Studies on the Cardiovascular Effects of Pindolol in Doca/Saline Hypertensive Rats

Abstract

1 A hypotensive response to orally administered pindolol in conscious normotensive and deoxycorticosterone acetate (DOCA)/saline hypertensive rats (DS‐rats) is described. In DS‐rats, pindolol (10‐50 μg/kg) produced a dose‐dependent fall in blood pressure and elevation of resting heart rate. 2 The hypotensive response and tachycardia produced by oral pindolol (50 μg/kg) in DS‐rats were prevented by propranolol (5 mg/kg), suggesting that pindolol's effects are mediated by β‐adrenoceptor stimulation. 3 After mecamylamine (10 mg/kg), oral pindolol (50 μg/kg) produced a further fall in blood pressure in DS‐rats, suggesting that its hypotensive effects are probably mediated in the peripheral vasculature. 4 Pretreatment with oral pindolol (10 or 50 μg/kg) resulted in a reduction of neuronally‐induced tachycardia in pithed DS‐rats; neuronally‐evoked pressor effects were also antagonized by pindolol (50 μg/kg, orally). 5 Whereas pindolol, 50 μg/kg orally or intraperitoneally, produced a marked and progressive hypotensive response of rapid onset (20 min) in DS‐rats the same dose intravenously produced a smaller response of delayed onset (80 minutes). 6 In anaesthetized DS‐rats, an equivalent degree of cardiac β‐adrenoceptor blockade was produced by pretreatment with pindolol, 50 μg/kg orally (2 h previously) or intravenously (1 h previously). 7 After administration of pindolol, 2 mg/kg intravenously, to conscious DS‐rats, the tachycardia produced by intravenous isoprenaline, 3 μg/kg, was almost abolished for the first 60 min of the study, whereas a hypotensive response to pindolol was delayed in onset (100 minutes). 8 The hypotensive response and tachycardia produced by oral pindolol, 50 μg/kg, in DS‐rats were prevented by inhibition of metabolic enzyme activity by pretreatment with Proadifen (SKF 525‐A), 80 mg/kg. 9 The results suggest that pindolol's effects on blood pressure and heart rate in the conscious DS‐rat are mediated by a metabolite(s) acting by stimulation of peripheral β‐adrenoceptors.

Diminishing Hypotensive Effect of Increasing Doses of Pindolol in Doca/Saline Hypertensive Rats

“…Introduction The non-selective fl-adrenoceptor blocking drug, pindolol, has been shown to lower the blood pressure of deoxycorticosterone acetate (DOCA)-saline hypertensive (DS) rats after oral administration of small doses (Buckingham, Hamilton & Robson, 1977). The effect was dose-related and appeared to be mediated by a metabolite(s) acting by stimulation of vascular fi2-adrenoceptors.…”

“…Pindolol is extensively metabolized in rats (Kiechel, Niklaus, Schreier & Wagner, 1975) and has a short plasma half life after oral administration (Pacha, 1969). Our earlier studies (Buckingham et al, 1977) suggested that the hypotensive response to pindolol in the DS-rat is mediated through a metabolite(s) formed predominantly in the liver. Over-loading of the hepatic extraction process, by administration of a sufficiently large oral dose, would reduce the fraction of drug removed on its first passage through the liver, as occurs with propranolol in the rat (Shand, Rangno, & Evans, 1972).…”

“…Over-loading of the hepatic extraction process, by administration of a sufficiently large oral dose, would reduce the fraction of drug removed on its first passage through the liver, as occurs with propranolol in the rat (Shand, Rangno, & Evans, 1972). Since the hypotensive effect in the DS-rat is apparently due to stimulation of vascular /2-receptors (Buckingham et al, 1977) an increase in the fraction of circulating parent drug, with its inherent f3-adrenoceptor blocking properties, might be expected to attenuate the response. Subsequent metabolism of the parent drug would account for the diminution of differences in effect of the three pindolol doses at 3 and 4 hours.…”

“…Methods DS-rats were prepared by the method previously described (Buckingham et al, 1977). In some rats unilateral adrenalectomy and contralateral adrenal demedullation were performed at this operation (adrenal demedullated DS-rats).…”

Contrasts between pindolol and propranolol concentration‐response relationships.

“…Although metabolites of pindolol have been found to be pharmacologically active in the rat (Buckingham et al, 1977), no evidence of active metabolites of pindolol in man has been forthcoming (Aellig, 1976b). Although similar oral and intravenous doses produce the same 0-adrenoceptor blockade (Carruthers, 1982), there has never been any comparison of the plasma concentration-response relationships of pindolol after oral and intravenous administration in the manner described for oral and intravenous propranolol by Cleaveland & Shand (1972).…”