Abstract
By use of front-surface fluorometry and fura-2-loaded medial strips of the porcine coronary artery, cytosolic Ca++ concentration ([Ca++]i) and force development were monitored simultaneously to determine the mechanisms of vasorelaxation induced by the diadenosine polyphosphates (APnA) diadenosine 5′,5‴-P1,P4-tetraphosphate (AP4A) and diadenosine 5′,5‴-P1,P5-pentaphosphate (AP5A). APnA concentration-dependently inhibited the sustained elevations of [Ca++]iand force induced by U-46619, a thromboxane A2 analog, in the presence of extracellular Ca++. APnA shifted the [Ca++]i-force relation curves of contractions induced by various concentrations of high K+to the right. The AP4A-induced decreases in [Ca++]i and force were largely attenuated by tetrabutylammonium. The AP4A-induced decreases in force were attenuated by 4-aminopyridine and charybdotoxin. The AP5A-induced decreases in [Ca++]iand force were attenuated by tetrabutylammonium, 4-aminopyridine and charybdotoxin. In the absence of extracellular Ca++, APnA did not inhibit the transient elevations of [Ca++]i induced by histamine or caffeine. Both AP4A and AP5A increased intracellular cAMP content. We thus conclude that AP4A and AP5A relax the porcine coronary artery by decreasing [Ca++]i, possibly through the activation of K+ channels, but not through inhibition of intracellular Ca++ release and by decreasing the Ca++sensitivity of the contractile machinery. These effects were considered to be mediated by cAMP.
Footnotes
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Send reprint requests to: Professor Hideo Kanaide, M.D., Ph.D.. Division of Molecular Cardiology, Research Institute of Angiocardiology, Faculty of Medicine, Kyushu University, 3–1-1 Maidashi, Higashi-ku, Fukuoka 812–82, Japan.
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↵1 This study was supported in part by Grants-in-Aid for Developmental Scientific Research (no. 06557045), for General Scientific Research (nos. 07407022, 07833008) and for Creative Basic Research Studies of Intracellular Signaling Network from the Ministry of Education, Science, Sports and Culture, Japan, and also by Grants from Japan Research Foundation of Clinical Pharmacology and the Vehicle Racing Commemorative Foundation.
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↵2 Department of Anesthesiology and Critical Care Medicine, Faculty of Medicine, Kyushu University, Fukuoka 812–82, Japan.
- Abbreviations:
- [Ca++]i
- cytosolic Ca++ concentration
- APnA
- diadenosine polyphosphates
- AP4A
- 5′,5‴-P1,P4-tetraphosphate
- AP5A
- diadenosine 5′,5‴-P1,P5-pentaphosphate
- TBA
- tetrabutylammonium
- 4-AP
- 4-aminopyridine
- ChTX
- charybdotoxin
- cAMP
- cyclic AMP (adenosine 3′,5′-cyclic monophosphate)
- cGMP
- cyclic GMP (guanosine 3′,5′-cyclic monophosphate)
- PSS
- physiological salt solution
- EGTA
- ethyleneglycol-bis(β-aminoethyl ether)-N,N,N′,N′-tetraacetic acid
- Received March 7, 1997.
- Accepted July 16, 1997.
- The American Society for Pharmacology and Experimental Therapeutics
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