Loss of Coronary Dilation to N6-2-(4-Aminophenyl) Ethyladenosine in Isolated Hearts from Chronic Caffeine- and Nifedipine-Treated Rats

Abstract

Background: The effect of chronic administration of caffeine and/or nifedipine was investigated on functional cardiovascular responses and cardiac adenosine receptor and calcium-handling protein gene expression. Methods: Male Wistar rats (6 weeks) were either administered caffeine 0.06% in their drinking water, given nifedipine 10 mg/(kg$day) intraperitoneal (IP), or provided both caffeine and nifedipine over 14 days and compared with control age-matched rats. Isolated hearts were set up in Langendorff mode. Coronary vasodilation was evaluated using the adenosine receptor agonists 5¢-(N-ethylcarboxamido) adenosine (NECA) and N6-2-(4-aminophenyl) ethyladenosine (APNEA). The bradycardic effects were assessed using N6-(l-2-phenylisopropyl) adenosine (R-PIA). In addition, mRNA cardiac expression of adenosine receptors and calcium-handling proteins were investigated using quantitative polymerase chain reaction. Results: Chronic caffeine treatment did not alter functional responses to NECA or R-PIA but enhanced vasodilation mediated by APNEA ( p < 0.05). Chronic nifedipine treatment did not affect cardiovascular responses to all three adenosine receptor agonists tested ( p > 0.05). Combined 14-day treatment with both caffeine and nifedipine inhibited vasodilator responses to APNEA without affecting the concentration–response curves of NECA or RPIA. Chronic caffeine or nifedipine increased the expression of adenosine A2A and A3 receptors without changing adenosine A1 or A2B receptor mRNA levels, whereas chronic caffeine and nifedipine increased adenosine A2B receptor mRNA levels only ( p < 0.05). Conclusion: In conclusion, vasodilator responses mediated by the adenosine A3 receptor agonist APNEA was lost with chronic caffeine/nifedipine treatment in the rat heart. This was not due to loss of adenosine A3 receptor expression but possibly due to changes in signaling pathways.