Cardioprotective effects of carvedilol, a novel beta adrenoceptor antagonist with vasodilating properties, in anaesthetised minipigs: comparison with propranolol.

OBJECTIVE: The aim was to evaluate in a minipig model of acute myocardial infarction the cardioprotection provided by the beta adrenoceptor blocking and vasodilating activities present in carvedilol; comparison was made to the pure beta adrenoceptor antagonist, propranolol. METHODS: Experiments were performed in 25 Yucatan minipigs (9-12 kg), randomly assigned to receive vehicle (n = 7), carvedilol 0.3 mg.kg-1 (n = 6), carvedilol 1 mg.kg-1 (n = 6), or propranolol 1 mg.kg-1 (n = 6). Myocardial infarction was produced by occlusion of the left anterior descending coronary artery for 45 min followed by 4 h of reperfusion. Vehicle, carvedilol (0.3 and 1 mg.kg-1) or propranolol (1 mg.kg-1) were given intravenously 15 min before the coronary artery occlusion. At the end of the reperfusion period, infarct size was determined using Evans blue dye and triphenyltetrazolium chloride staining. Infarct volumes were visualised using computer assisted three dimensional image analysis of the stained myocardial tissue sections. Myeloperoxidase activity was measured in tissue samples removed from normal, infarcted, and at risk areas. RESULTS: Carvedilol (1 mg.kg-1) reduced infarct size by over 90% without producing pronounced changes in systemic haemodynamic variables. The ability of carvedilol to reduce infarct size was clearly dose dependent. Thus infarct size, which represented 27.5(SEM 2.3)% of the area at risk in the vehicle treated group, was only 13.1(4.0)% (p < 0.05) and 2.4(1.5)% (p < 0.01) in pigs treated with carvedilol at 0.3 and 1 mg.kg-1, respectively. In animals treated with propranolol (1 mg.kg-1), infarct size represented 10.9(2.4)% of the area at risk (p < 0.05). The 60% and 91% reductions in infarct size produced by propranolol (1 mg.kg-1) and carvedilol (1 mg.kg-1), respectively, were clearly evident upon three dimensional image analysis. The reduction in infarct size was significantly greater for carvedilol (1 mg.kg-1) compared to propranolol (1 mg.kg-1) at equivalent beta adrenoceptor blocking doses. Pretreatment with propranolol did not reduce the increases in myeloperoxidase activity observed in the area at risk or in the infarcted area. In contrast, carvedilol produced a dose dependent reduction in myeloperoxidase activity in these areas. CONCLUSIONS: Carvedilol limits myocardial necrosis resulting from coronary artery occlusion and reperfusion in a more pronounced manner than the pure beta adrenoceptor antagonist, propranolol. The cardioprotective effect of carvedilol, which reduced infarct size by 91%, may result from the combined effects of beta adrenoceptor blockade and vasodilatation, and possibly also from inhibition of intracellular calcium overload in cardiac cells resulting from antagonism of myocardial alpha 1 adrenoceptors and/or calcium channel blockade. The cardioprotection provided by carvedilol may ultimately be of benefit in hypertensive patients who are at risk for acute myocardial infarction.

Diproteverine (BRL 40015): a new type of calcium antagonist with potential antianginal properties.

The calcium channel-blocking activity and associated cardiovascular effects of diproteverine, a novel compound derived from papaverine, were investigated. Electrophysiological measurements in sheep Purkinje fibres showed diproteverine to reduce the amplitude of the slow action potential (IC30 = 2 microM) and to shorten the duration of the fast action potential at 50% repolarisation (IC30 = 2.5 microM). Higher concentrations (4-5 times) were required to block block the sodium channel, as assessed by a reduction in Vmax of the fast action potential. Papaverine was found to possess marginal membrane channel-blocking activity and to be much more potent than diproteverine as a cAMP-phosphodiesterase inhibitor. The most significant haemodynamic property of diproteverine, seen in anaesthetised dogs and conscious dogs pretreated with atropine, was to cause a reduction in heart rate. This appeared to be a particular feature of diproteverine as the other calcium antagonists studied produced either a smaller decrease in heart rate or tachycardia as a reflex response to hypotension. In a chronic myocardial infarct model in dogs, diproteverine caused a redistribution of the available coronary blood flow, to the benefit of an ischaemic area of the myocardium. Diproteverine resembled diltiazem in its effects on coronary blood flow, with both these agents being preferable to nifedipine and verapamil, which caused coronary steal in this model. The combination of the reduction in heart rate, to lower cardiac oxygen demand, with the beneficial action on coronary blood flow should result in diproteverine being particularly beneficial for the treatment of angina pectoris.

Effects of triethyltin on brain octopamines and their metabolism in the rat.

The effects of triethyltin given acutely on the cerebral level of p- and m-octopamines were studied in rats. These octopamines were reduced drastically in hypothalamus and brainstem, while noradrenaline and dopamine were only slightly decreased. No important changes were observed in the activities of tyrosine hydroxylase, dopamine beta-hydroxylase or monoamine oxidase. However, the activity of aromatic L-amino acid decarboxylase was significantly reduced. The addition of the inhibitor of dopa decarboxylase, Ro 44602, caused a total inhibition of this enzyme activity. These results are discussed in terms of the possible use of the triethyltin-induced cerebral oedema as a model for the study of some aspects of the phenolamine changes related to cerebral oedema processes.

[Comparative activity of ethaverine and papaverine on chronotropic and dromotropic cardiac functions in the anesthetized dog]. / Activit comparée de l'ethavérine et de la papavérine sur les fonctions cardiaques chronotrope et dromotrope chez le chien anesthésié

Ethaverine inhibits both atrioventricular conduction and heart rate, starting at a dosage of 1 mg/kg, injected i.v. into the anaesthetized dog. In the experimental conditions used, ethaverine is clearly different from papaverine, which stimulates both at a dosage between 1 and 10 mg/kg, and which only produces an inhibitory effect starting at a dosage of 20 mg/kg, with the appearance of cardiotoxic phenomena. After total cardiac denervation the inhibitory action of ethaverine persists partially, especially at the atrioventricular level, which is probably due to a direct effect on the heart muscle. The observed differences can hardly be explained by a more pronounced cardiac toxicity. Consequently, the ethyl-derivative of papaverine constitutes, in certain aspects, a molecule with original pharmacological properties.

[Modifications by 1-eburnamonine and vincamine on 2,3-diphosphoglycerate blood levels in the presence or absence of histotoxic hypoxia produced by potassium cyanide in the awake rat]. / Modifications par la 1-éburnamonine et la vincamine du taux sanguin de 2,3-diphosphoglycérate en présence ou en l'absence de l'hypoxie histotoxique provoquée par le cyanure de potassium chez le rat éveillé.

The influence of 1-éburnamonine (1-E) and vincamine (Vi) on 2,3-disphosphoglycerate (2,3-DPG) blood level was investigated in awake rats when cyanide (KCN) induced hypoxia was present or not. Used alone, KCN, 1-E and Vi (i.p. route) increased 2,3-DPG blood level. Used with KCN, 1-E or Vi produced a very more important increase of 2,3-DPG than that observed when both drugs were used alone. In all cases, the observed increase was attributed to red cells 2,3-DPG since hematocrite, red-cells count and hemoglobin level were unmodified. The results suggest that the KCN induced increase of 2,3-DPG constitutes a response to hypoxia. On the contrary, that of 1-E or Vi seems to be the result of a metabolic stimulation and could explain in part their antihypoxic properties previously described at cerebral level.

[Study of the effect of ethaverine and papaverine on post-ischemic arrhythmias in the awake dog]. / Etude des effets de l'éthavérine et de la papavérine sur les dysrythmies post-ischémiques chez le chien éveillé.

Influence of ethaverine was compared to papaverine on the development of dysrhythmias observed in the unanesthetized dog following coronary ligation. Papaverine generally induced the reappearance of ectopic beats. In most cases, ethaverine induced the normalization of the electrocardiogram. This favourable effect of ethaverine distinguished it from papaverine; however it was moderate, transient and weaker than that of classical antidysrhythmic drugs. According to these results and those of previous experimental data, ethaverine seems to be devoid of "malignant properties".

[Comparative activity of ethaverine and papaverine on the effective refractory period of the isolated guinea pig atrium]. / Activité comparée de l'éthavérine et de la papavérine sur la période réfractaire effective de l'oreillette isolée de cobaye.

From lower concentrations (from 10(-7) to 10(-5) M) ethaverine reduces the maximal following frequency (MFF) of isolated guinea-pig's right atrium during its electrical driving at increasing frequencies. On the other hand, papaverine assumes a variable effect according to its concentration: increase (10(-7) M) or decrease (10(-6) M) of MFF. Modifications of MFF are related with those of atrial effective refractory period (ERP). These results show that ethaverine induces a lengthening of ERP whereas papaverine reduces or increases ERP. These observations are discussed comparatively with previous personal data on anesthetized dogs (Lacroix et al.) and with local anesthetic properties of ethaverine.

Effects of some coronary vasodilator drugs on collateral hemodynamics after chronic myocardial ischemia in the anesthetized dog: appropriate or inappropriate redistribution?

These effects of dipyridamole, carbochromen, pentaerythritol tetranitrate (PETN), papaverine and ethaverine on collateral hemodynamics were investigated in anesthetized dogs 5 weeks after experimental coronary occlusion. The retrograde pressure, flow and resistance (RP, RF and RR) and the pressure, flow and resistance of the nonoccluded artery (CP, CF and CR) were measured; the pressure, flow and resistance ratios, i.e., the circulatory relationships which appeared between areas localized on both sides of the well-developed collateral channels, were calculated. Dipyridamole and carbochromen provoked an inappropriate and long-lasting redistribution to the detriment of ischemic areas: RF and RP decreased, whereas CF increased; RP/CP and RF/CF decreased; RR/CR increased. PETN provoked a redistribution in favor of ischemic areas: RF increased and RR decreased; RP/CP and RF/CF increased; RR/CR decreased. These main effects of PETN appeared after a first short period during which the changes in normal and ischemic areas were almost identical. Like PETN, papaverine and ethaverine provoked an appropriate redistribution during a second period. These results are discussed in terms of the selectivity of coronary dilator action on large or small vessels. The methodology used appears to be adequate to evaluate the activities of various drugs on a well-developed collateral coronary circulation.

[Influence of age on the modifications of cerebral electrogenesis in the curarized rat induced by acute and repeated asphyxic anoxia]. / Influence de l'âge sur les modifications de l'électrogenèse cérébrale du rat curarisé induites par l'anoxie asphyxique aiguë et itérative.

In curarized rats, acute and iterative asphyxic anoxia produced large modifications of the cerebral electrogenesis, whose intensity could be evaluated, during each anoxia, by measurements of three parameters : the resistance to anoxia, the post-asphyxic recuperation and the cerebral electric silence. Comparative trials, carried out on animals of the same stock, showed that the cerebral sensibility towards anoxia was very different according to their age : maximal sensibility in 2 or 28 months old rats, minimal sensibility between 8 to 15 months. These results are discussed in terms of choice of animal material and specially of the age of rats used for study of the cerebral anoxia, as well as for the study of cerebral anti- hypoxic drugs.

[Effect of L-eburnamonine on bronchial respiratory resistance in the anesthetized guinea pig. Comparison with vincamine]. / Action de la l'éburnamonine sur la résistance des bronches à l'insufflation chez le cobaye anesthésié. Comparaison avec la vincamine.

In anesthetized guinea pigs, i.v. injection of l-eburnamonine (l-E) induced a moderate constriction of bronchia. This bronchoconstriction was partially antagonized by atropine and brompheniramine and nearly completely inhibited by papaverine; methysergide was devoid of antagonistic activity. It was suggested that the contractive activity of l-E is complex and not specific. Similar results were obtained with vincamine (Vi) but vincamine's bronchoconstriction was not completely inhibited by papaverine. Furthermore, the bronchoconstrictor activity of Vi was more important and more durable than that of l-E.

[Study of the antihypoxic effect of eburnamonine in acute and recurrent anoxia on the cerebral electric activity in curarized rats. Comparison with vincamine]. / Etude de la protection exercée par la l-éburnamonine vis-à-vis de l'anoxie asphyxique alguë et itérative sur l'activité électrique cérébrale du rat curarisé. Comparaison avec la vincamine.

Using venous infusion (0.25 mg/kg min.), l-eburnamonine decreases the electroencephalographic modifications induced by acute asphyxic anoxia in curarized rats. This activity appears when the total dose administrated before the first asphyxia is approximatively 5 mg/kg. In such conditions, its protective activity is precocious and long lasting. In the same experimental conditions, vincamine assumes a protective activity only during a short time. The results are discussed in terms of selectivity of the method used and in terms of cerebral antihypoxic properties of l-eburnamonine.

[Action of 3-beta adrenolytics on plasma renin activity measured by radioimmunology in genetically hypertensive rats]. / Action de trois adrénolytiques bêta sur l'activité rénine plasmatique mesurée par radio-immunologie chez le rat génétiquement hypertendu.

Spontaneously hypertensive rats (SHR) have basal levels of plasma renin activity (PRA) lower than the ones observed in normal Sprague Dawley rats. Three beta blocking agents are orally administered to unanesthetized spontaneously hypertensive and normotensive rats. Propranolol and S 464 reduce PRA in spontaneously hypertensive and normotensive control rats. Pindolol do not lower PRA in normotensive rats but increases levels of PRA in spontaneously hypertensive rats. These results are discussed.

Experimental approach of activity and mechanism(s) of action of drugs used in cerebral metabolic insufficiency. Application to 1-eburnamonine.

The authors described an experimental approach, specially using oral administration, of drugs used in cerebral metabolic insufficiencies and its application to l-eburnamonine (l-EB). Administered orally, l-EB: (1) significantly increased the cerebral consumption of [14C]- deoxyglucose in normoxic mice; (2) decreased the fall in cerebral energy charge (ECP) of rats after an acute normobaric hypoxia, and (3) stimulated the glycolysis of red blood cells (RBC) in healthy volunteers (repeated administrations) as demonstrated by important increases in 2,3-DPG and ATP, i.e., in factors involved in the bioavailability of oxygen (oxygen transport activity and RBC deformability). The results therefore demonstrate oral activity of l-EB in animals and man. They are in agreement with previous data showing cerebral metabolic stimulant and antihypoxic effects following parenteral administration, in animals. They allow to propose that l-EB acts both at cerebral and extracerebral levels and constitute objective biochemical proof of the activity of l-EB in man. The study of new drugs may be done using the same experimental approach.

Cerebral metabolic and hemodynamic activities of l-eburnamonine in the anesthetized dog. A comparison with vincamine.

1. The cerebral metabolic and hemodynamic activities of l-eburnamonine (l-E) were investigated in anesthetized dogs and compared with those of vincamine (Vi). 2. The injection of l-E (2 mg/kg i.v.) increased vertebral, carotid and femoral blood flows (VBF, CBF, FBF) while corresponding resistances decreased. aortic blood flow (A0 BF) and systolic ejection volume (SEV) increased. Cerebral O2 and glucose consumption (CMRO2, CMRG) increased as did the O2 extraction coefficient and the O2 supply. This last increase was due to the simultaneous increase of VBF, hemoglobin (Hb) and arterial pO2.