thromboxane-b2 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

We studied the effects of cicletanine, an anti-hypertensive drug, on reperfusion arrhythmias in relation to 6-keto-PGF1 alpha, thromboxane B2 (TXB2), and ion shifts (Na+, K+, Ca2+, and Mg2+) induced by ischemia and reperfusion in hearts isolated from spontaneously hypertensive rats. Hearts were subjected to 30-min global ischemia followed by 10-min reperfusion. 6-keto-PGF1 alpha and TXB2 concentrations were determined by radioimmunoassay (RIA) from coronary effluents, and myocardial Na+, K+, Ca2+, and Mg2+ contents were measured by atomic absorption spectrophotometry from myocardial tissue. Two basic protocols were used: (a) acute administration when 3, 10, 30, or 100 mg/L cicletanine was included in the perfusion buffer; and (b) chronic application, in which rats received cicletanine 3, 10, 30, or 100 mg/kg/day orally for 14 days. Acute administration of the drug in low concentrations (3 or 10 mg/L), significantly increased endogenous 6-keto-PGF1 alpha production before ischemia and during reperfusion, whereas higher doses of cicletanine (30 or 100 mg/L) as well as chronic application of the drug failed to increase production of 6-keto-PGF1 alpha in the myocardium. TXB2 production was not influenced by either acute or chronic treatment with the drug. Neither treatment changed myocardial ion contents in comparison with control values (Na+ = 45 +/- 4, K+ = 252 +/- 7, Ca2+ = 1.4 +/- 0.1, and Mg2+ = 12.5 +/- 0.3 mmol/kg dry weight) in nonischemic hearts. Thirty-minute ischemia resulted in a two- and fourfold accumulation of myocardial Na+ and Ca2+ and a 50% decrease in both K+ and Mg2+.(ABSTRACT TRUNCATED AT 250 WORDS)

Topics: 6-Ketoprostaglandin F1 alpha; Animals; Anti-Arrhythmia Agents; Body Water; Calcium; Coronary Disease; Diuretics; Electrocardiography; In Vitro Techniques; Magnesium; Myocardial Reperfusion Injury; Myocardium; Potassium; Pyridines; Rats; Rats, Inbred WKY; Sodium; Thromboxane B2

Isolated hearts, excised from spontaneously hypertensive male rats treated orally with cicletanine, a new furopyridine anti-hypertensive drug, were subjected to 30 min of global ischemia followed by 10 min of reperfusion. The effect of cicletanine on reperfusion-induced arrhythmias in relation to 6-keto-PGF1 alpha and thromboxane (TXB2) release was studied. After 30 min of global ischemia, the incidence (total) of ventricular fibrillation (VF) and ventricular tachycardia (VT) was reduced by 2-week pretreatment of the rats with 30 and 100 mg/kg of cicletanine (VF, 33% at 30 mg/kg and 25% at 100 mg/kg vs. 91% in untreated rats; VT, 42% at 30 mg/kg and 42% at 100 mg/kg vs. 100% in untreated rats), while lower doses of cicletanine (3 and 10 mg/kg) failed to reduce the incidence of reperfusion-induced rhythm disturbances. Reperfusion of the ischemic myocardium resulted in a fivefold increase of 6-keto-PGF1 alpha and TXB2 release in the perfusion effluent of fibrillated hearts but not in the perfusion effluent of nonfibrillated hearts. Cicletanine failed to influence the reperfusion-stimulated release of 6-keto-PGF1 alpha and TXB2. These results indicate that the anti-arrhythmic effect of cicletanine in the reperfused myocardium is not related to PGI2 and thromboxane A2 release.

Topics: 6-Ketoprostaglandin F1 alpha; Animals; Anti-Arrhythmia Agents; Arrhythmias, Cardiac; Diuretics; Epoprostenol; Male; Myocardial Reperfusion Injury; Myocardium; Pyridines; Rats; Rats, Inbred SHR; Rats, Inbred WKY; Thromboxane A2; Thromboxane B2

An in vivo animal model was developed in the rabbit for the study of the mechanisms involved in the generation and release of prostanoids. Following heparinization and, if required, further sensitization of the animals by intravenous administration of haemolysed blood, injection of doses of arachidonic acid not exceeding 180 micrograms/kg induced a marked fall in arterial blood pressure on condition that the plasma anti-inflammatory protein levels were within the normal range. Cicletanine, certain diuretics (furosemide and bumetanide), as well as calcium-entry blockers such as verapamil and the association of insulin and potassium ions, all markedly decreased the AA50 value and were accompanied by a significant increase in the plasma levels of 6-oxo-PGF1 alpha, enhancing as such the ratio of 6-oxo-PGF1 alpha versus TXB2 in plasma. The infusion of insulin in association with potassium ions induced a similar but less sustained effect. Drugs which affect membrane ion transport were investigated in relation to an enhancing effect on the generation and release of prostanoids following the administration of arachidonic acid.

Topics: 6-Ketoprostaglandin F1 alpha; Animals; Arachidonic Acid; Arachidonic Acids; Blood Pressure; Bumetanide; Diuretics; Ethylmaleimide; Furosemide; Insulin; Male; Models, Biological; Potassium; Prostaglandin-Endoperoxide Synthases; Pyridines; Rabbits; Thromboxane B2; Time Factors; Verapamil

The effect of cicletanine, an antihypertensive drug, was studied in two in vivo models. It was demonstrated that the drug markedly affected the response of intravenously administered arachidonic acid in the rabbit. In this model a marked increase of 6-oxo-PGF1 alpha was observed when challenged by the intravenous injection of 50 micrograms/kg b.w. of arachidonic acid. In the rat model used for the study of platelet-vessel wall interaction, it was demonstrated that the inhibition of prostacyclin synthetase could be offset by cicletanine. These results indicate that the drug modulates the generation of prostacyclin and as such is capable of affecting the peripheral resistances which determine the level of the blood pressure.

Topics: 6-Ketoprostaglandin F1 alpha; Animals; Antihypertensive Agents; Arachidonic Acid; Arachidonic Acids; Cytochrome P-450 Enzyme System; Diuretics; Epoprostenol; Furosemide; Intramolecular Oxidoreductases; Isomerases; Pyridines; Rabbits; Rats; Thromboxane A2; Thromboxane B2; Tranylcypromine

An animal model was developed, permitting the study of thromboxane A2 and prostacyclin neoformation, after arachidonic acid (AA) injection. Two types of physiopathological responses were observed, according to the rabbit strains. In the first type, prostacyclin neoformation was predominant, AA injection inducing only reversible hypotension. In the second type, thromboxane A2 neoformation was prevalent, AA injection inducing irreversible hypotension, marked myocardial troubles, shock, and death. In both types, injection of cicletanine (5 x 10(-5) mole/kg) significantly enhanced prostacyclin neoformation. After cicletanine, a new hypertensive drug, rabbits of the second type responded like those of the first type, without severe physiopathological responses to AA injections.

Topics: 6-Ketoprostaglandin F1 alpha; Animals; Antihypertensive Agents; Arachidonic Acid; Arachidonic Acids; Blood Pressure; Diuretics; Epoprostenol; Kinetics; Male; Pyridines; Rabbits; Thromboxane A2; Thromboxane B2

1. The kinetics of a single oral dose (300 mg) of cicletanine a new antihypertensive drug with diuretic properties, and its effects on the urinary excretion of electrolytes and of the major stable metabolites of prostacyclin and thromboxane A2 were studied in patients with normal renal function (n = 6), mild (n = 9) and severe (n = 10) renal insufficiency. 2. In normotensive subjects with normal renal function, cicletanine was rapidly and regularly absorbed, its apparent elimination half-life established around 7 h, and both its renal clearance (0.4 ml min-1) and its cumulative renal excretion (0.85% of the administered dose), were low. Mild renal insufficiency did not significantly alter these parameters, while severe renal impairment reduced the renal clearance and the cumulative urinary excretion of cicletanine and increased its apparent elimination half-life (31 h). However the area under the plasma curve was not changed due to reduced plasma concentrations in these patients. 3. Cicletanine induced a rapid and marked (four fold as a mean) increase in the urinary excretion of water, sodium and potassium which lasted for 6 to 10 h, in subjects with normal renal function. Renal insufficiency did not alter the slope of the calculated plasma concentration-effects curves but reduced the maximum effect observed for water, sodium and potassium. 4. A single oral dose of cicletanine did not change the urinary excretion of 6-keto-prostaglandin F1 alpha and thromboxane B2 in the three groups of patients studied, the basal values of which being found to be closely related to the creatinine clearance.(ABSTRACT TRUNCATED AT 250 WORDS)

Topics: 6-Ketoprostaglandin F1 alpha; Adult; Aged; Creatinine; Diuretics; Electrolytes; Female; Glomerular Filtration Rate; Humans; Kidney Diseases; Male; Middle Aged; Prostaglandins; Pyridines; Thromboxane B2

Altering the buffer K+/Na+ ratio ([K+]o/[Na+]o) resulted in a biphasic change in the basal release of prostaglandin E2, 6-ketoprostaglandin F1 alpha (the stable breakdown product of prostaglandin I2) and thromboxane B2 (the stable metabolite of thromboxane A2), from resident rat peritoneal macrophages. Changing the [K+]o (at the expense of [Na+]o) from 15 mM to 0 mM or 75 mM (combined concentration of [K+]o and [Na+]o was maintained at 150 mM) resulted in a stimulation of 6-ketoprostaglandin F1 alpha and thromboxane B2 release. Prostaglandin E2 synthesis was also stimulated when the [K+]o was decreased from 15 mM to 0 mM. When the [K+]o was increased to 45 mM, prostaglandin E2 formation was inhibited but returned to values observed at 15 mM K+ when the [K+]o was further increased to 75 mM. Prostaglandin E2 synthesis at 75 mM K+ was still only 40% of that measured in the absence of K+, however. When cells were incubated in a Ca2+-free medium (+EDTA) eicosanoid release was drastically reduced and the changes in arachidonic acid metabolite release observed on changing the buffer [K+]o/[Na+]o were abolished. Total release of radiolabel ([14C]arachidonic acid and its radiolabelled metabolites) from macrophages prelabelled with [14C]arachidonic acid followed the same pattern as basal eicosanoid release, suggesting that changing [K+]o influenced phospholipase A2 activity, and hence, substrate availability. At all [K+]o values, from 0 mM to 75 mM, cicletanide reduced the release of radioactivity from macrophages prelabelled with [14C]arachidonic acid (by about 15%). In the presence of [K+]o, cicletanide had a stimulatory effect on the metabolism of the free fatty acid which masked the decrease in eicosanoid release expected due to inhibition of arachidonic acid release from phospholipid. In the presence of 5 mM K+, cicletanide inhibited the basal release but enhanced the arachidonic acid-stimulated synthesis of eicosanoids from resident macrophages in a dose-related fashion, confirming the dual action of the drug, i.e., the inhibitory effect on arachidonic acid release and the stimulation of arachidonic acid metabolism. The possible in vivo significance of these results is discussed.

Topics: 6-Ketoprostaglandin F1 alpha; Animals; Arachidonic Acid; Arachidonic Acids; Buffers; Calcium; Dinoprostone; Diuretics; Eicosanoic Acids; Macrophages; Potassium; Prostaglandin-Endoperoxide Synthases; Prostaglandins E; Pyridines; Rats; Sodium; Thromboxane B2