Muscarinic type 1 receptors mediate part of nitric oxide's vagal facilitatory effect in the isolated innervated rat right atrium.
We investigated whether vagal cardiac cholinergic facilitation by nitric oxide (NO) is mediated by cardiac muscarinic receptor subtypes in the vagally innervated rat right atrium in vitro. Experiments were carried out in the presence of atenolol (4 microM). The right vagus was stimulated at 4, 8, 16, 32 Hz; pulse duration 1 ms at 20 V for 20s; vagal postganglionic activation was achieved using nicotine (0.1, 0.3, 0.5, 1mM) and the effect on cardiac interval (ms) assessed. Pirenzepine (1 microM), a M1 antagonist, attenuated vagally induced increase in cardiac interval. L-Arginine (0.34 mM) superfused with pirenzepine failed to reverse this attenuation, however, L-arginine applied alone reversed the reduction vagal cardiac slowing. Similarly, sodium nitroprusside (10 microM) applied alone, and not together with pirenzepine, was able to reverse the attenuation of vagal effects caused by pirenzepine. Synthetic MT7 (1 nM) toxin, a selective M1 antagonist confirmed these results. M3 antagonism using para-fluorohexahydrosiladifenidol (p-F-HHSiD) (300 nM) and M4 antagonism with PD 102807 (200 nM) did not affect the vagally induced increase in cardiac interval. Nicotine induced increase in cardiac interval was not altered by pirenzepine. These results show that antagonism of M1 receptors on cardiac vagal preganglionic fibres reduces vagal efficacy which can be recovered by either a nitric oxide synthase substrate or a NO donor.
Hogan
K
K
School of Pharmacy & Pharmaceutical Sciences, Trinity College Dublin, Dublin 2, Ireland.
Markos
F
F
D000704:Analysis of Variance; D000818:Animals; D006325:Heart Atria / Q000187:drug effects / Q000294:innervation*; D066298:In Vitro Techniques; D018727:Muscarinic Antagonists / Q000494:pharmacology; D009538:Nicotine / Q000494:pharmacology; D009569:Nitric Oxide / Q000502:physiology*; D020030:Nitric Oxide Donors / Q000494:pharmacology; D009599:Nitroprusside / Q000494:pharmacology; D010890:Pirenzepine / Q000494:pharmacology; D051381:Rats; D017208:Rats, Wistar; D043643:Receptor, Muscarinic M1 / Q000502:physiology*
D018727:Muscarinic Antagonists; D020030:Nitric Oxide Donors; D043643:Receptor, Muscarinic M1; D009599:Nitroprusside; D009569:Nitric Oxide; D010890:Pirenzepine; D009538:Nicotine