Competitive and stereoselective histamine H1 antagonistic effect of cicletanide in guinea-pig isolated ileum

Schoeffter, Philippe; Ghysel-Burton, J; Cabanie, M.; Godfraind, Théophile

doi:10.1016/0014-2999(87)90716-3

Cited by 19 publications

(12 citation statements)

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“…The histamine response in mepyramine-and cicletanine-treated precontracted rings was biphasic : relaxations and contractions at low and high histamine concentrations respectively. In isolated guinea-pig ileum, the ( + )-enantiomer is devoid of histamine antagonistic activity (Schoeffter et al, 1987); this could account for the lesser HI-receptor antagonistic effect of the racemic mixture compared to mepyramine (Fig. It could be reasoned that the biphasic response to histamine in cicletamine-treated rings is a sum of 2 possible actions on the (-) and (+)-enantiomem of cicletanine in the racemic mixture employed.…”

Section: Discussionmentioning

confidence: 99%

“…Cicletanine is a diuretic and an antihypertensive furopyridine compound (Jouve et al, 1986) recently reported to exert histamine H, receptor antagonistic effect in isolated guinea-pig ileum (Schoeffter et a/., 1987) and human coronary arteries (Schoeffter and Godfraind, 1988). Optical isomers of cicletanine have been shown to antagonize histamine action differentially; the (+) enantiomer being i= 100 times less potent than the (-) enantiomer (Schoeffter et al, 1987).…”

Section: Introductionmentioning

confidence: 99%

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Effects of Cicletanine on Histamine‐induced Contractions of Isolated Rabbit Mesenteric Arteries

Ebeigbe

Cabanie²,

Godfraind

1989

Fundamemntal Clinical Pharma

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The antagonism by cicletanine of contractile responses to histamine has been examined in vitro on ring preparations of rabbit mesenteric arteries. Cicletanine (10(-8)-10(-6) M) caused a parallel rightward shift of histamine concentration response curve, with a pA2 value of 7.48 (slope = 0.89 +/- 0.19, not significantly different from unity). Histamine-induced contractions were nifedipine-sensitive and associated with cicletanine-sensitive increased 45Ca uptake. Endothelium removal resulted in enhanced contractile responses to histamine, but did not significantly modify cicletanine-induced antagonism: KB (dissociation constant) values for cicletanine antagonism in the presence or absence of endothelium were: 3.7 (+/- 0.1) X 10(-8) M and 3.6 (+/- 0.3) X 10(-8) M, respectively. Cicletanine (greater than 10(-4) M) also significantly attenuated 10 mM caffeine-induced contractions in rings exposed to Ca-free 100 mM K+ depolarizing medium. The results suggest that cicletanine-induced antagonisms of histamine H1 receptor-mediated contractions of rabbit mesenteric arteries is associated with interference with calcium entry as well as at high concentrations, release from intracellular stores.

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Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Effects of Cicletanine on Histamine‐induced Contractions of Isolated Rabbit Mesenteric Arteries

Ebeigbe

Cabanie²,

Godfraind

1989

Fundamemntal Clinical Pharma

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“…The specificity was confirmed by in vitro and ex vitro binding studies with [3H]pyrilamine ( K~ = 4.3 X M ) . This antagonism is specific for H1 receptors and does not involve H2 receptors (25,21). Cicletanine does not modify the H2-dependent increase in the rate of contractions of isolated guinea-pig atria (22).…”

Section: Interactions With Histamine Receptorsmentioning

confidence: 99%

Cicletanine

Chabrier

Guinot

Tarrade

et al. 1988

Cardiovascular Drug Reviews

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Cicletanine hydrochloride is a new antihypertensive molecule synthetized and studied in our laboratory. Its chemical structure is uncommon for an antihypertensive molecule; it is characterized by the presence of a furopyridine group. Cicletanine is, therefore, a member of a new family of compounds with primarily antihypertensive properties, although some of the furopyridine derivatives have also antiallergic and antiinflammatory effects.The mechanism by which cicletanine lowers blood pressure has not been definitively established, although it appears to differ from that of other classes of antihypertensive drugs. Cicletanine acts on vascular smooth muscle by increasing prostacyclin synthesis and by interacting either directly with cytosolic Ca2+ pools or indirectly through various agents capable of mobilizing intracellular Ca ' ' , e.g., histamine.Studies in animals and humans demonstrated that the antihypertensive effect of cicletanine is clearly dissociable from its renal effect, which can be seen only at highdose levels of the drug.Clinical trials have confirmed the efficacy and safety of cicletanine in the treatment of hypertension, both as monotherapy or in combination with other antihypertensive drugs. CHEMISTRYCicletanine was synthetized by Esanu et al. (9) in the research laboratories of Institute Henri Beaufour, Le Plessis-Robinson (France). It was selected from a large number of furopyridines for its specific antihypertensive activity and very low, if any, toxicity. The chemical structure of cicletanine ( HCl) : (-+ ) 3-(4-chloropheny1)-1,3dihydro-7-hydroxy-6-methyl furo[3,Cc]pyridine is shown in Fig. 1. Its chemical synthesis from 2-,2,8-trimethyl-5-formyl pyrido [ 4,3-el 1,3-dioxine has been described (9). Cicletanine HC1 has a molecular weight of 298.2. It is not soluble in 166 CICLE TANINE 167 water, but soluble in ethanol and dimethyl sulfoxide. It is a white crystalline powder with a melting point of 2 19-228°C. PHARMACOLOGY Effect on Blood PressureThe activity of cicletanine on blood pressure was evaluated in anesthetized normotensive rats and dogs and in several models of hypertensive rats: desoxycorticosterone acetate, spontaneously ( SH ) and stroke-prone spontaneously ( SH-SP) hypertensive rats and rats with stress-induced hypertension.In the anesthetized normotensive rat, cicletanine, administered orally at 100 and 300 mg/kg, did not affect either mean blood pressure or heart rate. The blood pressure effects of epinephrine, norepinephrine, acetylcholine, isoproterenol, or serotonin were not altered by pretreatment with cicletanine.The effect of intravenously injected cicletanine on the main hemodynamic cardiovascular parameters-systolic and diastolic aortic pressure, heart rate, aortic blood flow, coronary (circumflex artery) and femoral arterial blood flow-were studied in anesthetized normotensive dog. At doses higher than 5 mg/kg i.v., cicletanine produced only a slight and transient bradycardia, a minor reduction of systolic arterial pressure, and a brief decrease in diastolic pressure. F...

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“…This influence of the intracytosolic calcium of the vascular muscle cells is reinforced by the inhibitory action of cicletanine on the Hrreceptors, as has been shown in a number of pharmacological studies [149,156,230]. A central inhibitory effect of cicIetanine on the H I receptors has not yet been demonstrated [209].…”

Section: Prostacyc6n-stimulating Substancesmentioning

confidence: 99%

Prostacyclin and Hypertension

Bönner¹,

Rahn²

1990

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Competitive and stereoselective histamine H1 antagonistic effect of cicletanide in guinea-pig isolated ileum

Cited by 19 publications

References 9 publications

Effects of Cicletanine on Histamine‐induced Contractions of Isolated Rabbit Mesenteric Arteries

Effects of Cicletanine on Histamine‐induced Contractions of Isolated Rabbit Mesenteric Arteries

Cicletanine

Prostacyclin and Hypertension

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