Chronotropic and vasodilatory responses to adenosine and B-adrenoceptor activation in mouse hear: effects of adenosine A1 receptor overexpression
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1. Chronotropic and vasodilatory effects of adenosine receptor activation with 2-chloroadenosine (2-ClAdo) and ߭adrenoceptor activation with isoproterenol were studied in wild-type murine hearts and transgenic hearts overexpressing the A1 adenosine receptor. 2. Treatment of wild-type hearts with 2-ClAdo induced bradycardia (pEC50 6.4ᰮ2) and vasodilatation (pEC50 7.9ᰮ1; minimal resistance 2.2ᰮ2 mmHg/mL per min per g). The A1 receptor-mediated bradycardia was 20-fold more sensitive in transgenic hearts (pEC50 7.7ᰮ2), whereas coronary vasoactivity of 2-ClAdo was unaltered (pEC50 7.6ᰮ1). 3. ߭Adrenoceptor stimulation with isoproterenol increased heart rate (pEC50 8.5ᰮ2; maximal rate 594Ჳ b.p.m.) and produced vasodilation (pEC50 8.7ᰮ1; minimal resistance 1.7ᰮ2 mmHg/mL per min per g) in wild-type hearts. Treatment with 10 IU/mL adenosine deaminase increased the magnitude of the tachycardia (maximal rate 653Ჷ b.p.m.) without altering potency (pEC50 8.5ᰮ1). Antagonism of A1 receptors with 10 nmol/L 8-cyclopentyl-1,3-dipropylxanthine (DPCPX) produced a comparable increase in the magnitude of the chronotropic response (maximal rate 695Ჶ b.p.m.) without altering potency (pEC50 8.3ᰮ1). 4. Isoproterenol-mediated vasodilatation was unaltered by transgenic A1 receptor overexpression. Overexpression of A1 receptors significantly reduced the maximal heart rate during ߭adrenoceptor stimulation by 35% (to 381Ჸ b.p.m.) without altering potency (pEC50 8.4ᰮ2). At 10 nmol/L, DPCPX increased the magnitude of the chronotropic response to isoproterenol in transgenic hearts (maximal heart rate 484ᳶ b.p.m.) without altering potency (pEC50 8.3ᰮ2). 5. The data show that transgenic A1 receptor overexpression selectively sensitizes the cardiovascular A1 receptor response and that A1 receptor activation by endogenous adenosine depresses the magnitude, but not potency, of the ߭adrenoceptor-mediated chronotropic response in mouse heart. The A1 receptor-mediated depression of ߭adrenoceptor responsiveness is non-competitive (reduced response magnitude with no change in sensitivity). This indicates that A1 receptor activation non-competitively inhibits effector mechanisms activated by ߭adrenoceptors (e.g. adenylate cyclase) and/or A1 receptors activate unrelated but opposing mechanisms. This inhibitory response may have physiological importance during periods of sympathetic stimulation of cardiac work.
Clinical and Experimental Pharmacology & Physiology
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