OBJECTIVE: To determine the effect of trimetazidine on cardiac function and exercise tolerance in primary hypertension patients with type 2 diabetic. METHODS: In this randomized, double-blind, placebo-controlled prospective study, 60 primary hypertensive patients with diabetic were equally assigned into two groups, patients received trimetazidine (20 mg, 3 times a day) or placebo for 1 year. Echocardiography, cardiopulmonary exercise testing were performed; and the plasma N terminal pro B type natriuretic peptide (NT-ProBNP), hr-CRP, TNF-α, angiotensin Ⅱ and endothelin concentration were determined before and after treatment. RESULTS: In trimetazidine group, the left ventricular mass index, the mitral flow velocity E wave to A wave ratio (E/A), the peak early diastolic velocity (V) to late diastolic velocity (V) ratio (V/V) and the peak systolic velocity (Vs) were significantly improved, the plasma NT-ProBNP level was significantly decreased, and the exercise time, metabolic equivalent, maximal oxygen uptake and anaerobic threshold were significantly increased (all <0.05); plasma concentration of hr-CRP, TNF-α, angiotensin Ⅱ and endothelin were significantly reduced after trimetazidine treatment, compared with baseline (all <0.05) and with placebo (all <0.05). There were no significant differences in any of above parameters after treatment in placebo group (all >0.05). No severe adverse reaction was observed in both groups. CONCLUSIONS For patients with both hypertension and diabetes, trimetazidine can improve cardiac function and increase exercise tolerance.
Diabetes Complications ; complications ; Diabetes Mellitus ; drug therapy ; Double-Blind Method ; Exercise Tolerance ; drug effects ; Heart ; drug effects ; Humans ; Hypertension ; complications ; drug therapy ; Natriuretic Peptide, Brain ; blood ; Prospective Studies ; Treatment Outcome ; Trimetazidine ; pharmacology ; therapeutic use ; Vasodilator Agents ; pharmacology ; therapeutic use

OBJECTIVETo study the pharmacokinetics of puerarin (PUE) in Gegen Qinlian Decoction (, GQD), and the effects of PUE dosage variations on the pharmacokinetics of baicalin (BAL) in mice.

METHODSGQD is composed of the concentrated granules of four Chinese herbs. Three dosages with different levels of PUE, including GQD, GQD co-administered with PUE, and GQD co-administration with two times the amount of PUE, were used to research the pharmacokinetics of PUE and BAL in mice. The indirect competitive enzyme-linked immunosorbent assay (icELISA) methods based on an anti PUE-monoclonal antibody (MAb)and BAL-MAb were employed to determine the concentration of PUE and BAL in mice blood.

RESULTSAfter the co-administration of GQD with PUE, the area under the curves (AUC) of PUE increased 2.8 times compared with GQD. At the dose of GQD co-administration at two times that of PUE, the (AUC) of PUE was almost equal to that of GQD co-administration of PUE, showing non-linear pharmacokinetics. The (AUC) of BAL showed a good dose-related increase of PUE (r=0.993) in the range from 100 to 300 mg/kg, indicating that PUE dramatically affects the absorption of BAL in mice. There was no significant difference in the other pharmacokinetic parameters, such as the first time of maximum concentration (T), the second T, or the mean residence time.

CONCLUSIONSThe icELISA methods were successfully applied to pharmacokinetic studies of PUE and BAL in GQD in mice. The dosage variability of PUE of the main ingredient in GQD affects its own pharmacokinetic characteristics and the absorption characteristics of BAL.

Animals ; Drugs, Chinese Herbal ; pharmacokinetics ; Enzyme-Linked Immunosorbent Assay ; Flavonoids ; pharmacokinetics ; Herb-Drug Interactions ; Isoflavones ; pharmacology ; Male ; Mice ; Vasodilator Agents ; pharmacology

Previous studies have shown that paeonol can antagonize acute myocardial ischemia and infarction in rat. This study further researched the effects of paeonol on blood pressure and blood flow in the artery of spontaneously hypertensive rats and its mechanisms related on vasomotion. Firstly, thirty spontaneously hypertensive rats were randomly divided into spontaneously hypertensive control group and paeonol-treating groups of high dose and low dose, and also, the other ten Wistar rats as healthy control group. Before and after the intraduodenal administration of the drug, arterial blood pressure was measured by carotid artery and blood flow through the renal artery and carotid artery in vivo were measured by animal flowmeter. The same volume of solvent was given to the spontaneously hypertensive control group and the healthy control group, and the other operations were same. In order to further study the effect of paeonol on vasomotor function, the superior mesenteric artery, renal artery and coronary artery of the spontaneously hypertensive rat were removed and separated, precontracted by a certain concentration of potassium chloride (KCl) and 5-serotonin (5-HT) respectively, and dilatory responses were assessed by cumulative addition of paeonol. Results showed that after duodenal one-time delivery of paeonol, the blood pressure significantly lowered, the renal arterial blood flow and the carotid arterial blood flow significantly increased in spontaneously hypertensive rat. And also, paeonol relaxed the mesenteric artery, renal artery and the coronary artery of spontaneously hypertensive rat in a concentration-dependent manner. These results indicated that the effect of paeonol on decreasing arterial blood pressure and increasing the arterial blood flow was related to its vasodilative effect.
Acetophenones ; pharmacology ; Animals ; Blood Pressure ; drug effects ; Male ; Rats ; Rats, Inbred SHR ; Regional Blood Flow ; drug effects ; Vasodilator Agents ; pharmacology

Recent studies showed that pathology of alcoholic encephalopathy was associated with cerebral vascular damage. TMP (tetramethyl- pyrazine) is widely used in the treatment of cerebrovascular diseases, however, it has not been reported whether TMP can relieve alcohol-induced cerebral vascular damages. The study was performed to investigate the learning and memory, cerebrovascular pathological changes and the expressions of vascular endothelial growth factor (VEGF) and serum levelsofendothelin-1 (ET-1) in the rat model of chronic alcoholic encephalopathy, and explore the effects of TMP intervention on alcoholic encephalopathy. In the present study, the rat model of chronic alcoholic encephalopathy was established by the gavage administration of alcohol; the learning and memory ability was tested by Morris water maze; the expression of VEGF was measured by RT-PCR and Western blot; and the serum levels of ET-1 was measured by radioimmunoassay. We found that alcohol intoxication impaired learning and memory, induced VEGF overexpression and increased ET 1 concentrations. TMP intervention improved learning abilities, increased the VEGF expression and reduced ET-1 level. These results indicate that TMP exhibits therapeutic effects on chronic alcoholic encephalopathy.
Alcohol-Induced Disorders, Nervous System ; complications ; drug therapy ; physiopathology ; Animals ; Cerebrovascular Circulation ; drug effects ; Disease Models, Animal ; Endothelin-1 ; blood ; Learning ; drug effects ; Male ; Memory ; drug effects ; Pyrazines ; pharmacology ; therapeutic use ; Random Allocation ; Rats ; Rats, Wistar ; Vascular Endothelial Growth Factor A ; analysis ; Vasodilator Agents ; pharmacology ; therapeutic use

The present study was designed to determine the effects of puerarin pre-treatment on the pharmacokinetics of the oral anticoagulant agent warfarin and the antiplatelet agent clopidogrel in rats. In the treatment group, rats was gavaged with warfarin or clopidogrel after repeated treatment with puerarin at intraperitoneal doses of 20, 60, or 200 mg·kg(-1) for 7 days, while rats in the control group were administrated only with the same dose warfarin or clopidogrel. Plasma samples were obtained at the prescribed times and analyzed by liquid chromatography tandem mass spectrometry (LC-MS/MS). The results showed that rats treated with puerarin at all the test doses of 20, 60 and 200 mg·kg(-1) were found to affect the pharmacokinetics of warfarin, but not clopidogrel, suggesting a potential herb-drug interaction between puerarin and warfarin.
Animals ; Anticoagulants ; pharmacokinetics ; Chromatography, Liquid ; Clopidogrel ; Drug Administration Schedule ; Herb-Drug Interactions ; Injections, Intraperitoneal ; Isoflavones ; administration & dosage ; pharmacology ; Male ; Platelet Aggregation Inhibitors ; pharmacokinetics ; Rats ; Rats, Wistar ; Tandem Mass Spectrometry ; Ticlopidine ; analogs & derivatives ; pharmacokinetics ; Vasodilator Agents ; administration & dosage ; pharmacology ; Warfarin ; pharmacokinetics

To investigate the effects and potential mechanisms of hyperoside (Hyp) on the vascular endothelium function in middle cerebral artery (MCA) ex vivo in rats. Isolated arterial segments from MCAs of rats were used for surveying vasomotoricity in a pressurized chamber. Transmembrane potential was recorded by using glass microelectrodes to evaluate hyperpolarization. Hyp (1 x 10(-6)-1 x 10(-4) mol . L-1) was utilized to observe the effect on 1 x 10(-7) mol . L-1 U46619-preconstricted MCA in rats. The results showed that 1 x 10(-6)-1 x 10(-4) mol . L-1 Hyp significantly induced concentration-dependent vasodilatation and hyperpolarization, leading to the maximal diastolic ratio of (73. 2 ± 6. 1)% and maximal changes in membrane potentials of (-13. 2 ± 2. 2) mV. Hyp still elicited vasorelaxation and hyperpolarization by removal of endothelium in MCA of rat, which was notably attenuated as compared with vascular endothelium-intact group (P <0. 01). In the MCAs preconstricted by U46619 (1 x 10(-7) mol . L-1), Hyp (1 x 10(-6)-1 x 10(-4) mol . L-1) produced concentration-dependent vasorelaxation and hyperpolarizition that were partially attenuated by 3 x 10(-5) mol . L-1 L-NAME(a NOS inhibitor) plus 1 x 10(-5) mol . L-1 PGI2 ,(a synthetase inhibitor). The residual effects were further decreased by 1 x 10(-3) mol . L-1 TEA (an inhibitor of Ca2+-activated potassium channel) or 1 x 10(-5) mol . L-1 PPG (a blocker of endogenous H2S synthese-CSE). Similarly, 1 x 10(-5)-1 x 10(-3) mol . L-1 NaHS (a donor of exogenous H2S) or 1 x 10(-5)-1 x 10(-3) mol . L-1 L-Cys (the substrate of endogenous H2S synthesis) obviously evoked dose-dependent vasodilatation and hyperpolarization of MCA in rats. These findings indicated that Hyp may induce endothelium-dependent and endothelium-independent responses. And the endothelium-dependent vasodilatation may be related to the increases of endogenous H2S that has been promoted Hyp in the endotheliocyte of MCAs, and activated Kca and opening of Kca channels, resulting in the hyperpolarization of vascular smooth muscle cell membrane and subsequent reduction of Ca2+ influx and vasodilation.
Animals ; Endothelium, Vascular ; drug effects ; Enzyme Inhibitors ; pharmacology ; Female ; Male ; Middle Cerebral Artery ; Muscle, Smooth, Vascular ; drug effects ; Nitric Oxide ; metabolism ; Potassium Channels ; metabolism ; Quercetin ; analogs & derivatives ; pharmacology ; Rats ; Rats, Sprague-Dawley ; Sulfides ; metabolism ; Vasodilation ; drug effects ; Vasodilator Agents ; pharmacology

OBJECTIVETo study the selective dilatation effects of iptakalim (Ipt) on basilar and pulmonary arterioles, and endothelial cell function of these arterioles in hypoxic rats.

METHODSSD male rats were divided into 2 groups:control and hypoxic group fed in normobaric hypoxic environment (O2 7.8%, 8 h). Arteriole rings about (204 + 5) pm were isolated and the tension of hypoxic arterioles pre-contracted by 6 nmol/L endothelin-1 (ET-1) was observed with wire myograph system model (DMT 610 m). The relaxing response of hypoxic arterioles induced by different concentration of Ipt were detected and endothelial activity was also tested by acetylcholine.

RESULTS10(5) mol/L acetylcholine (ACh)-mediated vasodilatation of basilar and pulmonary arterioles was greatly reduced in the hypoxic group than those in control group (P < 0.05). Compared with normal group, a novel ATP-sensitive potassium channel opener Ipt at the concentration ranging from 10(-11) mol/L to 10(3) mol/L, caused stronger dose dependent vasodilatation on hypoxic pulmonary arterioles, and there was no significant difference between control and hypoxic basilar arterioles.

CONCLUSIONThe endothelial function of basilar and pulmonary arterioles was damaged under hypoxic state, and Ipt selectively increased dilatation effects on hypoxic pulmonary arterioles, but not on hypoxic basilar arterioles which could improve high altitude pulmonary edema pathological state and be the novel drug in the treatment of pulmonary hypertension.

Acetylcholine ; pharmacology ; Altitude ; Altitude Sickness ; physiopathology ; Animals ; Arterioles ; drug effects ; Dilatation ; Endothelin-1 ; pharmacology ; Hypoxia ; KATP Channels ; drug effects ; Male ; Propylamines ; pharmacology ; Rats ; Vasodilation ; Vasodilator Agents ; pharmacology

OBJECTIVEIn our study, the function of the third-order branches of the mesentenc artery was measured by microvascular ring technique, which can be used to detect microvascular function in some disease related to microvascular dysfunction.

METHODSIsolated, fixed, standardized and then activated the third-order branches of rat mesenteric artery. Microvascular tone was measured by systolic and diastolic drags respectively, with the help of DMT tension apparatus and PowerLab data acquisition system.

RESULTSThe third-order branches of rat mesenteric artery showed excellent response to vasoactive drugs. The contraction effect of norepinephrine (NE) reached 19 in mN. When acetylcholine (Ach) or sodium nitroprusside (SNP) of 10(9)-10(5)mol/L was added, vascular tones showed gradient drop: 80% of maximal relaxation when adding ACh, while 95% of maximal relaxation when adding SNP.

CONCLUSIONThe third-order branches of the mesenteric artery function was successfully detected by using microvascular ring technique.

Acetylcholine ; pharmacology ; Animals ; In Vitro Techniques ; Male ; Mesenteric Arteries ; drug effects ; physiology ; Nitroprusside ; pharmacology ; Norepinephrine ; pharmacology ; Rats ; Vasoconstrictor Agents ; pharmacology ; Vasodilation ; physiology ; Vasodilator Agents ; pharmacology

OBJECTIVETo investigate the changes of vasoconstriction and vasodilatation under different temperature conditions and the protective effects of Vitamin E (Vit E) against endothelial injury induced by hypothermia.

METHODSThe tail arterial rings were prepared for isometric tension recording using multi wire myograph system. The effect of temperature on relaxation and construction was evaluated. Incubate the arterial rings with different concentration of Vit E when they were exposed to hypothermia, then acetylcholine (ACh)-induced endothelium-dependent relaxation was investigated to evaluate the activity of endothelial.

RESULTS(1) The hypothermia could enhanced the dose-dependent construction induced by PE in mice tail artery. (2) Exposure to hypothermia also resulted in increase of sodium nitroprusside (SNP)-induced re-After incubation with Vit E, the vascular relaxation responses to ACh increased in an endothelium-dependent manner, when compared with the hypothermia-treated group.

CONCLUSIONThe vascular function of constriction was attenuated by hypothermia, while the relaxation was increased. Vit E could prevent the hypothermia-induced decrease in vascular endothelial cells.

Animals ; Arteries ; drug effects ; physiology ; Cold Temperature ; Hypothermia ; In Vitro Techniques ; Male ; Mice ; Prazosin ; pharmacology ; Solanaceous Alkaloids ; pharmacology ; Vasoconstriction ; drug effects ; Vasodilation ; drug effects ; Vasodilator Agents ; pharmacology ; Vitamin E ; pharmacology

OBJECTIVETo investigate the effect of Bushengzhuyang Fang (Yangjing Capsule, YJC) on penile erectile function and its action mechanisms in rats.

METHODSFifty-six male SD rats were randomly divided into seven groups of equal number: blank control, daidzein, daidzein + testosterone, daidzein + sildenafil, daidzein + low-dose YJC, daidzein + medium-dose YJC, and daidzein + high-dose YJC. The rats in the blank control group were treated intragastrically with normal saline and those in the other groups with daidzein at the dose of 100 mg per kg per day for 30 days. Then the last five groups received additionally testosterone (4 mg per kg per day), sildenafil (2.5 mg per kg per day), low-dose YJC, (0.315 mg per kg per day), medium-dose YJC (0.63 mg per kg per day), and high-dose YJC (1. 26 mg per kg per day), respectively. At 0, 30 and 60 days of treatment, we observed the apomorphine-induced spontaneous erectile response and pathological changes in the corpus cavernosum of the rats, recorded the number of penile erection and erectile incubation period, and determined the serum levels of testosterone (T) and luteinizing hormone (LH).

RESULTSAt 30 days of treatment, the number of apomorphine-induced erections was decreased, the erectile incubation period prolonged, and the serum levels of T and LH reduced remarkably in all groups of rats (P < 0.05). Compared with the findings at 30 days, the number of penile erections was significantly decreased at 60 days in the daidzein group (1.39 ± 0.42 vs 2.67 ± 0.33, P < 0.05) and daidzein + low-dose YJC group (1.33 ± 0.49 vs 2.83 ± 0.61, P < 0.05); the erectile incubation period was markedly ex- tended ([16.33 ± 3.11] vs [8.50 ± 0.93] min and [15.50 ± 3.21] vs [8.63 ± 1.54] min, P < 0.05); and the serum levels of T ([5.34 ± 0.89] vs [1.24 ± 0.30] ng/ml and [5.28 ± 1.12] vs [2.07 ± 0.76] ng/ml, P < 0.05) and LH ([3.62 ± 0.37] vs [2.09 ± 0.12] ng/ml and [3.79 ± 0.28] vs [2.17 ± 0.33] ng/ml, P < 0.05) were significantly reduced in the daidzein and daidzein + low-dose YJC groups, respectively. Pathological examination revealed slightly decreased cavernous sinuses and blood vessels in the corpus cavernosum of the rats in the daidzein + testosterone, daidzein + sildenafil, daidzein + medium-dose YJC, and daidzein + high-dose YJC groups as compared with those in the blank control group.

CONCLUSIONHigh-dose Yangjing Capsule is efficacious for the recovery of erectile function in rats, especially for phytoestrogen-induced erectile dysfunction.

Animals ; Apomorphine ; pharmacology ; Drugs, Chinese Herbal ; therapeutic use ; Erectile Dysfunction ; chemically induced ; drug therapy ; Humans ; Isoflavones ; pharmacology ; Luteinizing Hormone ; Male ; Penile Erection ; drug effects ; physiology ; Penis ; drug effects ; pathology ; Phytoestrogens ; Phytotherapy ; Piperazines ; therapeutic use ; Purines ; therapeutic use ; Rats ; Rats, Sprague-Dawley ; Sildenafil Citrate ; Sulfonamides ; therapeutic use ; Testosterone ; therapeutic use ; Vasodilator Agents ; therapeutic use