Increased sensitivity of neonate atrial myocytes to adenosine A1 receptor stimulation in regulation of the L-type Ca2+ current

Abstract

Adenosine has cardioprotective effects against ischemia, and newborn hearts show high resistance to ischemia. The effects of purinoceptor stimulation by adenosine and ATP on the L-type Ca²⁺ current (I_Ca) were examined in atrial cells from neonate and adult rabbits. I_Ca was measured by the membrane-perforated patch method. Adenosine inhibited the isoproterenol-stimulated I_Ca more potently in neonate cells than in adult cells. The high sensitivity of neonate myocytes to adenosine was accompanied not only by an increased maximum response but also by a lower IC₅₀ concentration. ATP also inhibited isoproterenol-stimulated I_Ca. The effect of ATP on neonate cells was stronger than that on adult cells at high concentrations (≥100 μM). The effect of adenosine was antagonized by an A₁ adenosine receptor antagonist, 1,3-dipropyl-8-cyclopentylxanthine (DPCPX). DPCPX or an ecto-5′-nucleosidase inhibitor (α,β-methylene-ADP) blocked most (∼60%) of the effect of ATP (30 μM), and co-addition of DPCPX and suramin (P₂ receptor blocker) abolished the effect of ATP. Suramin alone did not reduce the effect of ATP significantly in neonate cells. Both the effects of adenosine and ATP were eliminated by pre-treatment with pertussis toxin or by superfusion with forskolin plus 3-isobutyl-1-methylxanthine (IBMX). Inhibitors of the nitric oxide-cyclic GMP pathway did not affect the adenosine inhibition of I_Ca. In summary, neonatal myocardial cells are highly sensitive to adenosine A₁ receptor stimulation. ATP stimulates both the adenosine A₁ and P₂ receptors. Adenosine A₁ receptor stimulation, as a result of hydrolysis of ATP, predominantly mediates the effect of ATP, and the role of P₂ receptors in the ATP inhibition of I_Ca is relatively small in neonate cells. The high sensitivity to adenosine may contribute to the ischemic tolerance of newborn hearts.