The primary object of this fundamental research was to survey the synergistic cardiovascular effects of iptakalim, a novel ATP-sensitive potassium channel (K(ATP)) opener, and clinical first-line antihypertensive drugs, such as calcium antagonists, thiazide diuretics and β receptor blockers by a 2 x 2 factorial-design experiment. It would provide a theoretical basis for the development of new combined antihypertensive therapy program after iptakalim is applied to the clinic. Amlodipine besylate, hydrochlorothiazide and propranolol were chosen as clinical first-line antihypertensive drugs. Blood pressure, heart rate (HR) and cardiac functions were observed in anesthetized normal rats by an eight-channel physiological recorder. The results showed that iptakalim monotherapy in a low dose could produce significant antihypertensive effect. There was no interaction between iptakalim and amlodipine on the maximal changes of systolic blood pressure (SBP), diastolic blood pressure (DBP), mean arterial blood pressure (MABP), the left ventricular systolic pressure (LVSP), and the left ventricular end-diastolic pressure (LVEDP) (P > 0.05). However, the effects of combination iptakalim/amlodipine on the maximal changes of SBP, DBP, MABP, LVSP and LVEDP were more obvious than those of iptakalim or amlodipine monotherapy. And there was strong positive interaction between iptakalim and amlodipine on the maximal changes of HR (P>0.05). According to the maximal changes of DBP, MABP, LVSP and LVEDP (P < 0.05) of combination iptakalim with hydrochlorothiazide, there was strong positive interaction between them. But there was no interaction between iptakalim and hydrochlorothiazide on the maximal drop of SBP and HR (P > 0.05). According to the maximal drops of DBP, MABP of combination iptakalim with propranolol, there was strong positive interaction between them (P < 0.05). But there was no interaction between iptakalim and propranolol on the maximal changes of SBP, LVSP, LVEDP and HR (P > 0.05). In conclusion, it was the first time to study the effects of amlodipine, hydrochlorothiazide or propranolol, which had different mechanisms of action from iptakalim, on cardiovascular effects of iptakalim in anesthetized normal rats. This study proved that the combination of iptakalim with hydrochlorothiazide or propranolol respectively had significant synergism on lowering blood pressure, while the combination of iptakalim/amlodipine had additive action on lowering blood pressure. Meanwhile the antihypertensive effect was explicit, stable and long-lasting. Iptakalim thus appears suitable for the clinical treatment of hypertensive people who need two or more kinds of antihypertensive agents.
Amlodipine ; pharmacology ; Animals ; Antihypertensive Agents ; pharmacology ; Blood Pressure ; drug effects ; Drug Synergism ; Heart Rate ; Hydrochlorothiazide ; pharmacology ; Hypertension ; Propranolol ; pharmacology ; Propylamines ; pharmacology ; Rats

OBJECTIVETo investigate the effect of emodin on the contraction of jejunum smooth muscle and its underlying mechanisms.

METHODSRats were randomly divided into 7 groups (n = 6): control group, emodin group (1, 5, 10, 20 micromol/L), propranolol (PRO) plus emodin group, glibenclamide (GLI) plus emodin group, NG-Nitro-L-arginine Methyl Ester (L-NAME) plus emodin group, calcium free control group and calcium free emodin group. The rats were sacrificed by cervical dislocation and the small intestine was isolated. The jejunum segment specimens were mounted on an Organ Bath System with a tension transducer. The effect of emodin on contraction of jejunum smooth muscle was measured by BL-420E+ biological signal processing system and the amplitude (AM), tension (TE) and frequency (FR) of contraction were determined.

RESULTS(1) Emodin inhibited the tension and amplitude of jejunum smooth muscle contraction in a dose-dependent manner (P < 0.05, P < 0.01) while the frequency was not obviously influenced. (2) PRO (P < 0.05) or GLI (P < 0.01) partly abolished the inhibitory effect of emodin on jejunum smooth muscle. (3) L-NAME had no obvious effect on the inhibitory effect of emodin. (4) Emodin attenuated the contraction of jejunum smooth muscle induced by calcium chloride application into calcium free K-H solution (P < 0.01).

CONCLUSIONEmodin obviously inhibits the amplitude and tension, while has no influence on the frequency of jejunum smooth muscle contraction in rats. Activation of beta adrenergic receptor, open of ATP sensitive potassium channels, and inhibition of the extracellular calcium influx through calcium channels of smooth muscle cell membrane might be involved in the process.

Animals ; Calcium Signaling ; Emodin ; pharmacology ; Glyburide ; pharmacology ; Jejunum ; drug effects ; Muscle Contraction ; drug effects ; Muscle, Smooth ; drug effects ; NG-Nitroarginine Methyl Ester ; pharmacology ; Propranolol ; pharmacology ; Rats

OBJECTIVETo study the stereoselectivity of R-(+) and S-(-)-propranolol glucuronidation and metabolic interaction between R(+)- and S-(-)-propranolol.

METHODSA RP-HPLC analytical method was developed for determination of R-(+)-and S-(-)-propranolol glucuronide (PG) incubated with rat hepatic microsome induced with phenobarbital (PB). The method was applied to investigate the stereoselectivity metabolism of racemic propranolol glucuronidation in vitro.

RESULTIn control and PB group, the concentration of R-(+)-PG produced at different substrates was higher than that of S-(-)-PG. Compared with the control, the V(max) and Cl(int) for R(+)-and S-(-)-propranolol increased significantly the K(m) for R(+)-propranolol was elevated, while that for S-(-) propranolol was decreased.

CONCLUSIONThere is a stereoselectivity in glucuronidation of propranolol in rat hepatic microsome induced with PB and R-(+)-propranolol is preferred. Metabolic interaction between R-(+)-and S-(-)-propranolol exists with a concentration-dependent mode.

Animals ; Enzyme Induction ; Microsomes, Liver ; enzymology ; Phenobarbital ; pharmacology ; Propranolol ; analogs & derivatives ; metabolism ; Rats ; Rats, Sprague-Dawley ; Stereoisomerism

This study is to investigate the effects of phenytoin sodium, lidocaine (sodium channel blockers), propranolol (beta-adrenergic receptor antagonist), amiodarone (drugs prolonging the action potential duration) and verapamil (calcium channel blockers) on arrhythmia of mice induced by Bufonis Venenum (Chansu) and isolated mouse hearts lethal dose of Chansu. Arrhythmia of mice were induced by Chansu and then electrocardiograms (ECGs) were recorded. The changes of P-R interval, QRS complex, Q-T interval, T wave amplitude, heart rate (HR) were observed. Moreover, arrhythmia rate, survival rate and arrhythmia score were counted. Isolated mouse hearts were prefused, and the lethal dose of Chansu was recorded. Compared with control group, after pretreatment with phenytoin sodium, broadening of QRS complex and HR were inhibited, and the incidence of ventricular arrhythmia was reduced dramatically, while survival rate was improved; the isolated mouse hearts lethal dose of Chansu was increased significantly. After pretreatment with lidocaine, the prolongation of P-R interval and broadening of QRS complex were inhibited, and the incidences of ventricular arrhythmia were reduced dramatically, while survival rate was improved; the isolated mouse hearts lethal dose of Chansu was increased significantly. After pretreatment with propranolol, prolongation of P-R interval, broadening of QRS complex, prolongation of Q-T interval and HR were inhibited, and the incidences of both supraventricular and ventricular arrhythmias were reduced dramatically, while survival rate was improved. After pretreatment with amiodarone, HR was inhibited, the incidences of ventricular tachycardia were reduced dramatically. Lastly, after pretreatment with verapamil, the prolongation of P-R interval and Q-T interval were inhibited and the incidences of both supraventricular and ventricular arrhythmias were reduced dramatically; the isolated mouse hearts lethal dose of Chansu was reduced significantly. In in vivo experiments, phenytoin sodium was most effective against the mice arrhythmias induced by Chansu while cautious use of verapamil for Chansu inducing arrhythmia should be noted. It is also concluded that mice ventricular arrhythmias induced by Chansu might be most closely related to sodium channel, supraventricular arrhythmias might be related to beta-adrenergic receptor, and calcium channel plays an important role in conduction block. In in vitro experiments, phenytoin sodium was most effective, followed by lidocaine and propranolol, and amiodarone had no obvious effect and verapamil reduced the lethal dose of Chansu.
Amiodarone ; pharmacology ; Animals ; Anti-Arrhythmia Agents ; pharmacology ; Arrhythmias, Cardiac ; chemically induced ; physiopathology ; Bufanolides ; toxicity ; Electrocardiography ; drug effects ; Female ; Heart Rate ; drug effects ; In Vitro Techniques ; Lethal Dose 50 ; Lidocaine ; pharmacology ; Male ; Mice ; Phenytoin ; pharmacology ; Propranolol ; pharmacology ; Verapamil ; pharmacology

The effects of several antihypertensive drugs on bone mineral density (BMD) and micro-architectural changes in ovariectomized (OVX) mice were investigated. Eight-week-old female C57/BL6 mice were used for this study. Three days after ovariectomy, mice were treated intraperitoneally with nifedipine (15 mg/kg), telmisartan (5 mg/kg), enalapril (20 mg/kg), propranolol (1 mg/kg) or hydrochlorothiazide (12.5 mg/kg) for 35 consecutive days. Uterine atrophy of all mice was confirmed to evaluate estrogen deficiency state. BMD and micro-architectural analyses were performed on tibial proximal ends by micro-computed tomography (micro-CT). When OVX mice with uterine atrophy were compared with mice without atrophy, BMD decreased (P < 0.001). There were significant differences in BMD loss between different antihypertensive drugs (P = 0.005). Enalapril and propranolol increased BMD loss in mice with atrophied uteri compared with control mice. By contrast, thiazide increased BMD in mice with uterine atrophy compared with vehicle-treated mice (P = 0.048). Thiazide (P = 0.032) and telmisartan (P = 0.051) reduced bone loss and bone fraction in mice with uterine atrophy compared with the control. Thiazide affects BMD in OVX mice positively. The reduction in bone loss by thiazide and telmisartan suggest that these drugs may benefit menopausal women with hypertension and osteoporosis.
Animals ; Antihypertensive Agents/*pharmacology ; Atrophy ; Benzimidazoles/pharmacology ; Benzoates/pharmacology ; Bone Density/*drug effects ; Enalapril/pharmacology ; Female ; Mice ; Mice, Inbred C57BL ; Ovariectomy ; Propranolol/pharmacology ; Thiazides/pharmacology ; Tibia/radiography ; Tomography, X-Ray Computed ; Uterus/anatomy & histology/pathology

The effects of several antihypertensive drugs on bone mineral density (BMD) and micro-architectural changes in ovariectomized (OVX) mice were investigated. Eight-week-old female C57/BL6 mice were used for this study. Three days after ovariectomy, mice were treated intraperitoneally with nifedipine (15 mg/kg), telmisartan (5 mg/kg), enalapril (20 mg/kg), propranolol (1 mg/kg) or hydrochlorothiazide (12.5 mg/kg) for 35 consecutive days. Uterine atrophy of all mice was confirmed to evaluate estrogen deficiency state. BMD and micro-architectural analyses were performed on tibial proximal ends by micro-computed tomography (micro-CT). When OVX mice with uterine atrophy were compared with mice without atrophy, BMD decreased (P < 0.001). There were significant differences in BMD loss between different antihypertensive drugs (P = 0.005). Enalapril and propranolol increased BMD loss in mice with atrophied uteri compared with control mice. By contrast, thiazide increased BMD in mice with uterine atrophy compared with vehicle-treated mice (P = 0.048). Thiazide (P = 0.032) and telmisartan (P = 0.051) reduced bone loss and bone fraction in mice with uterine atrophy compared with the control. Thiazide affects BMD in OVX mice positively. The reduction in bone loss by thiazide and telmisartan suggest that these drugs may benefit menopausal women with hypertension and osteoporosis.
Animals ; Antihypertensive Agents/*pharmacology ; Atrophy ; Benzimidazoles/pharmacology ; Benzoates/pharmacology ; Bone Density/*drug effects ; Enalapril/pharmacology ; Female ; Mice ; Mice, Inbred C57BL ; Ovariectomy ; Propranolol/pharmacology ; Thiazides/pharmacology ; Tibia/radiography ; Tomography, X-Ray Computed ; Uterus/anatomy & histology/pathology

Effects of beta-adrenergic blockers and related agents were investigated on experimental convulsions of chicks induced with strychnine, pentylenetetrazol or electroshock and on thiopental sleeping time of rabbits. Convulsions of chicks due to strychnine were significantly inhibited by all beta-adrenergic blockers except dichloroisopreterenol. Propranolol inhibited electroshock convulsion as well, but none of the blockers inhibited pentylenetetrazol convulsion. Furthermore, the mortality of chicks due to large dose of pentylenetetrazol was greatly increased by treatment of beta-adrenergic blockers. Pindolol alone showed diazepam-like anticonvulsive effect against low doses of pentylenetetrazol. Pretreatment with beta-adrenergic blockers caused a marked increase in thiopental sleeping time in rabbits. Prolongation of thiopental sleep due to propranolol was abolished by premedication of animals with reserpine or tranylcypromine. Thiopental sleeping time was prolonged by Zizyphus extract, though less effective than beta-adrenergic blockers. It is felt that the anticonvulsive or sleep enhancing effect of beta-adrenergic blocking agents has an intimate relationship with endogenous adrenergic amines and the receptors.
Adrenergic beta-Antagonists/pharmacology* ; Anesthesia ; Animal ; Anticonvulsants* ; Blood Pressure/drug effects ; Chickens ; Convulsions/chemically induced ; Heart Rate/drug effects ; Male ; Propranolol/pharmacology* ; Rabbits ; Strychnine/antagonists & inhibitors ; Thiopental

AIMTo explore the effect and mechanism of interleukin-2 (IL-2) on the rhythm of isolated rat heart and neonatal myocytes.

METHODSCultured neonatal rat cardiomyocytes and isolated perfused rat heart were used.

RESULTS(1) IL-2 (2.5-200 u/ml) reduced the spontaneous beating rate of cultured neonatal rat cardiomyocytes in a dose-dependent manner. (2) IL-2 at 50 u/ml increased both the heart rate and the number of premature ventricular excitation in the isolated heart. (3) Pretreatment with propranolol abolished the effect of 50 u/ml IL-2 on the isolated heart. (4) Heat inactivated IL-2 had no significant effect on the cultured cardiomyocytes and isolated hearts.

CONCLUSIONIL-2 inhibited the auto rhythmic of cultured cardiomyocyte directly while the positive chronotropic and arrhythmogenic effects of IL-2 in the isolated rat heart may be mediated by endogenous catecholamine.

Animals ; Animals, Newborn ; Cells, Cultured ; Heart ; drug effects ; Heart Rate ; drug effects ; In Vitro Techniques ; Interleukin-2 ; pharmacology ; Myocytes, Cardiac ; drug effects ; physiology ; Propranolol ; pharmacology ; Rats ; Rats, Sprague-Dawley

OBJECTIVETo demonstrate the vasodilatation activity of the coumarin-containing Angelica dahurica var. formosana and to further analyze active components in the herb extracts.

METHODS(1) The vasodilatation effects induced by different extracts (cyclohexane, ethyl acetate, acetone, methanol, 95 % ethanol and water) of Angelica dahurica var. formosana on mouse thoracic aorta pre-contracted with phenylephrine were investigated. (2) The amount of imperatorin and isoimperatorin in each extract was measured by high-performance liquid chromatography. (3) The vasodilatation effects of imperatorin and isoimperatorin on mouse thoracic aorta were compared using the same in vitro method. (4) The vasodilatation mechanism of imperatorin in the mouse thoracic aorta pre-contracted with phenylephrine was studied using the methods of denuded endothelium, NG-nitro-L-arginine methylester (L-NAME, a nitric oxide synthase inhibitor), and propranolol.

RESULTS(1) The cyclohexane and ethyl acetate extracts of Angelica dahurica var. formosana decreased the maximal response of phenylephrine-induced mouse thoracic aorta contraction dose-dependently, with 50% inhibiting concentration (IC(50)) values of 35.3+/-12.4 mg/L and 40.5+/-12.0 mg/L, respectively. The vasodilatation effect of imperatorin and isoimperatorin was dose-dependent. (2) The cyclohexane extract, showing the strongest vasodilatation effect, possessed the highest contents of imperatorin (4.09%) and isoimperatorin (0.27%, w/w). There was a correlation between the vasodilatation activity and the contents of imperatorin and isoimperatorin in the extracts. (3) The vasodilatation effect of imperatorin was about 4-fold stronger than that of isoimperatorin. (4) The vasodilatation effect of imperatorin was signifificantly attenuated to 24.88%+/-4.06% in the denuded endothelium group compared with the intact endothelium group. And 1 mmol/L L-NAME reduced the imperatorin-induced vasorelaxation by 32.18 %+/-11.29 %.

CONCLUSIONSThe principal effective component of Angelica dahurica var. Formosana was found to be imperatorin. Imperatorin-induced vasodilatation is at least partially regulated by nitric oxide, and has no correlation to beta-receptor.

Angelica ; chemistry ; Animals ; Chromatography, High Pressure Liquid ; Endothelium, Vascular ; physiology ; Furocoumarins ; analysis ; pharmacology ; Male ; Mice ; NG-Nitroarginine Methyl Ester ; pharmacology ; Nitric Oxide ; physiology ; Phenylephrine ; pharmacology ; Plant Extracts ; pharmacology ; Propranolol ; pharmacology ; Vasodilation ; drug effects

AIMTo investigate the influence and the mechanism of SK on the contractility of cultured cardiomyocytes of rats.

METHODSThe primary cultured single myocardial cell was treated with SK and the contraction frequency and size of cardiomyocyte were determined by a computer image analysis system. At the same time the effects of propranolol (a beta receptor antagonist), phentolamine (a alpha receptor antagonist), DSP (a tachykinin receptor antagonist) on the action of SK were investigated.

RESULTSSK increased contractive extend of the cardiomyocyte, in which a dose-response relationship of SK at 1.78 x 10(-8) - 1.78 x 10(-5) mol/L exists. But the frequency of contraction did not change, pretreatment with propranolol, phentolamine had no action on the effect of SK, but DSP markedly attenuated the effects of SK.

CONCLUSIONSK may directly enhance the contractility of single cardiomyocyte, which may be related with the tachykinin receptor.

Animals ; Animals, Newborn ; Benzylamines ; pharmacology ; Cells, Cultured ; Dose-Response Relationship, Drug ; Myocardial Contraction ; drug effects ; Myocytes, Cardiac ; drug effects ; physiology ; Neurokinin A ; pharmacology ; Phentolamine ; pharmacology ; Propranolol ; pharmacology ; Rats ; Rats, Wistar ; Receptors, Tachykinin ; antagonists & inhibitors