[I(KACh) inhibitor 2-[(4-methylphenyl)sulfonylcarbamido]-1-(4-nitrobenzyl)pyridinium bromide (2-AP27) is a muscarinic M(2) receptor antagonist].
Aminopyridines are known to inhibit acetylcholine-activated K(+) current (I(KACh)) in cardiac myocytes. The aim of this study was to examine the effect of 2-aminopyridine sulfonylcarbamide derivative 2-AP27 on isoprenaline-stimulated L-type Ca(2+) current (I(CaL)) and to identify whether 2-AP27 acts via blocking of muscarinic M(2)-receptors in frog cardiomyocytes. The whole-cell configuration of the patch-clamp technique was used to record I(CaL) in enzymatically isolated cardiac myocytes. Isoprenaline (0.1 microM), an agonist of beta(1)-beta(2)-adrenoreceptors, stimulated the I(CaL) up to 475+/-61% (n=4) (P<0.05) vs. control. Then, in the first series of experiments, carbachol (0.01 microM), an agonist of M(2 )muscarinic receptors, reduced the stimulatory effect of isoprenaline to 42+/-15% vs. isoprenaline alone. 2-AP27 (100 microM) alone completely abolished the inhibitory effect of carbachol on isoprenaline-stimulated I(CaL), which recovered to 95+/-5.8% of the effect of isoprenaline. In the second series of experiments, adenosine (1microM), an agonist of A(1)-adenosine receptors, reduced the stimulatory effect of isoprenaline on I(CaL) to 56+/-10% (n=3) (P<0.05). Then 2-AP27 (100 microM) applied in the presence of adenosine, had no effect on I(CaL), which remained at 51+/-7.9% (n=3) (P<0.05) of the effect of isoprenaline. These results suggest that 2-AP27, a new derivative of 2-AP, containing 4-toluolsulfonylcarbamide instead of amino group and quaternizated nitrogen by 4-nitrobenzylbromide in pyridine ring, is acting as an antagonist of muscarinic M(2) receptors in frog ventricular myocytes.
Skeberdis
Vytenis Arvydas
VA
Institute of Cardiology, Kaunas University of Medicine, Sukileliu 17, 50161 Kaunas.
Gendviliene
Vida
V
Zablockaite
Danguole
D
Martisiene
Irma
I
Stankevicius
Antanas
A
D000241:Adenosine / Q000494:pharmacology*; D000818:Animals; D002217:Carbachol / Q000494:pharmacology*; D006168:Guinea Pigs; D007545:Isoproterenol / Q000494:pharmacology; D018727:Muscarinic Antagonists; D032383:Myocytes, Cardiac / Q000187:drug effects*; D018408:Patch-Clamp Techniques; D011726:Pyridinium Compounds / Q000494:pharmacology*; D011898:Ranidae; D011976:Receptors, Muscarinic / Q000187:drug effects*; D013268:Stimulation, Chemical
D018727:Muscarinic Antagonists; D011726:Pyridinium Compounds; D011976:Receptors, Muscarinic; D002217:Carbachol; D000241:Adenosine; D007545:Isoproterenol