dinoprost and cicletanine

The effect of cicletanine (BN 1270), a new furopyridine derivative, on human prostaglandin metabolism was investigated in a single-blind, two-way crossover study in healthy volunteers. Two dosages, 150 and 300 mg, were prescribed in single and 14-day regimens. There was a rapid and sustained increase in urinary excretion of the prostacyclin metabolite 6-keto-prostaglandin F1a which was independent of duration of treatment and urine flow. This response supports earlier evidence for an important stimulatory effect of cicletanine on prostacyclin synthesis and may contribute to the mechanism of antihypertensive action of the drug.

Topics: 6-Ketoprostaglandin F1 alpha; Administration, Oral; Dinoprost; Dinoprostone; Diuretics; Drug Administration Schedule; Drug Tolerance; Humans; Prostaglandins; Prostaglandins E; Prostaglandins F; Pyridines; Random Allocation; Thromboxane B2; Urination

The mechanism by which cicletanine (3-(4-chlorophenyl)-1,3-dihydro-7-hydroxy-6-methylfuro-[3,4-c]pyri dine) induces vasodilatation was examined in isolated vascular smooth muscle. Cicletanine inhibited the contraction induced by high K+, norepinephrine (NE) and prostaglandin F2alpha in a concentration-dependent manner in rat aorta. High K+ (15.8-72.7 mM) elicited elevation of cytosolic Ca2+ level ([Ca2+]i) and contraction in a concentration-dependent manner. Cicletanine (300 microM) inhibited the high K+-induced contractions without changing the [Ca2+]i/tension relationship. NE (3-300 nM) elicited greater contractions than high K+ at a given [Ca2+]i, suggesting that NE increased Ca2+ sensitivity of the contractile elements. Cicletanine inhibited the NE-induced contractions without changing the slope of the [Ca2+]i/tension relationship. Cicletanine inhibited the transient increases in both [Ca2+]i and muscle tension elicited by NE but not the transient increase in [Ca2+]i elicited by caffeine in Ca2+-free solution. Cicletanine did not inhibit contraction induced by Ca2+ in the permeabilized rabbit mesenteric artery with alpha-toxin. These results suggest that cicletanine inhibits vascular smooth muscle contraction by multiple mechanisms: 1) inhibition of Ca2+ influx via voltage-dependent Ca2+ channel and 2) inhibition of Ca2+ release mediated by the alpha-adrenoceptors, but not by caffeine.

Topics: Animals; Antihypertensive Agents; Aorta, Thoracic; Caffeine; Calcium; Central Nervous System Stimulants; Cyclic GMP; Cytosol; Dinoprost; Dose-Response Relationship, Drug; Male; Muscle Contraction; Muscle, Smooth, Vascular; Norepinephrine; Potassium Chloride; Pyridines; Rabbits; Rats; Rats, Wistar; Receptors, Adrenergic, alpha; Vasodilation

Decreased response to vasopressor agents characterizes pregnancy. Endothelium-derived relaxing factors and vasodilating prostaglandins play an important role in the vascular tone during pregnancy. Since inhibition of nitric oxide (NO) biosynthesis induced by NO2-arginine enriched diet produced hypertension we measured in vivo cardiovascular responses to PGF2 alpha, L-arginine (L-arg) and cicletanine (Cic, IPSEN, France) which enhances PGI2 production. From day 13 to day 20 of gestation 4 groups of female Wistar rats were fed NO2-arg (31 mg/kg/d), NO2-arg+Cic (10 mg/kg/d), Cic enriched or control diet (C). Mean arterial pressure (MAP) was measured via a carotid catheter in anesthetized rats. Injection of PGF2 alpha (50 micrograms/kg) in jugular vein significantly increased MAP in the NO2-arg group versus, NO2-arg+Cic, Cic and C group (+23.5 +/- 3.3 vs +15.7 +/- 2.2, +15.8 +/- 2.2 and +17 +/- 1.85 mmHg; p < 0.01). Injection of L-arg (100 mg/kg) or Cic (1 mg/kg) 5 min before PGF2 alpha produced no modification in MAP in C and Cic group. Likewise in NO2-arg group injection of L-arg or Cic produced a diminished pressor response to PGF2 alpha (+23.5 +/- 3.3 vs -17.5 +/- 1.7 mmHg; p < 0.05 and +15.2 +/- 2.4 mmHg; p < 0.01 respectively). In NO2-arg+Cic group, only injection of Cic induced a diminished pressor response to PGF2 alpha which is more important without L-arg (+15.7 +/- 2.2 vs +9.1 +/- 1.3 mmHg; p < 0.001) or with L-arg (+13.6 +/- 1.5 vs +9.1 +/- 1.3 mmHg; p < 0.01). Cicletanine also significantly diminished the proteinuria in the NO2-arg+Cic group versus NO2-arg group (13.9 +/- 4.36 vs 63.4 +/- 21.6 mmHg; p < 0.01). IN CONCLUSION, chronic NO synthesis inhibition enhanced blood pressure and pressor responses to PGF2 alpha during pregnancy in rats. Chronic administration of cicletanine in Wistar pregnant rats decreases the response to vasopressor agents like PGF2 alpha. Moreover acute and chronic administration of cicletanine blunted the pressor effect, which was lower than in normal gestation.

Topics: Animals; Antihypertensive Agents; Arginine; Blood Pressure; Dinoprost; Enzyme Inhibitors; Female; Hypertension; Nitric Oxide; Nitroarginine; Oxytocics; Pregnancy; Pregnancy Complications, Cardiovascular; Pregnancy, Animal; Prostaglandins F; Proteinuria; Pyridines; Rats; Rats, Wistar; Vasoconstriction