Adenosine has been shown to have a negative dromotropic effect and has been implicated in mediating atrioventricular conduction disturbances induced by
hypoxia. This study was designed to determine the ability of various alkylxanthines including two novel derivatives, i.e.,
BW A533U and
BW A1433U, to 1) attenuate
adenosine- and
hypoxia-induced atrial to His bundle (AH) interval prolongation, 2) compete for binding of 125I-aminobenzyladenosine to ventricular membranes and 3) inhibit myocardial
phosphodiesterase. In normoxic isolated perfused hearts (n = 20) instrumented for measurement of atrioventricular conduction time and left ventricular pressure,
BW A1433U (0.1 microM) or
BW A533U (5 microM) attenuated AH interval prolongation induced by
adenosine (5 microM) by 90%, but neither
xanthine derivative attenuated the AH interval prolongation induced by
acetylcholine (0.11 microM),
digoxin (0.91 microM) or
D600 (1.3 microM). In four additional hearts,
BW A1433U at concentrations of up to 10 microM had no effect on left ventricular pressure or AH interval.
BW A1433 or
BW A533U (50 microM) inhibited myocardial
cyclic AMP phosphodiesterase by only 11.5 +/- 1.6 and 26.6 +/- 2.6%, respectively. Schild analysis of
adenosine concentration-response curves obtained in the absence and presence of
BW A533U and
BW A1433U (n = 14) yielded pA2 values of (mean +/- S.E.M.) 6.32 +/- 0.10 and 7.70 +/- 0.08, respectively. pKd values for
BW A533U and
BW A1433U binding to
adenosine receptors on ventricular membranes were 6.36 and 6.94, respectively. In a separate series of 19 hearts,
BW A533U and
BW A1433U were shown to attenuate
hypoxia-induced AH interval prolongation.(ABSTRACT TRUNCATED AT 250 WORDS)