Chronotropic and vasodilatory responses to adenosine and isoproterenol in mouse heart: Effects of adenosine A(1) receptor overexpression

1. Chronotropic and vasodilatory effects of adenosine receptor activation w ith 2-chloroadenosine (2-ClAdo) and beta-adrenoceptor activation with isopr oterenol were studied in wild-type murine hearts and transgenic hearts over expressing the A(1) adenosine receptor. 2. Treatment of wild-type hearts with 2-ClAdo induced bradycardia (pEC(50) 6.4 +/- 0.2) and vasodilatation (pEC(50) 7.9 +/- 0.1; minimal resistance 2. 2 +/- 0.2 mmHg/mL per min per g). The A(1) receptor-mediated bradycardia wa s 20-fold more sensitive in transgenic hearts (pEC(50) 7.7 +/- 0.2), wherea s coronary vasoactivity of 2-ClAdo was unaltered (pEC(50) 7.6 +/- 0.1). 3. beta-Adrenoceptor stimulation with isoproterenol increased heart rate (p EC(50) 8.5 +/- 0.2; maximal rate 594 +/- 23 b.p.m.) and produced vasodilati on (pEC(50) 8.7 +/- 0.1; minimal resistance 1.7 +/- 0.2 mmHg/mL per min per g) in wild-type hearts. Treatment with 10 IU/mL adenosine deaminase increa sed the magnitude of the tachycardia (maximal rate 653 +/- 27 b.p.m.) witho ut altering potency (pEC(50) 8.5 +/- 0.1). Antagonism of A(1) receptors wit h 10 nmol/L 8-cyclopentyl-1,3-dipropylxanthine (DPCPX) produced a comparabl e increase in the magnitude of the chronotropic response (maximal rate 695 +/- 26 b.p.m.) without altering potency (pEC(50) 8.3 +/- 0.1). 4. Isoproterenol-mediated vasodilatation was unaltered by transgenic A(1) r eceptor overexpression. Overexpression of A(1) receptors significantly redu ced the maximal heart rate during beta-adrenoceptor stimulation by 35 % (to 381 +/- 28 b.p.m.) without altering potency (pEC(50) 8.4 +/- 0.2). At 10 n mol/L, DPCPX increased the magnitude of the chronotropic response to isopro terenol in transgenic hearts (maximal heart rate 484 +/- 36 b.p.m.) without altering potency (pEC(50) 8.3 +/- 0.2). 5. The data show that transgenic A(1) receptor overexpression selectively s ensitizes the cardiovascular A(1) receptor response and that A(1) receptor activation by endogenous adenosine depresses the magnitude, but not potency , of the beta-adrenoceptor-mediated chronotropic response in mouse heart, T he A(1) receptor-mediated depression of beta-adrenoceptor responsiveness is non-competitive (reduced response magnitude with no change in sensitivity) . This indicates that A(1) receptor activation non-competitively inhibits e ffector mechanisms activated by beta-adrenoceptors (e.g. adenylate cyclase) and/or A(1) receptors activate unrelated but opposing mechanisms, This inh ibitory response may have physiological importance during periods of sympat hetic stimulation of cardiac work.