Michel Mestre

Electrophysiological and pharmacological evidence that peripheral type benzodiazepine receptors are coupled to calcium channels in the heart.

PK 11195, an antagonist of the peripheral type benzodiazepine receptor, does not affect either the duration of the action potential or the tension of the guinea pig papillary muscle. However, it antagonized the effects of the calcium channel blockers, nitrendipine, verapamil, diltiazem, and of BAY K8644, a calcium channel agonist in this heart preparation. On the other hand, PK 11195 does not change the increase in the action potential duration provoked by the potassium channel blocker tetraethylammonium. RO5-4864, an agonist of the peripheral type benzodiazepine receptor, decreased the tension of the guinea pig papillary muscle. The effect was reversed by increasing extracellular Ca2+ concentrations up to 4 mM. These results suggest that in the heart the peripheral type benzodiazepine receptors are coupled to calcium channels.

Electrophysiological and pharmacological characterization of peripheral benzodiazepine receptors in a guinea pig heart preparation.

RO5-4864 decreased in a dose-dependent manner, from 3 X 10(-9) M to 3 X 10(-6) M, the duration of intracellular action potential and the contractility in a guinea pig preparation. Diazepam was less effective and clonazepam inactive. The effects of RO5-4864 were GABA-independent and antagonized by PK 11195 but not by the selective antagonist of the brain type benzodiazepine receptors RO15-1788. These results show the pharmacological relevance of peripheral type benzodiazepine binding sites at the cardiac level.

PK 11195, an antagonist of peripheral benzodiazepine receptors, reduces ventricular arrhythmias during myocardial ischemia and reperfusion in the dog

PK 11195, an antagonist of peripheral type benzodiazepine receptors, in doses from 5 to 25 mg/kg i.d. protected in a dose-dependent manner dogs against both early and delayed ventricular arrhythmias induced by 20 min ischemia and against ventricular fibrillation following reperfusion. Thus, peripheral-type benzodiazepine receptors might represent a novel target in the treatment of angina and cardiac ischemia.

Is the sigma 2 receptor in rat brain related to the K+ channel of class III antiarrhythmic drugs?

The sigma 2 receptor subtype was studied in rat cerebral cortex and in C6 glioma cells homogenates using various compounds including class III antiarrhythmic drugs. The characteristics of (+)-[3H]-3-(3-hydroxyphenyl)-N-(1-propyl)piperidine ((+)-[3H]-3-PPP) binding were assessed in competition experiments with different displacers which revealed the presence of sigma 2 receptors. Various class III antiarrhythmic drugs inhibited (+)-[3H]-3-PPP binding with high affinity and their binding affinity was found to correlate with the potency of these compounds to increase the duration of action potentials measured in Purkinje fibers in electrophysiological studies. Since class III antiarrhythmic drugs are known to interact with voltage-dependent K+ channels, the present results provide evidence that the (+)-[3H]-3-PPP binding sites in rat brain possess the characteristics of K+ channels of class III antiarrhythmic drugs.

Comparative effects of heparin and PK 10169, a low molecular weight fraction, in a canine model of arterial thrombosis

The comparative properties of heparin and PK 10169, a low molecular weight fraction, were studied using an antithrombotic test in anaesthetized dogs. The antithrombotic properties of the two compounds were evaluated by measuring inhibition of thrombus formation following transluminar stimulation of coronary artery with anodal current and by measuring anticoagulant properties, anti Xa and anti IIa activities. The results show that PK 10169 displayed significant antithrombotic activities above 0.625 mg/kg and was equipotent at 2.5 mg/kg s.c. with heparin 10 mg/kg s.c. No correlation could be observed between antithrombotic/anti Xa ratio of both compounds. Moreover it was shown that, unlike heparin, PK 10169 s.c. was devoid of obvious anticoagulant properties and induced a negligible anti IIa activity contrasting with a high anti Xa level. A similar dissociation between anti Xa and anti IIa activities was observed following i.v. administration of 2.5 mg/kg of PK 10169 but not with heparin. This low molecular weight heparin fraction might thus be regarded as a potential arterial antithrombotic agent devoid of appreciable anticoagulant effect.

Enoxaparin (Clexane®, Lovenox®), a low molecular weight heparin, enhances t-PA-induced coronary thrombus lysis in anesthetized dogs without inducing hypocoagulability

An occlusive coronary thrombus was obtained in barbiturate anesthetized dogs within 60 min following the angiographic placement of a copper coil into the left descending coronary artery. This thrombus persisted for the 60 min experimental period, within which the effects of i.v. t-PA (10 micrograms/kg/min for 30 min) alone or combined with i.v. heparin (0.63 mg/kg twice) or enoxaparin (1.5 mg/kg twice) were evaluated. t-PA alone achieved recanalization for 20 min in only 2 out of the 5 dogs studied. Combination of t-PA with either heparin or enoxaparin produced this effect in all the 5 dogs studied. In dogs treated with t-PA associated to either heparin or enoxaparin, the thrombus weight was smaller (decreases of 34% and 44% respectively) than in animals given t-PA alone. The plasma amidolytic activity, expressed as t-PA activity, was greater 15 min after the beginning of t-PA infusion, in dogs pretreated with either heparin or enoxaparin than in animals given t-PA alone. Conversely, during t-PA infusion, the apparent t-PA inhibitor and antiplasmin activities were no longer measurable in the plasma, but reappeared 10 min after the end of t-PA infusion. Plasma coagulation time was not modified by t-PA, but was slightly prolonged (2-fold) by enoxaparin and markedly (7-fold) by heparin on initiation of t-PA infusion. Plasma anti-IIa activity was 3-fold higher in dogs pretreated with heparin as opposed to enoxaparin. On the contrary, both compounds increased similarly plasma anti-Xa activity. In conclusion, these results indicate that enoxaparin, like heparin, enhances the thrombolytic effects of t-PA. This favourable effect occurs independently of a plasma hypocoagulable state, which was clearly produced by heparin but not enoxaparin. Its mechanism may be the significant elevation of plasma t-PA activity produced by both heparin and enoxaparin during t-PA infusion.

PK 10139 and quinidine: interactions with digoxin concentrations in rats and dogs

Quinidine induced an increase in digoxin plasma concentrations in rats and dogs. PK 10139, an antiarrhythmic agent 10 times more potent than quinidine, did not change digoxin plasma concentrations in these species. The results indicate that PK 10139 could be associated with digoxin without risk of side‐effects.