thromboxane-a2 and cicletanine

We designed experiments to reveal the antihypertensive properties of cicletanine, a novel antihypertensive drug, in Dahl salt-sensitive (Dahl-S) rats. Cicletanine (39 mg/kg body weight per day for 6 weeks) ameliorated the development of hypertension in Dahl-S rats fed a high-salt (4% NaCl) diet. This blood pressure reduction was associated with a decrease in heart weight and vascular wall thickness. Moreover, urinary prostacyclin (PGl2) excretion was increased with cicletanine treatment, being inversely related to systolic blood pressure. Proteinuria and urinary excretion of n-acetyl-beta-D-glucosaminidase were decreased and glomerular filtration rate was increased with this treatment. Morphological investigation revealed an improvement in glomerulosclerosis, renal tubular damage and intrarenal arterial injury in the salt-induced hypertensive rats. In contrast, trichloromethiazide, which decreased blood pressure to the same extent as cicletanine, lowered urinary PGl2 excretion and generally did not ameliorate the deteriorated renal functions and morphological abnormalities. Thus, these data indicate that cicletanine ameliorates the development of hypertension in Dahl-S rats and protects the cardiovascular and renal systems against the injuries seen in the hypertension. The enhanced vasodepressor PGl2 synthesis probably participates, to some extent, in these beneficial properties of long-term cicletanine treatment.

Topics: Animals; Antihypertensive Agents; Dinoprostone; Diuretics; Eicosanoids; Epoprostenol; Glomerular Filtration Rate; Hypertension; Kidney; Myocardium; Organ Size; Pyridines; Rats; Rats, Inbred Strains; Sodium; Sodium Chloride; Thromboxane A2

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

The administration of arachidonic acid to live rabbits if followed by the generation of prostacyclin and/or thromboxane. Cicletanine increased the production of prostacyclin in a first group of rabbits and amplified the prostacyclin/thromboxane ratio in a second group of the thromboxane type. The most probable mechanism for this action is activation of prostacyclin synthase by cicletanine. This was confirmed in the in vivo model by a study of the platelet-vascular wall interaction: tranylcyprominE, a prostacyclin synthase inhibitor, increased the interaction. Under these experimental conditions, cicletanine inhibited the effect of tranylcypromine and completely restored the enzymatic activity of prostacyclin synthase.

Topics: Animals; Diuretics; Epoprostenol; Furosemide; Pyridines; Rabbits; Rats; Rats, Inbred Strains; Thromboxane A2; Tranylcypromine

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