With the aim of gaining more insight into the metabolism of adenine nucleotides in working normoxic guinea-pigs and in hearts subjected to 45 min of global ischaemia and subsequent reperfusion for 25 min, we evaluated the effect of nifedipine, verapamil, diltiazem, bepridil, CERM 11956, lidoflazine, mioflazine and dipyridamole on the adenine nucleotide catabolite levels in these hearts. The drugs were applied at the concentrations that reduced the aortic dP/dt of normoxic working hearts by 10% (EC10) and 30% (EC30). In globally ischaemic hearts there was a large accumulation of adenine nucleotide catabolites. Inosine proved to be the major catabolite. The drugs, with the exception of bepridil, CERM 11956 and dipyridamole (3 mumol/l), decreased the accumulation of catabolites. In hearts treated with mioflazine and dipyridamole the amount of adenosine increased. A deficit in the balance between adenine nucleotides and catabolites indicated that in globally ischaemic hearts there was a large accumulation of inosine monophosphate. Indeed, a substantial amount of inosine monophosphate was determined in untreated hearts, and hearts treated with nifedipine (EC30) and mioflazine (EC10). During the first 5 min of reperfusion a large quantity of catabolites, mainly inosine, was washed out. During 20 min of subsequent reperfusion in untreated hearts and in nifedipine and mioflazine-treated hearts the efflux of catabolites returned to normoxic values. Similar to the effect in ischaemic hearts, in early perfusate from lidoflazine, mioflazine and dipyridamole-treated hearts the adenosine/inosine ratio was increased.(ABSTRACT TRUNCATED AT 250 WORDS)

1989-07-01·Naunyn-Schmiedeberg's Archives of Pharmacology4区 · 医学

A comparison of the cardioprotective effects of calcium antagonists from different classes upon ischaemic damage in the guinea-pig working heart

4区 · 医学

Article

作者: J. J. Beekeringh ; M. J. Mathy ; P. A. van Zwieten ; H. W. G. M. Boddeke ; J. G. Hugtenburg ; R. D. Veldsema-Currie

The cardioprotective effects of nifedipine, verapamil, diltiazem, bepridil, CERM 11956, lidoflazine, mioflazine and the coronary vasodilator dipyridamole were evaluated in the guinea-pig working heart with respect to cardiac function and high energy phosphate content after 45 min of global ischaemia and 25 min of reperfusion. All drugs, with the exception of dipyridamole, induced a negative inotropic effect, which resulted in a decrease of the aortic pressure (AoP), of its first derivative dAoP/dt and the cardiac output. To compare the anti-ischaemic effect of the calcium antagonists, concentrations were selected that reduced the dAoP/dt by 10% (EC10) and 30% (EC30), respectively. With the exception of nifedipine at the EC10 and bepridil and CERM 11956 at the EC30, perfusion with the calcium antagonists and dipyridamole (3 mumol/l) improved the recovery of contractile function after global ischaemia and reperfusion to a value between 60 and 80% of the controls in normoxic hearts. Pretreatment with nifedipine, verapamil, diltiazem, lidoflazine and mioflazine, but not with bepridil, CERM 11956 and dipyridamole led to slightly increased ATP levels in ischaemic hearts as compared to the control value in ischaemic hearts. After subsequent reperfusion for 25 min, for all drugs, ATP levels were further enhanced to 50% of the level in normoxic hearts; phosphocreatine levels reached normoxic values. In particular at the EC30, the effects of calcium antagonists on cardiac function varied in accordance with their known pharmacological and physiological profile. However, there appeared to exist no direct relationship between their beneficial effects on contractile activity and those on the levels of high energy phosphates after ischaemia and reperfusion.

1988-05-01·European Journal of Pharmacology3区 · 医学

The anti-ischaemic activity of the novel compound, CERM 11956, compared with that of bepridil and nifedipine in isolated guinea-pig hearts

3区 · 医学

Article

作者: Bob Wilffert ; Pieter A. Van Zwieten ; Walther T.J. Jap ; Robin D. Veldsema-Currie ; Jaap B. Heynis ; Erik W.G.M. Boddeke ; Jacqueline G. Hugtenburg

A comparison between the protective activity of bepridil, its novel derivative, CERM 11956, and nifedipine in isolated electrically paced guinea-pig hearts after 60 min of global ischaemia followed by 30 min of reperfusion has been made. All three compounds exerted a significant anti-ischaemic effect, as indicated by an improved recovery of functional parameters (left ventricular pressure and coronary perfusion), a delayed onset of the ischaemic contracture, and an enhanced recovery of biochemical (CrP, ATP and adenylate energy charge) parameters. The most pronounced anti-ischaemic activity was shown by the compound CERM 11956 at concentrations that displayed only minor negative inotropic activity. From the results it may be concluded that the new bepridil derivative, CERM 11956, is a promising and potent anti-ischaemic compound, which has little influence on haemodynamic parameters.

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