Ischaemically induced alterations in electrical activity and mechanical performance of isolated blood perfused canine myocardial preparations.

STUDY OBJECTIVE: The aim was to investigate the direct effect of ischaemic insult on the electrical activity or mechanical performance of the sinoatrial node, atrioventricular node or Purkinje fibres (ventricular papillary muscle) of the dog heart. DESIGN: The three isolated tissues independently mounted in a water jacketed glass container were cross circulated through their respective arteries at a constant pressure (120 mm Hg) with arterial blood from a heparinised supporting dog under sodium pentobarbitone anaesthesia. Rate of automatic rhythmical contractions (automaticity) or tension development was measured before, during, and after ischaemia (30 min). EXPERIMENTAL PREPARATIONS: Seven sinoatrial nodes, five atrioventricular nodes, and 11 papillary muscles were prepared from the heart of mongrel dogs, weighing 11.5-15 kg. MEASUREMENTS AND MAIN RESULTS: The automaticity of the sinoatrial node and atrioventricular node exhibited a high degree of resistance to ischaemia, whereas both the automaticity (Purkinje fibres) and the tension development of papillary muscle were more susceptible to ischaemia and ultimately disappeared during ischaemia. Upon resumption of the blood supply, contractility rapidly returned to preischaemic levels. However, force-frequency analyses revealed that even after reperfusion, papillary muscle had lost the ability to respond normally to stimulus frequencies greater than 2 Hz. CONCLUSIONS: The findings suggest (1) that in the special excitatory and conductive system, the more distal the segment is to the sinoatrial node, the more vulnerable it is to ischaemia; (2) that the myocardium impaired by ischaemic insult lacks functional reserve, as evidenced by enlargement of the differences between the alternate tensions of pulsus alternans; and (3) that cessation of the blood supply does not predominantly damage those tissues whose functions are mainly regulated by a slow inward calcium current.

Cerebral ischemia decreases the behavioral effects and mortality rate elicited by activation of NMDA receptors in mice.

The purpose of this study was to determine whether prior transient cerebral ischemia, in conscious mice, would alter the biological responses resulting from excessive activation of N-methyl-D-aspartate (NMDA) receptors, in an early stage. The responses to the activation of NMDA receptors by an intracerebroventricular injection of NMDA, such as wild running, tonic and clonic convulsions, absence of the visual placing reflex, loss of the righting reflex, impaired motor function and a high mortality rate, were to a large extent prevented if 30 min before treatment, either a 10-min period of global cerebral ischemia was induced or a 1 nmol intraventricular injection of NMDA was given but not if either of the above procedures was done one day before the test dose of NMDA. In contrast, behavioral symptoms, in response to activation of non-NMDA-type glutamate receptors elicited by intraventricular injection of either kainic acid or AMPA, were not clearly affected. Transient systemic hypercapnic anoxia (22-sec exposure to 100% CO2 gas), before treatment with NMDA did not significantly reduce the NMDA-induced behavior. The severity of these behavioral responses and high mortality rate observed after intraventricular injection of pentylenetetrazole (PTZ, 30 mumol) were not altered by either prior global ischemic insult or by a preexposure to NMDA given intraventricularly. The NMDA antagonist, MK801 (0.1 and 0.3 mg/kg i.p.) greatly reduced the behavioral effects and mortality rate, resulting from the intraventricular injection of NMDA and somewhat reduced the effects of the intraventricular injection of PTZ.(ABSTRACT TRUNCATED AT 250 WORDS)

A method for recording smooth muscle and vascular responses of the blood-perfused dog trachea in situ.

1 A method is described for measuring responses of dog tracheal musculature and vasculature in situ. 2 The upper two thirds of the trachea was perfused with blood through both cranial thyroid arteries at a constant pressure. The blood flow through the arteries was measured with an electromagnetic flowmeter. The response of the tracheal musculature was measured as a change in pressure in a water-filled cuff inserted into the trachea via the mouth. Drugs were injected close-arterially. 3 Acetylcholine produced dose-dependent increases in blood flow rate (vasodilatation) and in tracheal intraluminal pressure (tracheal constriction). These responses were antagonized by atropine. 4 Isoprenaline produced vasodilatation which was blocked by propranolol. Adrenaline and noradrenaline caused vasocontriction which was blocked by phentolamine. 5 All three catecholamines produced a decrease in tracheal intraluminal pressure (tracheal dilatation). The tracheal dilatation in response to adrenaline and noradrenaline was converted to constriction by propranolol. The tracheal constriction thus unmasked was abolished specifically by phentolamine. 6 From these results it is concluded that the tracheal musculature and vasculature contain muscarinic receptors, and excitatory alpha- and inhibitory beta-adrenoceptors. In the tracheal musculature beta-adrenoceptors predominate over alpha-adrenoceptors; the reverse is true in the tracheal vasculature.

Assessment of the selectivity of OPC-2009, a new beta2-adrenoceptor stimulatn, by the use of the blood-perfused trachea in situ and of the isolated blood-perfused papillary muscle of the dog.

1 The potency and selectivity of 5-(1-hydroxy-2-isopropylamino)butyl-8-hydroxy carbostyril hydrochloride hemihydrate (OPC-2009), a new beta(2)-adrenoceptor stimulant, was compared with those of isoprenaline, trimetoquinol and salbutamol by the use of blood-perfused tracheal preparations in situ and of blood-perfused papillary muscle preparations of the dog. All drugs were injected intra-arterially.2 All the four drugs decreased tracheal intraluminal pressure (tracheal relaxation) and increased tracheal blood flow in a dose-dependent manner. The four drugs produced a dose-dependent increase in developed tension of papillary muscles. In both preparations the duration of action of isoprenaline and salbutamol was short, whereas that of OPC-2009 and trimetoquinol was long. These effects were antagonized by propranolol.3 Dose-response curves to the four drugs for tracheal relaxation were almost parallel. OPC-2009 was 2.4 times more potent, and trimetoquinol and salbutamol were 2.2 and 6.2 times less potent than isoprenaline in causing tracheal relaxation.4 Dose-response curves to the four drugs for tracheal vasodilatation were also parallel. OPC-2009, trimetoquinol and salbutamol were 3.9, 6.7 and 23 times less potent than isoprenaline.5 Slopes of the dose-response curves to the four drugs for increased developed tension were not parallel; that of OPC-2009 was the least steep, whereas that of isoprenaline was the steepest. Trimetoquinol, salbutamol and OPC-2009 were about 18, 570 and 2400 times less potent than isoprenaline.6 Selectivity calculated from relative potencies indicate that OPC-2009 was about 6000 times, salbutamol about 92 times and trimetoquinol about 8.2 times more selective than isoprenaline for tracheal smooth muscle as compared to ventricular muscle.7 The high potency and selectivity of OPC-2009 for tracheal smooth muscle and its long duration of action suggest its potential usefulness for treatment of bronchial asthma.8 The present results are also compatible with the concept that beta(1)-adrenoceptors in cardiac muscle and beta(2)-adrenoceptors in tracheal and vascular smooth muscle can be distinguished. Furthermore, the results revealed that the beta-adrenoceptors mediating tracheal relaxation and vasodilatation may also be different.

Differential effects of the calcium-antagonistic vasodilators, nifedipine and verapamil, on the tracheal musculature and vasculature of the dog.

In anaesthetized dogs the trachea in situ was perfused arterially with blood, and drugs were injected intraarterially. Isoprenaline and the calcium-antagonistic vasodilators, nifedipine and verapamil, increased tracheal blood flow and decreased resting tone of the trachea. Isoprenaline was equi-effective in producing tracheal vasodilatation and tracheal dilatation. The two calcium-antagonistic vasodilators were less effective tracheal dilators than tracheal vasodilators.

Pharmacological analysis of histamine receptors in musculature and vasculature of the dog trachea in situ.

1 The role of histamine H1- and H2-receptors in the musculature and vasculature of the dog trachea was investigated in the blood-perfused trachea in situ. 2 Histamine and acetylcholine caused increases in blood flow (tracheal, vasodilatation) and in intraluminal pressure (tracheal constriction) in a dose-dependent manner. Histamine was almost equipotent to acetylcholine in causing tracheal vasodilatation but was about 30 times less potent in causing tracheal constriction. 3 The histamine H2-receptor agonist, dimaprit, caused a dose-dependent increase in tracheal blood flow but failed to cause tracheal constriction. 4 The tracheal constriction produced by histamine was inhibited strongly by diphenhydramine but not modifed by metiamide. The tracheal vasodilatation produced by histamine was antagonized by both diphenhydramine and metiamide; diphenhydramine was more effective than metiamide. 5 It is concluded that in the tracheal musculature, histamine receptors are exclusively of the H1-type and mediate constriction, whereas in the tracheal vasculature, both histamine H1- and H2-receptors mediate vasodilatation but histamine H1-receptors are predominant.

Dextrorphan attenuates the behavioral consequences of ischemia and the biochemical consequences of anoxia: possible role of N-methyl-d-aspartate receptor antagonism and ATP replenishing action in its cerebroprotecting profile.

The acute anti-ischemic and anti-anoxic effects of dextrorphan (DX) were compared with those of dizocilpine (MK-801) in a variety of animal models, and in vivo and in vitro testings under anoxic conditions. DX reduced the incidence of death in ischemic mice and improved the rotarod performance of mice with brain ischemia. The ischemically-impaired memory of mice treated with DX markedly improved, as shown in the step-through type passive avoidance test, Morris water maze and in the habituation of exploratory behavior test. MK-801 likewise improved the water maze performance of the ischemically-impaired mice, but to a lesser extent. The step-through type passive avoidance performance of ischemic mice was not improved by MK-801. In the passive avoidance task with normal mice, DX, like MK-801, produced anterograde amnesia at doses higher than those needed to attenuate the behavioral effects of ischemia. DX, intravenously or centrally administered, markedly and dose-dependently reduced the incidence of death in mice receiving potassium cyanide (KCN). DX lessened the reduction in adenosine triphosphate (ATP) and increased lactate contents in mice dosed with KCN and also lessened the reduction in ATP in the TCA cycle and oxidative phosphorylation reactions caused by KCN (0.58 mmol/l), whereas MK-801 failed to show any effect on ATP formation pathways in vivo and in vitro, and failed to protect mice against KCN-induced lethal toxicity in vivo. In the in vitro studies, DX increased the adenylate kinase activity of the rat brain homogenate. DX was found to be a cerebroprotectant with anti-ischemic and anti-anoxic actions, the effects probably stemming from its N-methyl-d-aspartate receptor antagonistic property in cooperation with its ATP replenishing action.

Effects of CCK antagonists on CCK-induced suppression of locomotor activity in mice.

Sulfated cholecystokinin octapeptide (CCK-8) was administered either intraperitoneally or into the cerebral ventricle of fully conscious mice, and locomotor activity was quantified. CCK-8 administered by either route suppressed locomotor activity. Subcutaneously administered selective CCK-A receptor antagonist, L-364,718 (1 mg/kg), reversed the inhibitory effect of centrally as well as peripherally administered CCK-8, but the selective CCK-B receptor antagonist, L-365,260 (1 mg/kg), did not. These results demonstrate that centrally as well as peripherally administered CCK-8 suppresses locomotor activity in mice through an interaction with CCK-A, but not CCK-B, receptors.

Analysis of the vasodilator action of alprenolol.

The effect of alprenolol and other beta-adrenoceptor antagonists, including d-isomers, on blood flow in femoral, coronary and mesenteric vascular beds was measured in anesthetized dogs. Under conditions of constant perfusion pressure, intra-arterial injection of beta-adrenoceptor antagonists produced vasodilation. Propranolol and alprenolol were approximately equipotent in coronary and mesenteric beds but alprenolol was significantly more potent in the femoral bed. Practolol was virtually inactive in all beds. The vasodilating potency of d-alprenolol and d-propranolol was not significantly different from that of the respective racemic mixtures. The vasodilator response to alprenolol was not affected by pretreatment with atropine, diphenhydramine or propranolol. In conscious normotensive dogs i.v. injections of d,l- and d-alprenolol produced dose-dependent decreases in blood pressure and increases in heart rate. Under similar conditions, i.v. d,l-propranolol was without effect on either measurement. The results suggest that the hypotensive action of alprenolol in dogs may derive from its vasodilator activity.

Effects of hexoestrol on the contractility of the isolated, blood-perfused canine papillary muscle and of the guinea-pig ileum.

The effects of hexoestrol were studied on the blood flow and the tension development of the isolated, blood-perfused papillary muscle of the dog, as well as on the contractions of the guinea-pig ileum induced by acetylcholine, histamine or BaCl2. Hexoestrol caused an increase in coronary blood flow and a negative inotropic effect in a dose-dependent manner. High doses of hexoestrol produced a loss of contractility of the papillary muscle without significant alterations of the amplitude and shape of the electrical activity recorded extracellularly. Hexoestrol had a strong non-selective relaxant effect on the guinea-pig ileum and was 10-20 times more potent than papaverine in antagonizing contractions induced by the 3 agonists. These results indicate that hexoestrol probably acts by blocking certain steps in the process by which extracellular and/or superficially bound Ca ions move to the contractile machinery in cardiac and in smooth muscle cells. Thus, it may bear some resemblance to the so-called calcium antagonists.

Antagonism of various tonic convulsions in mice by dextrorphan and dizocilpine.

To define their efficacy and mechanism of action, the possible antagonistic effects of intravenously administered dextrorphan and dizocilpine, non-competitive N-methyl-D-aspartic acid (NMDA) receptor antagonists, on tonic convulsions and death in a variety of experimental mice models were compared. Dextrorphan not only produced dose-dependent protection against the tonic convulsions caused by an intracerebroventricular injection of NMDA, but also showed a broad spectrum of anticonvulsant activities against tonic convulsions caused by alpha-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA), kainic acid (KA), bicuculline, pentylenetetrazole or electroconvulsive shock. The anticonvulsant action of dizocilpine was found to be more efficacious for any type of tonic convulsions and was 20- to 70-fold more potent than that of dextrorphan. Dizocilpine, unlike dextrorphan, impaired motor function at doses showing its anticonvulsant activity. Bay k-8644 (a Ca2+ channel agonist)-induced seizures were not antagonized by dextrorphan. Dextrorphan and dizocilpine were characteristically selective for protective functions against death, especially with three subtypes of glutamate receptors, as death caused by NMDA but not by AMPA and KA was selectively and markedly inhibited by both dextrorphan and dizocilpine. In view of these results, the efficacy of dextrorphan and dizocilpine as antagonists of convulsant effects appears to be consistent with the interpretation that a variety of convulsants cause tonic convulsions via direct or indirect interaction with the NMDA receptor complex. Furthermore, it is suggested that influx of Ca(2+) and intracellular Ca(2+) activity, such as the Bay k-8644-modulated activation of Ca(2+) binding proteins, are not directly modified by the administration of dextrorphan, itself.

Release of noradrenaline proposed as a mechanisms for the positive inotropic action of dipyridamole.

In the arterially blood-perfused canine papillary muscle, i.a. injections of dipyridamole (10-300 mug) produced a dose-dependent increase in developed tension amounting to about 45% of the basal developed tension at 300 mug. The positive inotropic response to dipyridamole was greatly reduced by a prior i.a. injection of propranolol (10 mug) or by pretreatment with reserpine (0.2 mg/kg s.c. for 3 consecutive days) but not affected by a prior i.a. injection of tetrodotoxin (1 mug) or desmethylimipramine (3-10 mug). The positive inotropic response to dipyridamole reduced by pretreatment with reserpine was restored by i.a. infusion of noradrenaline (0.03 mug/min). Dipyridamole did not modify the positive inotropic responses to noradrenaline and tyramine. These results suggest that the positive inotropic response to dipyridamole is largely due to noradrenaline released from adrenergic nerve endings by a mechanism that differs from those operative in the action of tyramine or in liberation of noradrenaline upon excitation.

Duration and selectivity in beta-adrenoceptor blocking action of a beta-adrenoceptor blocking drug, D-32 in conscious dogs.

In conscious dogs, the selectivity and duration of beta-blocking activity, and serum concentration of a beta-blocking agent, D-32 [dl-1-tert-butylamino-3-(2,3-dimethylphenoxy)-2-propanol hydrochloride] was compared to that of propranolol, pindolol, atenolol and IPS-339 [dl-1-tert-butylamino-3-(-9-fluorenylideneaminoxy)-2-propanol hydrochloride]. Ratios of doses causing a 50% inhibition of tachycardia to that on hypotension induced by isoprenaline were as follows: D-32 (0.69), propranolol (0.67), atenolol (0.03) and IPS-339 (6.3). Thus, present experiments indicate that, unlike atenolol and IPS-339, D-32, propranolol and pindolol are non-selective beta-adrenoceptor blocking agents. Atenolol and IPS-339, however, selectively blocked cardiac beta1, receptors and vascular beta2-receptors respectively, as would be expected. In an optimal dose range these two drugs can be used satisfactorily as a pharmacological tool for inhibiting responses mediated via the respective beta-receptors. After oral administration, the pharmacological half-life (time required for 50% recovery of beta-blocking action) was 15.8 +/- 4.5 h for propranolol (3 mg/kg), 21.8 +/- 6.4 h for D-32 (0.5 mg/kg), 30.5 +/- 3.1 h for atenolol (6 mg/kg) and 30-35 h for pindolol (0.2 mg/kg). The pharmacological half-life after i.v. administration was 4.4 +/- 0.7 h for propranolol (300 microgram/kg) and 5.9 +/- 0.4 h for D-32 (150 microgram/kg), whereas the serum half-like (time required for 50% decrease in serum concentration) of propranolol was 1.4 h and that of D-32 was 1.3 h. The values for pharmacological half-life and serum half-life were significantly different. Thus, for determination of administration frequency and dosage of beta-adrenoceptor blocking drugs, not only pharmacokinetic but also pharmacological data (duration of action) are essential.

Role of beta 2-adrenoceptor blockade and circulating adrenaline level for the pressor responses to beta-adrenoceptor blocking drugs in rats.

The present experiments were designed to elucidate what mechanism(s) would be responsible for beta-adrenoceptor blocking drugs (beta-blockers)-induced pressor responses in rats. In urethane-anaesthetized rats, 6 beta-blockers at i.v. doses ranging from 0.3 to 300 micrograms/kg evoked the pressor response in a dose-dependent manner. The relative potency in causing the pressor action was correlated not to their beta 1-blocking activities (r = 0.374, P greater than 0.05) but to their beta 2-blocking ones (r = 0.856, P less than 0.05). In pithed or adrenalectomized rats with low levels of plasma catecholamines, however, propranolol failed to exert its sustained pressor action. Propranolol (300 micrograms/kg i.v.) distinctly potentiated the pressor responses not to noradrenaline but to adrenaline and to electrical stimulation of the sympathetic outflow (E.S.) in pithed rats. On the contrary, there was not any potentiation of pressor response to E.S. in pithed, adrenalectomized rats treated with propranolol (300 micrograms/kg i.v.). In rats treated with phenoxybenzamine (5 mg/kg i.v.), adrenaline was shown to have much more potent vasodilating action resulting from beta 2-stimulation than noradrenaline, the dose difference for causing the diastolic blood pressure decrease by a 25 mm Hg being almost 80 times. In pithed rats, infusion of adrenaline at the rate of 0.02 micrograms/min caused a significant increase in plasma adrenaline level from 0.02 +/- 0.01 to 0.45 +/- 0.048 ng/ml, being close to basal level obtained in urethane-anaesthetized rats. Under this situation, propranolol (1-100 micrograms/kg i.v.) showed a distinct pressor response in a dose-dependent fashion as observed in adrenal intact rats anaesthetized with urethane.(ABSTRACT TRUNCATED AT 250 WORDS)

Negative and positive effects of intracerebroventricular scopolamine on memory in mice undergoing passive avoidance and escape tests.

The effects of intracerebroventricular administration of scopolamine on memory and learning in the conscious, freely moving mouse were evaluated using step-down passive avoidance and water maze tests. A new technique was used that allows convenient injection into the cerebral ventricles without disturbing the animal's behavior. No significant changes in locomotor activity were observed after low doses of scopolamine (0.1 and 1.0 microgram). However, 10 micrograms produced an increase in locomotor activity, while 100 micrograms caused an initial decrease followed by an increase in activity. In the passive avoidance test, scopolamine significantly impaired memory acquisition at doses higher than 1.0 microgram, consolidation at a dose of 100 micrograms, and retrieval at doses of 10 and 100 micrograms. In contrast, a dose of 0.1 microgram significantly improved consolidation and retrieval. In the water maze with a bridge, scopolamine either impaired memory acquisition, consolidation, and retrieval, or had no significant effect in the dose range tested. These results suggest that there are differences in the process of memory formation in the passive avoidance and escape tests.

Responses of isolated rabbit thoracic aortae to endothelin-1 and several vasoactive substances. A new blood perfusion circuit under the controlled conditions of resistance and flow.

Analysis of the reactivity of isolated rabbit thoracic aorta to isoproterenol and norepinephrine injected into a blood perfusion circuit intraarterially (i.a.) under controlled conditions of resistance and flow using conscious support rabbits revealed that with pressure loads of 10-20 mmHg for a vessel-holding chamber and 60 mmHg for a Starling pneumatic resistance set, a suitable vasodilation or vasoconstriction can be obtained. This leads us to assume that the system could be used to assess the direct influence of vasoactive substances on vasomotor tone and, furthermore, the support rabbit could be used for systemic hemodynamic variables and behavior observation. The i.a. injection of increasing doses of endothelin-1 (ET) (0.01-0.3 microgram) caused a weak but long-lasting and dose-dependent vasoconstriction of the thoracic aorta; its effect was less potent than that of angiotensin II or norepinephrine when their peak responses were compared. The duration of vasoconstriction caused by 0.3 microgram i.a. of ET was approximately 30 min and much longer than that of angiotensin II and norepinephrine. Histamine, serotonin, and prostaglandin E2 produced noticeable dose-dependent vasoconstriction. When ET (0.1-3 micrograms) was injected i.v. to conscious rabbits, the systemic blood pressure, which first dropped and then rose, was accompanied by significant changes in the heart rate in a reciprocal way. The observed rise in the blood pressure with the accompanying decrease in the heart rate lasted for at least 30 min following 1 microgram i.v. of ET.(ABSTRACT TRUNCATED AT 250 WORDS)

Amelioration by aniracetam of abnormalities as revealed in choice reaction performance and shuttle behavior.

To delineate the possible effects of aniracetam PO on abnormal behaviors, we analyzed disrupted shuttle behavior and choice reaction (CR) performance in both aged and juvenile animals subjected to an ischemic (permanent occlusion of both carotid arteries)-hypoxic (17-min exposure to 93% N2 and 7% O2 mixture gas) or ischemic (20-min occlusion of both carotid arteries) insult and/or treated with methamphetamine given IP. Aniracetam at single PO doses of 10 and 30 mg/kg significantly decreased the number of incorrect lever pressings induced by IP methamphetamine in young adult rats subjected to the CR test battery. A 21-day PO regimen with aniracetam (30 mg/kg/day) resulted in an increase in the number of correct responses and a decrease in the CR latency as detected in the CR task with young adult rats inflicted with an ischemic-hypoxic insult. Aniracetam (1-100 mg/kg PO) was also evaluated in the electrostimulation-induced hyperreactivity assay (an increase in the number of shuttle responses) in both juvenile and aged mice subjected to a 20-min ischemic insult; there again a significant improvement of performance was clearly observed. The outcomes of these behavioral pharmacological analyses suggest that aniracetam has the ability to normalize the disrupted behavior, cognition, and self-regulation or decision-making process in a comprehensive way.

Aniracetam, a pyrrolidinone-type cognition enhancer, attenuates the hydroxyl free radical formation in the brain of mice with brain ischaemia.

We demonstrate here that aniracetam has the ability to block the formation of cytotoxic hydroxyl radicals (.OH) during ischaemia-reperfusion of mouse brain. The fact that brain ischeamia for 40 min followed by reperfusion increased .OH was evidenced by detection of a peaked increase at 20 min after an ischaemic insult in the formation of 2,3-dihydroxybenzoate (DHBA) from salicylate in cerebroventricular perfusate, a means of monitoring .OH formation. A clearcut increase in dopamine was also observed during and after brain ischaemia. The ischaemia-reperfusion mice given aniracetam at an intraperitoneal dose of 30 or 100 mg kg-1 showed a smaller increase in the formation of DHBA than those given the vehicle only. Aniracetam at 100 mg kg-1 significantly suppressed the formation of DHBA by approximately 80%, becoming evident at 20 min after reperfusion and thereafter. Protection against death in mice insulted with a 40-min brain ischaemia (3/13 vs 13/25) was observed following 100 mg kg-1 aniracetam. The increase in the dopamine levels was substantially reduced following aniracetam treatment and the reduction became significant at 20 min after reperfusion and thereafter in parallel with attenuation by aniracetam of DHBA formation. This finding suggests that the inhibitory activity of aniracetam in attenuating the hydroxyl free-radical formation in ischaemic mice is probably due, at least in part, to its palliative action on the dopaminergic neurons.

Different responses to beta-adrenoceptor blocking drugs of the blood pressure and heart rate in the urethane-anesthetized dog and rat.

I.v. propranolol (Prop) produced sustained pressor responses in rats but not in dogs under urethane anesthesia. In the dogs there was a progressive reduction in systolic blood pressure (SBP) in accordance with a significant heart rate (HR) reduction. Even at the i.v. dose (5 mg/kg) where vasoconstrictor response to i.v. norepinephrine (NE) is changed to the vasodilator one in rats, phenoxybenzamine could not completely suppress the NE-induced vasoconstriction in dogs. In pithed dogs, unlike pithed rats, i.v. Prop augmented neither sympathetic nerve stimulation- nor i.v. epinephrine (Epi)-induced pressor responses. Urethane anesthesia brought much higher concentrations in plasma Epi and NE in the dog than in the rat. In comparison with their respective values under the conscious state, SBP and HR of the dog were higher and those of the rat were lower under urethane anesthesia. As in urethane-anesthetized dogs, i.v. Prop elicited remarkable HR reduction accompanied by progressive hypotension in coronary-ligated rats with high sympathetic activity. Thus the reason for the absence of pressor response to beta-receptor blockage in the dog may be due to less functional significance of beta 2-adrenoceptor-mediated vasodilation in determining the peripheral vascular tone; and also, the possibility that there may be the involvement of an inverse influence of urethane on the cardiovascular regulatory system in terms of enhancing sympathetic nervous activity in the dog and a decreasing one in the rat can not be ruled out.