Effect of tienoxolol, a new diuretic beta-blocking agent, on urinary prostaglandin excretion in the rat.
1. The effects of tienoxolol, (ethyl 2-[3-[(1,1-dimethylethyl)amino]-2-hydroxypropoxy]-5- [(2-thienylcarbonyl) amino] benzoate, hydrochloride), a novel drug exhibiting both diuretic and beta-adrenoceptor blocking properties, were investigated on urinary 6-keto-prostaglandin F1 alpha (6-keto-PGF1 alpha) and PGE2 excretion in the rat and compared to those of reference diuretic (furosemide) and beta-adrenoceptor antagonists (acebutolol, propranolol). Since tienoxolol was shown to bind to A1 and A2 adenosine receptors, the action of theophylline was also evaluated. 2. Tienoxolol (8-128 mg kg-1, p.o.) induced a dose-related increase of 6-keto-PGF1 alpha excretion from 32 mg kg-1 but a significant elevation of urinary PGE2 levels was only reached after administration of 128 mg kg-1. However, renal prostaglandin concentrations were not modified by tienoxolol. 3. Furosemide (32 mg kg-1) displayed a strong diuretic activity but did not enhance 6-keto-PGF1 alpha excretion. Likewise, the latter was unaffected by acebutolol and propranolol (128 mg kg-1) and no significant diuresis was observed following administration of these two beta-blocking agents. Theophylline (64 mg kg-1), like tienoxolol, was able to induce both diuresis and urinary prostaglandin excretion. Furthermore, they bound with similar affinities to A1 and A2 adenosine receptors. This led to the suggestion that a relationship between P1-purinoceptors, prostaglandin release, diuresis and natriuresis could exist. 4. Oral co-administration of NECA (0.2 mg kg-1) with tienoxolol markedly reduced the urinary 6-keto-PGF1 alpha excretion observed when tienoxolol was administered alone. However, neither diuresis nor natriuresis were modified, demonstrating that the proposed relationship was untenable. 5. In conclusion, PGI2 probably does not participate in the diuretic and natriuretic activity oftienoxolol. The increase of urinary 6-keto-PGF1alpha excretion may result not only from the haemodynamic properties of the drug but also from the rise of the urinary flow induced by tienoxolol.
Caussade
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Laboratoires UPSA, Rueil-Malmaison, France.
Cloarec
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A
D015121:6-Ketoprostaglandin F1 alpha / Q000652:urine; D000241:Adenosine / Q000031:analogs & derivatives / Q000378:metabolism / Q000494:pharmacology; D019830:Adenosine-5'-(N-ethylcarboxamide); D000319:Adrenergic beta-Antagonists / Q000494:pharmacology*; D000818:Animals; D001923:Brain Chemistry / Q000187:drug effects; D015232:Dinoprostone / Q000652:urine; D004231:Diuresis / Q000187:drug effects; D011464:Epoprostenol / Q000096:biosynthesis; D005665:Furosemide / Q000494:pharmacology; D008297:Male; D009318:Natriuresis / Q000187:drug effects; D011412:Propanolamines / Q000494:pharmacology*; D011453:Prostaglandins / Q000302:isolation & purification / Q000652:urine*; D011863:Radioimmunoassay; D011869:Radioligand Assay; D051381:Rats; D011919:Rats, Inbred Strains; D011983:Receptors, Purinergic / Q000187:drug effects / Q000378:metabolism; D013806:Theophylline / Q000494:pharmacology; D014665:Vasodilator Agents / Q000494:pharmacology
D000319:Adrenergic beta-Antagonists; D011412:Propanolamines; D011453:Prostaglandins; D011983:Receptors, Purinergic; D014665:Vasodilator Agents; D019830:Adenosine-5'-(N-ethylcarboxamide); C056983:tienoxolol; D015121:6-Ketoprostaglandin F1 alpha; D005665:Furosemide; D013806:Theophylline; D011464:Epoprostenol; D000241:Adenosine; D015232:Dinoprostone