Effects of the endogenous cannabinoid anandamide on voltage-dependent sodium and calcium channels in rat ventricular myocytes.
OBJECTIVE
The endocannabinoid anandamide (N-arachidonoyl ethanolamide; AEA) exerts negative inotropic and antiarrhythmic effects in ventricular myocytes.


METHODS
Whole-cell patch-clamp technique and radioligand-binding methods were used to analyse the effects of anandamide in rat ventricular myocytes.


RESULTS
In the presence of 1-10 μM AEA, suppression of both Na(+) and L-type Ca(2+) channels was observed. Inhibition of Na(+) channels was voltage and Pertussis toxin (PTX) - independent. Radioligand-binding studies indicated that specific binding of [(3) H] batrachotoxin (BTX) to ventricular muscle membranes was also inhibited significantly by 10 μM metAEA, a non-metabolized AEA analogue, with a marked decrease in Bmax values but no change in Kd . Further studies on L-type Ca(2+) channels indicated that AEA potently inhibited these channels (IC50 0.1 μM) in a voltage- and PTX-independent manner. AEA inhibited maximal amplitudes without affecting the kinetics of Ba(2+) currents. MetAEA also inhibited Na(+) and L-type Ca(2+) currents. Radioligand studies indicated that specific binding of [(3) H]isradipine, was inhibited significantly by metAEA. (10 μM), changing Bmax but not Kd .


CONCLUSIONS
Results indicate that AEA inhibited the function of voltage-dependent Na(+) and L-type Ca(2+) channels in rat ventricular myocytes, independent of CB1 and CB2 receptor activation.
Laboratory of Functional Lipidomics, Department of Pharmacology, UAE University, Al Ain, UAE.
Lina T
LT
Al Kury
Oleg I
OI
Voitychuk
Keun-Hang Susan
KH
Yang
Faisal T
FT
Thayyullathil
Petro
P
Doroshenko
Ali M
AM
Ramez
Yaroslav M
YM
Shuba
Sehamuddin
S
Galadari
Frank Christopher
FC
Howarth
Murat
M
Oz
D000818:Animals; D001095:Arachidonic Acids / Q000494:pharmacology*; D002121:Calcium Channel Blockers / Q000494:pharmacology*; D015220:Calcium Channels / Q000378:metabolism; D002186:Cannabinoids / Q000494:pharmacology*; D004305:Dose-Response Relationship, Drug; D063388:Endocannabinoids / Q000494:pharmacology*; D006352:Heart Ventricles / Q000166:cytology*; D032383:Myocytes, Cardiac / Q000187:drug effects* / Q000378:metabolism*; D053284:Polyunsaturated Alkamides / Q000494:pharmacology*; D051381:Rats; D017208:Rats, Wistar; D026941:Sodium Channel Blockers / Q000494:pharmacology*; D015222:Sodium Channels / Q000378:metabolism; D013329:Structure-Activity Relationship
D001095:Arachidonic Acids; D002121:Calcium Channel Blockers; D015220:Calcium Channels; D002186:Cannabinoids; D063388:Endocannabinoids; D053284:Polyunsaturated Alkamides; D026941:Sodium Channel Blockers; D015222:Sodium Channels; C078814:anandamide
L-type Ca2+ channel; anandamide; Na+ channel; endocannabinoid; ventricular myocyte