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Negative chronotropic and inotropic effects exerted by diadenosine hexaphosphate (AP 6 A) via A 1 ‐adenosine receptors
Author(s) -
Vahlensieck U.,
Bokník P.,
Knapp J.,
Linck B.,
Müller F.U.,
Neumann J.,
Herzig S.,
Schlüter H.,
Zidek W.,
Deng M.C.,
Scheld H.H.,
Schmitz W.
Publication year - 1996
Publication title -
british journal of pharmacology
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 2.432
H-Index - 211
eISSN - 1476-5381
pISSN - 0007-1188
DOI - 10.1111/j.1476-5381.1996.tb15748.x
Subject(s) - chronotropic , isoprenaline , medicine , contractility , endocrinology , adenosine , contraction (grammar) , chemistry , guinea pig , calcium , biology , heart rate , stimulation , blood pressure
1 Diadenosine hexaphosphate (AP 6 A) exerts vasoconstrictive effects. The purpose of this study was to investigate whether AP 6 A has any effect on cardiac function. 2 The effects of AP 6 A (0.1 −100 μ m ) on cardiac contractility and frequency were studied in guinea‐pig and human isolated cardiac preparations. Furthermore, the effects of AP 6 A on the amplitude of the L‐type calcium current, on the adenosine 3′:5′‐cyclic monophosphate (cyclic AMP) content and on the phosphorylation of regulatory phosphoproteins, i.e. phospholamban and troponin inhibitor, were investigated in guinea‐pig isolated ventricular myocytes. 3 In isolated spontaneously beating right atria of the guinea‐pig AP 6 A exerted a negative chronotropic effect and reduced the rate of contraction maximally by 35% (IC 20 = 35 μ m ). 4 In isolated electrically driven left atria of the guinea‐pig AP 6 A exerted a negative inotropic effect and reduced force of contraction maximally by 23% (IC 20 = 70 μ m ). 5 In isolated electrically driven papillary muscles of the guinea‐pig AP 6 A alone was ineffective, but attenuated isoprenaline‐stimulated force of contraction maximally by 23% (IC 20 = 60 μ m ). Furthermore, AP 6 A attenuated the relaxant effect of isoprenaline. 6 In human isolated electrically driven ventricular preparations AP 6 A alone was ineffective, but attenuated isoprenaline‐stimulated force of contraction by maximally 42% (IC 20 = 18 μ m ). Moreover, AP 6 A attenuated the relaxant effect of isoprenaline. 7 All these effects of AP 6 A were abolished by the selective A ‐ ‐adenosine receptor antagonist 1,3‐dipropyl‐cyclopentyl‐xanthine (DPCPX, 0.3 μ m ), whereas the M‐cholinoceptor antagonist atropine (10 μ m ) and the P 2 ‐purinoceptor antagonist suramin (300 μ m ) failed to abolish the effects of AP 6 A. 8 AP 6 A 100 μ m had no effect on the amplitude of the L‐type calcium current, but attenuated isoprenaline‐stimulated L‐type calcium current. The maximum of the current‐voltage relationship ( I ‐V curve) was shifted to the left by isoprenaline and additional application of AP 6 A shifted the I ‐V curve back to the right to the control value. The phosphorylation state of phospholamban and the troponin inhibitor was unchanged by AP 6 A alone, but was markedly attenuated by AP 6 A in the presence of isoprenaline. Cyclic AMP levels remained unchanged by AP 6 A, even after stimulation with isoprenaline. 9 In summary, AP 6 A exerts negative chronotropic and inotropic effects in guinea‐pig and human cardiac preparations. These effects are mediated via A 1 ‐adenosine receptors as all effects were sensitive to the selective A ‐ ‐adenosine receptor antagonist DPCPX. Furthermore, the effects of AP 6 A on cyclic AMP levels, protein phosphorylation and the L‐type calcium current are in accordance with stimulation of A 1 ‐adenosine receptors.