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-') 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-ketoprostaglandin Fla 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. 5 It was concluded that i) from a pharmacokinetic view point, the dosage of cicletanine should only be slightly reduced in patients with a glomerular filtration rate below 30 ml min-', ii) as with most of the diuretic agents, its natriuretic properties were markedly decreased in these patients and iii) an alteration in the renal synthesis of prostacyclin or thromboxane seems unlikely to participate in the pharmacological effects of cicletanine.
To determine whether the increased renal synthesis of thromboxane (Tx)A2 found in genetically hypertensive rats also occurred in rats with a sodium-dependent form of hypertension, the urinary excretion of 6-keto-prostaglandin F1 alpha (6KPGF1 alpha) and of TxB2 was measured by a sensitive and specific radioimmunoassay in hypertension-prone (SBH), -resistant (SBN) and unselected (SB) female rats of the Sabra strains. Rats of the three strains were studied before (9 weeks of age) and after five weeks of deoxycorticosterone (DOCA)-salt treatment. Before treatment, the urinary 6KPGF1 alpha did not differ among the three strains while a higher TxB2 excretion was seen in the SBN rats. After treatment, the urinary excretion of TxB2 increased significantly in SBH and SB but not in SBN rats, while the urinary 6KPGF1 alpha remained unchanged in SBH, increased moderately in SB and markedly in SBN controls. Consequently, DOCA-salt-induced changes in blood pressure and in urinary 6KPGF1 alpha observed in the three strains of rats were inversely related (r = -0.78; P less than 0.001). It is concluded that the high blood pressure developed after DOCA-salt treatment in SBH rats is more likely to depend upon a defect in the renal production of prostacyclin rather than upon an increased synthesis of thromboxane A2.
1 In order to assess the effects of atrial natriuretic factor on the renal biosynthesis of prostaglandins (PG), the urinary excretion of PGE2, PGF20,, 6-keto-PGF10, and thromboxane (Tx)B2 were followed in eight salt-loaded healthy volunteers infused for 2 h with a non hypotensive dose of human atrial natriuretic peptide (hANP, 0.7 nmol min-1).2 Within 1 h, hANP, infusion produced a marked increase in the urinary PG output, especially of PGE2 and 6-keto-PGF10, (188 ± 21% and 202 ± 24% of the pre-infusion values respectively), followed by a significant decrease during the recovery period. 3 No correlations could be uncovered between the urinary excretion of sodium and that of any of the PGs. In contrast, during the infusion of hANP, the urinary output of PGE2 and of 6-keto-PGF10, was found positively related to the urinary flow rate (r = 0.42; P < 0.05; n = 32 and r = 0.43; P < 0.05; n = 32 respectively) as well as during the recovery period (r = 0.66, P < 0.001; n = 32 and r 0.55; P < 0.01; n = 32 respectively). 4 It was concluded that, in man, infusion of a non hypotensive dose of hANP is followed by a rise in urinary PG excretion presumably reflecting enhanced renal PG biosynthesis. This increased urinary PG excretion does not seem to be involved in the natriuretic action of hANP but might participate to its diuretic effect.
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