ISSN:
1432-1912
Keywords:
Inotropic Effect
;
Butyryl Derivatives of c-AMP
;
Non-Cyclic Tributyryl-AMP
;
Isolated Rat Auricles
Source:
Springer Online Journal Archives 1860-2000
Topics:
Medicine
Notes:
Summary This study was designed to further elucidate relevance and mechanism of the positive inotropic action of cyclic N6-2′-O-dibutyryl-AMP (DB-c-AMP). For this purpose the effects of cyclic N6-monobutyryl-AMP (N6-MB-c-AMP), noncyclic N6-2′-O-3′-O-tributyryl-5′-AMP (TB-AMP), c-AMP, adenosine and various adenine nucleotides (ATP, ADP, AMP) on myocardial contractile force (CF) were investigated and compared to that of DB-c-AMP. The experiments were performed on isolated, electrically driven (frequency 2 Hz) rat left auricles, i.e. on a preparation in which DB-c-AMP consistently produced positive inotropic effects. The following results were obtained: 1. N6-MB-c-AMP (2×10−4–5×10−3 M) produced a concentration-dependent positive inotropic effect (Fig. 2). This effect began 5.5 to 1.8 min after addition of the drug (Table 2), developed gradually (Fig.2), and was maximal within 44.5 to 9.5 min (Table 2). It was preceded by a transitory decrease in CF which was also concentration-dependent (Fig.2, Table 1). 2. The inotropic effects of cyclic N6-MB-AMP and cyclic DB-AMP were qualitatively similar. Quantitatively, the positive inotropic effect of N6-MB-c-AMP developed more slowly (Table 2) and was smaller in magnitude than that of DB-c-AMP (Fig.2). The initial negative inotropic effect, however, was more pronounced (Table 1) and longer in duration (Table 2) with N6-MB-c-AMP than with DB-c-AMP. 3. The time course of the reversal of the positive inotropic effects during washout in drug-free solution was practically not different with both drugs (Fig.3). Predrug levels were reached within 50–60 min. 4. No positive inotropic effects were found with the non-cyclic but butyryl substituted adenine nucleotide, TB-AMP. In contrast, this compound (10−7 to 10−3 M) produced a concentration-dependent decrease in CF (Fig.4). 5. c-AMP, ATP, ADP, AMP and adenosine depressed CF. No secondary positive inotropic effects could be detected within 60 min (Fig.5; Fig.6). From the failure of non-cyclic TB-AMP to increase contractile force it is concluded that the positive inotropic effects seen with cyclic DB-AMP and cyclic N6-MB-AMP are due to both acyl substitution and the intact cyclophosphate structure. In so far we probably have ruled out one of the objections to the view that the positive inotropic responses to acyl substituted derivatives of c-AMP are “representative” for c-AMP itself. Since the effects of cyclic DB-AMP and cyclic N6-MB-AMP were qualitatively similar and since the time course of the loss of the positive inotropic effects during washout were practically not differen with both drugs, one may further conclude that within the cell both drugs are likely to act via the same compound. This agent could be c-AMP. However, cyclic N6-MB-AMP as the active intracellular compound cannot be ruled out.
Type of Medium:
Electronic Resource
URL:
http://dx.doi.org/10.1007/BF00500648
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