Functional genomics of transgenic overexpression of A1 adenosine receptors in the heart

The advent of transgenic techniques provides a unique opportunity to study adenosine receptor-mediated cardioprotection. Transgenic A(1) receptor overexpression increases myocardial protection without impairing intrinsic function, but at the expense of resting bradycardia and a blunted response to catecholamine stimulation. Thus, we investigated whether an optimal degree of A(1) receptor overexpression exists whereby hearts would be protected from ischemic injury with minimal sequelae. Hearts from two transgenic lines were evaluated thigh-level expressors, HL, and low-level expressors, LL) and compared to controls. Both transgenic lines showed enhanced myocardial protection as measured by postischemic recovery of developed tension (HL 49 +/- 3% Of baseline, LL 45 +/- 3%, and control 31 +/- 3%; P < 0.05). Resting heart rates in conscious restrained mice were lowest in HL(620 +/- 14 bpm, intermediate in LL(681 +/- 11 bpm), and highest in control (713 +/- 8 bpm), P < 0.05, while systolic blood pressure was similar in all groups. The inotropic response to isoproterenol was comparably blunted in HL and LL hearts (+dP/dt increased 33 +/- 4% and 39 +/- 3%, respectively) compared to control (58 +/- 7%), P < 0.05 beta-adrenergic receptor density was upregulated only in the HL hearts (90 +/- 12 fmol/mg) compared to LL and control (41 +/- 9 and 32 +/- 5, respectively, P < 0.05). In summary, both HL and LL hearts afforded cardioprotection from ischemia, with LL hearts exhibiting less bradycardia and less beta-adrenergic cross-regulation. While the data suggest that genetic manipulation of receptor systems may provide a powerful tool to improve myocardial tolerance to injury, they also highlight the need for careful screening for effects on the integrated physiology of the system. Drug Dev. Res. 45:402-409, 1998. (C) 1998 Wiley-Liss. Inc.