F. Clostre

Endothelin and Ca++ agonist Bay K 8644: different vasoconstrictive properties

The mechanism of vasoconstriction induced by endothelin was investigated in rat isolated aorta in comparison with the Ca++ agonist, Bay K 8644. Endothelin (EC50 = 4 nM) induced a slow and sustained contraction in control medium whereas the one elicited by Bay K 8644 (EC50 = 14 nM) necessitating a partly K+ depolarized medium was fast with superimposed rhythmic contraction. By opposition with Bay K 8644, endothelin contraction was not inhibited by the calcium antagonists (1 microM), nifedipine, diltiazem and D 600, and substantially persisted in Ca++ free medium or after depletion of intracellular Ca++ by phenylephrine (1 microM). These data show that endothelin does not act as an activator of potential dependent Ca++ channels but probably through specific receptor(s) as suggested by its mode of vasoconstriction.

Further characterization of the behavioral despair test in mice: Positive effects of convulsants

Abstract The behavioral despair test in mice has been further characterized using three convulsant agents (at non-convulsant doses), pilocarpine, and several other substances. False positive responses (reductions in immobility) produced by orally-administered strychnine-SO 4 , bicuculline, picrotoxin and pilocarpine further limit the use of this test as a method of screening for antidepressants, unless it is considered that these substances have potential value as antidepressants.

Effects of the specific platelet-activating factor antagonists, BN 52021 and BN 52063, on various experimental gastrointestinal ulcerations

Platelet-activating factor (PAF) has been shown recently to induce gastrointestinal damage similar to that evoked by endotoxin, suggesting that the autacoid could be implicated in other types of gastrointestinal damage. Thus, the effects of BN 52021 and BN 52063, two specific PAF antagonists, were investigated in various experimental models of gastrointestinal damage in rats. BN 52021 and BN 52063, markedly reduced both the PAF- and endotoxin-induced alterations of the mucosa, suggesting a role for the autacoid in the latter process. BN 52021 and another unrelated PAF antagonist, triazolam, partially reduced the restraint-stress-induced gastric damage in young female, but not male, rats. Similar partial protection was obtained in rats with ethanol-induced gastric damage. In contrast with atropine and ranitidine, BN 52021 did not affect the gastric hypersecretion in pylorus-ligated rats nor the aspirin-induced gastric ulcerations. The present results indicate that PAF plays a major role in the gastric damage induced by endotoxin and may also partially contribute to the gastric lesions induced by ethanol and stress. The results suggest that there is a potential therapeutic use for PAF antagonists in certain types of gastrointestinal lesions in man.

Effects of Ginkgo biloba on arterial smooth muscle responses to vasoactive stimuli.

1. An extract of Ginkgo biloba (Gb), at a concentration (100 microgram/ml) that did not provoke isometrically-recorded contractions of rabbit aorta, was tested on the contractile effects of norepinephrine (NE), serotonin (5-HT) and dopamine (DA). 2. Gb potentiated the contractile effect of NE (reduced the EC50 from 75 to 36 nM), but had no obvious action on the contractile effects of 5-HT or DA. 3. These results indicate that low concentrations of Gb might influence catecholaminergic systems by an indirect mechanism.

Effects of an extract of Ginkgo biloba and diverse substances on the phasic and tonic components of the contraction of an isolated rabbit aorta.

1. The effects of phentolamine, propranolol, D 600, theophylline, papaverine and an extract of Ginkgo biloba were studied with respect to the two phases of the contractile response induced by norepinephrine in an isolated rabbit aorta. 2. Phentolamine (3 x 10(-6) M) inhibits the rapid phase of the contraction of the rabbit aorta brought on by norepinephrine (NE) 10(-5) M more strongly than the tonic phase. Propranolol (10(-6) M) potentiates this rapid phase. 3. D 600 inhibits the slow phase with an EC50 = to 3.8 x 10(-8) M. 4. Papaverine and theophylline increase the relaxation that follows the rapid phase of contraction. The slow phase is inhibited only by papaverine. 5. The extract of Ginkgo biloba (Gb) at a concentration of 3 mg/ml has the same type of effect as papaverine 3 X 10(-5) M.

Verapamil as an apparent competitive antagonist of the serotonin receptor of rabbit isolated aorta.

The actions of four Ca2+-antagonists (verapamil, diltiazem, nifedipine and flunarizine) were tested on serotonin- (5-HT-) induced contraction of rabbit isolated aorta. Verapamil produced a dose-dependent, parallel shift to the right of the concentration-response curve for 5-HT (pA2 approximately equal to 7.13; Schild slope approximately equal to 1.01), indicative of competitive antagonism. The effects of diltiazem, nifedipine and flunarizine were much less pronounced and best characterized as non-competitive interactions. The effect of verapamil, which likely involves its antagonism of smooth muscle 5-HT2-receptors, might be useful in explaining its therapeutic actions and/or its side-effects.

Effects of an extract of Ginkgo biloba on rabbit isolated aorta

1. Extract of Ginkgo biloba (Gb) provoked a dose-dependent contraction of spirally-cut rabbit aortic strips (EC50 congruent to 1.0 mg/ml) by an action that was antagonized by phentolamine (10(-7) M). 2. Inhibitors of catecholamine re-uptake, cocaine (10(-5) M) and desipramine (10(-7) M) potentiated the contractile effect of norepinephrine (NE), but inhibited the contractile effects of Gb and tyramine. 3. A comparison of the actions of Gb, NE and tyramine using aortic strips prepared from control and reserpine-treated rabbits revealed that reserpine treatment increased the response to NE but decreased the response to Gb and tyramine. 4. The contractile action of Gb on rabbit isolated aorta involves, at least in part, a release of catecholamines from endogenous tissue stores.

Competitive inhibition of 5-HT receptors in rabbit isolated aorta by the Ca2+-antagonist methoxyverapamil (D 600)

Experiments conducted with rabbit isolated aorta have revealed that the Ca(2+)-antagonist 3-methoxy-verapamil (D 600) is a potent competitive antagonist of the contractile action of 5-HT. Thus, the anti-hypertensive action of D 600, as well as some of its side effects, could be related to its antagonism of 5-HT receptors. D 600 might be useful in neurochemical and neurophysiological experiments that are aimed at examining 5-HT receptors, as well as in treating certain cerebrovascular disorders of man (e.g., migraine).

Effects of antidepressants on receptor-activated and Ca2+-activated contractions of rabbit isolated aorta

Helically-cut strips of rabbit aorta were used to examine the inhibitory effects of some antidepressants on the contractile responses produced by norepinephrine (NE), serotonin (5-HT) or K+. The order of potency of antidepressants in antagonizing 5-HT-induced responses was: mianserin greater than amitriptyline greater than imipramine (IMI) greater than desipramine greater than or equal to nomifensine. With NE as agonist, the order of potency was: amitriptyline greater than mianserin greater than IMI greater than desipramine greater than or equal to nomifensine. Viloxazine (10(-5) M) was ineffective on 5-HT- or NE-induced contractions. For K+-induced contraction (which is mediated by Ca2+ entry into smooth muscle cells) tricyclic antidepressants were about equipotent with mianserin; nomifensine and viloxazine were relatively ineffective. These results indicate that certain antidepressants have multiple effects on arterial smooth muscle. Such effects could underlie not only the side-effects, but also the therapeutic actions of these agents.

Antihypertensive profile of cicletanine, a furopyridine derivative: comparison with captopril, indapamide and prazosin.

The effects of cicletanine were compared with those of three other antihypertensive drugs: prazosin, a highly selective alpha 1 antagonist, captopril an angiotensin converting enzyme inhibitor and indapamide a diuretic antihypertensive agent, on young stroke-prone SHR rats with high salt diet; furthermore, vascular reactivity to cicletanine was studied on isolated rat aorta. At an equal dose (30 mg/kg per os) all the drugs prevent the onset of hypertension with the same intensity. The minimal effective dose on blood pressure was 1 mg/kg for both cicletanine and captopril, and 3 mg/kg for indapamide. The action on diuresis and electrolyte excretion occurs at a dose of cicletanine 10 to 30 times higher than that required to produce the anti-hypertensive effect. One of the possible mechanisms of the antihypertensive effects of cicletanine could be due to a direct action of the drug on the vascular wall. This vascular impact could be an interaction with the alpha-adrenoceptor system (apparent pA2 cicletanine = 5.12) or a decrease in the vascular spasmogenic response whatever agonist was studied.