The mechanism of positive inotropy induced by adenosine triphosphate in rat heart.
When applied extracellularly in the micromolar range, ATP and related compounds induced a positive inotropy in the rat papillary muscle. This was also true in the rat auricle after pertussis toxin treatment. Then, in both tissues, ATP further increased the contraction after a maximal beta-adrenergic stimulation. The increase in contractile force could be related to the increase in the calcium current. The L-type calcium current was measured by whole-cell patch-clamp recording in single cells isolated from the rat ventricle after the sodium and potassium currents were inhibited by tetrodotoxin and cesium, respectively. When added alone, 10 microM ATP increased the calcium current by 60%. Adenosine 5'-O-(3-thiotriphosphate) was also able to increase calcium current. Adenosine was much less effective, and GTP, UTP, CTP, and ITP were without effect. A similar increase in calcium current was observed when ATP was added in addition to a maximal stimulation by a beta-adrenergic agonist or after internal perfusion with cyclic AMP. However, this increase was preceded by a transient decrease whose origin could not be attributed to a P1-purinergic agonistic effect of ATP. The transient decrease was not elicited by adenosine or in a magnesium-free HEPES solution and was not suppressed after pertussis toxin treatment. This effect appeared related to the variations in the holding current also observed upon ATP application. Together with vasodilation, ATP and adenine compounds induced positive inotropy. The latter effect could be attributed in part to the increase in calcium current and was independent of cyclic AMP. Both effects are complementary with the beta-adrenergic stimulation and can help healthy cells to compensate the failing zone from which ATP could be released.
Laboratoire de Physiologie Cellulaire Cardiaque, INSERM U-241, Université Paris-Sud, Orsay, France.
F
F
Scamps
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Legssyer
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Mayoux
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Vassort
D015056:1-Methyl-3-isobutylxanthine / Q000494:pharmacology; D000225:Adenine / Q000494:pharmacology; D000255:Adenosine Triphosphate / Q000494:pharmacology*; D000818:Animals; D015220:Calcium Channels / Q000187:drug effects / Q000502:physiology; D000242:Cyclic AMP / Q000494:pharmacology; D004553:Electric Conductivity; D005260:Female; D007545:Isoproterenol / Q000494:pharmacology; D008297:Male; D008564:Membrane Potentials / Q000502:physiology; D009200:Myocardial Contraction / Q000187:drug effects*; D010210:Papillary Muscles / Q000502:physiology; D037342:Pertussis Toxin; D051381:Rats; D011919:Rats, Inbred Strains; D013268:Stimulation, Chemical; D010566:Virulence Factors, Bordetella / Q000494:pharmacology
D015220:Calcium Channels; D010566:Virulence Factors, Bordetella; D000255:Adenosine Triphosphate; D000242:Cyclic AMP; D037342:Pertussis Toxin; D000225:Adenine; D007545:Isoproterenol; D015056:1-Methyl-3-isobutylxanthine