Central cardiovascular effects of acetylcholine in the conscious dog.

1. The effects of central cholinomimetic drugs on cardiovascular and vasoactive hormonal responses (blood pressure, heart rate, catecholamines, vasopressin, atrial natriuretic factor, neuropeptide Y plasma levels and plasma renin activity) were investigated in conscious Beagle dogs. For this purpose a catheter was chronically implanted into each dog's cisterna magna to allow repeated central injections in the awake animals. 2. Intracisternal acetylcholine (20 micrograms kg-1) significantly increased systolic and diastolic blood pressure. These changes were accompanied by an initial short term tachycardia followed by a long lasting bradycardia. Intracisternal acetylcholine also increased noradrenaline, adrenaline and vasopressin plasma levels, decreased plasma renin activity but did not modify plasma levels of neuropeptide Y and atrial natriuretic factor. 3. The effects of acetylcholine were completely abolished by pretreatment with intracisternal injection of the muscarinic antagonist, atropine (5 micrograms kg-1) but not by the intracisternal injection of the nicotinic antagonist, mecamylamine (25 micrograms kg-1). 4. The present results demonstrate that there are qualitative and quantitative differences between the central cardiovascular effects of acetylcholine in conscious dogs compared to what we previously reported, using a comparable protocol, in anaesthetized dogs. Under both conditions, we observed a central cholinergically mediated increase in blood pressure secondary to an increase in sympathetic tone and vasopressin release but these responses were shorter (less than 10 min) in the conscious dogs than in anaesthetized dogs (more than 10 min).(ABSTRACT TRUNCATED AT 250 WORDS)     

清醒Beagle犬安全药理心血管呼吸遥测系统验证研究

目的选用呼吸系统阳性药对Beagle犬心血管呼吸遥测系统进行性能验证。方法 8只埋植植入子的清醒Beagle犬隔日依次静脉注射给予生理盐水、盐酸多沙普仑(4 mg·kg-1)、盐酸瑞芬太尼(4μg·kg-1)和盐酸索他洛尔(10 mg·kg-1)。实验时连续获取每次给药前至少2 h及给药后24 h内数据,包括血压、心电图、呼吸等指标。结果生理盐水对各参数无明显影响。呼吸兴奋药盐酸多沙普仑可导致动物呼吸频率和潮气量明显增加,伴有血压及心率的增加。呼吸抑制药盐酸瑞芬太尼可导致动物呼吸潮气量明显减少,对呼吸频率作用不明显。QT间期(QTcf)延长阳性药盐酸索他洛尔可导致动物心电图心率校正的QTcf明显延长,最大变化率约11%。结论本系统可灵敏检测到心血管、呼吸系统的相关变化,可用于清醒动物心血管呼吸系统安全药理学研究。     

Effects of hypoxia and hypoglycaemia on DC potentials recorded from the gerbil hippocampus in vitro

Summary The acute effects of hypoxia and/or hypoglycaemia on DC potentials recorded from CA1 pyramidal neurones of the gerbil hippocampal slice maintained in vitro were investigated. Depolarizing potential changes were recorded when the slice was superfused with the excitatory amino acid agonists: NMDA (N-methyl-D-aspartic acid; 3 – 30 M), AMPA ((RS)-amino-3-hydroxy-5-methyl-4-isoxazole-propionate; 1 – 30 M), kainate (3 – 100 g M) and L-glutamate (1 – 10 mM). In response to a 20 min period of superfusion with an hypoxic artificial CSF solution at 30°C, a transient depolarization occurred followed by a marked hyperpolarization. A further hyperpolarization occurred when superfusion of the slice with an oxygenated artificial CSF recommenced. Post-hypoxia, when the neurones had repolarized, the response to NMDA (10 M) was less than the pre-hypoxic response. The extent of the depression of the NMDA response was found to depend on three variables: (a) the duration of the period of hypoxia, (b) the glucose concentration of the artificial CSF, and (c) the temperature of the slice. As the duration of hypoxia was increased, the depression of the NMDA response was more marked. Reduction of the glucose concentration from 11 mM to 2 mM by partial substitution with sucrose (9 mM) made the tissues more sensitive to the effects of hypoxia, whereas reduction of the temperature from 30°C to 20°C made them less sensitive. The depression of the response to NMDA was observed over a range of concentrations of NMDA. The concentration response curve for AMPA was also flattened, however, the depolarizations in response to kainate or GABA were preserved. Thus, the gerbil hippocampal slice responds to hypoxia with a depolarizing/hyperpolarizing sequence of potential changes, and a post-hypoxic depression of the response of the slice to NMDA or AMPA. The present experiments do not distinguish between receptor desensitization or acute neurotoxicity as the mechanism of the depression of neuronal responses.Send offprint requests to H. Rogers at the above address     

Effects of enprostil on cardiovascular and respiratory parameters in the dog, and on hematologic parameters in the rat, monkey, and human

The effects of enprostil (+/-)-7-[(1R*,2R*,3R*)-3-hydroxy-2-[(E)-(3R*)-3-hydroxy-4-phenoxy-1- butenyl]-5-oxocyclopentyl]-4,5-heptadienoate) were studied on cardiovascular and respiratory parameters in the dog and on hematologic parameters in the rat, monkey, and human. Anesthetized dogs were instrumented to allow measurement of heart rate, systemic blood pressure, respiratory rate or tracheal pressure, and ventricular contractile force after intragastric (i.g.) or intravenous (i.v.) administration of enprostil in the presence or absence of autonomic challenges. The effects of intraduodenal (i.d.) enprostil on arterial and venous PO2, PCO2, and pH; respiratory rate, flow rate, and volume; blood pressure (b.p.); and heart rate were also examined. Enprostil i.v. (0.3-10 micrograms/kg) significantly increased tracheal pressure in a dose-dependent manner, but minimally altered b.p., heart rate, and ventricular contractile force. Enprostil i.v. (1-10 micrograms/kg) significantly inhibited pressor and depressor responses to several autonomic challenge agents at the highest dose level, indicative of a nonspecific inhibitory effect on b.p. responses. Cardiovascular effects of enprostil (1-100 micrograms/kg i.g.) were absent. Enprostil (10-3,000 micrograms/kg i.d.) had no noteworthy effects on respiratory parameters in the dog. Platelet aggregation effects of enprostil were studied in vitro using platelet rich plasma (PRP) from the rat, monkey, and human; whole blood clotting time and prothrombin time after oral enprostil were studied in the rat; and ex vivo effects on platelet activation were studied in humans.(ABSTRACT TRUNCATED AT 250 WORDS)     

小檗碱对清醒家兔脑电图及功率谱的影响

目的观察小檗碱(berberine,Ber)对清醒家兔脑电图(EEG)及功率谱的影响 ,探讨Ber改善学习记忆的神经生物学机制。方法利用慢性埋藏电极记录清醒家兔海马和脑皮层EEG及功率谱。结果Ber1～4mg·kg-1iv能使清醒家兔脑皮层区EEG出现持续低振幅快波 ,其主频率功率明显减少 ,并使海马区EEG出现持续且有规律的θ节律 ,海马区主频率从δ段右移至θ段 ,主频率功率明显减少。Ber2mg·kg-1iv可逆转氢溴酸东莨菪碱0.3mg·kg-1iv引起的高振幅慢波和主频率增高的作用 ,同样家兔侧脑室每只注射Ber0.05mg 所引起的EEG及功率谱变化亦可被氢溴酸东莨菪碱0.2mg·kg-1iv所逆转 ,而不能通过血脑屏障的丁溴酸东莨菪碱0.4mg·kg-1iv却无此作用。结论Ber通过影响中枢胆碱能系统在海马产生θ节律 ,减低皮层功率 ,可能是其改善和促进学习记忆的神经生物学机制之一。     

Effects of ranitidine and oxmetidine on gastrointestinal motility in conscious dog

Two histamine H2-receptor antagonists ranitidine and oxmetidine were tested for their effects on gastrointestinal motility in conscious fasted dogs chronically fitted with intraparietal electrodes on the antrum, duodenum and jejunum. Intravenous administration of ranitidine (3 mg/kg) stimulated gastrointestinal spiking activity through a cholinergic mechanism and increased the duration of the cycles of migrating myoelectric complexes. Oxmetidine at the same dose did not modify the gastrointestinal motor profile. These results showed clearcut differences in nonspecific effects of two H2-antagonists equipotent on gastric acid secretion.     

Comparison of atenolol and propranolol during insulin-induced hypoglycaemia.

The effects of atenolol, a new beta1-blocking drug, on pulse rate, sweating, and blood glucose levels during insulin-induced hypoglycaemia were studied in a double-blind crossover trial in eight normal subjects using placebo and propranolol as reference agents. The intensity of induced hypoglycaemia was identical for atenolol, propranolol, and placebo. Propranolol prolonged hypoglycaemia, but atenolol did not. Atenolol may therefore be safe for use in patients receiving insulin.     

应用清醒大鼠遥测模型评价AF114注射液的心血管系统的安全性

目的:应用可在清醒自由活动状态下长期监测心血管系统参数和体温变化的大鼠遥测模型评价AF114注射液对心血管系统及体温的影响。方法:通过手术将可遥测大鼠血压、心电图、体温的植入体植入大鼠体内,建立清醒大鼠遥测模型。经颈静脉置入导管,经皮下穿刺将导管从颈后侧引出,固定,用于给药或采血。动物术后恢复1周,用阳性药物垂体后叶素验证模型的反应性。验证后用该模型评价AF114注射液对心血管系统及体温的影响。结果:32只大鼠手术后有29只恢复良好,无感染,均可监测到腹主动脉血压、心电图、体温等生理信号。经腹腔注射给予清醒大鼠垂体后叶素1 U.kg-1后,观察到平均动脉压升高,射血时间延长,体温降低,心率减慢。经静脉注射给予AF114注射液后,引起大鼠平均动脉压升高,心率加快,体温升高,对血小板计数和红细胞计数无明显影响。结论:清醒大鼠心血管遥测模型可用于长期、连续、动态监测心血管功能;静脉注射AF114注射液后可引起清醒大鼠血压升高、心率加快和体温升高。     

Effects of combined treatment with sildenafil and itraconazole on the cardiovascular system in telemetered conscious dogs

Sildenafil, a potent PDE5 inhibitor, is widely prescribed as a treatment of erectile dysfunction. Itraconazole is an inhibitor of CYP3A4, a metabolic enzyme of sildenafil. In the current study, we investigated the effects of single treatment with sildenafil and combined treatment with sildenafil and itraconazole on blood pressure, heart rate, and QT interval in conscious beagle dogs. After a transmitter was implanted to beagle dogs for conscious state experiments, a single oral dose of sildenafil was administered to the beagle dogs at dose levels of 3, 15, and 30 mg/kg. Blood pressure, heart rate, and lead II ECG were measured prior to dosing and at 0.5, 1, 2, 4, 6, and 24 h postdosing. In the study of combined treatment with sildenafil and itraconazole, the 100 mg/kg dose of itraconazole was orally administered 1 h prior to oral administration of sildenafil. No changes in blood pressure were observed at any doses in animals receiving either single treatment with sildenafil or combined treatment with sildenafil and itraconazole. Increased heart rate from 0.5 h to 6 h postdosing and decreased QT interval were observed in animals receiving single treatment with sildenafil at 15 or 30 mg/kg. When 30 mg/kg of sildenafil was coadministered with 100 mg/kg of itraconazole, drug-related effects such as increased heart rate and decreased QT interval were significantly enhanced as compared to sildenafil-alone administration at 6 h postadministration. These results demonstrated that increased heart rate and decreased QT interval, the adverse effects of sildenafil, were enhanced and prolonged when sildenafil was coadministered with itraconazole. Therefore, caution should be taken when sildenafil is coadministered with itraconazole, a CYP3A4 inhibitor, or when administered to elderly patients or patients with hepatic or renal impairment who cannot metabolize and excrete sildenafil normally.     

Intrapulmonary and intravenous administrations of dihydroergotamine mesylate have similar cardiovascular effects in the conscious dog

BACKGROUND AND PURPOSE: The effects of intrapulmonary artery (i.p.a.) administration of dihydroergotamine mesylate (DHE) were evaluated. EXPERIMENTAL APPROACH: Conscious beagle dogs (n=4) were given DHE via the i.p.a. or i.v. route as two 0.014 mg kg(-1) doses and a 0.14 mg kg(-1) dose given 60 min apart. A recovery period of > or =45 h occurred before crossover to the alternative route. Physiological parameters were monitored by telemetry or direct measurement, and venous blood samples were collected for pharmacokinetic assessments. KEY RESULTS: No meaningful differences between i.v. and i.p.a. treatments were observed for heart rate, systemic pressures and vascular pressures. Aortic resistance increased 8, 27 and 70%, respectively, following three doses of i.v. DHE compared with 11, 37 and 57%, respectively, with i.p.a. DHE. Carotid artery resistance increased 22, 40 and 87%, respectively, following three doses of i.v. DHE, compared with 17, 45 and 67%, respectively, following i.p.a. DHE. Increases in coronary artery resistance were of similar magnitude following i.v. and i.p.a. DHE administration. Increases in left ventricular systolic and diastolic pressures were seen following all doses of i.v. and i.p.a. DHE. Changes following DHE 0.014 mg kg(-1) were minimal and not clinically significant. With DHE 0.14 mg kg(-1) by either route, emesis was the most common adverse event. CONCLUSIONS AND IMPLICATIONS: DHE has comparable effects delivered via simulated deep inhalation (i.p.a.) or i.v. administration. The risk of cardiovascular complications is unlikely to be greater following inhalation of DHE.     

Comparison of propranolol, metoprolol, and acebutolol on insulin-induced hypoglycaemia.

Metoprolol and acebutolol, two supposedly cardio-selective beta-adrenergic recptor blocking agents, were tested in healthy volunteers against propranolol, a non-selective drug, for their effect on blood glucose levels during insulin-induced hypoglycaemia. There was not significant difference between propranolol and metoprolol, which both potentiated the initial hypoglycaemic action of the insulin and delayed the return to normoglycaemia. Acebutolol, even though potentiating the initial hypoglycaemia, did not possess a significant delaying effect. A similar trial should be undertaken in diabetics to determine with certainty the safety of such drugs in diabetes mellitus.     

Dopamine in the conscious dog with chronic heart-block

Summary The chronotropic effects of dopamine were studied in the conscious dog with chronic A-V block. Dopamine at 12.5–200 g/kg and 12.5–50 g/kg/min lowered atrial rate independently of dose. After blockade of muscarine receptors or alpha-adrenoceptors, it raised atrial rate. After blockade of dopamine receptors, dopamine still lowered atrial rate, and did so dose-relatedly after blockade of beta-adrenoceptors. It raised ventricular rate, and at high doses also induced ventricular rhythm disorders. Blockade of muscarine receptors enhanced the ventricular cardioaccelerator effect of dopamine (P<0.025) at 100 g/kg, while blockade of alpha-adrenoceptors reduced it (P<0.05). Blockade of dopamine receptors did not modify this effect, but blockade of beta-adrenoceptors reversed it. Dopamine at 25–200 g/kg raised mean blood pressure. This effect was enhanced by blockade of muscarine receptors, reversed by blockade of alpha-adrenoceptors, and was unaffected by blockade of beta-adrenoceptors or dopamine receptors. These results show that the atrial cardiomoderator effect of dopamine is a vagal reflex response to its hypertensive action, and that it is limited by its direct beta-adrenergic stimulating action. They also show that the ventricular cardioaccelerator effect of dopamine is attenuated by a reflex vagal depressor effect consequent to the induced hypertension. No evidence was found for the existence of positive chronotropic dopamine receptors in either atria or ventricles.A preliminary report of these findings was presented at the Symposium on Peripheral Dopaminergic Receptors, July 1978, in Strasbourg, France (Boucher et al. 1979b)     

Detection of QTc interval prolongation using jacket telemetry in conscious non-human primates: comparison with implanted telemetry

Background and Purpose: During repeat-dose toxicity studies, ECGs are collected from chemically or physically-restrained animals over a short timeframe. This is problematic due to cardiovascular changes caused by manual restraint stress and anesthesia, and limited ECG sampling. These factors confound data interpretation, but may be overcome by using a non-invasive jacket-based ECG collection (JET). The current study investigated whether a jacketed external telemetry system could detect changes in cardiac intervals and heart rate in non-human primates (NHPs), previously implanted with a PCT transmitter.Experimental Approach: Twelve male cynomolgus monkeys were treated weekly with vehicle or sotalol (8, 16, 32 mg kg⁻¹) p.o. ECGs were collected continuously for 24 hours, following treatment, over 4 weeks. A satellite group of six NHPs was used for sotalol toxicokinetics.Key Results: Sotalol attained C_max values 1–3 hours after dosing, and exhibited dose-proportional exposure. In jacketed NHPs, sotalol dose-dependently increased QT/QTc intervals, prolonged PR interval, and reduced heart rate. Significant QTc prolongation of 27, 54 and 76 msec was detected by JET after 8, 16, and 32 mg kg⁻¹ sotalol, respectively, compared with time-matched vehicle-treated animals. Overall, JET-derived PR, QT, QTc intervals, QRS duration, and heart rate correlated well with those derived from PCT.Conclusions and Implications: The current findings clearly support the use of JET to quantify cardiac interval and rhythm changes, capable of detecting QTc prolongation caused by sotalol. JET may be a preferred method compared to restraint-based ECG because high-density ECG sampling can be collected in unstressed conscious monkeys, over several weeks.     

Suppression by dexamethasone of the plasma cortisol response to insulin-induced hypoglycaemia

Summary

Intravenous administration of 8?mg. dexamethasone has been found to suppress completely the plasma 11-hydroxycorticosteroid (11-OHCS) response to insulin-induced hypoglycaemia in 6 patients with rheumatoid arthritis. It is suggested that the 'stress' response fails to override the negative feedback mechanism if the circulating level of corticosteroid is suficiently high, or if the pharmacological 'stress' is qualitatively or quantitatively inadequate to override the normal physiological control.     

Effects of beta 2-adrenoceptor stimulation on cardiac metabolism in the conscious dog.

1 The effects of the beta 2-adrenoceptor stimulant, salbutamol, on cardiac metabolism have been studied in conscious mongrel dogs. The potential effects of anaesthesia on the study of cardiac metabolism have been avoided by prior implantation of arterial (A) and coronary sinus (CS) catheters for blood sampling and a central venous catheter for infusion. Extraction of substrates for myocardial energy metabolism (CA-CS) was assessed 3 to 24 days post-operatively. A 100 micrograms bolus of salbutamol was given followed by an infusion of 3 micrograms/min for 1 h. 2 Although heart rate increased significantly from 106 to 165 beats/min, fractional extraction of oxygen tended to fall from 84% to 77%. Thus an increase in coronary blood flow rather than in oxygen extraction must have maintained an oxygen supply commensurate with the salbutamol-induced tachycardia. 3 Neither CA-CS glucose nor fractional glucose extraction altered significantly during salbutamol infusion despite increases in arterial concentration (CA) of glucose and arterial insulin immunoreactivity and a decrease in CA of free fatty acids (FFA). This suggests that an insulin-antagonistic action accompanies the infusion of salbutamol. 4 The fractional extraction of lactate increased during salbutamol infusion. In part, this may have been a reflection of a decreased myocardial extraction of FFA with salbutamol in this model.     

MIF-1 does not act like naloxone in antagonizing the cardiovascular activity of leucine-enkephalin in the conscious dog

MIF-1 (Pro-Leu-Gly-NH2), a hypothalamic tripeptide, has been demonstrated to stimulate naloxone in antagonizing the effects of opioid peptides in a number of experimental systems including enkephalin-induced analgesia in the tail-flick assay, beta-endorphin induced hypothermia and hypomotility, deprivation-induced drinking, and analgesia in goldfish. MIF-1, however, has no effect upon the activity of enkephalins in the mouse vas deferens or enkephalin binding in the rat striatum. We have studied the interactions of MIF-1 with Leu5-enkephalin (Leu5-ENK) in the conscious, chronically instrumented dog. Although naloxone inhibits both the elevations of heart rate and blood pressure produced by IV Leu5-ENK in the conscious state and the depressions in these variables produced by Leu5-ENK after pentobarbital anesthesia, MIF-1 has no effect upon the Leu5-ENK response in either state. However, both naloxone and MIF-1 seem to raise mean arterial pressure in the conscious dog. These results indicate that MIF-1 does not act like naloxone in antagonizing the peripheral effects of Leu5-ENK and lend further support to the existence of mechanistic differences among opiate-mediated behavior, analgesia, and cardiovascular activity.     

The effects of morphine and nalorphine on the plasma 11-hydroxycorticosteroid response to insulin-induced hypoglycaemia in patients with rheumatoid arthritis.

Morphine in therapeutic dosage has been shown to impair the plasma 11-hydroxycorticosteroid response to the stress of insulin-induced hypoglycaemia. Nalorphoine in similar dosage produced no impairment of the response to hypoglycaemia.