Effect of hypnorm, chloralosane and pentobarbital on the ultrastructure of the inner membrane of rat heart mitochondria.

Rat heart mitochondria were isolated from four groups of animals treated in a different way. The animals of the first group were killed after decapitation (D-group) without previous anaesthesia. The three other groups of animals were anaesthetised with different anaesthetics. The second group (N-group) was anaesthetised with nembutal (sodium pentobarbital), the third group with chloralosane (C-group) and the fourth group with hypnorm (H-group). From these three anaesthetics only nembutal is known to interact with mitochondria. After retrograde perfusion and excision of the heart, mitochondria were prepared from the ventricles by standard methods. After freeze-fracturing the mitochondrial suspension, the intramembrane particle dimension and density on both fracture faces of the inner mitochondrial membrane were measured. The intramembrane particle diameter on the P-face of the inner membrane of the N-group mitochondria was significantly different from D-, C- and H-group mitochondria. Also the density and diameter of the intramembrane particles on the mitochondrial inner membrane of D-group mitochondria compared to C- and H-group mitochondria were significantly different at the 95% level of confidence. Between C- and H-group mitochondria no differences of these parameters were observed. From these results it is clear that, depending on the pretreatment of the animals, a different substructure of the inner membrane of heart mitochondria is obtained.

Stabilization of native matrix granules in isolated rat heart mitochondria.

The osmiophilic granules present in the mitochondrial matrix of rat myocardium are very sensitive to changes in the energy status of the cell and in the activity of the mitochondrial electron transport. These granules can be stabilized in isolated mitochondria by blocking the electron transport with Na2S. The behaviour of these native matrix granules is similar to that expected for Ca ++ containing entities.

[Effect of the hypothalamus on membrane permeability to ionic calcium currents]. / Influence de l'hypothalamus sur la perméabilité membranaire aux courants ioniques calciques.

The hypothalamus contains two distinct zones which affect the activity of myocardial and vascular muscle. The median ventricular nucleus stimulates the liberation of peripheral catecholamines and, by so stimulating the adrenoreceptors, opens up the slow calcium canals. The resulting stimulation of the myocardial and vascular muscle cells causes tachycardia, and an increase in myocardial contraction and in peripheral resistance. The paraventricular nucleus antagonises these effects by inhibiting peripheral catecholamine secretion so blocking or slowing the passage of Ca++ through the slow calcium canals. The study of effective, active concentration of D 600, a powerful calcium antagonist, shows that the paraventricular nucleus is not a direct calcium antagonist like D 600 whose effects are not potentiated, and confirms that it acts indirectly by inhibiting peripheral noradrenaline secretion.

[Effect of stimulation of the hypothalamic paraventricular nucleus on the electrical and contractile characteristics of the myocardium in dogs]. / Influence de l'excitation du noyau paraventriculaire hypothalamique sur les caractéristiques électriques et contractiles du myocarde chez le chien.

Electrical stimulation of the hypothalamic paraventricular nucleus results in bradycardia and hypotension. A direct transtemporal approach was used to implant an insulated electrode in the site of the third ventricle. The bradycardia and hypotension have been studied previously and have been shown to be due to inhibition of the alpha and beta vascular and myocardiac adrenergic receptors. The effects of this inhibition on the electrical appearances and the mechanical and phonocardiographic parameters of myocardial contractility were observed in this present study. The force and velocity of LV isometric contraction were reduced as shown by reduction in dP/dT, the delay in its peak and the reduction of the angle between the upstroke of ventricular contraction with the base line. The onset of left ventricular ejection was delayed. The high frequency (60 and 140 Hz) components of the first heart sound disappeared, confirming their contribution to the intensity of this sound. The ECG rapid QRS phase and AV conduction time were unchanged, but the slow phase of the T wave became more negative as the depressant effect on the myocardium increased.

[Electrocardiographic changes during stimulation of the hypothalamus in the dog]. / Modifications électrocardiographiques au cours de l'excitation hypothalamique: étude expérimentale sur le chien.

Electrical stimulation in the area around the ventro-median nuclei of the hypothalamus of the dog produced changes suggestive of ischaemia in the standard bipolar and epicardial leads, principally over the apical, lateral and diaphragmatic walls of the left ventricle. It is suggested that these changes may be the central expression of orthosympathetic stimulation by released catecholamines on the permeability and membrane potentials of the myocardial cells with respect to ions, especially Ca++.

Influence of some hypotensive drugs on the effects of hypothalamic stimulation.

Clonidine, L-alpha-methyldopa, propranolol as well as noradrenaline, when injected directly into the hypothalamic paraventricular (PV) nucleus area, enhance the activity of this center. Lidoflazine appears to be inactive. Since the electrical, chemical and pharmacological stimulation of the PV area elicits the same depressor cardiovascular reactions, a specific differentiation of this nucleus as a depressor center is proposed. The above-mentioned drugs, when introduced into the ventromedial nucleus area, enhance the pressor effects produced by stimulation of this nucleus. Thus, the hypothalamic depressor activity is not linked with an inhibition of the ventromedial pressor activity.

Arterial and venous responses to hypothalamic stimulation in the dog.

Stimulation of the ventro-medial nucleus of the hypothalamus induces active constriction of both pre- and post-capillary vessels in the dog's hindlimb. Alpha-adrenolytic agents reduce these responses, indicating that they are mediated by the sympathetic nervous system. Stimulation of the paraventricular nucleus dilates both resistance and capacitance vessels. The present study demonstrates that hypothalamic neurones can control venomotor tone.

[New data concerning hypothalamic cardiovascular regulation and its importance]. / Nouvelles données concernant la régulation cardiovasculaire hypothalamique et son importance.

The regulation of cardiovascular function by the pressor centres of the hypothalamus located in the ventro-medical nucleus of the hypothalamus is discussed, together with the baro-receptor control, the part played by the release of catecholamines, and the limitations of this control. The depressor part of the hypothalamus, located in the paraventricular nucleus, is characterised by its haemodynamic and pharmacological properties. This study throws light on new areas of possible treatment of angina pectoris and so-called essential hypertension, which are more appropriate to the clinical findings.

New approach of the cardio-vascular depressive mechanism during lateral hypothalamic stimulation.

Paraventricular nucleus stimulation acts directly on the alpha- and beta-adrenoreceptors in heart and arterioles, eliciting arterial hypotension and cardiac chronotropism and inotropism decrease. Efferent pathways follow sympathetic nervous fibres through the medulla and the thoraco-lumbar ganglionic chain. The role of the alpha- and beta-adrenoreceptors in these depressive reactions is discussed.

Absence of a prostaglandinic mediator in the lateral hypothalamic cardio-vascular inhibition.

The cardio-vascular inhibition elicited by electrical stimulation of the paraventricular nucleus in the lateral hypothalamus of anaesthesized and desafferentiated dogs is not linked with a mediator release like PGE. The effect of this biological agent is not registered in the isolated femoral artery of a receiver, after deviation by a cruised circulation of the arterial blood of a hypothalamic stimulated donor dog. Antipyretics, which are also prostaglandin-synthetase inhibitors, enhance the lateral hypothalamic reactions. As the thermoregulation centre is localized in the same region as the cardio-vascular inhibition centre and because lowering of temperature depends upon vasodilation and decrease in the general cellular metabolism, both functions of the paraventricular nucleus activity, a hypothesis is proposed that thermoregulation and cardio-vascular inhibition centres are a functional and anatomical unity.

Characteristics of hypotension elicited by electrical stimulation of the lateralhypothalamusin anaesthetized dogs.

Electrical stimulation of the lateral hypothalamus near the paraventricular nucleus hypothalami, resulted in : hypotension, light bradycardia, decrease of the left ventricular systolic pressure without increase of the left ventricular end-diastolic pressure or left ventricular output, femoral vasodilatation and occasionally renal vasodilatation. The hypotensive reactions were potentiated by baroreceptor deafferentation. They were not blocked by anticholinergic, antihistaminic or antidopaminergic agents.

Hypothalamic depressor reactions in anaesthetized dogs after baroreceptor exclusion and during norepinephrine infusions.

The stimulation of the paraventricular hypothalamic centre inhibits the vasoconstriction of the peripheric arterioles and the myocardial effects elicited by endogenous or exogenous increased catecholaminaemia.

Vascular and noradrenalic reactions in the musculocutaneous bed during hypothalamic stimulation.

When electrical stimulation is applied to the ventromedial hypothalamic zone one observes an increase in systemic blood pressure. There also occur blood pressure variations in the isolated femoral circuit: two distinct phenomena were observed. The early event, being either an increase or a decrease in peripheral resistance, is directly related to the amount of noradrenaline produced locally. The late event is due to catecholamines arriving from the general circulation. Inhibition of local catecholamine release through the baroreceptor reflex and inhibition of ganglionic transmission by a large and sudden increase in adrenaline blood levels do influence the response in the isolated femoral circuit. Moreover the peripheral vasomotor tonus seems to be influenced by yet another mechanism, independent of local catecholamine release. This delicate mechanism depends on the balance between the degree of excitation of hypothalamic pressor (medial) and depressor (lateral) zones.

Unusual mechanism of hypotensive activity exerted by erytrho-1-(1-[2-(1,4-benzodioxan-2-yl)-2-OH-ET-a1-4-piperidyl)-2-benzimidazolinone (R 28935).

In the dog, erythro-1-[2-(1,4benzodioxan-2-yl)-2-OH-ET]-4-piperidyl)-2-benzimidazolinone (R 28935) lowers the blood pressure for several hours at dosages of 80 mug/kg when injected intravenously, of 10 mug/kg when injected into the vertebral artery and of 1.25 mug/kg when injected suboccipitally. No alpha- or beta-receptor blocking activity can be elicited at these doses. The carotid occlusion reflex is markedly reduced by low doses of R 28935 (40 to 80 mug/kg i.v.), whereas the pressor response elicited by electrical stimulation of the hypothalamus remains unimpaired. The hypotensive effect of R 28935 is not antagonized by piperoxan, desmethylimipramine or nalorphine. This lowering of the blood pressure is associated with a decrease of the peripheral vascular resistance and with a slight tendency towards bradycardia. It is concluded that R 28935 is a potent blood pressure lowering drug, acting on the brain stem, presumably in the pontomedullary region--although the drug has no alpha-sympathomimetic activity.

Influence of electrical stimulation of the posterior hypothalamus on musculocutaneous and renal circulation in anesthetized dogs.

Hypertension and tachycardia were consistently induced by electrical stimulation of the median posterior hypothalamus in dogs under chloralose anesthesia, curarized and artificially ventilated. When renal and femoral vascular beds were perfused at a constant blood flow, the renal perfusion pressure markedly increased, whereas only minor variations of the femoral perfusion pressure occurred. When the renal and femoral vessels were perfused by the heart at the prevailing blood pressure, peri-arterial electromagnetic flow measurements revealed that renal flow decreased and that femoral flow increased during hypothalamic hypertension, both before and after vagotomy. In the same animals, no significant changes of renal or femoral flow occurred during reflexogenic hypertension induced by carotid occlusion. These marked hemodynamic differences between the reflexogenic and the hypothalamic type of hypertension were consistently and repeatedly observed. The indications that baroreflex counter-regulation and ganglionic inhibition due to elevated catecholaminemia contribute to the relative lack of femoral vasoconstriction during hypothalamic hypertension, are discussed.