异钩藤碱的降压及血流动力学作用(英文)

在清醒正常血压大鼠,iv Isorhy2.5 mg/kg对BP及HR均无明显影响,iv5 mg/kg则使DAP和HR降低,但SAP无变化,剂量加大至10 mg/kg时,上述各项指标均明显降低。经十二指肠内给Isorhy10 mg/kg后20 min出现BP及HR降低,而20mg/kg剂量组于10 min开始出现BP及HR的进一步下降.Isorhy(10mg/kg和2 mg/kg,iv)亦能分别降低肾性高血压清醒大鼠和麻醉犬的BP。icv表明中枢不是降压作用的主要部位,在体条件下无α-受体和神经节阻断作用。Isorhy使清醒大鼠和麻醉犬的LVSP,dP/dt_(max),V_(max)等左室收缩性能指标短暂下降,而BP呈持久性降低。在麻醉犬给药后CO,CI,HR及LVWI下降的同时SV和SI不变,TPVR降低,反映心肌氧耗的TTI明显减少.结果提示Isorhy具有肯定的降压作用,其持续降压与扩张血管及减慢心率导致CO下降有关,而其负性肌力作用亦可能参与了早期的降压机理.Isorhy能减少心肌氧耗对高血压心肌劳损可能有保护意义。     

CARDIOVASCULAR EFFECTS OF AMITRIPTYLINE IN ANAESTHETIZED DOGS

1. The effect of amitriptyline on cardiovascular variables has been studied in anaesthetized dogs. 2. In small doses (0.25 mg/kg) amitryptyline caused small increases in heart rate, contractility, blood pressure, coronary blood flow and aortic flow. 3. Larger doses produced initial depressant effects on myocardial contractility and rate and blood pressure, which were followed by secondary reflex rises in these measurements. 4. The depressant effects were dose-related and were accompanied by marked increases in coronary flow and smaller increases in aortic flow. 5. The secondary reflex rises in cardiac parameters were abolished by propranolol and that of the blood pressure was much reduced.     

Combined alpha- and beta-adrenoceptor blocking drug AH 5158: further studies on alpha-adrenoceptor blockade in anaesthetized animals.

1. AH 5158, 5-(1-hydroxy-2-((1-methyl-3-phenylpropyl)amino)ethyl)salicylamide, competitively antagonised phenylephrine-induced vasopressor responses in anaesthetized dogs, thus confirming that the drug possesses alpha-adrenoceptor blocking activity. 2. In contrast, AH 5158 was a relatively ineffective antagonist of vasopressor responses to noradrenaline in anesthetized dogs. Thus, at the lowest dose-level tested (1 mg/kg) AH 5158 abolished the increase in pulse width caused by noradrenaline, but otherwise had little or no blocking effect in doses as high as 10 mg/kg. Propranolol (0.1 mg/kg) also abolished the increase in pulse width caused by noradrenaline. With both drugs this effect is thought to be a consequence of blockade of the beta-adrenoceptor-mediated cardia stimulant action of noradrenaline. 3. The interaction between AH 5158 and noradrenaline in spinal dogs, anaesthetized cats and pithed rats was very similar to that seen in anaesthetized dogs. 4. Noradrenaline pressor responses were effectively antagonized by AH 5158 in anaesthetized dogs pretreated with cocaine. The degree of block was similar to that obtained when phenylephrine was the agonist in untreated dogs. 5. These results are consistent with the hypothesis that AH 5158 blocks a cocaine-sensitive inactivation process for noradrenaline in addition to blocking alpha- and beta-adrenoceptors. The resultant increase in the level of circulating noradrenaline would tend to counteract the adrenoceptor blocking action of the drug. 6. The implications of these findings are discussed.     

Cardiovascular effects of intravenous pentazocine and cyclazocine in conscious, curarized-conscious, and anesthetized dogs

The cardiovascular effects of intravenous pentazocine and cyclazocine in dogs were studied under conscious, curarized-conscious (paralyzed by gallamine), and anesthetized states. In the conscious state, blood pressure and heart rate were dose-dependently increased by pentazocine (1, 2, 3 mg/kg) and to a lesser extent by cyclazocine (0.3 mg/kg). In all subsequent experiments on dogs, the results were obtained using 3 mg/kg pentazocine and 0.3 mg/kg cyclazocine. Pentazocine accelerated breathing, peaking at about 10 min, whereas cyclazocine reduced breathing to a minimum in 1 min, followed by a gradual recovery thereafter. In the curarized-conscious state, the blood pressure response to pentazocine was biphasic, namely an initial decrease followed by an increase; chronotrophic activity was stimulated. Pretreatment with either ganglionic or alpha andrenergic blocking agents not only significantly antagonized the pressory responses to the drug but also potentiated the initial decreases in blood pressure and unmasked a bradycardic component, but these parameters were not altered by 0.3 mg/kg naxalone. In open-chest anesthetized dogs, blood pressure, heart rate, contractility, and mean peripheral vascular resistance were simultaneously decreased by both pentazocine and cyclazocine, initially accompanied by increases in aortic blood flow. During the later stages of drug action, only the blood pressure and contractility were increased above control levels (biphasic effect). A comparison of blood pressure and heart rate responses to pentazocine in dogs kept under differing experimental conditions revealed that conscious dogs were more sensitive than curarized conscious and anesthetized animals to pentazocine action. In isolated guinea pig atria, the effect of adrenaline (0.1, 0.3, or 1 mg/mL) on the spontaneous breathing rate was significantly augmented by 10 mg/mL pentazocine (p < 0.02 for 0.3 g/mL; p < 0.01 for 0.1 g/mL adrenaline). In dogs, however, adrenaline (1 mg/kg)-induced increases in heart contractility, aortic blood flow, and blood pressure remained almost unaltered in the presence of pentazocine. We concluded that the abovementioned cardiovascular responses to pentazocine and cyclazocine are a consequence of the sum of the two following opposing effects: (i) an indirect reflex activation of sympathetic neuromediation in the periphery, and (ii) a direct membrane effect on the heart leading to bradycardia and a depression in myocardial contractility.     

In vivo pharmacological studies with SK&F 94836, a potent inotrope/vasodilator with a sustained duration of action.

1. SK&F 94836 (racemate) was studied in vivo for its cardiovascular properties in cats and dogs. 2. In anaesthetized cats and dogs SK&F 94836 administered intravenously caused increases in left ventricular contractility and decreases in peripheral vascular resistance at similar doses, thus demonstrating the compound to be a mixed acting positive inotropic/vasodilator agent. 3. In conscious instrumented dogs SK&F 94836 was active via the oral as well as intravenous route. 4. The inodilator activity of SK&F 94836 in conscious and anaesthetized animals occurred in association with minimal changes in either blood pressure or heart rate. 5. Detailed studies carried out on anaesthetized cats indicated that SK&F 94836 caused a balanced dilatation of both resistance and capacitance blood vessels. 6. Haemodynamic studies in anaesthetized cats indicated that as a consequence of the inotropic/vasodilator actions, SK&F 94836 caused significant increases in cardiac output and stroke volume. 7. Detailed studies in anaesthetized dogs indicated that significant inodilator activity occurred in the absence of an increase in myocardial oxygen consumption. 8. The duration of action of SK&F 94836 was sustained following both i.v. and oral administration. 9. We conclude that SK&F 94836, as an orally active inotropic/vasodilator agent with a sustained duration in vivo, has potential utility in the treatment of congestive heart failure.     

7-溴化乙氧苯四氢巴马汀的抗心律失常作用

7-溴化乙氧苯四氢巴马汀(EBP)10mg/kg对小鼠乌头碱、豚鼠哇巴因、兔肾上腺素诱发的心律失常有明显对抗作用;2mg/kg对大鼠冠脉结扎和再灌注引起的心律失常有保护作用;EBP能降低离体豚鼠乳头状肌及右房自律性,延长不应期,增加收缩性。EBP明显延长豚鼠乳头状肌APD_(20),APD(90),不影响APA,RP,OS,V_(max)。     

黄耆的利尿与降压作用

给大白鼠皮下注射及麻醉狗静脉注射黄耆0.5克/公斤后,均可产生显著的利尿作用;给正常人口服0.2克/公斤后亦可产生显著的利尿作用.黄耆的利尿作用持续时间较长,给大白鼠皮下注射后,利尿作用可持续7天,连续给药7天后无耐受性.大白鼠皮下注射0.5克/公斤的利尿效价与氨茶碱0.05克/公斤及双氢氯噻嗪0.2毫克/公斤者相当.给麻醉狗静脉注射或灌胃黄耆0.5克/公斤后,均可引起明显的降压作用,重复静脉注射时出现快速耐受性.黄耆的毒性很小,给小白鼠灌胃75克/公斤无异常症状,小白鼠的半数致死量(腹腔注射)为40±5克/公斤,大白鼠慢性毒性试验未出现不良反应.     

The effect of Kö 1173, a new anticonvulsant agent on experimental cardiac arrhythmias

1. The effects of the intravenous injection of Kö 1173, a new anticonvulsant drug, phenytoin and procainamide were studied on three types of cardiac arrhythmia in dogs.2. Ventricular ectopic beats produced by intravenous injection of adrenaline in anaesthetized dogs respired with halothane were abolished by Kö 1173, 0·6 ± 0·1 mg/kg, phenytoin, 1·1 ± 0·3 mg/kg and procainamide, 4·1 ± 1.8 mg/kg.3. Ventricular tachycardia was produced in anaesthetized dogs by the intravenous injection of ouabain and the three drugs infused intravenously at 0·2 (mg/kg)/min until sinus rhythm returned. Kö 1173 was effective in 8 out of 9 dogs after a mean dose of 1·3 ± 0·3 mg/kg; phenytoin in all 3 dogs after 2·7 ± 0·6 mg/kg and procainamide in the 3 dogs tested after 16·6 ± 1·3 mg/kg.4. The intravenous injection of Kö 1173, 8·0 mg/kg, greatly reduced the number of ventricular ectopic beats occurring in conscious dogs 18-44 h after ligation of the anterior descending branch of the left coronary artery, with a resultant increase in the number of sinus beats. Phenytoin, 8·0 mg/kg, had a similar effect but procainamide was much less effective.5. These results indicate that Kö 1173 is effective in abolishing experimental cardiac arrhythmias and suggest that its effects should be studied in patients.     

Cardiovascular pharmacology of the cardiotonic,imazodan (Cl-914)

Imazodan is a novel pyridazinone derivative. It was evaluated in excised cardiac tissue, anesthetized dogs and monkeys, and conscious dogs. Imazodan, 10^?5–10^?3M, produced dose-dependent increases in guinea pig atrial and rabbit papillary muscle contractility. In ansthetized dogs and rhesus monkeys, imazodan, 0.001–1.0 mg/kg IV, produced dosedependent increases of 10–150% in myocardial contractility (dP/dt max of left ventricular pressure), and decreases of 1–31% in aortic blood pressure. Heart rate increases were minimal (0–34%) in comparison to the changes in contractility and they occurred only at the higher doses. The positive inotropic action of imazodan was not blocked by β-adrenoceptor blockade with propranolol. Forelimb perfusion studies in the anesthetized dog demonstrated that imazodan produces a dose-dependent direct peripheral vasodilator action. This agent was also demonstrated to be a highly effective cardiotonic when administered orally (0.1–1.0 mg/kg) to conscious dogs. The results of these studies indicate that imazodan is an orally effective cariotonic that possesses balanced positive inotrophic and peripheral vasodilator activities and possesses a wide margin of cardiac safety.     

Cardiovascular effects of delta9-tetrahydrocannabinol in conscious and anaesthetized dogs.

1. Temporal effects of delta9-tetrahydrocannabinol (THC) on heart rate and blood pressure in conscious dogs were compared to those in anaesthetized dogs. 2. In conscious dogs, THC in doses of 0.25 and 0.1 mg/kg resulted in maximal heart rate reductions of 48 and 41%, respectively, and in no significant change in blood pressure. 3. In anaesthetized animals THC in doses of 0.5 and 0.25 mg/kg caused a peak reduction in heart rate of 38 and 34%, and of blood pressure of 24 and 8%, respectively. 4. The results demonstrate that the bradycardia in response to THC in dogs is independent of the concomitant anaesthesia. 5. We conclude that the discrepancy between heart rate response to THC in dogs and in man is due to a species difference.     

Atenolol, its cardioselective property for adrenergic beta-receptor blocking action and effect on the cardiac function (author's transl)

Cardioselective property of the beta-adrenoceptor blocking action of atenolol and its effect on the AV conduction, the atrial muscle refractory period and the cardiac contractility were studied in comparison with these of propranolol. A ratio of pA2 values obtained in the isolated right-atrial preparations and the isolated tracheal preparations of guinea pigs demonstrated that atenolol was highly cardioselective, while propranolol was non-selective. This cardioselective property of atenolol was confirmed in in vivo experiments using guinea pigs. Atenolol increased the AV conduction time and decreased the cardiac contractility dose-dependently in anesthetized dogs of which the heart was electrically driven at fixed rates. At 140 beats/min, AV block was observed at 10 mg/kg, i.v. in 3 of 8 dogs, and further increase in a dose ti 30 mg/kg resulted in acute heart failure in one of remaining 5 dogs, while propranolol, though showing a tendency to be less potent in depressing AV conduction in a dose range less than 0.3 mg/kg, produced a state of heart failure in 2 of 5 dogs at 3 mg/kg, i.v. and AV block in all of the remainder at 10 mg/kg, i.v. Functional refractory period of AV node as well as functional and effective refractory period the the atrial muscle were increased dose-dependently by atenolol and propranolol. There were no significant differences between both drugs regarding these effects. Further increase in a pacing rate to 160 and 180 beats/min augmented the depressing effect of both drugs on the AV conduction.     

防己生物碱的毒性及降压作用

正常狗2只,以防己生物碱連日給药,最高一次灌胃量达160毫克/公斤,为降压有效量16倍,无急性不良反应发生,服药过程中体重、食量及外表皆无明显改变。实驗治疗的3只高血压皮桥狗,无論心电图、血清磺溴酞鈉存留率及全血非蛋白氮含量皆属正常;但个別狗首次給药曾发生特异反应,大剂量长期給药可使全血非蛋白氮含量稍高,临床試用尚宜适当注意。总碱对麻醉或不麻醉实驗动物无論靜脉注射或灌胃都有肯定的急性降压效果,其作用特点为降压迅速、显著,持續时間約2—4小时,連續多次給药有快速耐受現象。对慢性实驗治疗狗的疗效不著,可能与其作用特点有关,可考虑与作用緩慢而持久的降压药合并应用。总碱的降压与其抗腎上腺素作用及神經反射机制有关。总碱无阻断神經节作用,其降压与M-胆碱反应系統无关,也非組織胺释放所致。在本实驗条件下未見总碱有直接扩张血管的作用。靜脉注射1—2毫克/公斤,对麻醉狗的心輸出量有抑制性影响,总外周阻力的降低不明显。     

Pharmacodynamic profile of the selective beta 1-adrenoceptor antagonist bisoprolol

The pharmacodynamic activity of (+/-)-1-[4-(2-isopropoxyethoxymethyl)-phenoxy]-3-isopropylamino-2- propranol- hemifumarate (bisoprolol, EMD 33 512) has been investigated under in vitro and in vivo conditions. Bisoprolol was found to be an effective beta-adrenoceptor antagonist, the pA2 values determined against isoprenaline in guinea pig atria and tracheal muscle being 7.45 and 6.41, respectively. Thus, the selectivity ratio of bisoprolol in favour of beta 1-adrenoceptors is 11. Inhibition of the isoprenaline-induced tachycardia in guinea pigs indicated a long duration of action for bisoprolol. The compound was devoid of intrinsic sympathomimetic activity as shown by the lack of effect on heart rate in anaesthetized and reserpine pretreated rats. Studies in rabbits and guinea pigs revealed a local anaesthetic activity of bisoprolol at high concentrations. Bisoprolol protected the hearts of anaesthetized dogs against the sequelae of intermittent coronary occlusions, as judged by the reduction of the ST-segment elevation in the epicardial ECG. Bisoprolol exerted a blood pressure lowering effect in conscious renal hypertensive dogs after oral administration of 30 micrograms/kg. There was no indication of any action on the CNS in monkeys following an oral dose of up to 8 mg/kg.     

The effect of a combination of 1-(4'-hydroxyphenyl)-2-methyl-aminopropanol-(1)-hydrochloride with a nucleotide containing heart muscle extract on the heart and circulatory system of the dog]

The heamodynamic activity of Carnigen, which is a blood pressure stabilizer consisting of 1-(4'-hydroxyphenyl)-2-methylaminopropanol-(1)-hydrochloride (Suprifen) and a nucleotide containing heart muscle extract, was investigated in 15 anaesthetized dogs following intraduodenal application (0.3--1--3 mg/kg body weight). The following results were obtained: 1. The stroke volume and cardiac output were raised significantly exhibiting a dose dependent activity follwoing Carnigen application. 2. The cardiac work exhibited a dose dependent rise which was significant after 3 mg/kg. 3. The contractility of the left ventricle increased following each of the tested dosages. This was expressed by a significant rise in the dp/dt value as well as in the quotient (see article). 4. The mean femoral blood pressure exhibited a moderate rise in the test range from 0.3--3 mg/kg. 5. The heart rate increased by a few beats follwoing doses of 0.3--1 mg/kg. 6. The total peripheral resistance was reduced in a dose dependent manner. 7. The respiration volume was slightly increased following 0.3 and 1 mg/kg Carnigen, 3 mg/kg caused a quite moderate respiration stimulation.     

Effect of intracisternal 5,-7-dihydroxytryptamine on the acute antihypertensive action of propranolol in the sino-aortic denervated anaesthetized dog.

1 The anti-hypertensive effects of intravenously and intracisternally administered (+/-)-propranolol were studied in anaesthetized dogs with acute neurogenic (sino-aortic denervation) hypertension. The animals were pretreated 7 days earlier with intracisternally administered 5,7-dihydroxytryptamine (5,7-DHT 200 microgram/kg plus desipramine 5 mg/kg i.v.). 2 5,7-DHT (plus desipramine) failed to decrease both basic blood pressure and heart rate measured before sino-aortic denervation. After 5,7-DHT (plus desipramine) pretreatment, acute sino-aortic denervation induced a rise in blood pressure and stimulated the heart rate, these effects being similar (in intensity and duration) to those observed in control (saline-pre-treated) debuffered dogs during the first hour following the deafferentation. 3 In debuffered dogs, (+/-)-propranolol given by intracisternal (50 microgram/kg) or intravenous (300 microgram/kg) routes decreased both blood pressure and heart rate. 4 5,-DHT (plus desipramine) pretreatment abolished the antihypertensive effect of intracisternal propranolol whereas the action of intravenous propranolol was only delayed. In contrast, this pretreatment failed to reduce and even sometimes enhanced the negative chronotropic response induced by propranolol. 5 These results suggest that central 5-hydroxytryptaminergic pathways play an important role in the acute hypotension elicited by intracisternal (+/-)-propranolol in debuffered hypertensive anaesthetized dogs, but little, if any in propranolol-induced bradycardia.     

The effect of prazosin on the hemodynamics of the anesthetized dog

Effect of prazosin (0.1 and 1.0 mg/kg b.w. i.v.) on the cardiovascular system was investigated in six anaesthetized Beagles (Na-pentobarbital 35 mg/kg i.p.) using the thermodilution and catheter methods. The following parameters were measured: a) mean arterial blood pressure, b) heart rate, c) total peripheral resistance, d) cardiac output, e) cardiac work, f) stroke volume and g) cardiac contractility. Results can be summarized as follows: 1. Prazosin in dose of 0.1 mg/kg i.v. caused a slight drop in arterial blood pressure; prazosin administered in dose of 1.0 mg/kg i.v. decreased blood pressure significantly. 2. Following doses of 0.1 and 1.0 mg/kg i.v. of prazosin, heart rate was significantly increased in each of six dogs. 3. When prazosin was given i.v. (0.1 and 1.0 mg/kg), an initial increase in cardiac output occurred. Later, a reduction in cardiac index below the control values could be observed. 4. The contractility parameters of the left ventricle--dp/dtmax and VCE--were increased after i.v. administration of 0.1 and 1.0 mg/kg b.w. of prazosin.     

水杨酸双异丙胺降压作用的药理研究

静脉或十二指肠注射水杨酸双异丙胺对麻醉大鼠和狗均有快速显著的降压作用。给清醒的肾性高血压狗以50～100mg/kg灌胃亦有降压效果,一般持续1.5～5小时。其降压作用主要为总外周血管阻力的降低,而对心肌收缩性无明显抑制。动脉内注射也不直接扩张血管。推动脉与静脉注射1mg/kg的降压效果以及对血流动力学的作用相似。提示主要不是中枢性降压。2～5mg/kg静注能阴滞烟碱的心血管作用。说明隆压可能与阴滞神经节有关。     

Cardiovascular effects of B-HT 958, an alpha-adrenoceptor agonist with a high pre/postsynaptic activity ratio

B-HT 958 (2-amino-6-(p-chlorobenzyl)-4H-5,6,7,8-tetrahydrothiazolo[5,4-d]az epine), chemically related to clonidine-like drugs of the azepine type, was described previously as a partial alpha 2-adrenoceptor agonist which acted presynaptically mainly as agonist and postsynaptically as antagonist. Following i.v. infusion in anaesthetized cats, 3 mg/kg of B-HT 958 lowered blood pressure, heart rate, cardiac output and total peripheral vascular resistance. A small central nervous component was indicated, since 100 micrograms/kg injected into the vertebral artery was equipotent to 300 micrograms/kg i.v. in lowering blood pressure and heart rate. The drug (1 mg/kg i.v.) decreased the discharge rate of the preganglionic sympathetic splanchnic nerve, but in contrast to the effect of clonidine this could not be demonstrated in decerebrate cats. As blood pressure and heart rate were decreased by B-HT 958 in decerebrate cats, the main site of action was assumed to be peripheral. Also in contrast to clonidine, B-HT 958 did not induce vagal baroreflex bradycardia in anaesthetized dogs with blocked beta-adrenoceptors following intracisternal (30 micrograms/kg as well as 3 mg/kg) injection. In anaesthetized rats the decrease in blood pressure and heart rate caused by 1 mg/kg B-HT 958 i.v. was antagonized by 0.5 mg/kg piperoxan i.v. It is suggested that the cardiovascular effects of B-HT 958 depend on its high selectivity for alpha 2-adrenoceptors and are due to its agonist action presynaptically on peripheral adrenergic nerve terminals.     

Catecholamine uptake blockade in anaesthetized dogs: influence on cardiovascular responses.

The effects of differential and combined catecholamine uptake antagonism on cardiovascular responses of anaesthetized dogs to isoprenaline, noradrenaline, and electrical stimulation of the left ansa subclavia nerve have been studied. Uptake1 inhibition by cocaine HCl (5 mg kg-1 and 1 mg kg-1 every 45 min) enhanced responses to noradrenaline (0.1 to 2.0 micrograms kg-1 i.v.) and sympathetic nerve stimulation (1 to 20 Hz), but did not affect those to isoprenaline. Uptake2 inhibition by metanephrine (40 micrograms kg-1 min-1) enhanced cardiac responses to isoprenaline (0.05 to 1.0 microgram kg-1 i.v.), but did not significantly alter those to noradrenaline or nerve stimulation. Responses to all agonist interventions were increased by the combined administration of cocaine and metanephrine. Cocaine preferentially enhanced the positive chronotropic cardiac response to noradrenaline, but metanephrine did not differentiate between heart rate and contractility. These results have been discussed in the light of the mechanism of drug action involved.     

The mode of antiarrhythmic action of melperone

We studied the mode of antiarrhythmic action of melperone by His bundle electrography combined with programmed electrical stimulation in 21 pentobarbital anaesthetized dogs. Melperone alone (0.5 to 12.5 mg/kg) as well as melperone after sympathetic and parasympathetic blockade caused a dose-dependent increase in the ventricular and, even more, the atrial effective refractory period without affecting atrial and ventricular conduction times. Melperone shortened the atrioventricular nodal conduction time regardless of sympathetic and parasympathetic blockade. We conclude that the antiarrhythmic effect of melperone in most likely primarily due to a direct class III antiarrhythmic action.