THE CHRONOTROPIC ACTION OF ATP AND RELATED COMPOUNDS STUDIED BY DIRECT PERFUSION OF THE SINUS NODE

¹ Section on Cardiovascular Research, Henry Ford Hospital, Detroit, Michigan

ATP has an immediately profound but relatively transient negative chronotropic effect on direct perfusion of the sinus node of the dog. This effect is not altered by atropine.

Adenosine, A5MP and ADP have actions similar to ATP. Adenine and creatine phosphate have no significant chronotropic action. Therefore, in ATP the phosphate bonds are not essential to its chronotropic action but the D-ribose chain is.

Inosine, which has no chronotropic action, differs from adenosine only by having a hydroxyl group instead of an amino group at the 6-carbon position. Therefore, the amino group and D-ribose chain are both necessary for the negative chronotropic effect of adenosine (and ATP).

Guanosine differs from adenosine principally in the location of an amino group at the 2-carbon instead of the 6-carbon, and its chronotropic effect (acceleration) is opposite to that of adenosine. Therefore, the position of the amino group has an important influence on the chronotropic action of these purine nucleosides.

A2MP, A3MP and cyclic AMP all have a similar negative chronotropic action, which differs from that of ATP by being slower in onset and less marked in maximal degree but of longer duration. Therefore, the position of phosphate bonds on the D-ribose chain of adenine nucleotides modifies the nature of their negative chronotropic action.

Two pyrimidine nucleosides (cytidine and uridine) and their nucleotides have no significant chronotropic action. The nucleotide of inosine is active, resembling ATP, while inosine is not. The nucleotide of guanosine is inactive, while guanosine accelerates the sinus node, an action which is unaffected by beta-receptor blockade. The significance of different actions by inosine and guanosine and their nucleotides is uncertain.

DNP produces relatively gradual development of bradycardia on direct perfusion of the sinus node, and is unaffected by atropine. The negative chronotropic effect of DNP is not reversible with ATP but is reversed with CP (although not consistently). Reversal of DNP effect with CP indicates the canine sinus node can utilize CP as an energy source.

On the basis of the present studies plus previous ones from this laboratory, and in light of other recent observations, it is suggested that the negative chronotropic action of dipyridamole is due to its adenosine-sparing effect.

The possible significance of the negative chronotropic action of adenosine and ATP relative to the pathophysiology of depressed sinus node function in some cases of human acute myocardial infarction is discussed.

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