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Mediation by nitric oxide of the indirect effects of adenosine on calcium current in rabbit heart pacemaker cells
Author(s) -
Shimoni Y.,
Han X.,
Severson D.,
Giles W.R.
Publication year - 1996
Publication title -
british journal of pharmacology
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 2.432
H-Index - 211
eISSN - 1476-5381
pISSN - 0007-1188
DOI - 10.1111/j.1476-5381.1996.tb16059.x
Subject(s) - chronotropic , adenosine , nitric oxide , agonist , medicine , endocrinology , nitric oxide synthase , patch clamp , pacemaker potential , omega n methylarginine , adenosine a1 receptor , chemistry , pharmacology , electrophysiology , adenosine receptor , receptor , heart rate , blood pressure
1 Adenosine (ADO) is a potent negative chronotropic agent in the mammalian myocardium. We have used single myocytes from rabbit sino‐atrial node (SAN) to examine whether nitric oxide (NO) is a significant mediator of the effects of ADO on the pacemaker activity, or the underlying Ca 2+ and K + currents. 2 SAN pacemaker cells were isolated from rabbit hearts by enzymatic dispersion, and Ca 2+ and K + currents were recorded by the nystatin‐perforated patch voltage clamp method. ADO was applied in the presence of the β‐adrenoceptor agonist, isoprenaline (Iso) to mimic the adrenergic tone which the SAN is subjected to in vivo3 Control experiments confirmed that isolated SAN cells responded to ADO (10–100 μ m ) with the expected (i) small increase in background inwardly rectifying K + current, I K‐ADOi and (ii) pronounced decrease in L‐type Ca 2+ current, I Ca‐L These effects were mimicked by a selective A 1 purinoceptor agonist, N 6 ‐cyclopentyladenosine (CPA, 10 μ m ); and were inhibited following bath application of the antagonist, DPCPX (10 μ m ), which selectively blocks A 1 purinoceptors. DMPX (10 μ m ), a blocker of A 2 purinoceptor, had no effect on the actions of ADO. 4 A nitric oxide synthase inhibitor, L‐NMMA (100 μ m ), abolished the inhibitory effect of ADO on I Ca‐L but did not alter activation of I K‐ADO After L‐NMMA washoff, it was possible to obtain the normal response (inhibition) of I Ca‐L to ADO in the same cell. 5 To evaluate whether the observed effect of nitric oxide (NO) on I Ca‐L was mediated by an increase in guanylyl cyclase (GC) activity and cyclic GMP formation, the guanylyl cyclase inhibitor, LY 83583 (40 μ m ) was applied prior to ADO. Under these conditions, the inhibitory effect of ADO on I Ca‐L was abolished, but the activation of I K‐ADO was still observed. 6 In combination, these findings strongly suggest that in mammalian primary pacemaker tissue which is under adrenergic tone, the effects of ADO on I Ca‐L are mediated by NO.