[Effects of alpha and beta blocker properties of parahydroxybenzonitrile on the cardiovascular system of rats]. / Etudes des effets alpha et beta bloquants du parahydroxybenzonitrile sur le système cardiovasculaire du Rat.

The study of parahydroxybenzonitrile on the cardiovascular system of the Rat shows alpha blocker properties.

A comparative study of the effects of sparteine, lupanine and lupin extract on the central nervous system of the mouse.

Lupin is toxic because of its alkaloid content, sparteine and lupanine in particular. Although the pharmacological properties of sparteine are well known those of lupanine have not been much studied. This paper reports procedures for extraction, purification and crystallization of lupanine, and methods for the preparation of an extract for injection of Lupinus mutabilis Sweet, and for the determination of the acute toxicity and maximum non-lethal dose (DL0) of lupanine, sparteine and lupin extract in the mouse. The three substances were tested on the central nervous system (CNS) for locomotor activity, for interaction with specific drugs used for treatment of the CNS (the stimulant drugs amphetamine and pentetrazol and the depressant drugs pentobarbital and chlorpromazine) and for analgesic activity. The results indicate that lupanine and lupin extract are less toxic than sparteine and that at the doses studied the three products have a weak sedative effect on the CNS.

[Psychopharmacological study of two 3-arylsulfonyl 4-hydroxy-coumarines]. / Etude psychopharmacologique de deux 3-arylsulfonyl 4-hydroxy-coumarines.

The pharmacological study of 3-(4-chlorophenylsulfonyl) 4-hydroxy-7-methoxy- coumarine and 3-(4-methylphenylsulfonyl) 4-hydroxy-7-methoxy-coumarine shows that these derivatives present low sedative effects on the central nervous system, particularly due to their actions upon temperature and motility, more accentuated for the chloro-substituted derivative.

Increased cardiac types I and III collagen mRNAs in aldosterone-salt hypertension.

Cardiac fibrosis is one of the deleterious events accompanying hypertension that may be implicated in the progression toward heart failure. To determine the mechanisms involved in fibrosis and the role of hemodynamic versus humoral factors, we studied the expression of genes involved in hypertrophy and fibrosis in the heart of rats treated with aldosterone for 2 months with addition of 1% NaCl and 0.3% KCl in water. This treatment induced arterial hypertension, a moderate left ventricular hypertrophy, and a decrease in plasma thyroxine. Equatorial sections of hearts from treated rats showed numerous foci of proliferating nonmuscular cells and a biventricular fibrosis. Computerized videodensitometry demonstrated an increase of collagen volume fraction by 152% and 146% and of the ratio of the perivascular collagen area and vascular area by 86% and 167% in left and right ventricles, respectively. As measured by slot blot, this cardiac fibrosis was accompanied by an increase in alpha 1-I procollagen mRNA by 75% and 160% (P < .01) and in alpha 1-III mRNA by 76% and 319% (P < .01) in left and right ventricles, respectively. Atrial natriuretic peptide mRNA was induced only in the hypertrophied left ventricle. We conclude that fibrosis is occurring and involves pretranslational regulation of collagen synthesis. Whereas hypertrophy and atrial natriuretic peptide mRNA increase are restricted to the left ventricle, fibrosis is initiated in both ventricles, supporting the hypothesis that this cardiac response is independent of hemodynamic factors.

Taurine and myocardial noradrenaline.

Taurine (CAS 107-35-17) is an anticonvulsant used also as an adjunct in the treatment of cardiovascular disorders. Therefore, we studied its effects noradrenergic transmission in the isolated rabbit heart prelabelled with 3H-noradrenaline. At the concentrations of 1 and 10 mmol/l taurine treatment was without effect on the neuronal and extraneuronal uptake of noradrenaline by the myocardial tissue. At the highest concentration, it decreased the spontaneous release of the transmitter and enhanced its catabolism. Without any significant effect on tyramine-induced noradrenaline release, taurine decreased the release of the amine induced by dimethylphenylpiperazinium and nerve stimulation. These results suggested that taurine may reduce the peripheral sympathetic activity by accelerating noradrenaline catabolism and decreasing its release probably via its ability to prevent a rise of intracellular calcium ion.

Efficacy of lactobionate-enriched cardioplegic solution in preserving compliance of cold-stored heart transplants.

Cardioplegic solutions of the extracellular type are commonly used as storage media for heart transplants. Because this type of formulation was not originally designed for preventing hypothermically induced edema, we assessed the effects of supplementing a standard, extracellular-like cardioplegic solution with the high molecular weight impermeant lactobionate on water content and postischemic compliance of isolated rat hearts. In one series of experiments, hearts were immersed in either a standard cardioplegic solution of the extracellular type or in the same solution supplemented with lactobionate (80 mmol/L). Hearts were then processed for measurements of water content after 4 hours, 6 hours, and 8 hours of storage at 4 degrees C. In a second series of experiments, hearts were stored in the same solutions for 4 hours and 8 hours and subsequently reperfused for 1 hour on a Langendorff column, at which time left ventricular pressure-volume curves were constructed and compared with those obtained during the preischemic perfusion. Lactobionate-treated hearts gained significantly less water than controls after 4 hours and 6 hours of storage, but the difference was no longer significant at the 8-hour time point. In contrast, the treated group yielded a significantly better recovery of compliance after both 4 hours and 8 hours of storage, suggesting that lactobionate might exert protective effects in addition to those caused by its impermeant properties, possibly involving calcium chelation and subsequent limitation of calcium-dependent contracture. Extracellular-type cardioplegic solutions are attractive because a single solution can be used during all phases of the transplantation procedure.(ABSTRACT TRUNCATED AT 250 WORDS)

Normal and hypertrophied senescent rat heart: mechanical and molecular characteristics.

The energetics of the senescent (S) rat heart and the mechanisms by which it adapts to pressure overload have been investigated by simultaneous cardiac mechanical, energetic, and molecular biological studies. Compared with young adult (YA), S papillary muscles had an improved economy of contraction since the curvature (G) of Hill's (Proc. R. Soc. Lond. B. Biol. Sci. 126:136-195, 1938) hyperbola was increased (S, 1.93 +/- 0.13; YA, 1.60 +/- 0.07, P < 0.05). In addition, the maximum unloaded shortening (Vmax) and relengthening velocities were both reduced in S. In parallel, both alpha-myosin heavy chain (MHC) and sarcoplasmic reticulum (SR) Ca(2+)-adenosinetriphosphatase (ATPase) mRNA contents were reduced (-30 and -28%, respectively), whereas beta-MHC mRNA was increased (+91%). The active tension (S, 40.0 +/- 2.6; YA, 50.1 +/- 2.5 mN/mm2, P < 0.01) was depressed although the active force remained unchanged (S, 52.0 +/- 4.0; YA, 47.5 +/- 2.5 mN). Pressure overload in senescent deoxycorticosterone acetate (DOCA)-salt rats induced a left ventricular hypertrophy (+43%) and a further decrease in both Vmax (S, 2.81 +/- 0.10; DOCA-salt, 2.55 +/- 0.13 initial length corresponding to peak of length-active curve/s, P < 0.05) and alpha-MHC mRNA (-30%) content. Senescence modifies mechanics and gene expression in a way similar to pressure overload. During senescence, an additional overload induces left ventricular hypertrophy and attenuates Vmax without worsening the economy of the contraction.

[Synthesis and pharmacological activity of ethyl N-acetic and N-malonic esters of heterocyclic derivatives]. / Synthèse et activité pharmacologique d'esters N-éthyl acétiques et maloniques de dérivés hétérocycliques.

The pharmacological study of heterocyclic N-ethylacetic and N-ethylmalonic esters indicate a stimulating effect on central nervous system. Some derivatives show antidepressive and psychostimulant activities.

Effects of glycerol acetonide on adrenergic neurotransmission in isolated rabbit heart.

In the present investigation, the solvent glycerol acetonide (GA, CAS 100-79-8) was added (110 mg/min) to the Tyrode buffer perfusing an isolated rabbit heart preloaded with 14C-noradrenaline (NA). GA inhibits the neuronal uptake of NA but stimulates its spontaneous release. The latter effect was not ascribed to the stimulation of NA biosynthesis or to an inhibition of its catabolism. Moreover GA inhibits the evoked-release of the transmitter by tyramine and dimethyl phenyl piperazinium (DMPP). By stimulating the spontaneous release of NA, GA may induce both a depletion of myocardial stores and an important increase of the transmitter, inhibiting thereby the evoked-release by a negative feed-back mechanism on presynaptic alpha 2 adrenoceptors. Hence, the impact of GA on some steps of the cardiac adrenergic transmission may provide an adequate explanation for its observed hypotensive effect.

Biological basis of diastolic dysfunction of the hypertensive heart.

To study the diastolic properties of the heart includes examining active relaxation, passive ventricular stiffness and atrial contraction. (i) The main determinant of active relaxation is the adenosine triphosphate (ATP) concentration. Relaxation needs to occur so that the ATP content of the cell can be decreased by activation of the myosin ATPase, which in turn depends upon an intracellular messenger, elevation of the calcium transient. In a model of cardiac hypertrophy active relaxation is always slower. This slowing accompanies a slowing of the calcium transient, a diminution in the activity of the Na+/Ca2+ exchanger, a change in the properties of Na+, K+ ATPase and a decreased concentration of Ca2+ ATPase in the sarcoplasmic reticulum. (ii) Chamber stiffness is likely to be increased only in relation to the degree of ventricular hypertrophy. The main, if not unique, determinant of ventricular diastolic tissue stiffness is the structure and concentration of the collagen. Consequently tissue stiffness is augmented in cardiac hypertrophy in which the ventricular collagen concentration is elevated. It is important that both clinically and experimentally cases of cardiac hypertrophy, even those resulting from pressure overload in which myocardial stiffness and cardiac collagen concentration remain unchanged, have been documented. A good example of this is the DOCA-salt model of arterial hypertension. (iii) Atrial contraction is normally more rapid than ventricular contraction, the biological basis for which is the difference in isomyosin content.(ABSTRACT TRUNCATED AT 250 WORDS)

Inotropic and chronotropic effect of glycerol formal on the isolated rabbit heart.

Glycerol formal (CAS 5464-28-8), an organic solvent used to vehicle drugs to target cells, has been shown to possess its own toxicopharmacological properties. The present work was undertaken to study its direct effect on the isolated rabbit heart. At 2.3 and 4.6 mmol/l (bolus) glycerol formal exerted a positive inotropic effect. Upon a perfusion of 4.5 mmol/l/h, the left ventricular pressure and the coronary flow were increased, while at 11 mmol/l/h these two parameters showed a tendency to decrease. Glycerol formal upon a perfusion at 11 mmol/l/h decreased mildly the positive inotropic effect of noradrenaline, and strongly that produced by acetylcholine at a nicotinic dose, while it accentuated the bradycardia induced by acetylcholine at a muscarinic dose. On the contrary it potentiated the stimulant effect of nicotine. The positive inotropic effects of tyramine, dimethylphenylpiperazinium and potassium chloride were decreased showing an inhibition of noradrenaline liberation induced by glycerol formal at the doses used. The action of glycerol formal on agents inducing a positive inotropic effect, except nicotine, and its cardiodepressant effect are probably partly due to its action on the Ca2+ ion.

[Spasmolytic and antinoradrenergic activities of para-hydroxybenzonitrile on the isolated duodenum and vas deferens in rats]. / Activités spasmolytique et antinoradrénergique du para-hydroxybenzonitrile sur le duodénum et le canal déférent isolés du rat.

The para-hydroxy-benzonitrile (PHB) show spasmolytic activity of the muscular of duodenum provoked by acetylcholine or barium chloride. The results obtained on the vas deferent of the rat versus the contracture effects of norepinephrine show that PHB is an antagonist of the neuromediator on the post-synaptic alpha adrenoceptors.

Left ventricular compliance in the DOCA-salt model of hypertension in the rat. Effects of propranolol.

The aim of this study was to see if an enhanced myocardial stiffness is an inevitable consequence of the increase in cardiac mass and to analyze the effects of beta-adrenergic blockade on this parameter. The DOCA-salt model of hypertension was used to induce cardiac hypertrophy in the rat. After 6 weeks, the hearts of the DOCA-salt-treated animals were hypertrophied by 67%, and the left ventricular weight, the left ventricular/body weight ratio and the left/right ventricular weight ratio were similarly increased. Isolated hearts were retrogradely perfused at a constant flow of 15 ml/min/g tissue. Contractile parameters were recorded using an intraventricular balloon whose volume was manually adjusted. For each heart, a sequence of three systolic and diastolic pressure-volume curves were constructed: in Krebs alone, after addition of 10(-6) M of propranolol, and after KCl-arrest. In spite of a pronounced degree of hypertrophy, the DOCA-salt hearts had a normal diastolic pressure-volume curve and both the chamber and tissue stiffness constants were not modified. This result indicates that a depressed compliance does not necessarily accompany hypertrophy, especially in a DOCA-salt model in which the collagen content of the heart is unchanged. The systolic pressure-volume curve was greatly modified and shifted to the left indicating an enhanced capacity of the hypertrophied heart to generate force. This increase persisted even when the systolic pressure has been divided by the heart weight. beta-Blockade slightly depressed the contractility of the isolated heart at pharmacological concentrations. At high concentrations, cardiac dilatation was induced. This enhancement in ventricular distensibility had no consequences on diastolic compliance constants. It is thus concluded that, during cardiac hypertrophy, the changes in passive stiffness of the ventricle are more related to collagen content than to the cardiac mass and that beta-adrenergic blockade has no effect on the passive properties of the ventricle.

Effects of glycerolformal on sympathetic neurotransmission in the isolated rabbit heart.

Glycerolformal (CAS 5464-28-8; a mixture of 1,3-dioxan-5-ol and 1,3-dioxolane-4-methanol) used as an organic solvent or vehicle for drugs has been shown to possess its own toxicopharmacological activities. The aim of the present investigation was to determine the effects of glycerolformal on sympathetic neurotransmission in the isolated rabbit heart. At concentrations between 0.05 and 1 mmol/l glycerolformal inhibits both the neuronal and extraneuronal uptake of noradrenaline and its metabolism degradation which could explain the initial positive inotropic action of glycerolformal on the heart by increasing noradrenaline concentration in the synaptic cleft. However, the preponderant effect of glycerolformal was an inhibition of noradrenaline release, resulting in a myocardial depression which may explain the hypotension observed in the anesthetized rat. Hence, it is important to take into account the interference effects of glycerolformal with other molecules, when used as solvent or vehicle for drugs.

Effect of two flavonoid compounds on central nervous system. Analgesic activity.

The psychopharmacological profile of quercetin (Q) and penta-O-ethylquercetin (PQ) showed for both compounds a sedative effect on central nervous system in mice. In this set of pharmacological tests (hypothermia, spontaneous motility, psychomotor activity) penta-O-ethylquercetin always exerted a more pronounced effect than quercetin, probably due to the difference of lipophilicity. In analgesia experiments such as acetic acid-induced writhings, penta-O-ethylquercetin showed a significant dose-related effect whereas quercetin was inactive. As pretreatment with naloxone failed to antagonize the analgesic activity of penta-O-ethylquercetin, it was suggested that penta-O-ethylquercetin acted mainly peripherally.

Effects of corticoadrenal extract on haemorrhagic shock-induced perturbation of systemic haemodynamics and general metabolism in anesthetized dogs.

The effects of intravenous administration of corticoadrenal extract on anesthetized dogs subjected to repeated haemorrhagic shock were studied by measuring 10 variables of respiration, general metabolism and systemic haemodynamics. Haemorrhagic shock induced a slowing down of respiratory rate and a decrease in the ventilatory output, stimulated the general metabolism, depressed cardiac performance and provoked a decrease in the total peripheral resistance and elastic resistance of arteries. In the group of animals treated with corticoadrenal extract (10 U/kg/min), the slowing down of respiratory rate was completely abolished as well as the depression of the total peripheral and elastic resistance of arteries. Meanwhile general metabolism was stimulated. These results suggest that corticoadrenal extract protect anesthetized dogs against the hypotension induced by a sudden fall of blood volume.