Protective effects of calcium antagonists, chlorpromazine (CPZ) and nimodepine (NI-MO), on cadmium-induced toxicity were investigated. After giving CdCl2 (0. 44mg Cd/kg,ip), CPZ (5mg/kg, ip) or NIMO (8mg/kg, po) were ...Protective effects of calcium antagonists, chlorpromazine (CPZ) and nimodepine (NI-MO), on cadmium-induced toxicity were investigated. After giving CdCl2 (0. 44mg Cd/kg,ip), CPZ (5mg/kg, ip) or NIMO (8mg/kg, po) were administered every day to Sprague-Dawley (S. D. ) rats for a week. Then, urinary N- acetyl-β-D- glucosaminidase (NAG ), uri -nary cadmium and bloocl cadmium were measured. The accumulation of cadmium in the kid-ney cortex, content of renal calmodulin, hemoglobin and the ultrastructural damage of proxi-mal convoluted tubules of rats were examined three weeks after the last administration. Re-sults indicated that the calcium antagonists partly protected against toxic effects induced bycadmium in different manners. These data provide further evidence for the new hypothesisthat the cross effect of cadmium and calcium in calmodulin regulated systems may be responsi-ble for the mechanism of cadmium intoxication. 'The results suggested that the calcium antag-onists could be a new and promising approach in the therapy of heavy metaLinduced diseases展开更多
The authors report the effects of a calcium antagonist, nimodipine, on severe craniocerebral trauma.A total of 488 cases of severe craniocerebral trauma with Glasgow Coma Scale (GCS) 3～8 score were recruited into the...The authors report the effects of a calcium antagonist, nimodipine, on severe craniocerebral trauma.A total of 488 cases of severe craniocerebral trauma with Glasgow Coma Scale (GCS) 3～8 score were recruited into the clinical study. The patients were divi展开更多
Objective To explore the toxic effects of mercuric chloride (HgCl 2) on vascular smooth muscle as well as its relationship to calcium antagonist. Methods By using isolated vascular tension methods, we studied the...Objective To explore the toxic effects of mercuric chloride (HgCl 2) on vascular smooth muscle as well as its relationship to calcium antagonist. Methods By using isolated vascular tension methods, we studied the effect of HgCl 2 on isolated rabbit aortic rings. Results HgCl 2 (1-100 μmol·L -1) caused a concentration-dependent contraction of rabbit aortic rings, which did not change with phentolamin or without endothelium. In KH solution with Ca 2+ , the maximum contraction amplitude reduced by(61.2±3.3)%. Nifedipine produced a concentration-dependent decrease of the maximum contraction amplitude. Conclusion Calcium antagonist has protective effects on vascular smooth muscle against damage induced by HgCl 2.展开更多
Intracellular Ca2＋ and Ca2＋-dependent signaling molecule play an essential role in the genesis of long-QT （LQT） syndrome-related ventricular arrhythmias. The effect of calcium-channel antagonist verapamil on repol...Intracellular Ca2＋ and Ca2＋-dependent signaling molecule play an essential role in the genesis of long-QT （LQT） syndrome-related ventricular arrhythmias. The effect of calcium-channel antagonist verapamil on repolarization heterogeneity of ventricular myocardium was assessed in an in vitro rabbit model of LQT syndrome. By using the monophasic action potential （MAP） recording technique, MAPs of epicardium, mid-myocardium and endocardium were simultaneously recorded by specially designed plunge-needle electrodes across the left ventricular free wall in rabbit hearts purfused by Langendorff method with standard Tyrode＇s solution. Bradycardia was induced by com- plete ablation of atrioventricular node. A catheter was introduced into the right ventricle to pace at the cycle lengths （CLs） of 1500, 1000, and 500 ms, successively. Quinidine （2 μmol/L） prolonged QT interval and ventricular MAP duration （MAPD）, and increased transmural dispersion of repolarization （TDR） in a reverse rate-dependent fashion in isolated rabbit heart. No polymorphic ventricular tachycardias were induced under this condition. The effective free therapeutic plasma concentrations of verapamil （0.01--0.05μmol/L） used in this experiment had no effect on quinidine-induced changes of QT interval, MAPD and TDR. This study demonstrated that, in this model of LQT syndrome, blockade of calcium-channel with verapmil had no effect on quinidine-induced changes of repolatiation heterogeneity of ventricular myocardium.展开更多
A new method for the synthesis of 1,4-dihydropyridine(1,4-DHP)calcium channel antagonists felodipme, nitrendipine and their derivatives via papain-catalyzed three-component reactions of aldehyde,methyl acetoacetate an...A new method for the synthesis of 1,4-dihydropyridine(1,4-DHP)calcium channel antagonists felodipme, nitrendipine and their derivatives via papain-catalyzed three-component reactions of aldehyde,methyl acetoacetate and ethyl 3-aminocrotonate was developed.Operational simplicity,mild reaction conditions and eco-friendliness are the key features of this protocol.展开更多
AIM:To investigate the relationship between exerciseprovoked esophageal motility disorders and the prognosis for patients with chest pain.METHODS:The study involved 63 subjects with recurrent angina-like chest pain no...AIM:To investigate the relationship between exerciseprovoked esophageal motility disorders and the prognosis for patients with chest pain.METHODS:The study involved 63 subjects with recurrent angina-like chest pain non-responsive to empirical therapy with proton pump inhibitor(PPI).In all,a coronary artery angiography,panendoscopy,24-h esophageal pH-metry and manometry,as well as a treadmill stress test with simultaneous esophageal pH-metry and manometry monitoring,were performed.Thirtyfive subjects had no significant coronary artery lesions,and 28 had more than 50% coronary artery narrowing.In patients with hypertensive esophageal motility disorders,a calcium antagonist was recommended.The average follow-up period was 977 ± 249 d.RESULTS:The prevalence of esophageal disorders,such as gastroesophageal reflux or diffuse esophageal spasm,was similar in patients both with and without significant coronary artery narrowing.Exercise prompted esophageal motility disorders,such as a decrease in the percentage of peristaltic and effective contractions and their amplitude,as well as an increase in the percentage of simultaneous and non-effective contractions.In 14(22%) patients the percentage of simultaneous contractions during the treadmill stress test exceeded the value of 55%.Using Kaplan-Meier analysis and the proportional hazard Cox regression model,it was shown that the administration of a calcium channel antagonist in patients with such an esophageal motility disorder significantly decreased the risk of hospitalization as a result of a suspicion of acute coronary syndrome after the 2.7-year follow-up period.CONCLUSION:In patients with chest pain non-responsive to PPIs,a diagnosis of exercise-provoked esophageal spasm may have the effect of lowering the risk of the next hospitalization.展开更多
Objective To investigate the spasmolytic and anti-diarrheal activities of 3,4-dihydro-2-(4-morpholinylmethy)-1(2H)-naphthalenone(CY),which was first synthesized by Welch,Willard M et al.in 1977.Methods The spasmolytic...Objective To investigate the spasmolytic and anti-diarrheal activities of 3,4-dihydro-2-(4-morpholinylmethy)-1(2H)-naphthalenone(CY),which was first synthesized by Welch,Willard M et al.in 1977.Methods The spasmolytic effects of CY were tested on isolated rabbit small intestine at the concentration of 0.01 to 3 mM;the diarrheal-index was evaluated on diarrhea mice to study the anti-diarrheal activities of CY.Results CY(0.1-1 mM)inhibited spontaneous motility of rabbit small intestine and at the concentration of 0.01 to 3 mM CY inhibited the contractile response of rabbit small intestine and colon induced by acetylcholine(10-2 mg·mL-1),high K+(60 mM)and BaCl2(1 mg·mL-1).When tested against calcium channel blocked in rabbit small intestine and colon,CY caused a rightward shift in the Ca2+ dose-response curves,similar to that produced by verapamil,a well-known calcium antagonist.CY could inhibit the diarrhea induced by castor oil,MgSO4 and liquid paraffin and LD50 of CY is 277.2 mg·kg-1.Conclusions CY may produce its spasmolytic and anti-diarrheal effects as a calcium antagonist.展开更多
The aim of this study was to clarify the response of sympathetic activity to antihypertensive drugs using a mental stress test in hypertensive patients and to determine the effects of antihypertensive drugs on the sym...The aim of this study was to clarify the response of sympathetic activity to antihypertensive drugs using a mental stress test in hypertensive patients and to determine the effects of antihypertensive drugs on the sympathetic activitymediated hemodynamic response to mental stress. Hypertensive patients were divided into three groups according to the type of drug(s) being taken: a calcium antagonist group, an angiotensin II receptor blocker group, and a combination therapy group of calcium antagonists and angiotensin II receptor blockers. The Stroop color-word conflict test was applied as a mental stress test and hemodynamic responses to mental stress were measured, including blood pressure, pulse rate, and skin blood flow. Elevation of blood pressure by mental stress was suppressed in the combination therapy group compared with the calcium antagonist group. Reduction of skin blood flow by mental stress was suppressed in both the angiotensin II blocker group and the combination therapy group compared with the calcium antagonist group. In conclusion, skin blood flow can be a useful tool to evaluate sympathetic activity and combination therapy with calcium antagonists and angiotensin II receptor blockers were the most useful therapy for suppressing the hemodynamic response to mental stress.展开更多
AIM: To investigate the pathway (s) mediating rat antral circular smooth muscle contractile responses to the cholinomimetic agent, bebhanechol and the subtypes of muscarinic receptors mediating the cholinergic contrac...AIM: To investigate the pathway (s) mediating rat antral circular smooth muscle contractile responses to the cholinomimetic agent, bebhanechol and the subtypes of muscarinic receptors mediating the cholinergic contraction. METHODS: Circular smooth muscle strips from the antrum of Sprague-Dawley rats were mounted in muscle baths in Krebs buffer. Isometric tension was recorded. Cumulative concentration-response curves were obtained for (+)-cisdioxolane (cD), a nonspecific muscarinic agonist, at 10^-8-10^-4mol/L, in the presence of tetrodotoxin (TTX, 10^-7mol/L). Results were normalized to cross sectional area. A repeat concentration-response curve was obtained after incubation of the muscle for 90min wibh antagonists for M1(pirenzepine), M2(methoctramine) and M3(darifenacin) muscarinic receptor subtypes. The sensitivity to PTX was tested by the ip injection of 100mg/kg of PTX 5d before the experiment. The antral circular smooth muscles were removed from PTX-treated and non-treated rats as strips and dispersed smooth muscle cells to identify whether PTX-linked pathway mediated the contractility to bethanechol. RESULTS: A dose-dependent contractile response observed with bethanechol, was not affected by TTX. The pretreatment of rats with pertussis toxin decreased the contraction induced by bethanechol. Lack of calcium as well as the presence of the L-type calcium channel blocker, nifedipine, also inhibited the cholinergic contraction, with a reduction in responsefrom 2.5±0.4g/mm^2 to 1.2±0.4g/mm^2(P<0.05), The doseresponse curves were shifted to the right by muscarinic antagonists in the following order of affinity: darifenacin (M3)>methocramine (M2)>pirenzepine (M1). CONCLUSION: The muscarinic receptors-dependent contraction of rat antral circular smooth muscles was linked to the signal transduction pabhway(s) involving pertussis-toxin sensitive GTP-binding proteins and to extracellular calcium via L-type voltage gated calcium channels. The presence of the residual contractile response after the treatment with nifedipine, suggests that an additional pathway could mediate the cholinergic contraction. The involvement of more than one muscarinic receptor (functionally predominant type 3 over type 2) also suggests more than one pathway mediating the cholinergic contraction in rat antrum.展开更多
Primary aldosteronism(PA)is the most common form of secondary hypertension,with its main manifestations including hypertension and hypokalemia.Early identification of PA is extremely important as PA patients can easil...Primary aldosteronism(PA)is the most common form of secondary hypertension,with its main manifestations including hypertension and hypokalemia.Early identification of PA is extremely important as PA patients can easily develop cardiovascular complications such as atrial fibrillation,stroke,and myocardial infarction.The past decade has witnessed the rapid advances in the genetics of PA,which has shed new light on PA treatment.While surgery is the first choice for unilateral diseases,bilateral lesions can be treated with mineralocorticoid receptor antagonists(MRAs).The next-generation non-steroidal MRAs are under investigations.New medications including calcium channel blockers,macrophage antibiotics,and aldosterone synthase inhibitors have provided a new perspective for the medical treatment of PA.展开更多
文摘Protective effects of calcium antagonists, chlorpromazine (CPZ) and nimodepine (NI-MO), on cadmium-induced toxicity were investigated. After giving CdCl2 (0. 44mg Cd/kg,ip), CPZ (5mg/kg, ip) or NIMO (8mg/kg, po) were administered every day to Sprague-Dawley (S. D. ) rats for a week. Then, urinary N- acetyl-β-D- glucosaminidase (NAG ), uri -nary cadmium and bloocl cadmium were measured. The accumulation of cadmium in the kid-ney cortex, content of renal calmodulin, hemoglobin and the ultrastructural damage of proxi-mal convoluted tubules of rats were examined three weeks after the last administration. Re-sults indicated that the calcium antagonists partly protected against toxic effects induced bycadmium in different manners. These data provide further evidence for the new hypothesisthat the cross effect of cadmium and calcium in calmodulin regulated systems may be responsi-ble for the mechanism of cadmium intoxication. 'The results suggested that the calcium antag-onists could be a new and promising approach in the therapy of heavy metaLinduced diseases
文摘The authors report the effects of a calcium antagonist, nimodipine, on severe craniocerebral trauma.A total of 488 cases of severe craniocerebral trauma with Glasgow Coma Scale (GCS) 3～8 score were recruited into the clinical study. The patients were divi
文摘Objective To explore the toxic effects of mercuric chloride (HgCl 2) on vascular smooth muscle as well as its relationship to calcium antagonist. Methods By using isolated vascular tension methods, we studied the effect of HgCl 2 on isolated rabbit aortic rings. Results HgCl 2 (1-100 μmol·L -1) caused a concentration-dependent contraction of rabbit aortic rings, which did not change with phentolamin or without endothelium. In KH solution with Ca 2+ , the maximum contraction amplitude reduced by(61.2±3.3)%. Nifedipine produced a concentration-dependent decrease of the maximum contraction amplitude. Conclusion Calcium antagonist has protective effects on vascular smooth muscle against damage induced by HgCl 2.
基金This project was supported by a grant from the National Natural Sciences Foundation of China (No 30470714)
文摘Intracellular Ca2＋ and Ca2＋-dependent signaling molecule play an essential role in the genesis of long-QT （LQT） syndrome-related ventricular arrhythmias. The effect of calcium-channel antagonist verapamil on repolarization heterogeneity of ventricular myocardium was assessed in an in vitro rabbit model of LQT syndrome. By using the monophasic action potential （MAP） recording technique, MAPs of epicardium, mid-myocardium and endocardium were simultaneously recorded by specially designed plunge-needle electrodes across the left ventricular free wall in rabbit hearts purfused by Langendorff method with standard Tyrode＇s solution. Bradycardia was induced by com- plete ablation of atrioventricular node. A catheter was introduced into the right ventricle to pace at the cycle lengths （CLs） of 1500, 1000, and 500 ms, successively. Quinidine （2 μmol/L） prolonged QT interval and ventricular MAP duration （MAPD）, and increased transmural dispersion of repolarization （TDR） in a reverse rate-dependent fashion in isolated rabbit heart. No polymorphic ventricular tachycardias were induced under this condition. The effective free therapeutic plasma concentrations of verapamil （0.01--0.05μmol/L） used in this experiment had no effect on quinidine-induced changes of QT interval, MAPD and TDR. This study demonstrated that, in this model of LQT syndrome, blockade of calcium-channel with verapmil had no effect on quinidine-induced changes of repolatiation heterogeneity of ventricular myocardium.
基金the National Natural Science Foundation of China(No.21706236)the China Postdoctoral Science Foundation (No.2016M592012)the Foundation for Selected Postdoctoral Project of Zhejiang Province,China(No.BSH1502150).
文摘A new method for the synthesis of 1,4-dihydropyridine(1,4-DHP)calcium channel antagonists felodipme, nitrendipine and their derivatives via papain-catalyzed three-component reactions of aldehyde,methyl acetoacetate and ethyl 3-aminocrotonate was developed.Operational simplicity,mild reaction conditions and eco-friendliness are the key features of this protocol.
基金Supported by A Grant from the Nicolaus Copernicus University in Toruń, Ludwik Rydygier Collegium Medicum in Bydgoszcz for the statutory activity of the Department of Gastroenterology, Vascular Diseases, and Internal Medicine
文摘AIM:To investigate the relationship between exerciseprovoked esophageal motility disorders and the prognosis for patients with chest pain.METHODS:The study involved 63 subjects with recurrent angina-like chest pain non-responsive to empirical therapy with proton pump inhibitor(PPI).In all,a coronary artery angiography,panendoscopy,24-h esophageal pH-metry and manometry,as well as a treadmill stress test with simultaneous esophageal pH-metry and manometry monitoring,were performed.Thirtyfive subjects had no significant coronary artery lesions,and 28 had more than 50% coronary artery narrowing.In patients with hypertensive esophageal motility disorders,a calcium antagonist was recommended.The average follow-up period was 977 ± 249 d.RESULTS:The prevalence of esophageal disorders,such as gastroesophageal reflux or diffuse esophageal spasm,was similar in patients both with and without significant coronary artery narrowing.Exercise prompted esophageal motility disorders,such as a decrease in the percentage of peristaltic and effective contractions and their amplitude,as well as an increase in the percentage of simultaneous and non-effective contractions.In 14(22%) patients the percentage of simultaneous contractions during the treadmill stress test exceeded the value of 55%.Using Kaplan-Meier analysis and the proportional hazard Cox regression model,it was shown that the administration of a calcium channel antagonist in patients with such an esophageal motility disorder significantly decreased the risk of hospitalization as a result of a suspicion of acute coronary syndrome after the 2.7-year follow-up period.CONCLUSION:In patients with chest pain non-responsive to PPIs,a diagnosis of exercise-provoked esophageal spasm may have the effect of lowering the risk of the next hospitalization.
文摘Objective To investigate the spasmolytic and anti-diarrheal activities of 3,4-dihydro-2-(4-morpholinylmethy)-1(2H)-naphthalenone(CY),which was first synthesized by Welch,Willard M et al.in 1977.Methods The spasmolytic effects of CY were tested on isolated rabbit small intestine at the concentration of 0.01 to 3 mM;the diarrheal-index was evaluated on diarrhea mice to study the anti-diarrheal activities of CY.Results CY(0.1-1 mM)inhibited spontaneous motility of rabbit small intestine and at the concentration of 0.01 to 3 mM CY inhibited the contractile response of rabbit small intestine and colon induced by acetylcholine(10-2 mg·mL-1),high K+(60 mM)and BaCl2(1 mg·mL-1).When tested against calcium channel blocked in rabbit small intestine and colon,CY caused a rightward shift in the Ca2+ dose-response curves,similar to that produced by verapamil,a well-known calcium antagonist.CY could inhibit the diarrhea induced by castor oil,MgSO4 and liquid paraffin and LD50 of CY is 277.2 mg·kg-1.Conclusions CY may produce its spasmolytic and anti-diarrheal effects as a calcium antagonist.
文摘The aim of this study was to clarify the response of sympathetic activity to antihypertensive drugs using a mental stress test in hypertensive patients and to determine the effects of antihypertensive drugs on the sympathetic activitymediated hemodynamic response to mental stress. Hypertensive patients were divided into three groups according to the type of drug(s) being taken: a calcium antagonist group, an angiotensin II receptor blocker group, and a combination therapy group of calcium antagonists and angiotensin II receptor blockers. The Stroop color-word conflict test was applied as a mental stress test and hemodynamic responses to mental stress were measured, including blood pressure, pulse rate, and skin blood flow. Elevation of blood pressure by mental stress was suppressed in the combination therapy group compared with the calcium antagonist group. Reduction of skin blood flow by mental stress was suppressed in both the angiotensin II blocker group and the combination therapy group compared with the calcium antagonist group. In conclusion, skin blood flow can be a useful tool to evaluate sympathetic activity and combination therapy with calcium antagonists and angiotensin II receptor blockers were the most useful therapy for suppressing the hemodynamic response to mental stress.
文摘AIM: To investigate the pathway (s) mediating rat antral circular smooth muscle contractile responses to the cholinomimetic agent, bebhanechol and the subtypes of muscarinic receptors mediating the cholinergic contraction. METHODS: Circular smooth muscle strips from the antrum of Sprague-Dawley rats were mounted in muscle baths in Krebs buffer. Isometric tension was recorded. Cumulative concentration-response curves were obtained for (+)-cisdioxolane (cD), a nonspecific muscarinic agonist, at 10^-8-10^-4mol/L, in the presence of tetrodotoxin (TTX, 10^-7mol/L). Results were normalized to cross sectional area. A repeat concentration-response curve was obtained after incubation of the muscle for 90min wibh antagonists for M1(pirenzepine), M2(methoctramine) and M3(darifenacin) muscarinic receptor subtypes. The sensitivity to PTX was tested by the ip injection of 100mg/kg of PTX 5d before the experiment. The antral circular smooth muscles were removed from PTX-treated and non-treated rats as strips and dispersed smooth muscle cells to identify whether PTX-linked pathway mediated the contractility to bethanechol. RESULTS: A dose-dependent contractile response observed with bethanechol, was not affected by TTX. The pretreatment of rats with pertussis toxin decreased the contraction induced by bethanechol. Lack of calcium as well as the presence of the L-type calcium channel blocker, nifedipine, also inhibited the cholinergic contraction, with a reduction in responsefrom 2.5±0.4g/mm^2 to 1.2±0.4g/mm^2(P<0.05), The doseresponse curves were shifted to the right by muscarinic antagonists in the following order of affinity: darifenacin (M3)>methocramine (M2)>pirenzepine (M1). CONCLUSION: The muscarinic receptors-dependent contraction of rat antral circular smooth muscles was linked to the signal transduction pabhway(s) involving pertussis-toxin sensitive GTP-binding proteins and to extracellular calcium via L-type voltage gated calcium channels. The presence of the residual contractile response after the treatment with nifedipine, suggests that an additional pathway could mediate the cholinergic contraction. The involvement of more than one muscarinic receptor (functionally predominant type 3 over type 2) also suggests more than one pathway mediating the cholinergic contraction in rat antrum.
基金Supported by the Non-profit Central Research Institute Fund of Chinese Academy of Medical Sciences(2019XK320027).
文摘Primary aldosteronism(PA)is the most common form of secondary hypertension,with its main manifestations including hypertension and hypokalemia.Early identification of PA is extremely important as PA patients can easily develop cardiovascular complications such as atrial fibrillation,stroke,and myocardial infarction.The past decade has witnessed the rapid advances in the genetics of PA,which has shed new light on PA treatment.While surgery is the first choice for unilateral diseases,bilateral lesions can be treated with mineralocorticoid receptor antagonists(MRAs).The next-generation non-steroidal MRAs are under investigations.New medications including calcium channel blockers,macrophage antibiotics,and aldosterone synthase inhibitors have provided a new perspective for the medical treatment of PA.
