Hemodynamic and myocardial effects of (-)-delta9-trans-tetrahydrocannabinol in anesthetized dogs

(?)-Δ⁹-trans-tetrahydrocannabinol (Δ⁹-THC) (39 μg–2.5 mg/kg, i.v.) decreased blood pressure, heart rate, cardiac output and right ventricular contractile force in a dose-related manner in intact dogs under pentobarbital anesthesia. The Δ⁹-THC-induced hypotension appeared to result mainly from a consistent and reproducible attenuation of cardiac output since no marked alteration in total peripheral resistance occured. In these animals the decrease in cardiac output appeared to be related to the bradycardia since there was no change in stroke volume following Δ⁹-THC. However, when the change in heart rate was prevented by atrial pacing or cardiac denervation, a less but significant reduction in cardiac output was induced by Δ⁹-THC. Under these experimental conditions Δ⁹-THC also significantly attenuated stroke volume. In contrast, Δ⁹-THC did not induce any significant changes in cardiac output, blood pressure, and heart rate of dogs pretreated with a ganglionic blocker.Δ⁹-THC appeared to be devoid of any measurable direct effect on the myocardium since the compound neither significantly altered right ventricular contractile force of the denervated or ganglionic blocker-pretreated hearts nor interfered with the positive inotropic responses to i.v. calcium and isoproterenol.In the major vessel occlusion preparation administration of Δ⁹-THC was followed by a reduction in venous tone. Furthermore, measurements of blood and plasma volume excluded an effect of Δ⁹-THC in these parameters.From these findings it is suggested that the reduction in cardiac output induced by Δ⁹-THC is the result of the action of this compound on cardiac rate as well as venous return; no evidence could be documented for a direct effect of this compound on the myocardium.     

Centrally mediated hypotension and bradycardia by methysergide in anesthetized dogs.

In anesthetized dogs, methysergide (1 and 3 mg/kg i.v.) caused reductions in systolic and diastolic blood pressure, heart rate, left ventricular pressure and peripheral resistance. Caardiac output was unchanged because of an increase in stroke volume. Methysergide exhibited no alpha-receptor, ganglion, or adrenergic neuron-blocking properties nor did it have marked direct vasocilator action. The BCO, but not the orthostatic, reflex was severely inhibited by the drug, evidence for a central inhibitory action. Atropine, vagotomy or carotid sinus debuffering had little or no effect on the hypotension and bradycardia produced by methysergide, whereas guanethidine pretreatment essentially abolished these effects. Direct intracerebronventricular administration of small doses of methysergide (0.2 mg/kg) caused significant hypotension and bradycardia. It is concluded that methysergide causes centrally mediated hypotension and bradycardia, the mechanism of which is not clearly understood.     

Urinary metabolites of N,N-dimethylaniline produced by dogs

Summary From urine of dogs injected with N,N-dimethylaniline the following metabolites were isolated as crystalline hydrochlorides and identified by their UV and IR spectra: 4-aminophenol, 4-methylaminophenol, 4-dimethylaminophenol, 2-aminophenol, and N-methylaniline. 2-Dimethylaminophenol was identified only by UV spectra, as the amount of crystalline hydrochloride was too small for an IR spectrum. The presence of 2-methylaminophenol in the urine was demonstrated by R_f values of the compound and its oxalate and color reaction. Aniline was not found in urine of the dogs injected with N,N-dimethylaniline, but nearly 2×10^–5 M aniline was determined in the blood of dogs injected with N,N-dimethylaniline, 40 mg/kg.The results have been briefly reported at a meeting of the Deutsche Pharmakologische Gesellschaft in Mainz 1971 (Kiese and Renner, 1971).     

The role of presynaptic receptors in the cardiovascular actions of N,N-di-n-propyldopamine in the cat and dog

Summary Intravenous administration of N,N-di-n-propyldopamine (DPDA: 50 and 200 g/kg/min, i. v.) produces hypotensive and bradycardic effects in anaesthetized cats and dogs. These effects were abolished by ganglionic blockade and antagonized by haloperidol or (SR)-sulpiride suggesting a neurogenic mechanism of action, mediated by specific dopamine receptors. The renal blood flow increases to DPDA in dogs were resistent to ganglionic blockade indicating some activity at postsynaptic vascular dopamine receptors. Studies with DPDA in vivo administered via the intravertebral and intravenous routes suggested a peripheral site of action for the hypotensive effects of this compound.In vitro, in isolated perfused cat spleens prelabeled with ³H-noradrenaline, DPDA (0.01–1 M) produced a concentration-dependent inhibition of tritium release elicited by nerve stimulation at 1 Hz which was selectively antagonized by 1 M (SR)-sulpiride implicating presynaptic inhibitory dopamine receptors in the mediation of this effect. In isolated rabbit splenic arteries, contracted by prostaglandin-F₂ , dopamine, ADTN (2-amino-6,7-dihydroxytetrahydronaphthalene) and apomorphine produced concentration-dependent relaxations while DPDA exhibited only weak postsynaptic dopamine-like effects.In vivo DPDA reduced, in a frequency dependent manner, the end organ responses to sympathetic nerve stimulation in the cat nictitating membrane and in the dog renal vascular bed. Both effects were mediated through activation of presynaptic inhibitory dopamine receptors by DPDA.In conclusion these results suggest a predominantly presynaptic agonist effect for DPDA in vitro and a similarly important action in vivo, mediated mainly via dopamine receptors. Furthermore evidence is presented which suggests that pre- and postsynaptic dopamine receptors may differ in their pharmacological properties and that presynaptic dopamine receptors could be important target receptors in the development of novel antihypertensive drugs.     

N,N-双乙酰胱氨酸在毕格犬体内的药动学

目的研究毕格犬静脉注射不同剂量N,N-双乙酰胱氨酸(DiNAC)后的药动学。方法毕格犬12只随机分成3组,分别静脉注射DiNAC 25,12.5,6.25 mg/kg,在设定的时间点采血,反相高效液相色谱法测定血浆中的DiNAC浓度,DAS程序计算其药动学参数。结果毕格犬静脉给予DiNAC后,其血药浓度-时间曲线符合二室模型一级动力学过程。AUC0→∞分别为3849.7±157.7,1683.0±90.5,757.1±344.2 mg/(L.min),与给药剂量成良好的线性关系(r=0.9993);Cmax分别为91.99±15.13,53.37±3.88,23.20±7.07 mg/L,与给药剂量呈线性关系(r=0.993);而t1/2α为1.1~1.9 min,t1/2β为34.2~47.3 min,分布容积(Vd)为0.38~0.49 L/kg,显示非剂量依赖性特征。结论DiNAC在毕格犬体内的药动学过程为二室模型一级动力学过程,具有分布快,消除迅速的特点。     

The effects of clonidine, prazosin, and propranolol on short-term and long-term habituation of the acoustic startle response in rats

The unique effect of clonidine in facilitating habituation of the acoustic startle response [10] was replicated. However, clonidine had no effect on between-session habituation, showing a pharmacological dissociation between short- and long-term habituation. Systematic manipulation of ISI showed clonidine's habituation-facilitating effect to be most striking with longer within-session ISIs where habituation was relatively weak in controls. Comparing clonidine's effect to that of two other hypotensive agents, prazosin and propranolol, showed that the habituation-facilitating effect was not due to blood pressure effects. Prazosin, an alpha₁-adrenergic blocker, facilitated short-term habituation, but significantly less so than did clonidine, an alpha₂-agonist. Propranolol, a beta-adrenergic blocker, had no effect of short-term habituation. Both prazosin and propranolol impaired long-term habituation, but propranolol did so without suppressing initial response levels. The data suggest that a synapse with both alpha-₁- and alpha₂-adrenoceptors may be critically involved in habituation of the acoustic startle response. A beta-adrenergic involvement in long-term habituation is tentatively suggested.     

Studies on the bradycardia induced by (-)- -trans-tetrahydrocannabinol in anesthetized dogs

(?)-Δ⁹-trans-tetrahydrocannabinol (Δ⁹-THC) (39 μg-5 mg/kg, i.v.) decreased heart rate in a dose related manner in dogs under pentobarbital anesthesia. This cardiac effect of Δ⁹-THC was neither due to an impairment of transmission across the sympathetic ganglia nor to a specific stimulation of parasympathetic ganglia. Selective blockade of either parasympathetic (atropine, bilateral vagotomy) or sympathetic (propranolol, spinal section at C₂C₄ neurogenic activity to the heart partially prevented the negative chronotropic effect of Δ⁹-THC. However the bradycardic effect of Δ⁹-THC was completely abolished in animals in which the autonomic pathways to the heart were pharmacologically or surgically inactivated.Administration of Δ⁹-THC into the vascularly isolated, neurally intact cross-perfused head of dogs significantly slowed the heart rate in intact as well as debuffered recipients. This bradycardia was reduced in recipients in which the trunk was atropinized prior to cerebral administration of Δ⁹-THC into the femoral vein of the recipient in the dog cross circulation preparation also caused a significant decrease in heart rate which was essentially abolished either by bilateral vagotomy or by atropinization of the recipients.These results are compatible with the hypothesis that the negative chronotropic effects of Δ⁹-THC in dogs under pentobarbital anesthesia is of central origin and involves both a direct and reflexogenic alteration of central autonomic outflow regulating the heart rate.     

Renal vascular and sympathetic nerve responses to hypotension induced by platelet-activating factor in anesthetized dogs

This experiment was designed to determine renal sympathetic and renal vascular responses to platelet-activating factor (PAF)-induced hypotension in anesthetized dogs with and without systemic baroreceptor denervation. The left kidney was perfused at a constant flow, and renal perfusion pressure and efferent left renal sympathetic nerve activity were measured simultaneously. Intrarenal injection of PAF (1.25−5.0×10⁻² μg/kg, N = 6) produced a dose-dependent increase in renal perfusion pressure without any change in systemic blood pressure. An intravenous injection of PAF (10 μg/kg) to intact animals (n = 7) caused an initial increase in renal nerve activity (157±14%) followed by a gradual reduction below baseline (72±7%) with concomitant systemic hypotension (from 116±7 to 46±6 mmHg). Renal perfusion pressure increased significantly from 84±2 to 161±33 mmHg concomitant with an increase in renal nerve activity at 1 min and was maintained at this elevated level throughout the experiment. Similar responses of renal nerve activity and renal perfusion pressure were found in animals with complete systemic baroreceptor denervation (n = 7). These renal suggest that renal vascular response during PAF-induced hypotension may presumably be mediated by a direct vasoconstrictor effect of PAF on the renal vasculature and that baroreceptor reflex is not involved in either renal sympathetic or renal vascular changes.     

Differential labelling of dopamine receptors in rat brain in vivo: Comparison of [3H]piribedil, [3H]S 3608 and [3H]N,n-propylnorapomorphine

The in vivo distribution of radioactivity in brain and labelling of cerebral dopamine receptors in rats derived from the administration of the atypical dopamine agonists [³H]piribedil and [³H]S 3608 has been compared to that of the classical dopamine agonist [³H]N,n-propylnorapomorphine (NPA). Radioactivity derived from [³H]piribedil accumulated in the substantia nigra, nucleus accumbens and cervical spinal cord, and this accumulation was prevented by administration of (+)-butaclamol and apomorphine only in substantia nigra and the nucleus accumbens. Radioactivity derived from [³H]S 3608 accumulated in the same areas and, additionally, in the frontal cortex and tuberculum olfactorium; this accumulation was prevented by administration of (+)-butaclamol and apomorphine only in substantia nigra, nucleus accumbens and tuberculum olfactorium. Neither ligand caused accumulation of radioactivity in the striatum. In contrast, radioactivity derived from [³H]NPA accumulated in the substantia nigra, nucleus accumbens, striatum, and tuberculum olfactorium. Radioactivity derived from [³H]NPA was prevented from accumulating in all these areas by (+)-butaclamol and by apomorphine, but piribedil only prevented accumulation in the substantia nigra and nucleus accumbens and S 3608 only prevented accumulation in substantia nigra, tuberculum olfactorium and nucleus accumbens. Neither piribedil nor S 3608 prevented accumulation of radioactivity derived from [³H]NPA in the striatum. Piribedil and S 3608 showed equal capacity in vitro to displace [³H]spiperone and [³H]NPA from striatal or nucleus accumbens tissue preparations. These results suggest that, in vivo piribedil and S 3608 selectively interact with dopamine receptors in the substantia nigra and nucleus accumbens, but not with those in striatum, perhaps due to differential distribution within brain.     

Circadian variation in the head twitch response produced by 5-methoxy-N1,N1-dimethyltryptamine and p-chloroamphetamine in the mouse

Circadian fluctuations were measured in the head twitch response produced by 5-methoxy-N¹,N¹-dimethyltryptamine (5-MeODMT) and p-chloroamphetamine (PCA) in male BK. TO mice. The effects of depleting brain 5-hydroxytryptamine (5-HT) with p-chlorophenylalanine (PCPA) on the 5-MeODMT in the mouse were also studied. Changes in brain 5-HT and 5-hydroxyindoleacetic (5-HIAA) were concomitantly determined. PCPA (400 mg/kg IP twice on consecutive days) significantly increased the number of head twitches induced by 5-MeODMT (5 mg/kg IV) on days 3 and 5 after the initial injection of PCPA when 5-HT and 5-HIAA were also significantly reduced. On day 12, there was no significant difference in the number of head twitches between mice administered PCPA and those given saline, and 5-HT and 5-HIAA levels were nearly back to normal. PCPA, using the same dose schedule, significantly reduced the number of head twitches induced by PCA when PCA was administered 24h after the second injection of PCPA (day 3). Mice maintained on a 12-h light-dark cycle showed a maximum response to the direct 5-HT receptor agonist 5-MeODMT (5 mg/kg IV) towards the end of the dark period, when the 5-HT level was at its lowest. p-Chloroamphetamine, which causes release of 5-HT from pre-synaptic neurones, produced a peak head twitch response in the middle of the light period when 5-HT and 5-HIAA levels were maximal, while the response towards the end of the dark period was significantly less than that at other tines tested. It is concluded that 5-HT receptor response shows a circadian rhythm related to both pre-synaptic availability of 5-HT and post-synaptic receptor sensitivity.     

Effects of stimulation of putative dopamine autoreceptors on electroencephalographic power spectrum in comparison with effects produced by blockade of postsynaptic dopamine receptors in rats

Alterations in cortical EEG activity in male rats produced by putative agonists at dopamine (DA) autoreceptors and by antagonists at postsynaptic DA receptors were compared in order to study, whether an impairment in dopaminergic neurotransmission via two different mechanisms might result in similar or different effects. Simultaneously to the EEG recordings, gross behaviour was observed. Putative agonists at DA autoreceptors (apomorphine 0.05 mg/kg, quinpirole 0.05 mg/kg, or talipexole 0.02 mg/kg s.c.) produced increases in the power iin all of the frequency bands, except beta-2, with the most pronounced increase in the delta band. These EEG alterations were accompanied by hypokinesia, ptosis and yawning. In contrast, antagonists at DA receptors (haloperidol 0.1 mg/kg i.p., D₂ blocker) or SCH 23390 (0.2 mg/kg i.p., D₁ blocker) led to little increases in the delta band, but more pronounced increases in the alpha-2 band. Behavioural signs were hypokinesia, but little ptosis and yawning. The combination of both blockers produced, in addition, strong increases in the delta band and behavioural signs of ptosis and yawning. These results suggest that activation of putative dopamine autoreceptors produced EEG patterns and behavioural patterns different from those produced by blockade of either D₁ or D₂ postsynaptic dopamine receptors. In contrast, the effects following a stimulation of putative DA autoreceptors, which are expected to decrease the release of the agonist and its action at postsynaptic D₁ and D₂ receptors, were very similar to those found after a combined blockade of both types of postsynaptic dopamine receptors.     

Metabolism and hepatotoxicity of N,N-dimethylformamide,N-hydroxymethyl-N-methylformamide,and N-methylformamide in the rat

The metabolism and hepatotoxicity ofN,N-dimethylformamide (DMF) and two of its metabolites,N-hydroxymethyl-N-methylformamide (HMMF) andN-methylformamide (NMF) were evaluated over a 4-day period in rats. DMF toxicity was dose dependent and delayed toxicity after the administration of a high DMF dose (13.7 mmol/kg) in comparison to a lower dose (4.1 mmol/kg) was observed. Treatment of rats with 13.7 mmol/kg DMF, HMMF, or NMF showed i) that DMF is more toxic than HMMF or NMR, and ii) that hepatotoxicity occurs later for DMF than for HMMF or NMF. Analysis of serum and urine samples demonstrated that DMF is first metabolized to HMMF, which is then partially converted to NMF. After HMMF administration, NMF was found both in serum and in urine. The time course of DMF and HMMF toxicity in relation to NMF formation fitted the hypothesis that the hepatotoxicity of DMF and HMMF is mediated via NMF. The degree of hepatotoxicity after HMMF and NMF treatment is similar. However, the degree of DMF hepatotoxicity is much higher than in the case of NMF or HMMF. The role of NMF as an obligatory intermediate in DMF and HMMF hepatotoxicity is discussed.     

Differential alterations in striatal dopamine receptor sensitivity induced by repeated administration of clinically equivalent doses of haloperidol,sulpiride or clozapine in rats

Rats received therapeutically equivalent doses of either haloperidol (1.7–1.9 mg/kg/day), sulpiride (112–116 mg/kg/day) or clozapine (30–35 mg/kg/day) continuously for 4 weeks. Treatment with haloperidol, but not sulpiride or clozapine, caused inhibition of stereotyped behaviour induced by apomorphine (0.125–0.25 mg/kg SC). Following drug withdrawal for up to 7 days, haloperidol and sulpiride, but not clozapine treatment caused an exaggeration of stereotyped behaviour induced by apomorphine.B_max values for striatal ³H-spiperione binding were erevated in animals treated for 2 and 4 weeks with haloperidol, but not with sulpiride or clozapine. Following drug withdrawal, haloperidol, but not sulpiride or clozapine, treatment caused an increase in B_max for striatal ³H-piperone binding.B_max values for striatal ³H-NPA binding revealed no change during haloperidol or clozapine treatment. Sulpiride treatment for 1 week caused an increase in B_max for ³H-NPA binding, which returned to control levels at 2 and 4 weeks. Following drug withdrawal, there was an increase in B_max for ³H-NPA binding in rats treated with haloperidol and sulpiride, but not clozapine.On continuous treatment and following withdrawal from haloperidol, sulpiride, or clozapine the ability of dopamine to stimulate striatal adenylate cyclase activity did not differ from that in control animals.Repeated administration of sulpiride or clozapine may not induce striatal dopamine receptor supersensitivity when given in clinically relevant doses, although haloperidol does.     

n,n′-二乙酰-L-胱氨酸对半乳糖胺联用脂多糖引起小鼠免疫性肝衰竭的作用

目的研究n,n′-二乙酰-L-胱氨酸(DiNAC)对免疫性肝衰竭的治疗作用。方法观察DiNAC对Balb/C小鼠由半乳糖胺联用脂多糖引起免疫性肝衰竭的作用。半乳糖胺/脂多糖攻击6 h后，小鼠血清ALT，AST和外周血T细胞亚群分别用全自动生化仪、流式细胞仪测定，并用光镜观察肝组织病理切片，统计半乳糖胺/脂多糖攻击24 h后的小鼠存活率。结果给肝衰竭小鼠ip DiNAC(50，200，800 mg·kg^-1)，能明显阻止小鼠血清ALT和AST活力增高，使肝组织损害减轻及提高小鼠存活率，并呈剂量依赖关系；DiNAC能增强免疫性肝衰竭小鼠外周血CD4⁺,CD8⁺,Th1和Th2 T淋巴细胞的增殖分化。结论DiNAC对免疫性肝衰竭动物有明显的治疗作用，这一作用与其免疫调节有关。     

Alpha-adrenergic activity of N,N-dimethyldopamine (DMDA).

The autonomic and cardiovascular activity of N,N-dimethyldopamine (DMDA) was studied in the dog and rabbit. DMDA appears to be a postganglionic sympathetic alpha-adrenoceptor agonist since it consistently caused vasconstriction in several isolated vascular beds, even in the presence of ganglionic blockade. The pressor activity of DMDA was attenuated by the alpha-adrenergic antagonist phentolamine. Calculated pA2 values for phentolamine against both DMDA and norepinephrine in isolated rabbit arteries were in close agreement. DMDA inhibits cardioaccelerator nerve stimulation induced chronotropic responses by a mechanism which appears to be alpha-adrenergic in the dog.     

Receptor alterations in manganese intoxicated monkeys

The density of four different receptors and one marker of dopamine uptake sites were analyzed in monkey brains after manganese exposure (0.1 g manganese per month during 26 months, a dose comparable to that workers might inhale in dusty environments) by means of quantitative receptor autoradiography. The binding of³H-mazindol to the dopamine uptake sites was reduced by 75% in both the head of the caudate nucleus and putamen, while it remained unchanged in the other regions analyzed. The binding of the D1 receptor ligand³H-SCH 23 390 was reduced about 45% in the same areas as mazindol binding, while the density of D2 receptors was unaffected. The muscarinic acetylcholine receptors as well as GABA_A receptors remained also unchanged in all brain areas analyzed after manganese exposure. Thus the dopaminergic neurons must be considered to be vulnerable to manganese concentrations attainable in the work environment. Our results also indicate that postsynaptic structures containing D1 receptors are sensitive while cells containing D2 receptors are either spared or compensated for by up-regulation of the number of receptors on remaining sites.     

盐酸头孢吡肟中残留溶剂N,N-二甲基甲酰胺的检测方法

目的 建立顶空气相色谱法测定盐酸头孢吡肟中残留溶剂N,N-二甲基甲酰胺的含量的方法.方法 色谱柱为DB-624毛细管柱(30m×0.53m,3μm),柱温:程序升温,90℃维持18min,以每分钟20℃升温至200℃,维持5min;检测器温度为250℃;进样口温度为200℃,分流比1:1.顶空进样,项空瓶平衡温度为90℃,平衡时间为40min,进样体积为1.0mL.结果 N,N-二甲基甲酰胺在0.0290mg·mL-1～0.2 07mg·mL-1浓度范围内线性关系良好(r值为0.99975),平均回收率为101.1%(RSD为1.7%).结论 该方法准确灵敏,可用于盐酸头孢吡肟中二甲基甲酰胺的检测.     

Conditioning of behavioural effects produced by an intermediate dose of apomorphine: hypokinesia,ptosis and stereotypies

Summary Apomorphine, in an intermediate dose (0.18 mg/ kg s.c.) decreased dopamine turnover and produced signs generally attributed to a decrease in dopaminergic neurotransmission, e.g. ptosis and yawning, as well as signs of an increased stimulation of dopamine receptors in dopaminoceptive target neurones, e.g. stereotyped sniffing. In contrast, the former signs were exclusively observed after smaller doses and the latter after larger doses of apomorphine. Since it had been shown in previous studies that these signs, except yawning, could be conditioned in association with discriminative stimuli in the environment, the present study using conditioning experiments with this intermediate dose aimed at determining, 1. the time course of each conditioned response, 2. the interaction of conditioned and unconditioned responses, and 3. the conditions under which hypokinesia occurred. In each series, conditioned animals were compared with pseudoconditioned controls. Rats were conditioned for 8 days with apomorphine, and on day 9, treated with saline in presence of the conditional stimuli (a test cage in combination with acoustic and olfactory stimuli). In contrast to pseudoconditioned controls, ptosis and stereotyped behaviour were observed in conditioned rats, sometimes occurring alternatingly. These signs closely resembled the direct, unconditioned pharmacological effects. In addition, akinesia occurred after conditioning, although it was never manifest as a pure drug response, nor during the conditioning period. In contrast, yawning was observed in pseudoconditioned as well as in conditioned rats, although slightly more frequently in the former animals. Subsequently, the rats were again conditioned (or pseudoconditioned) on days 10–14 with apomorphine and both groups tested with the same dose (0.18 mg/kg) of apomorphine in the presence of the conditional stimuli. Both ptosis and stereotypies were significantly enhanced in conditioned animals, indicating synergistic interactions between conditioned and direct, pharmacological behavioural effects. In all cases the conditioned effects lasted for about 30 min.The results show that, after conditioning with an intermediate dose of apomorphine, both signs typical of a low dose of apomorphine and those characteristic of a large dose can be conditioned and sometimes occur alternately. Send offprint requests to K. Kuschinsky     

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.     

Limitation of myocardial infarct size by atenolol, nadolol and propranolol in dogs

The importance of cardioselectivity and membrane depressant activity in the ability of beta-adrenergic antagonists to limit myocardial infarct size was assessed in the dog. Infarction was produced by a 60 min occlusion of the left circumflex coronary artery followed by reperfusion into a critical stenosis. Infarct size was significantly reduced by atenolol, nadolol and propranolol. Thus, limitations of infarct size by beta-adrenergic antagonists occur with agents which possess or lack cardiac selectivity or membrane depressant activity.