence response of PMA-stimulated PMN. These findings confirmed that SF is a direct scavenger of oxygen free radicals (14). SF would, therefore, be expected to not only protect membrane lipids from the effects of free radicals, but also directly scavenge oxygen free radicals. These actions determine the antioxidant effects of SF on lipid peroxidation. In the isolated perfused hearts of rat, SF (1.69 mmol L) significantly decreased the production of MDA, increased the activity of myocardium superoxide dismutase (SOD) and reduced ultrastructural damage of myocardial cell during oxygen paradox (44). In ethanol, carbon tetrachloride-, paracetamol-, or prednisolone-induced liver toxicity in mice, SF, 0.1 g kg intragastrically, daily for 10 days inhibited the rise of liver lipid peroxides MDA content and alleviated liver lesions by stabilizing glutathione (GSH) and related enzymes levels (32,33,41,42). In glycerol-induced renal oxidative injury in mice SF, at 0.2 g kg i.p., reversed the increase of renal MDA content and the decrease of GSH content, glutathione peroxidase (GSH-Px), glutathione S-transferase (GST), catalase (Cat), and SOD activities induced by glycerol injection, and improved renal histology (16). In vitro SF ( mmol L) prevented, in a concentration-dependent manner,

4 164 B.-H. WANG AND J.-P. OU-YANG oxygen free radicals-induced injury of rat liver mitochondria (18). SF also exerted significant protective effects in acute oxygen intoxication of rabbits (9). Effects on Serum Lipids Biochemical and pharmacological studies indicated that SF dose-dependently reduces rat liver cholesterol synthesis by inhibiting activity of liver mevalonate-5-pyrophosphate dehydrogenase, leading to a decrease in serum lipid levels (15,25). Our group also found that SF reduces serum triglycerides (TG) in hyperlipidemic rabbits (29). Cardiovascular Activity SF has a clear protective effect in experimental myocardial ischemia. In rabbits SF reduced the area of experimental myocardial infarction by 41% and decreased the oxygen consumption of guinea pig myocardial homogenates (45). At 0.3 g kg SF significantly decreased myocardial oxygen consumption in mice. In rabbits at 0.4 g kg i.v. SF altered pituitrin-induced ischemic changes in the electrocardiogram (ECG) (43). In primary cultured myocardial cells from rats, SF preconditioning (1.68, 0.42, mmol L for 20 min) was effective in protecting cells from anoxia reoxygenation and exerted significant cardioprotective effects (8). SF has also a protective effect in myocardial ischemia reperfusion injury of rats. In isolated rat hearts perfused according to Langendorff, SF (5 mg L) inhibited production of MDA and thromboxane B 2 (TXB 2 ), reduced the release of lactate dehydrogenase (LDH), accelerated the production of 6-keto-PGF 1á and alleviated myocardial edema (6). In the rat myocardial ischemia reperfusion injury model produced by the occlusion of the left coronary artery and subsequent release, SF, 0.8 g kg by daily intragastric pretreatment for 15 days, significantly improved myocardial SOD activity, reduced MDA content and cardiac creatine phosphokinase (CPK) release. It also protected myocardial ultrastructure from damage by the oxygen free radicals (60). The mechanism of SF-induced protection from myocardial ischemia reperfusion injury appears to involve inhibition of arachidonic acid (AA) metabolism, inhibition of the oxygen free radicals and of subsequent lipid peroxidation. Recently, SF was found to act as a novel non-peptide endothelin antagonist and to prevent the binding of ET-1 to its receptor (31). SF, mg kg i.p., protected mice from acute death induced by ET-1 in a dose-dependent manner. In vitro, at mmol L SF antagonized ET-1-induced vasoconstriction of rat isolated aortic rings. At mmol L SF inhibited the proliferation of rabbit vascular smooth muscle cells (VSMC) induced by ET-1 in vitro. By intravenous injection SF reduced pressure effects of ET-1 in rats. SF exerts its protective effect on ischemia perfusion injury by antagonising the effect of ET-1 and by accelerating the production of nitric oxide (NO). In rabbit model of ischemia perfusion injury, SF markedly decreased the plasma levels of ET-1 and increased the plasma levels of NO (21). Furthermore, SF has an anti-atherogenetic effect in animal models. In vitro SF (40, 80, 120 mg L) inhibited oxidation of LDL and oxidized LDL-induced proliferation of smooth

5 SODIUM FERULATE 165 muscle cells (SMCs) from rabbit aorta (56,28). In vivo, by intragastric administration to rabbits or quails, SF, 0.2 g day for 9 to 10 weeks, accelerated NO production from atherosclerotic arterial wall (7,29). Antiarrhythmic Effects The antiarrhythmic effects of SF have been demonstrated in experimental animal models of arrhythmia, but not yet in clinical studies. In isolated ventricular preparations SF increased the action potential duration (APD) and the effective refractory period (ERP), but had no effect on the amplitude of monophasic action potential (MAPA). When MAP technique was used in vivo, SF produced similar electrophysiological effects on rabbit s right ventricular myocardium. Like with amiodarone, a typical class III antiarrhythmic agent, these effects were not frequency-dependent. The group of Zeng (19,64,65) studied the antiarrhythmic effects of SF in several animal models of arrhythmias. In guinea pig model of ouabain-induced arrhythmia, SF, 0.6 g kg i.v. bolus, increased the threshold dose of oubain causing ventricular premature contractions (VPC), ventricular tachycardia (VT), ventricular fibrillation (VF), and cardiac arrest (CA). It also delayed the onset time for VPC, VT, VF and CA. In the rabbit model of epinephrine-induced arrhythmias, pretreatment with SF prevented epinephrine-induced shortening of monophasic action potential duration (MAPD). The number of episodes, latency and duration of ventricular arrhythmia as well as the occurrence and duration of ischemic changes in ECG were significantly reduced by SF. In guinea pig model of epinephrine-induced arrhythmias SF, 0.6 g kg by i.v. bolus, delayed the onset time, shortened the duration of arrhythmias and decreased animal mortality. In the rat model of myocardial ischemia-induced arrhythmias, SF, 0.6 g kg by i.v. bolus, delayed the onset time of VPC, shortened the duration of VT and decreased the occurrence of VF and the animal mortality. At the same dose SF had no effect on aconitine-induced arrhythmias in either guinea pigs or rats. The mechanism of antiarrhythmic effect of SF appears to be related to the blockade of potassium channels and of â-adrenoceptors. The results suggested that SF might conceivably be clinically useful as an antiarrhythmic drug. PHARMACOKINETICS In rats, after single i.v. dose of SF (0.04 g kg) the decline of SF blood levels was consistent with one-compartment open model. The elimination half-life was 9.86 min (2). After intragastric administration of SF (0.1 g kg) to rat, gastrointestinal elimination halflife was 10 min. Thirty minutes later, gastrointestinal recovery rate was only 11.69%. These findings indicated that SF was rapidly and almost completely absorbed. SF was excreted mainly by the kidneys and did not accumulate. The in vivo metabolism of SF was rapid. SF passes blood-brain barrier, but in low concentrations (1). After intragastric administration of SF (0.025 g kg) to rabbits, blood levels also followed one-compartment open model. The absorption half-life was 2.16 min, the elimination half-life min and the time to peak concentration was 7.1 min (20).

6 166 B.-H. WANG AND J.-P. OU-YANG TOXICOLOGY The acute oral LD 50 of SF in mice was 3.2 g kg. In subchronic toxicity study in rats SF, 0.6 g kg day for 3 months by intragastric administration, produced no hematological changes. Pathophysiological analysis revealed also no SF-induced changes in the main organs. CLINICAL USE As an effective component of Chinese traditional herb medicine, SF has been widely used in China to treat cardiovascular and cerebrovascular diseases and to prevent thrombosis. SF is now available in the form of tablets and solution for injections. It is one of 104 new drugs developed by the State of China and approved for clinical use on the basis of its safety and efficacy. However, large-scale, double blind clinical studies with SF alone are still needed to prove its efficacy. Coronary Heart Disease (CHD) and Atherosclerosis CHD, also known as ischemic heart disease, is commonly caused by atheromatous lesions of the coronary artery. Animal experiments in vivo and in vitro demonstrated antiatherogenic and myocardial antiischemic effects of SF in rabbits, rats and quails. The therapeutic effect of SF in CHD patients was first reported by Feng in In his study, 94 CHD patients were treated by SF, 0.08 g day i.v. After 3 to 7 days of therapy the patients were relieved of symptoms of angina pectoris (59). Subsequently, additional clinical studies with SF in CHD patients were carried on. In vitro study demonstrated that SF inhibits platelet aggregation, as well as TXA 2 production and release in platelets from CHD patients (10). In other studies SF (0.3 g per day i.v. for 7 to 10 days) increased SOD activity, decreased lipid peroxide (LPO) content, enhanced fibrinolysis by decreasing plasminogen activator-1 (PAI-1) activity and increasing plasminogen activator (t-pa) activity. It also improved vascular endothelial function by decreasing plasma ET-1 level and increasing plasma NO level in CHD patients (40,58). In CHD patients with hyperlipidemia SF has been reported to decrease serum lipid levels (17). SF alone or in combination with Western drugs appeared to have a therapeutically beneficial effect in patients with angina pectoris and acute myocardial infarction, the major clinical manifestations of CHD. SF was administered alone at 0.2 to 0.3 g per day for one to two weeks. The combined treatment with SF and Western drugs, such as nitrates, aspirin, â-adrenoceptor antagonists, calcium channel antagonists, and angiotensin-converting enzyme inhibitors, produced better results than Western drugs alone. The combined therapy improved clinical symptoms (incidence of angina attacks, dose of intravenous nitroglycerin, analgesic effects), specific ischemic ECG changes, heart function tests (stroke volume, cardiac output, left ventricular ejection fraction, systolic time interval) and peak levels of myocardial enzymes (glutamic oxaloacetic transaminase,

7 SODIUM FERULATE 167 creatine kinase, creatine kinase isoenzyme, LDH); it also reduced the incidence of heart failure and arrhythmias during hospitalization (34,37,39,52,53,57). In CHD patients who could not tolerate nitrates or â-adrenoceptor antagonists, because of adverse effects such as nausea and vomiting, upset stomach, dizziness and headache, SF injections alone markedly improved the clinical symptoms and ECG changes (22,61). The details of these clinical studies are listed in Tables 1 and 2. SF appears to relieve symptoms in CHD patients with angina pectoris possibly by dilating coronary arteries, inhibiting platelet aggregation, antagonizing myocardial ischemia and hypoxia, improving hematology and decreasing blood viscosity. Pulmonary Heart Disease (PHD) SF has been considered to represent a new kind of non-peptide endothelin (ET) antagonist. Since ET is known to be involved in the pathophysiology of pulmonary hypertension, SF may conceivably be useful in the treatment of pulmonary hypertension and PHD. Clinical studies revealed that SF inhibits ET-1 production and thrombi formation in small pulmonary arteries and arterioles of PHD patients. Moreover, the therapeutic effect of SF on PHD patients has been confirmed. The therapeutic regimen with SF, 0.3 g per day for one to two weeks, was found to be appropriate. In chronic PHD patients, SF injection significantly reduced mean and systolic pulmonary artery pressures, prolonged ejection time, shortened pre-ejection period and significantly improved pulmonary function (11,35). In chronic patients with hyperviscosity syndrome, SF improved hemorheology (27). SF was also used to treat chronic HPD patients with heart failure. It was added to routine therapy, such as oxygen, antiinfective, spasmolytic, and antiasthmatic drugs. In these patients SF significantly improved clinical symptoms and markedly decreased the early mortality (12,63). In the study of 65 PHD patients, SF was beneficial in 91% of patients, as compared to only 63% in the control group (63). Hypertension Hypotensive action of SF may be related to its ET-1 antagonistic effect. In normotensive rats, SF, given i.v., markedly blunted the elevation of blood pressure induced by intravenous administration of ET-1. In deoxycorticosterone acetate (DOCA) hypertensive rats, SF (0.05, 0.1, 0.2 g kg p.o., daily for 6 weeks) markedly decreased blood pressure, inhibited the development of cardiovascular hypertrophy, reduced plasma ET-1 levels, decreased the gene expressions of ET-1, c-fos and heat shock protein 70 (HSP70) mrna. In cultured aortic SMCs from hypertensive patients, SF ( mg L) inhibited cell proliferation induced by ET-1 in a dose-dependent manner (4). In patients with essential hypertension, SF alone did not affect mean arterial pressure. However, combined therapy with SF and captopril produced stronger hypotensive effect than captopril alone. The increased urinary TXB 2 excretion caused by captopril was inhibited and the hypotensive effect of captopril potentiated by SF (51). Combined therapy with SF and indapamide decreased blood pressure in hypertensive patients more effectively than other antihypertensive drugs, restored diurnal rhythm and stabilized arterial

8 TABLE 1. Summary of SF s therapeutic effects in CHD patients Effects on clinical symptoms* Effects on ischemic ECG** Excellent Moderate None Efficacy Excellent Moderate None Group Other therapy (n) (n) (n) rate (%) (n) (n) (n) Ref. 34: UAP, n = 150 SF 0.1 g, i.v., q.d. for 14 d, n = 75 Unknown Salvia miltiorrhiza injection 30 ml, i.v., q.d. for 14 d, n =75 Ref. 37: CHD, n =56 SF 0.3 g, i.v., q.d. for d Nifedipine, 10 mg, p.o., t.i.d Ref. 39: UAP SF 0.2 g, i.v., q.d. for 14 d, n = 24 Nitrates, â-adrenoceptor antagonists, calcium channel antagonists Aspirin g, p.o., q.d. for 14 d, n =20 Nitrates, â-adrenoceptor antagonists, calcium channel antagonists Ref. 53: CHD, n = 246 SF 0.2 g, i.v., q.d. for 14 d, n = 164 Nitrates, â-adrenoceptor antagonists, etc. Salvia miltiorrhiza tablets 0.9 g, p.o., t.i.d. for 14 d, n =82 Nitrates, â-adrenoceptor antagonists, etc. Efficacy rate (%) Ref. 22: CHD, n =40 SF 0.5 g, i.v., q.d. for 12 d, n = 164 No other therapy Ref. 61: CHD, n =56 SF 0.2 g, i.v., q.d. for 10 d No other therapy Abbreviations: UAP, unstable angina pectoris; CHD, coronary heart disease. Data were compiled from refs. 22,34,37,39,53,61. * For clinical symptoms, excellent, the same level of labor does not induce chest distress or angina pectoris, or the number of anginal attacks is reduced by more than 80%; moderate, the number of chest distress and anginal attacks is reduced by 50% 80%; none, the number of chest distress or anginal attacks is reduced by less than 50%. ** For ECG: excellent, resting ECG is recovered to normal; moderate, after treatment resting ECG is recovered by 0.15 mv, or inverted T wave of the main lead recovered by more than 50%, or T wave changed from flat to elevated; none, resting ECG remains the same as before the therapy. 168 B.-H. WANG AND J.-P. OU-YANG

9 SODIUM FERULATE 169 TABLE 2. Comparison of therapeutic effects of SF + nifedipine with those of diltiazem + nifedipine in patients with acute myocardial infarction Therapy SF, 0.2 g, p.o., t.i.d., + nifedipine, 10 mg, p.o., t.i.d., for 4 weeks Diltiazem, 0.03 g, p.o., t.i.d. + nifedpine, 10 mg, p.o., t.i.d., for 4 weeks Number of patients Clinical symptoms Number of anginal attacks, per for 4 weeks 16.0 ± ± 2.0 Dose of intravenous nitroglycerin, mg 286 ± ± 38 Heart function tests Stroke volume (ml beat) 70±6 61±6 Cardiac output (L min) 4.2 ± ± 0.4 Left ventricular ejection fraction (%) 52 ± ± 10 Systolic time interval (PEP LVEF) 0.49 ± ± 0.03 Peak value of myocardium enzyme GOT (nmol sec/l) 1067 ± ± 150 CK (nmol sec/l) 1700 ± ± 183 CK-MB* 0.18 ± ± 0.08 LDH (ìmol sec/l) 3.4 ± ± 0.4 Incidence of other cardiovascular diseases number of patients (% of total) Heart failure 14 (31%) 20 (46%) Arrhythmias 18 (40%) 23 (52%) Abbreviations: GOT, glutamic oxaloacetic transaminase; CK, creatine kinase; CK-MB, creatine kinase isoenzyme; LDH, lactate dehydrogenase. Data from ref. 57. * The activity of CK-MB was detected by agarose gel electrophoresis. The unit is % of total CK activity. pressure at reduced levels. More clinical studies are, however, still needed to confirm the efficacy of SF in patients with hypertension. Adverse Reactions By long-term administration SF did not elicit any abnormal changes in liver, kidney, or blood. In rare instances SF caused headache, nausea, abdominal discomfort or skin rash. These adverse reactions disappeared rapidly after discontinuation of therapy. REFERENCES 1. Chang MX, Xu LM, Tao JS, M Y. Metabolism and pharmacokinetics of ferulic acid in rats. Zhongguo Zhong YaoZaZhi1993;18: (in Chinese). 2. Chang MX, Xu LY, Tao JS. Study on pharmacokinetics of sodium ferulate in rats. Northwest Pharm J China 1995;10:81 83 (in Chinese). 3. Chen W, Yao DP. Combined administration of indapamide and sodium ferulate in treating hypertension. Chin J Curr Trad Western Med 2003;1:508 (in Chinese).

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