Hypericin activates L-type Ca2+ channels in cardiac myocytes.
The effects and the mode of action of hypericin (1) were studied, in the dark, on the action potential (AP) and the L-type Ca2+ channel of frog atrial heart muscle, using intracellular microelectrode and patch-clamp techniques, respectively. In the presence of Ca2+ in Ringer solution, hypericin (1 to 4 microM) did not markedly modify the AP. Total replacement of Ca2+ by Sr2+ in the solution (Ringer Sr2+) revealed that hypericin (4 microM) prolonged the AP duration (APD). Hypericin dose-dependently increased the magnitude of the Sr2+current, which develops through L-type Ca2+ channels in the Ringer solution containing tetrodotoxin (0.7 microM) and tetraethylammonium (10 mM), but did not modify the kinetics of activation and inactivation. This revealed that hypericin increased L-type Ca2+ channel conductance, which accounted for the APD lengthening. The hypericin-induced APD lengthening recorded in the Ringer Sr2+ was not prevented by (i) a blockade of alpha- and beta-adrenoceptors by yohimbine (1 microM), urapidil (1 microM), and propanolol (50 microM), respectively, and (ii) PKC blockade by staurosporine (1 microM). The hypericin-induced APD lengthening recorded in the Ringer Sr2+ was prevented by blocking soluble guanylate cyclase (sGC) activity by 1H-[1,2,4]-oxadiazolo[4,3-a]quinoxalin-1-one (13 microM), which mimicked the effects of hypericin. Hypericin decreased the cellular cGMP level by 69% in atrial myocytes. The compound also decreased the cellular cGMP level by inhibiting sGC, thus cancelling the nucleotide inhibitory effect on the cardiac L-type Ca2+ channel.
Sauviat
Martin-Pierre
MP
Laboratoire d'Optique et Biosciences, U696 INSERM, UMR7645 CNRS, X/ENSTA, Ecole Polytechnique, Route de Saclay, 91128 Palaiseau Cedex, France. martin-pierre.sauviat@polytechnique.edu
Colas
Anthony
A
Chauveau
Marie-Jeanne
MJ
Drapier
Jean-Claude
JC
Négrerie
Michel
M
D000200:Action Potentials / Q000187:drug effects; D000818:Animals; D000873:Anthracenes; D020746:Calcium Channels, L-Type / Q000187:drug effects*; D006152:Cyclic GMP / Q000378:metabolism; D004305:Dose-Response Relationship, Drug; D006162:Guanylate Cyclase / Q000037:antagonists & inhibitors; D006321:Heart / Q000187:drug effects; D015394:Molecular Structure; D032383:Myocytes, Cardiac / Q000187:drug effects*; D052247:Nitric Oxide Synthase Type II / Q000378:metabolism; D010069:Oxadiazoles / Q000494:pharmacology; D010569:Perylene / Q000031:analogs & derivatives* / Q000737:chemistry / Q000494:pharmacology; D010749:Phosphoprotein Phosphatases / Q000378:metabolism; D011898:Ranidae; D018160:Receptors, Cytoplasmic and Nuclear / Q000037:antagonists & inhibitors; D000071756:Soluble Guanylyl Cyclase
C116907:1H-(1,2,4)oxadiazolo(4,3-a)-quiloxalin-1-one; D000873:Anthracenes; D020746:Calcium Channels, L-Type; D010069:Oxadiazoles; D018160:Receptors, Cytoplasmic and Nuclear; D010569:Perylene; C004965:hypericin; D052247:Nitric Oxide Synthase Type II; D010749:Phosphoprotein Phosphatases; D006162:Guanylate Cyclase; D000071756:Soluble Guanylyl Cyclase; D006152:Cyclic GMP