Renal,cardiac, and systemic hemodynamic effects of the dopamine receptor agonist SK&F 85174 in anesthetized dogs

SK&F 85174 is a mixed DA-1/DA-2 receptor agonist which is shown to inhibit sympathetic neurotransmission and cause hypotension in anesthetized animals. In this study, we have determined the regional and systemic hemodynamic effects of an intravenous infusion of SK&F 85174 (5 μg/kg/min for 5 min) in pentobarbital-anesthetized dogs and attempted to identify the dopamine receptor subtype(s) involved in the cardiac as well as vascular effects of this compound. SK&F 85174 produced significant decreases in mean blood pressure (MBP), left ventricular pressure (LVP), left ventricular dp/dt, total peripheral resistance (TPR) and renal vascular resistance (RVR), and a significant increase in renal blood flow (RBF). There were no significant changes in heart rate, cardiac output, coronary blood flow, or coronary vascular resistance. Prior treatment with SCH 23390 (DA-1 receptor antagonist) significantly attenuated the effects of SK&F 85174 on MBP, LVP, TPR, RBF, and RVR. In a second group of dogs S-sulpiride (DA-2 receptor antagonist) significantly antagonized the effects of SK&F 85174 on MBP, LVP, and dp/dt, but did not influence its effects on RBF, TPR, and RVR. These results show that (a) a decrease in total peripheral resistance and not the cardiac output accounts for the hypotensive action of SK&F 85174, (b) the renal hemodynamic effects of SK&F 85174 are mediated primarily via the activation of DA-1 receptors, and (c) whereas DA-1 receptors are involved primarily with the hypotensive action of this compound, it appears that activation of DA-2 receptors also contributes to the hypotension.     

Probucol reduces myocardial dysfunction during reperfusion after short-term ischemia in rabbit heart.

The effects of probucol, a lipophilic antioxidant, on the myocardial dysfunction (stunning) observed during reperfusion after 15-min ischemia in rabbit heart were studied. Rabbits received food with or without 1% probucol for 3 weeks. They were then anesthetized and prepared for recording of myocardial segment shortening, arterial blood pressure (BP), left ventricular pressure (LVP), rate of development of LVP (dP/dt), and a lead II ECG. Regional myocardial ischemia was produced by acute occlusion of the first marginal branch of the left coronary artery. Myocardial segment shortening was depressed after reperfusion in control rabbits. In comparison, myocardial segment shortening was significantly greater in probucol-treated rabbits than in control rabbits during reperfusion, indicating a beneficial effect. No hemodynamic or ECG changes measured could explain this difference. The number of premature ventricular contractions was reduced in the probucol-treated group, although the incidence of ventricular tachycardia (VT) and ventricular fibrillation (VF) were not. Concentrations of probucol in serum and heart of five rabbits were 15.0 +/- 1.2 micrograms/ml and 17.5 +/- 2.5 micrograms/g (mean +/- SEM), respectively. Only probucol concentrations in the serum were positively correlated with the improvement in myocardial segment shortening (r = 0.91, p = 0.03). We conclude that a clinically relevant serum concentration of probucol reduces ischemia-induced myocardial stunning in the rabbit.     

U50,488H抗大鼠缺血/再灌注损伤心律失常作用与抑制钠通道电流有关

目的观察κ阿片受体选择性激动剂(U50,488H)对大鼠心脏缺血/再灌注(ischemia and reperfusion,I/R)室性心律失常的影响并探讨其可能的机制。方法观察U50,488H对大鼠I/R整体动物模型血浆肌酸磷酸激酶(CK)、乳酸脱氢酶(LDH)水平的影响;分离正常大鼠心脏,采用Langen-dorff离体心脏灌流方法,预先给予U50,488H(5mmol·L-1)和NE(100μmol·L-1),测定其对血流动力学指标和对心律失常的影响;常规酶解法分离成年大鼠心室肌细胞,采用全细胞膜片钳技术观察U50,488H对钠电流的作用。结果①U50+I/R组血浆中CK和LDH的含量较I/R组明显降低(P<0.01)。②与I/R组相比,给予U50,488H后,心率明显下降(P<0.05)。③对照组偶发早搏,I/R组心律失常发生频率明显增加,与I/R组相比较,I/R+NE组心律失常评分明显增高(P<0.01);如果提前给予U50,488H,发现不仅可以明显降低I/R组缺血和再灌注期间室速和室颤的发生率(P<0.01)及降低I/R组心律失常的评分,而且明显降低I/R+NE组心律失常的评分(P<0.01)。④U50,488H(100μmol·L-1)可以明显降低心室肌细胞的钠电流(P<0.01)。结论κ阿片受体激动剂U50,488H对I/R时的心律失常有拮抗作用,其作用可能是通过抑制心肌细胞的钠电流而实现的。     

Increase of plasma renin activity after subcutaneous application of compound 48/80 in the rat

Subcutaneous (s.c.) administration of compound 48/80 (3.0 mg/kg) to conscious rats produced a time-dependent long-lasting increase of plasma renin activity (PRA). A dose-related increase of the hematocrit was also observed after injection of compound 48/80. The onset of the hematocrit increase preceded that of PRA increase. Pretreatment with a dose of more than 20 mg/kg of histamine H1-receptor antagonists such as tripelennamine or diphenhydramine prior to the injection of compound 48/80 (3.0 mg/kg s.c.) attenuated or abolished the effects of compound 48/80 on PRA, hematocrit and plasma extravasation. Pretreatment with cimetidine (histamine H2-receptor antagonist, 40 mg/kg i.p.) had no effect on these plasma variables. The increase of PRA caused by s.c. administration of compound 48/80 was not affected by the pretreatment with propranolol (beta-adrenoceptor antagonist, 10 mg/kg i.p.), which completely inhibited the isoproterenol (0.5 mg/kg s.c.)-induced PRA increase. Administration of compound 48/80 did not induce a significant PRA increase in the nephrectomized rats although the increase of hematocrit following s.c. administration of compound 48/80 persisted despite the absence of kidneys. S.c. administration of compound 48/80 (3.0 mg/kg) led to a significant decrease of histamine content at the site of injection and to a significant increase in plasma histamine concentration without affecting arterial blood pressure. The present data suggest that s.c. administration of compound 48/80 stimulates the release of histamine from cutaneous mast cells, which cause an increase in vascular permeability to plasma protein via the stimulation of histamine H1-receptors, then leads to hypovolemia. The resulting hypovolemia may directly stimulate the juxtraglomerular cells of the kidney to release renin.     

Congestive heart failure model in rabbits: effects of digoxin and a drug containing toad venom.

A low-output-type heart failure model was established in rabbits by protease treatment of the surface of the left ventricular anterior wall. Heart rate, aortic blood flow (AoF), left ventricular pressure (LVP) and maximal rate of rise of LVP (max dP/dt) in this model were maintained at lower levels than in normal rabbits, while left ventricular end-diastolic pressure (LVEDP) and systemic vascular resistance (SVR) were maintained at higher levels, and mean blood pressure (MBP) remained at a normal level. Intraduodenal administration of digoxin and a drug containing toad venom (Kyushin:KY) improved the hemodynamic parameters by increasing the AoF, LVP and max dP/dt and by decreasing the LVEDP and SVR without a significant change in MBP. These results suggest that the beneficial effects of digoxin and KY on this heart failure model originate from their cardiotonic activity.     

Effects of Y-27632, a selective Rho-kinase inhibitor, on myocardial preconditioning in anesthetized rats

The objective of this study was to examine the effects of Y-27632, a selective Rho-kinase inhibitor, on ischemic preconditioning (IP) and carbachol preconditioning (CP) in anesthetized rats. Administration of Y-27632 (0.1 mg/kg) produced slight, but not significant, reduction in mean arterial blood pressure and suppressed the total number of ventricular ectopic beats (VEBs). IP, induced by 5 min coronary artery occlusion and 5 min reperfusion, decreased the incidence of ventricular tachycardia (VT) from 100 (n=30) to 25% (n=24) and abolished the occurrence of ventricular fibrillation (VF) (40% in control group) during 30 min of ischemia. The incidences of VT and VF in Y-27632+IP group were found to be similar to IP group. Carbachol (4 microg/kg/min for 5 min) induced marked depressions in mean arterial blood pressure, heart rate and attenuated the total number of VEBs, but significant reductions in VT and VF incidences were noted in Y-27632+CP group. Y-27632 infusion for 5 min abolished VF occurrence. Marked reductions in plasma lactate levels were observed in all treatment and preconditioning groups. IP led to marked decrease in malondialdehyde levels. Decreases in infarct size were also observed with all groups when compared to control. These results suggest that infusion of Y-27632 was able to produce cardioprotective effects on myocardium against arrhythmias, infarct size or biochemical parameters and mimic the effects of ischemic preconditioning in anesthetized rats. Therefore, it is likely that inhibition of Rho-kinase is involved in the signaling cascade of myocardial preconditioning.     

MC(3) receptors are involved in the protective effect of melanocortins in myocardial ischemia/reperfusion-induced arrhythmias

Myocardial ischemia/reperfusion induces ventricular tachycardia (VT), ventricular fibrillation (VF) and a high degree of lethality. Since ACTH-(1-24) (adrenocorticotropin) protects against such injuries in rats, we investigated which melanocortin MC receptor is involved. Ischemia was produced in anesthetized rats by ligature of the left anterior descending coronary artery (5 min), and reperfusion-induced VT, VF, lethality and time-course of arterial blood pressure within the 5 min following reperfusion were evaluated. I.v. administration of the selective MC(3) receptor agonist gamma(1)-melanocyte-stimulating hormone (gamma(1)-MSH), as well as of an equimolar dose (162 nmol/kg) of both the non-selective agonist ACTH-(1-24) and alpha-MSH, significantly prevented VT and VF, and increased survival. Coronary reperfusion was followed by an abrupt and massive fall in mean arterial pressure and pulse pressure, in saline-treated rats. Treatment either with ACTH-(1-24) or gamma(1)-MSH completely prevented such fall. The protective effect of ACTH-(1-24) against the occurrence of VT, VF and lethality was neither affected by adrenalectomy, nor by i.v. pretreatment with the selective MC(4) receptor antagonist HS014 and the MC(4)-MC(5) antagonist HS059. On the other hand, the MC(3)-MC(4) receptor antagonist SHU 9119 prevented such protective effect. Moreover, the selective MC(1) receptor agonist MS05 (162 nmol/kg i.v.) failed to reduce the incidence of arrhythmias and lethality. These data demonstrate that MC(3) receptors mediate the protective effect of melanocortins in myocardial ischemia/reperfusion-induced arrhythmias, in rats.     

Role of endogenous serotonin and histamine in the pathogenesis of gastric mucosal lesions in unanaesthetised rats with a single treatment of compound 48/80, a mast cell degranulator.

In unanaethetised rats with a single injection of compound 48/80, a mast cell degranulator (0.75 mg kg-1, i.p.), gastric lesions occurred with increased serum serotonin and histamine levels and reduced gastric mucosal blood flow at 0.5 h after the injection and developed at 3 h. Pretreatment with either cyproheptadine (a serotonin and histamine antagonist) or methysergide (a serotonin antagonist) prevented the formation of gastric mucosal lesions with attenuation of reduced gastric mucosal blood flow at 0.5 h after compound 48/80 injection, while pretreatment with either amitriptyline (a selective inhibitor of histamine release from mast cells), tripelennamine (a histamine H1-receptor antagonist), famotidine (a histamine H2-receptor antagonist) or cimetidine (a histamine H2-receptor antagonist) had no effect. Pretreatment with either cyproheptadine, methysergide, amitriptyline or tripelennamine prevented the development of gastric mucosal lesions at 3 h after compound 48/80 injection, while pretreatment with either famotidine or cimetidine had no effect. These results indicate that in unanaesthetised rats with a single compound 48/80 treatment, acutely released endogenous serotonin causes gastric mucosal lesions, while released endogenous histamine mainly contributes to the lesion development and that gastric acid plays little role in the pathogenesis of the compound 48/80-induced acute gastric lesions.     

Lack of histamine involvement in parathyroid hormone hypotensive action

Promethazine and cimetidine blocked the hypotensive actions of 2-pyridylethylamine, and H1 agonist and dimaprit, an H2 agonist, respectively, but not that of bovine parathyroid hormone fragment [bPTH-(1-34)]. Rats were treated repeatedly with the histamine releaser, compound 48/80, until the release could no longer produce a decrease in blood pressure. The hypotensive action of bPTH-(1-34) could still be seen. Rats with histamine partially depleted with one injection of compound 48/80 were injected with cimetidine and pyrilamine, and H1 antagonist, which together blocked the hypotensive action of subsequent injections of compound 48/80, but not that of bPTH-(1-34). These data suggest that the vasodilatory action of bPTH-(1-34) does not involve the release or action of histamine.     

Peripheral hypotensive and central hypertensive effects of cimetidine

Rapid intravenous (i.v.) injections of high doses (16-128 mumol/kg) of cimetidine induced a short-lasting (5-15 min) hypotension in anaesthetized rats. Diastolic pressure was reduced more than systolic pressure, suggesting vasodilatation. Heart rate was not affected. Diphenhydramine pretreatment (100 mumol/kg i.v.) did not antagonize the hypotensive effect of cimetidine. However, in the presence of diphenhydramine, cimetidine induced bradycardia. Intracerebroventricular administration of cimetidine or metiamide (2 mumol/rat) increased the blood pressure and heart rate. It is concluded that the hypotension after i.v. cimetidine is mediated by peripheral mechanisms. Since diphenhydramine pretreatment had no antagonistic effect cimetidine-induced hypotension could not be due to indirect H1-receptor stimulation caused by histamine liberation.     

Cardiovascular and bronchial actions of famotidine in anesthetized dogs

The effects of famotidine (Gaster; CAS 76824-35-6) and cimetidine on cardiovascular and bronchial functions were investigated in anesthetized dogs. Famotidine did not affect heart rate, blood pressure, left ventricular pressure (LVP), max. dLVP/dt, cardiac output or coronary blood flow at i.v. doses of 1 to 30 mg/kg in open-chest dogs anesthetized with pentobarbital or a combination of nitrous oxide, oxygen and halothane (GOF). No hemodynamic changes were either observed after famotidine in pentobarbital anesthetized dogs whose cardiac function was depressed by propranolol (1 mg/kg i.v.). On the contrary, cimetidine dose-dependently decreased heart rate and blood pressure at doses greater than 3 mg/kg, and left ventricular pressure, cardiac output and coronary blood flow at the dose of 30 mg/kg. Regarding the electrocardiogram (ECG), famotidine did not produce any remarkable change at doses up to 30 mg/kg with the exception of a transient increase or decrease in the T-wave amplitude at a dose of 30 mg/kg. Cimetidine prolonged Q-T intervals of ECG in addition to changing the T-wave at a dose of 30 mg/kg. Neither famotidine nor cimetidine showed any effect on resting and histamine-increased bronchoresistance at doses up to 30 mg/kg. It is concluded that famotidine is superior to cimetidine with regard to safety because famotidine has no significant effects on cardiovascular functions in anesthetized dogs.     

Bethanidine Sulfate in Paroxysmal Ventricular Tachycardia: Toxicity and Antifibrillatory Actions

Programmed ventricular stimulation was used to test oral bethanidine sulfate in 10 patients with life-threatening ventricular arrhythmias. These patients had previously documented, recurrent, sustained ventricular tachycardia (VT) and/or ventricular fibrillation (VF) complicating stable heart disease. During control electrophysiologic studies, VT could be induced in all 10 patients: 6 with nonsustained VT, 3 with sustained VT, and 1 with VT/VF. After control, bethanidine 20–30 mg/kg was administered orally and beginning 60 minutes later, programmed ventricular stimulation was repeated. After bethanidine administration, VT could be induced in nine patients; in four, the VT was essentially unchanged from that induced during control studies. In four others, worse VT was induced after bethanidine. The remaining two patients had a potentially beneficial response to the drug. Bethanidine was poorly tolerated: seven patients had symptomatic orthostatic hypotension that persisted for several days despite concurrent protriptyline therapy. Furthermore, in four patients, spontaneous VT or VT/VF occurred 3–8 hours after the last dose. Nausea, vomiting, flushing, and blood pressure elevation were also noted. Bethanidine sulfate in the dosages used usually does not prevent the induction of VT by programmed ventricular stimulation and frequently causes serious toxicity. These findings suggest that the drug would be ineffective and poorly tolerated for long-term therapy in patients with serious ventricular arrhythmias.     

REPERFUSION ARRHYTHMIAS IN CLOSED-CHEST RATS: THE EFFECT OF MYOCARDIAL NORADRENALINE DEPLETION AND Ca2+-ANTAGONISM

1. The influence of myocardial noradrenaline depletion on the incidence and severity of reperfusion arrhythmias in closed-chest anaesthetized rats was investigated. Five-minute left coronary artery occlusion was carried out via an implanted occluder. Four groups of rats were studied: controls, rats treated with reserpine (5 mg/kg, intraperitoneally) 24 h before occlusion, and rats receiving 0.2 mg/kg gallopamil intravenously 5 min before occlusion either with or without reserpine pretreatment. 2. In the control group all animals had ventricular tachycardia (VT) and fibrillation (VF) immediately after reperfusion. Gallopamil reduced VT to 50% and VF to 25% (P less than 0.05 versus control). In the reserpine group all had VT, and 67% had VF, this being not significantly different from controls. Additional treatment with gallopamil markedly reduced VT and totally prevented VF (P less than 0.05 versus control). 3. Thus, total depletion of myocardial noradrenaline stores neither prevented the occurrence nor reduced the severity of reperfusion arrhythmia in rats, while gallopamil treatment was effective.     

急性心肌梗塞后QT离散度改变及临床意义

分析了６６例急性心肌梗塞（ＡＭＩ）病人的ＱＴ间期，ＱＴｃ离散度（ＱＴｃｄ），ＪＴｃ离散度（ＪＴｃｄ）ＱＲＳ离散度（ＱＲＳｄ）的变化。结果显示除ＱＴｃｍｉｎ，ＱＲＳｄ外ＱＴｃｍａｘ，ＱＴｃｄ，ＪＴｏｄ在ＡＭＩ后４８小时内均显著增加；第２周显著降低（Ｐ〈０．０１），其中溶栓治疗再灌注组国无灌注和非溶有下降更为显著（Ｐ〈０．０１）；第３～４周再灌注组明显回升（Ｐ〈０．０１），无再灌注和非溶栓组则无变化，     

Effect of cimetidine on the mucosal hydroxyproline content of rat gastric lesions induced by compound 48/80.

Extensive gastric mucosal lesions developed in rats after the administration of compound 48/80 at a dose of 0.75 mg/kg daily for 3 days. The hydroxyproline content of gastric mucosa was significantly increased 4 h after the last injection of compound 48/80, and subsequently decreased as the lesions healed. Treatment with cimetidine (CAS 51481-61-9) at a dose of 50 mg/kg (twice a day for 3 days) did not affect either the development or the healing of the compound 48/80-induced gastric lesions. However, the increase in mucosal hydroxyproline content was significantly reduced by treatment with cimetidine. This fact suggests that cimetidine might have an inhibitory effect on the regeneration of collagen in gastric mucosa.     

Pharmacology of Casimiroa edulis; II. Cardiovascular effects in the anesthesized dog

The cardiovascular effects of an aqueous extract of seeds of Casimiroa edulis were assessed in pentobarbital-anesthetized dogs. The extract produced marked hypotension which lasted more than two hours; it was accompanied by moderate and less persistent bradycardia. The histaminergic nature of these effects was investigated in animals pretreated with the specific antagonists diphenhydramine, cimetidine, or a combination of both agents. These experiments showed that both H1- and H2-receptors were involved in the hypotensive response, while the bradycardia was mediated solely through an H1-mechanism. In open-chest dogs instrumented for recording cardiac output (ascending aortic flow), left ventricular contractility (dp/dt), central venous pressure (superior vena cava), systemic blood pressure, heart rate, total peripheral resistance and stroke volume, the extract decreased blood pressure and peripheral resistance and increased cardiac output and stroke volume, without modifying the other parameters. It was concluded that the cardiovascular pattern of Casimiroa edulis in the dog is that of a peripheral arterial vasodilator and that it increases cardiac output by reducing left ventricular afterload.     

HISTAMINE ENHANCES HYPOXIA-INDUCED VENTRICULAR ARRHYTHMIAS IN ISOLATED RAT HEARTS

1. The effects of hypoxia, histamine-receptor agonist perfusion, and their combination on cardiac rhythm were studied in isolated rat hearts. 2. While hypoxia induced a high incidence of ventricular tachycardia or fibrillation, only a few preparations developed ventricular arrhythmias in response to perfusion with high concentration of histamine, 2-pyridylethylamine or impromidine. 3. The times of onset of hypoxia-induced ventricular arrhythmias were significantly shortened by perfusion with either histamine, 2-pyridylethylamine or impromidine. The accelerated occurrence of hypoxia-induced ventricular arrhythmias by histamine was significantly abolished by pretreatment with either diphenhydramine or cimetidine. 4. The results indicate that hypoxia and histamine can increase ventricular vulnerability of the rat heart to each other. It is also suggested that the arrhythmogenic actions of histamine in hypoxic rat hearts are mediated by both histamine H1-and H2-receptors.     

CDP-choline prevents cardiac arrhythmias and lethality induced by short-term myocardial ischemia–reperfusion injury in the rat: involvement of central muscarinic cholinergic mechanisms

In the present study, we aimed to determine whether cytidine-5'-diphosphatecholine (CDP-choline or citicoline) can improve the outcome of short-term myocardial ischemia-reperfusion injury in rats. Ischemia was produced in anesthetized rats by ligature of the left anterior descending coronary artery for 7 min followed by a reperfusion period of 7 min. Reperfusion-induced ventricular tachycardia (VT), ventricular fibrillation (VF), survival rate, and changes in arterial pressure were evaluated. Saline (1 ml/kg), CDP-choline (100, 250,and 500 mg/kg), or lidocaine (5 mg/kg) was intravenously injected in the middle of the ischemic period. Intracerebroventricular (i.c.v.) mecamylamine (50 microg) or atropine sulfate (10 microg) pretreatments were made 10 min before the coronary occlusion period. Pretreatment with intravenous (i.v.) atropine methylnitrate (2 and 5 mg/kg; i.v.) or bilateral vagotomy was performed 5 min before the induction of ischemia. An in vivo microdialysis study was performed in the nucleus ambiguus area (NA); choline and acetylcholine levels were measured in extracellular fluids. In control rats, VT, VF, and lethality were observed in 85%, 60% and 50% of the animals, respectively. Intravenous CDP-choline produced a short-term increase in blood pressure and reduced the incidence of VT, VF, and lethality dose-dependently when injected in the middle of the ischemic period. CDP-choline at doses of 250 and 500 mg/kg completely prevented death. Intracerebroventricular atropine sulfate pretreatment completely abolished the protective effect of CDP-choline, while mecamylamine pretreatment had no effect on the drug. CDP-choline increased the levels of extracellular choline and acetylcholine in the NA area. Bilateral vagotomy completely abolished the protective effect of CDP-choline in the reperfusion period. Moreover, the intravenous pretreatment with atropine methylnitrate produced dose-dependent blockade in the reduction of VT, VF, and mortality rates induced by CDP-choline. Neither of these pretreatments except mecamylamine affected the pressor effect of CDP-choline. Intracerebroventricular mecamylamine attenuated the increase in blood pressure induced by CDP-choline. In conclusion, intravenously injected CDP-choline prevents cardiac arrhythmias and death induced by short-term myocardial ischemia-reperfusion injury. Activation of central muscarinic receptors and vagal pathways mediates the protective effect of CDP-choline. The protective effect of CDP-choline is not related to its pressor effect.     

Effects of ranitidine and cimetidine on experimentally induced ventricular arrhythmias in anaesthetized rats

The effects of two histamine H2-receptor antagonists, ranitidine and cimetidine, on ventricular arrhythmias induced by acute coronary artery ligation and by aconitine infusion were studied in pentobarbitone-anaesthetized rats. The changes in arterial blood pressure and heart rate were also observed. It was found that both drugs significantly reduced the incidence, and prolonged the time of onset, of ventricular tachycardia and ventricular fibrillation following acute coronary artery ligation; however, they did not significantly alter the incidence or time of onset of ventricular dysrhythmias caused by aconitine infusion. These findings further support the hypothesis that histamine release may contribute to the genesis of early ventricular arrhythmias resulting from acute myocardial ischaemia. Since the decreased blood pressure induced by coronary artery ligation was not significantly prevented by pretreatment with either histamine H2-receptor blocker, this suggests that histamine may not be responsible for the blood pressure changes during acute myocardial ischaemia.