Short-chain aliphatic
esters and
amides of
adenosine-5'-carboxylic acid caused marked increases in coronary sinus
oxygen tension (PO2) in the dog; the
amides were generally more potent, causing additionally marked
hypotension and
tachycardia. The hypotensive effect was observed also in the spontaneously hypertensive rat. That the increase in coronary sinus PO2 paralleled an increase in coronary flow was verified with
ethyl adenosine-5'-carboxylate hydrochloride. This compound also increased the reactive hyperemic response.
Aminophylline blocked the increase in coronary flow. A representative
amide and
ester were very poor substrates for
adenosine and
adenylate deaminase in vitro; the
amide exhibited a weak inhibitor effect on the enzymic activities while the
ester was inactive. The observations that the compounds (1) cause marked pharmacological effects within seconds after
intravenous administration, (2) are blocked by
aminophylline like
adenosine, (3) are not deaminated significantly in vitro by either
adenosine or
adenylate deaminase, and (4) cannot be phosphorylated at the 5' terminus because the 5'-OH has been removed chemically, support the hypothesis that they are acting directly on an "
adenosine receptor" and have a prolonged duration of action because they are not metabolized significantly by the normal physiological pathways of
adenosine degradation.