The methylester of gamma-butyrobetaine, but not gamma-butyrobetaine itself, induces muscarinic receptor-dependent vasodilatation.
Gamma-butyrobetaine (GBB) is known mostly as a bio-precursor of carnitine, a key molecule in the regulation of myocardial energy metabolism. The metabolites of carnitine and GBB were investigated for acetylcholine-like activity decades ago. The present study shows that the methylester of GBB (GBB-ME) exerts its biological activity by binding to muscarinic acetylcholine receptors. GBB-ME dose-dependently decreased the blood pressure in anaesthetised rats and also produced endothelium-dependent vasodilation in the isolated guinea-pig heart. The biological effects of GBB-ME were inhibited partially by the NOS inhibitor N(omega)-nitro-L-arginine methylester (L-NAME) and abolished by the acetylcholine receptor antagonist atropine, thus supporting the hypothesis that GBB-ME acts as muscarinic agonist. Moreover, we have shown here for the first time that GBB-ME binds directly to transfected human muscarinic (m) acetylcholine receptors, the potency order being m2>m5> or =m4> or =m1>m3. GBB itself showed neither biological activity nor significant affinity for the m1-5 receptors. We conclude that GBB-ME, but not the parent GBB, possesses acetylcholine-like activity in vivo and in vitro.
Dambrova
Maija
M
Department of Medicinal Chemistry, Latvian Institute of Organic Synthesis, Aizkraukles 21, LV1006 Riga, Latvia. md@biomed.lu.lv
Chlopicki
Stefan
S
Liepinsh
Edgars
E
Kirjanova
Olga
O
Gorshkova
Olga
O
Kozlovski
Valery I
VI
Uhlen
Staffan
S
Liepina
Inta
I
Petrovska
Ramona
R
Kalvinsh
Ivars
I
D000109:Acetylcholine / Q000378:metabolism; D000818:Animals; D001622:Betaine / Q000031:analogs & derivatives* / Q000378:metabolism / Q000494:pharmacology*; D001794:Blood Pressure / Q000187:drug effects; D002331:Carnitine / Q000378:metabolism / Q000494:pharmacology*; D004730:Endothelium, Vascular / Q000187:drug effects; D004952:Esters; D005260:Female; D006168:Guinea Pigs; D008297:Male; D008958:Models, Molecular; D009131:Muscle, Smooth, Vascular / Q000187:drug effects*; D051381:Rats; D017208:Rats, Wistar; D011976:Receptors, Muscarinic / Q000187:drug effects* / Q000378:metabolism; D013329:Structure-Activity Relationship; D014664:Vasodilation / Q000187:drug effects*
D004952:Esters; D011976:Receptors, Muscarinic; D001622:Betaine; C002889:gamma-butyrobetaine; D000109:Acetylcholine; D002331:Carnitine