Preconditioning of rat hearts by adenosine A1 or A3 receptor activation
Introduction
Ischemic preconditioning refers to the paradoxical mechanism that short, pre-emptive periods of ischemia protect the heart from a subsequent period of prolonged ischemia (Murry et al., 1986). This phenomenon seems to occur in all vertebrates including humans Cleveland et al., 1997, Yellon et al., 1993. Of the humoral factors released during its induction that may trigger the event, adenosine is one of the most important. In most animal species and humans Carr et al., 1997, Lee et al., 1995, Leesar et al., 1997, adenosine's cardioprotective effects are mediated via adenosine A1 receptors located on the myocardial membrane. The recently discovered adenosine A3 receptor has also been implicated in preconditioning of chick Liang and Jacobson, 1998, Stambaugh et al., 1997, Strickler et al., 1996, rabbit Auchampach et al., 1997b, Hill et al., 1998, Rice et al., 1996, Tracey et al., 1998, Wang et al., 1997, and human (Carr et al., 1997) hearts. However, adenosine-mediated cardioprotection is believed to play no role in rat hearts (Ganote and Armstrong, 2000). In contrast, we De Jonge et al., 1998, De Jonge et al., 2001 and others Ford et al., 1998, Headrick, 1996 observed beneficial effects of adenosine A1 receptor stimulation in this species. To the best of our knowledge, no study has examined before the role of the adenosine A3 receptor in preconditioning of rat hearts. However, a one study (Thourani et al., 1999) observed improved functional recovery and reduced creatine kinase release after 30 min no-flow ischemia in isolated rat hearts pretreated with a selective adenosine A3 receptor agonist for 12 min without a washout period. Apart from reduced ventricular arrhythmias, infarct size, and contractile dysfunctioning, ischemic preconditioning has also been shown to reduce apoptosis in vitro (Gottlieb et al., 1996) and in vivo (Piot et al., 1997). No data exist as to whether ischemic preconditioning effects on apoptosis are also mimicked by stimulation of adenosine A1/A3 receptors prior to ischemia. Thus, this study examined the effectiveness of both adenosine A1 and A3 receptor stimulation in reducing contractile dysfunction and apoptosis in rat hearts after low-flow ischemia and reperfusion. This study shows that the adenosine A3 receptor, in addition to the adenosine A1 receptor, is involved in preconditioning of rat hearts. Although the degree of apoptosis was low, pharmacological preconditioning reduced its occurrence.
Section snippets
Methods
All animals were treated in conformation with the guiding principles in the care and use of animals as approved by the American Physiological Society. The Animal Welfare Committee, Erasmus University Rotterdam, approved the protocol.
Contractile function and coronary flow
Since preconditioning may affect recovery of developed pressure and heart rate to a different degree (Bradamante et al., 1993), the rate-force product will be presented in this study as a reliable index of contractile functioning. After 20 min stabilization, there were no differences between groups in rate-force product (mean and S.E.M. of all groups: 4510±224 g/min) or coronary flow rate (10±1 ml/min). Infusion of IB-MECA did not significantly affect preischemic rate-force product (Fig. 2) but
Role of the adenosine receptor in preconditioning of rat hearts
This is the first study in isolated rat hearts indicating that adenosine A3 receptors are also involved in protection by ischemic preconditioning in rat hearts. Furthermore, in this study we confirm earlier observations of our group De Jonge and De Jong, 1999, De Jonge et al., 2001 that CCPA, a selective adenosine A1 receptor agonist, reduces ischemic injury in rat hearts. Infusion of the selective adenosine A3 receptor agonist IB-MECA prior to ischemia, resulted in a similar degree of
Conclusion
The present study demonstrates that adenosine A1 and A3 receptors are implicated in preconditioning of rat hearts. The degree of apoptosis was low in hearts subjected to 30 min underperfusion and reperfusion and was reduced by pharmacological preconditioning. Adenosine A3 receptor agonists may represent a new, potentially useful therapeutic class of agents for providing cardioprotection as they lack cardiovascular side effects associated with adenosine A1 receptor activation.
Acknowledgements
We gratefully acknowledge the support of the Netherlands Heart Foundation (NHS 94.043) and would like to thank Ms. E. Keijzer for analytical support. We also appreciate the stimulating discussions in the Biomed Concerted action ‘The New Ischemic Syndromes’ (Biomed II, BMH4-CT950838).
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Adenosine and its receptors in the heart: Regulation, retaliation and adaptation
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Effects of postconditioning of adenosine and acetylcholine on the ischemic isolated rat ventricular myocytes
2006, European Journal of PharmacologyOpioid-induced preconditioning is dependent on caveolin-3 expression
2010, Anesthesia and AnalgesiaCitation Excerpt :It is thought that preconditioning involves activation of G protein– coupled receptors. Specific receptors that have been identified in producing preconditioning include A1 and A3 adenosine,10–12 adrenergic,13 M2 muscarinic,14,15 B2 bradykinin,16,17 δ-opioid,18 and cannabinoid19 receptors. Opioid receptor activation produces preconditioning and cardiac protection from myocardial I/R injury in experimental animals and in patients.20,21