Coronary vasomotor and cardiac electrophysiologic effects of diadenosine polyphosphates and nonhydrolyzable analogs in the guinea pig.
Platelet activation in heart disease is important owing to the effects of platelet-derived compounds on myocardial perfusion and cardiac electrophysiology. Diadenosine polyphosphates are secreted from platelets and present in the myocardium, but their electrophysiologic and vasomotor effects are incompletely understood. We used isolated guinea-pig hearts to study the effects of diadenosine triphosphate (Ap3A), tetraphosphate (Ap4A), pentaphosphate (Ap5A), and hexaphosphate (Ap6A) (10 pM-0.1 mM), comparing their actions to those of adenosine, adenosine triphosphate, and non-hydrolyzable Ap4A and Ap5A analogs. Diadenosine polyphosphates (0.1 nM-0.1 microM) transiently reduced coronary perfusion pressure, which recovered during the continued presence of the compounds. At concentrations greater than 0.1 microM effects were maximal and sustained (perfusion pressure decreased from 36.5+/-3.4 to 18.6+/-2.5 mm Hg, p < 0.001, with 1 microM Ap4A). The changes in action potential duration and refractory period developed slowly but were maintained (0.1 nM-1 microM). With 1 nM Ap4A, action potential duration increased from 170.6+/-2.6 to 187.3+/-3.8 ms, p < 0.05, and refractory period increased from 138.5+/-1.6 to 147.9+/-2.0 ms, p < 0.05. Ap4A and its analog reduced QRS duration (from 24.7+/-1.1 to 13.9+/-1.6 ms with 1 microM Ap4A, p < 0.05). P2-purinergic (adenosine triphosphate) receptor antagonism (suramin) reduced perfusion pressure but was without electrophysiologic effect. Other changes in coronary perfusion pressure and electrophysiologic variables associated with Ap4A were not seen in the presence of suramin. P1-(adenosine) antagonism (8-[p-sulfophenyl]theophylline) attenuated the electrophysiologic effects only. Diadenosine polyphosphates have potent cardiac electrophysiologic and coronary vasomotor effects via purinergic receptors, suggesting an important role during platelet activation in acute coronary syndromes.
Stavrou
B M
BM
Academic Cardiology Unit, National Heart and Lung Institute, Imperial College School of Medicine, London, UK.
Lawrence
C
C
Blackburn
G M
GM
Cohen
T
T
Sheridan
D J
DJ
Flores
N A
NA
D000200:Action Potentials / Q000187:drug effects* / Q000502:physiology; D000818:Animals; D003331:Coronary Vessels / Q000187:drug effects / Q000502:physiology; D015226:Dinucleoside Phosphates / Q000737:chemistry / Q000494:pharmacology*; D006168:Guinea Pigs; D006321:Heart / Q000187:drug effects* / Q000502:physiology; D006339:Heart Rate / Q000187:drug effects / Q000502:physiology; D006868:Hydrolysis; D008297:Male; D058915:Purinergic P1 Receptor Antagonists; D058919:Purinergic P2 Receptor Antagonists; D018047:Receptors, Purinergic P1 / Q000502:physiology; D018048:Receptors, Purinergic P2 / Q000502:physiology; D013329:Structure-Activity Relationship; D014662:Vasoconstrictor Agents / Q000737:chemistry / Q000494:pharmacology*; D014666:Vasomotor System / Q000187:drug effects* / Q000502:physiology
D015226:Dinucleoside Phosphates; D058915:Purinergic P1 Receptor Antagonists; D058919:Purinergic P2 Receptor Antagonists; D018047:Receptors, Purinergic P1; D018048:Receptors, Purinergic P2; D014662:Vasoconstrictor Agents; C012275:P(1),P(5)-di(adenosine-5'-)pentaphosphate; C020733:diadenosine tetraphosphate; C011440:diadenosine triphosphate; C070070:diadenosine 5',5''''-P1,P6-hexaphosphate