Activation of prostacyclin synthesis in cultured aortic smooth muscle cells by ‘diuretic-antihypertensive’ drugs

Dorian, B.; Larrue, J; DeFeudis, F.V.; Salari, Hassan; Borgeat, Pierre; Braquet, P.

doi:10.1016/0006-2952(84)90665-8

Cited by 35 publications

(20 citation statements)

References 17 publications

Supporting

Mentioning

Contrasting

Unclassified

Order By: Relevance

“…In rat cultured smooth muscle cells, cicletanine was demonstrated to enhance the production of prostacyclin from exogenous arachidonic acid ( 7 ) . As confirmed by experiments on human leukocytes, this effect was not mediated through an inhibition of lipoxygenase.…”

Section: Interactions With Prostacyclin Synthesismentioning

confidence: 97%

Cicletanine

Chabrier

Guinot

Tarrade

et al. 1988

Cardiovascular Drug Reviews

View full text Add to dashboard Cite

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...

show abstract

Section: Interactions With Prostacyclin Synthesismentioning

confidence: 97%

Cicletanine

Chabrier

Guinot

Tarrade

et al. 1988

Cardiovascular Drug Reviews

View full text Add to dashboard Cite

show abstract

“…3). Cic1etanine stimulates vascular prostacyc1in synthesis in vitro and in vivo [50,98] and can thus produce a marked vasodilatation [24]. Primary consideration in these studies was given to the older findings relating to the diuretics or ACE inhibitors, as these lead more frequently than any other group of agents to stimulation of prostacyclin synthesis.…”

Section: Prostacyc6n-stimulating Substancesmentioning

confidence: 99%

“…Primary consideration in these studies was given to the older findings relating to the diuretics or ACE inhibitors, as these lead more frequently than any other group of agents to stimulation of prostacyclin synthesis. Persistent increase in renal prostacyclin excretion in healthy subjects after 150 mg cicletanine orally (x ± SD) [98] of the arachidonic acid cascade with increased liberation of cyclooxygenase products [37,50,82,98,128]. A new substance has now been successfully developed which produces stimulation of prostacyc1in synthesis in vivo persisting for several hours (Fig.…”

Section: Prostacyc6n-stimulating Substancesmentioning

confidence: 99%

Prostacyclin and Hypertension

Bönner¹,

Rahn²

1990

View full text Add to dashboard Cite

“…However, these effects are not necessarily linked since the hypotensive action is observed at low dose in absence of any increase in urinary volume. However, both in vitro and in vivo studies with cicletanine hypothetize an enhancement of prostacyclin synthesis (Dorian et al, 1984;Deby et al, 1984). The mechanism by which cicletanine lowers blood pressure has not been definitely established, although it appears to differ from that of other classes of antihypertensive drugs.…”

Section: Introductionmentioning

confidence: 99%

Effects of cicletanine on vasoactive systems in conscious sinoaortic‐denervated dogs

Damase‐Michel

Bascands

et al. 1991

Fundamemntal Clinical Pharma

View full text Add to dashboard Cite

The present study investigates the antihypertensive action of cicletanine, a new antihypertensive compound with diuretic properties (or placebo), on vasopressor (catecholamines, renin-aldosterone) as well as vasodepressor (prostaglandins, kallikrein-kinin) systems in conscious chronic sinoaortic denervated (SAD) dogs. Cicletanine (10 mg/kg twice a day, per os, for one month) lowered blood pressure and heart rate. The antihypertensive action does not involve an effect on sympathetic tone (since plasma catecholamine levels were unmodified) or on plasma aldosterone levels. By contrast, urinary 6 keto PGF1 or PGE2 levels and kallikrein activity were enhanced. This result indicates that the antihypertensive effect of cicletanine is associated with a stimulation of potential vasodepressor systems (such as prostaglandins or kinins).

show abstract

Activation of prostacyclin synthesis in cultured aortic smooth muscle cells by ‘diuretic-antihypertensive’ drugs

Cited by 35 publications

References 17 publications

Cicletanine

Cicletanine

Prostacyclin and Hypertension

Effects of cicletanine on vasoactive systems in conscious sinoaortic‐denervated dogs

Contact Info

Product

Resources

About