Nakatsuka_1995_Neurochem.Int_27_345

The effect of adenosine or its stable analogues (2-chloroadenosine, CADO: 5'-N-ethyl-carboxamidoadenosine, NECA; and N6-cyclopentyladenosine, CPA) and a non-selective A1 and A2-receptor antagonist, 8-phenyltheophylline (8-PT), or an A1-receptor antagonist, 8-cyclopentyl-1,3-dipropylxanthine (DPCPX), on the stimulation-evoked release of [3H]norepinephrine ([3H]NE) and [3H]acetylcholine ([3H]ACh) from the isolated guinea pig right atrium was investigated. Adenosine and its stable analogues (CADO, NECA and CPA) inhibited the stimulation-evoked release of [3H]NE in a concentration-dependent manner. The order of potencies was CPA > NECA > CADO > adenosine. CGS 21680 (30 nM), an A2a receptor agonist, failed to affect the release. The inhibitory effect of adenosine and CADO on [3H]NE release was competitively antagonized by 8-PT. DPCPX also prevented the effect of adenosine (Kd = 5.2 nM) and CADO (Kd = 3.3 nM). The Kd value of 8-PT was 0.40 microM for the antagonism of CADO and 0.51 microM for the antagonism of adenosine. When the negative feedback modulation of NE release was inhibited by idazoxan, the inhibitory effect of adenosine and CADO on [3H]NE release was more pronounced. Under this condition DPCPX (10 nM) prevented the inhibitory effect of CADO, indicating that A1-purinoceptors are involved in this action. The release of [3H]NE is tonically modulated by ACh release from the vagal nerve endings, as evidenced by the finding that 4-diphenylacetoxy-N-methyl-piperidine methiodide (4-DAMP), a M3-subtype selective muscarinic receptor antagonist, and atropine significantly enhanced the release of NE. Adenosine, its stable analogues (CADO and NECA), and 8-PT inhibition was eliminated by atropine, adenosine and CADO did not have any effect on [3H]ACh release. Quinpirole, a selective D2-receptor agonist, and neuropeptide Y (NPY) failed to affect the release of ACh. However, atropine and 4-DAMP, a selective M3-receptor antagonist, significantly enhanced the stimulation-evoked release of [3H]ACh. These findings indicate that there are no presynaptic heteroceptors (adenosine, D2, and NPY) on the vagal nerve endings of the guinea pig right atrium. It is concluded that the sympathetic nerve endings of the guinea pig right atrium are equipped with A1-, subclass of purinoceptors and alpha 2B-, and muscarinic (M3)-receptors. Cholinergic vagal nerve endings in the heart are only equipped with muscarinic autoreceptors. Therefore, adenosine liberated during hypoxia inhibits NE release from the cardiac sympathetic nerve and thereby protects against tachyarrhythmia caused by myocardial hypoxia. In contrast, adenosine does not inhibit the vagal innervation of the right atrium.