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J Thorac Cardiovasc Surg 2000;120:829-830
© 2000 The American Association for Thoracic Surgery

Letters to the Editor

Are adenosine myocardial protective effects mediated through cAMP-independent effects or through cAMP inhibition/production?

Research Department
Kokura Memorial Hospital Kitakyushu-City, Japan

Koho-Julio Miyamoto, MD, PhD

Assistant Professor II Department of Physiology
University of Ryukyus School of Medicine Okinawa, Japan

To the Editor:

Fogelson and associates ¹ are to be congratulated for having demonstrated the receptor mediation of the myocardial protective effects of adenosine, rather than metabolic support, a conclusion with which we concur. Adenosine protection in the central nervous system (CNS) involves inhibition (via adenosine A₁ receptors) as well as stimulation (via adenosine A₂ receptors) of cyclic adenosine monophosphate (cAMP), depending basically on the amount of adenosine released by the ischemic insult. ^2-4

Because the authors used adenosine and 8-p-sulphophenyl-theophylline for their studies, both being nonspecific, identification of the type of A receptor is not possible. Although A₂ receptors have been described, reportedly A₁ receptors seem to be the prevailing type in the myocardium. ⁵

Do the authors assume that the effects observed were mediated by cAMP-independent effects of cardiac A₁ receptors ⁵ or by cAMP stimulation via any of the A₂ subtype receptors? ^5,6 Do they have a working hypothesis as to which type of receptor is the most likely involved, a subject that was not discussed in their article?

Given the large amount of adenosine used, 100 µmol/L, which is probably at least 12.5 to 125 times more concentrated than the amounts of adenosine present in the nonischemic myocardial interstitial fluid, ⁷ we assume that the effects observed were the sum of those mediated by cAMP stimulation and the cAMP-independent effects, the relative roles of which are unknown. However, if the proposed receptor-mediated effect would also involve adenylyl cyclase stimulation, then two other corollaries may be implicated:

1. Theoretically, the effect could be mimicked by the stimulation of endogenous cAMP production or the administration of exogenous cAMP in the form of dibutyryl-cAMP. Endogenous adenylyl cyclase stimulation could be obtained also with the ß-adrenergic receptor agonist, isoproterenol, besides adenosine, which is already approved as a pharmacologic agent by the Food and Drug Administration and is readily available in any hospital pharmacy.
   
2. The study has important implications if adenosine is to be added to the cardioplegic solution for patients with heavy coffee drinking habits or for patients with asthma who are receiving long-term theophylline treatment. Adenosine dosages may have to be adjusted to compensate for the up-regulation of adenosine receptors, a phenomenon that has been documented in the CNS, ⁸ if equivalent protective effects are to be obtained.
   

12/8/109551

doi:10.1067/mtc.2000.109551

References

1. Fogelson BG, Nawas SI, Law WR. Mechanisms of myocardial protection by adenosine-supplemented cardioplegic solution: myofilament and metabolic responses. J Thorac Cardiovasc Surg 2000;119:601-9.[Abstract/Free Full Text]
   
2. Fredholm BB. Adenosine receptors in the central nervous system. News in Physiological Sciences (NIPS) 1995;10:122-8.
   
3. Rudolphi KA, Schubert P, Parkinson FE, Fredholm BB. Adenosine and brain ischemia: cerebrovascular and brain metabolism reviews. Vol 4. New York: Raven Press; 1992. p. 346-69.
   
4. Schubert P, Kreutzberg GW. Cerebral protection by adenosine. Acta Neurochir (Suppl) 1993;57:80-8.
   
5. Kollias-Baker C, Shryock JC, Belardinelli L. Myocardial adenosine receptors. In: Belardinelli L, Pelleg A, editors. Adenosine and adenine nucleotides: from molecular biology to integrative physiology. Boston: Kluwer Academic Publishers; 1995. p. 221-8.
   
6. Mustafa SJ, Marala R, Abebe W, Jeansonne N, Olanrewaju H, Hussain T. Coronary adenosine receptors: subtypes, localization, and function. In: Belardinelli L, Pelleg A, editors. Adenosine and adenine nucleotides: from molecular biology to integrative physiology. Boston: Kluwer Academic Publishers; 1995. p. 229-39.
   
7. Lasley RD, Bünger R, Mentzer RM, Jr. Receptor-mediated and metabolic effects of adenosine in ischemic and postischemic myocardium. In: Belardinelli L, Pelleg A, editors. Adenosine and adenine nucleotides: from molecular biology to integrative physiology. Boston: Kluwer Academic Publishers; 1995. p. 351-60.
   
8. Hoppe E, Lohse MJ. Desensitization of A₁ adenosine receptors. In: Belardinelli L, Pelleg A, editors. Adenosine and adenine nucleotides: from molecular biology to integrative physiology. Boston: Kluwer Academic Publishers; 1995. p. 133-8.
   

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