Effect of tienoxolol, a new diuretic β-blocking agent, on urinary prostaglandin excretion in the rat

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Abstract
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 β-adrenoceptor blocking properties, were investigated on urinary 6-keto-prostaglandin F1α (6-keto-PGF1α) and PGE2 excretion in the rat and compared to those of reference diuretic (furosemide) and β-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-PGF1α 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-PGF1α 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 β-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-PGF1α 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 of tienoxolol. The increase of urinary 6-keto-PGF1α excretion may result not only from the haemodynamic properties of the drug but also from the rise of the urinary flow induced by tienoxolol.