Aminopyridazine derivatives and TXA2-PGI2 balance.

Experiments carried out under the conditions adopted showed the strong affinity of aminopyridazine derivatives for the eicosanoids TXA2 and PGI2. But this affinity depended on the chemical structure of the molecule: a small change in the radical grafted onto the pyridazine ring could completely modify the pharmacological activity of the molecule. Consequently it should be possible to control the properties of pyridazine derivatives according to pharmacological needs. Thus: --pyridazin-3-one derivatives were mainly active on TXA2 biosynthesis: 2-aminoalkyl 5-arylidene 6-methyl (4H) pyridazin-3-ones inhibited the TXA2-synthesizing activity of cardiac tissue whereas 3-amino 4,6-diaryl pyridazin-3-ones were specific inhibitors of the TXA2 synthetase in vitro, but these effects were weak. --pyridazine derivatives were devoid of any effect on the TXA2-synthesizing activity of cardiac tissue: they acted on either TXA2 synthetase or PGI2 synthetase according to the radicals grafted onto the pyridazine ring. --none of the compounds under study was active on the PGI2-synthesizing activity of cardiac tissue.

Creation of a strain of genetically obese-hypertensive rats.

A strain of genetically obese-hypertensive rats (SHR-fa/fa) was created by transferring the fatty/fa gene of hyperlipaemic obese non-inbred rats into the genome of an SHR inbred strain by five successive crossings of SHR-fa+ brother-sister matings. SHR-fa/fa rats were heavier than their SHR littermates. They showed a severe hypertension, their systolic arterial blood pressure being higher than that previously found in genetically hypertensive rats. Their blood glucose content was not significantly different from that of their SHR littermates but their plasma triglycerides were increased by more than 500 per cent. While obesity and hypertension occurred from the 5th week following the rat's birth, the increase in blood triglycerides was manifest earlier.

An inhibitor of prostacyclin biosynthesis derived from aminopyridazine.

The effects of 3-dimethylamino 5-(3' trifluoromethylbenzylidene) 6-methyl (4H)-pyridazine (PC88) on the biosynthesis of PGI2, using horse aorta microsomes as a source of enzyme and arachidonic acid as a substrate, were investigated. Under the experimental conditions adopted, PC88 was shown to dose-dependently inhibit PGI2 biosynthesis (ID50 = 6.9 x 10(-4) M +/- 1.87 x 10(-7) M). This inhibitory effect of PC88 was complex: it was of neither competitive nor non-competitive type. 3-dimethylamino 5-(2',6'-dichlorobenzylidene 6-methyl-(4H)-pyridazine (PC89) enhanced the biosynthesis of PGI2. It is worth noticing the replacement of the 2 Cl at carbon atoms 1 and 4 by a CF3 at carbon atom 2 of the phenol ring. This appears to reverse the activity of the molecule on the synthesis of PGI2. PC88 and PC89 were both inhibitors of TXA2 synthetase.

Taurine and icosanoids in the heart.

Experiments were carried out on non-working isolated rabbit hearts perfused by Tyrode solution: the effects of Taurine introduced into the coronary circulation were studied on the biosynthesis of the anti-thromboxane synthetase factor ("FATS") and on the TXA2 and PGI2 synthetase activities of cardiac tissue. The effects of Taurine were simultaneously studied on the biosynthesis of TXA2 and PGI2 in vitro. Experiments performed under the adopted conditions have shown that in vitro Taurine did not significantly modify the biosynthesis of TXA2 and PGI2; ex vivo Taurine did not change the biosynthesis of "FATS" but inhibited both TXA2 and PGI2 synthetase activities of the cardiac tissue: Taurine was more active on the TXA2 synthetase activity than on the PGI2 one. Thus Taurine promoted the formation of vasodilator and antiaggregating PGI2 at the expenses of vasoconstrictor and proaggregating TXA2. This could at least partly explain the beneficial effects of Taurine in the physiopathology of the heart.

Comparative effects of total flavonoids extracted from Ribes nigrum leaves, rutin and isoquercitrin on biosynthesis and release of prostaglandins in the ex vivo rabbit heart.

Experiments were carried out on isolated rabbit hearts: PG biosynthesis was induced by administration into the coronary circulation of a single dose of arachidonic acid (100 micrograms) and the PGs synthesized and released in the heart effluent were detected by bioassays. Total flavonoids (TF) extracted from Ribes nigrum leaves and their 2 major components, rutin and isoquercitrin had neither spasmodic nor relaxing activity on rat stomach strip. They were not capable of inducing any biosynthesis and release of PG-like substances and did not act on PGE2 receptors. They inhibited both biosynthesis and release of PG-like substances: TF were more active than rutin and isoquercitrin: ID30 was 1.03 +/- 0.24 mg/ml for TF versus 3.75 +/- 0.24 mg/ml and 2.31 +/- 1.4 mg/ml for rutin and isoquercitrin respectively.

Study of the PG E2 synthetase activity of different regions of dog and rabbit hearts.

Prostaglandin E2 synthetase activity of the microsomal fraction from different parts of dog and rabbit heart was tested with 3H-arachidonic acid as substrate. PG E2 synthesized was separated and purified by TLC and determined by the radiometric method or by bioassay. In the experimental conditions adopted, it was shown that the heart tissue is endowed with an enzyme system capable of synthesizing PG E2 but this PG E2 synthetase activity is not uniformly distributed in the different parts of the heart. It is highest in the right atrium and the activity of the atria is higher than that of the ventricles. It is species-dependent. The closely similar repartition of PG E2 synthetase activity and sympathetic nerve endings strongly suggests that PG E2 modulates adrenergic neurotransmission in the heart.

Cardiovascular activity of a deproteinized blood extract.

The cardiovascular effects of the deproteinized blood extract were investigated in anaesthetized dogs: respiration, general metabolism and systemic haemodynamics were tested and the changes in these parameters after the administration of the drug were studied. At 2 ml kg-1 i.v., the deproteinized blood extract induced a transient drop in arterial blood pressure and bradycardia. On the other hand, the total peripheral resistance and the elastic resistance, of the arteries were decreased and this effect was of longer duration. Moreover, the deproteinized blood extract stimulated the myocardium contractile force and dc/dt and increased the cardiac performances. The mechanism of action of this drug is discussed.

[Activity of rabbit heart on thromboxane synthetase]. / Etude de l'activité du Myocarde de lapin sur la thromboxane synthétase.

The soluble and microsomal fractions of Rabbit myocardium are not able to induce the synthesis of thromboxanes. On the contrary, they inhibit the thromboxane synthetase of various sources. The chemical structure of the active constituent responsible for this activity is not yet known: it is probably neither of an enzymatic nature, nor a protein of high molecular weight.

[Structure-activity relationship of various ephedrine isomers on noradrenaline uptake by the isolated perfused rabbit heart]. / Relation structure-acitivité de différents isomères de l'éphédrine sur la captation de la noradrénaline par le coeur isolé et perfusé de lapin.

(-)Ephedrine, (+) Ephedrine, (-) psi ephedrine and (+) psi ephedrine inhibit both the neuronal and extraneuronal uptakes of noradrenaline in isolated Rabbit heart. (-) ephedrine is the most active isomer for the inhibition of both neuronal and extraneuronal uptakes. The relative inhibition potential of the three other isomers is not the same when applied to one or other uptake.

[Modulator role of prostaglandins (Pg) in adrenergic neurotransmission in carotid sinus]. / Rôle modulateur des prostaglandines (Pg) dans la neurotransmission adrénergique au niveau des sinus carotidiens.

In Rabbit carotid sinus, the presence of sympathetic nerve endings capable of releasing noradrenaline has been demonstrated. The release of NA in response to sympathetic nerve stimulation was decreased by PgE2 and a precursor of Pg (arachidonic acid) but was strongly increased by an inhibitor of Pg biosynthesis (indomethacin). The experiments carried out demonstrated that freshly synthesized Pg acts in the same way as exogenous Pg and suggested that Pg could have a regulating effect on adrenergic neurotransmission in carotid sinus. The role of this regulating mechanism in the physiology of carotid sinus has been discussed.

[Role of alpha and beta adrenoceptors in the regulation of adrenergic neurotransmission in the carotid sinus]. / Rôle des alpha et des bêta adrénocepteurs dans la régulation de la neurotransmission adrénergique au niveau du sinus carotidien.

The experiments carried out showed the presence- in sympathetic nerve endings ot the carotid sinus- of alpha and beta adrenoceptors which by means of respective negative and positive feedback processes, modulated NA release induced by a sympathetic nerve stimulation. Similarly, Pgs acted by means of a negative feedback mechanism to regulated adrenergic neuro-transmission in carotid sinus but they could not be considered as the chemical mediators of either alpha or beta adrenoceptors.

Cardiovascular activity of 9-hydroxy-ellipticine.

The cardiovascular activity of 9-hydroxy-ellipticine (9-OH-E) has been studied on anaesthetized dogs. The drug has been administered intravenously in one dose ranging from 1 to 10 mg/kg. The variations in the myocardial contractility, the systemic haemodynamics, the respiration and the general metabolism of the anaesthetized dogs were studied to make evident the mechanism of 9-OH-E cardiostimulating action. 9-OH-E from 5 mg/kg i.v. stimulates the contractility of myocardium and improves the cardiac performances of the anaesthetized dogs. This heart-stimulating action is long-lasting and is not accompanied by any modification in the arterial blood pressure. It is inhibited or at least strongly attenuated by beta-adrenergic blocking agents and by the depletion of catecholamines.

Pharmacological aspects of pyrazoline derivatives from 2-hydroxy-butenolides.

A series of pyrazoline derivatives was synthetised and evaluated for toxicological and pharmacological effects; analgesic, hypnotic, anti-inflammatory, antipyretic and cardiovascular properties were screened. Tested compounds were found to have a low toxicity; one of them showed a good analgesic activity without side effects.