title: The hypotensive agent dodoneine inhibits L-type Ca2+ current with negative inotropic effect on rat heart.
abstract: Agelanthus dodoneifolius is one of the medicinal plants used in African pharmacopeia and traditional medicine for the treatment of cardiovascular diseases. A chemical analysis has identified one of the active principles: Dodoneine (Ddn). It is a new dihydropyranone which exerts hypotensive and vasorelaxant effects on rat. Since the mechanism of the hypotensive effect is unknown, we performed a variety of preclinical and mechanistic studies to characterize the specific cardiac effect of Ddn at tissue (ex-vivo) and cellular levels (in-vitro) in order to determine a molecular target. Ddn effects were evaluated in an isolated rat heart preparation using Langendorff retrograde perfusion and then, the effects of Ddn were characterized in freshly dissociated cardiac ventricular myocytes using the whole-cell patch-clamp configuration. Ex-vivo, Ddn produced a dose-dependent negative inotropic effect with an IC50 value of 10 µM without changed heart rate. 100 µM Ddn decreased left ventricular developed pressure of about 40%. In isolated cardiac myocytes, Ddn reduced I(Ca),L density of about 30% with an IC50 value estimated at 3 µM. Ddn did not change current-voltage relation but it shifted the inactivation curve toward negative potentials and modified the half inactivation potentials. Furthermore, Ddn induced a phasic-dependent blocking on ICa,L. This study demonstrates that the hypotensive property of dodoneine is likely associated with a negative inotropic effect and the blockade of the L-type calcium channels.
authors: Signalisation et Transports Ioniques Membranaires, Université de Poitiers, CNRS ERL 7368, 1 Rue Georges Bonnet, 86073 POITIERS Cedex 9, France.
authors: Grégoire
authors: G
authors: Carré
authors: Superacid Group in "Organic Synthesis" Team, Université de Poitiers, CNRS UMR 7285 IC2MP, 4, avenue Michel Brunet, F-86022 Poitiers Cedex, France.
authors: Hélène
authors: H
authors: Carreyre
authors: Université de Ouagadougou, Laboratoire de Physiologie Animale, UFR SVT, 03 BP 7021 Ouagadougou 01, Burkina Faso.
authors: Maurice
authors: M
authors: Ouedraogo
authors: Signalisation et Transports Ioniques Membranaires, Université de Poitiers, CNRS ERL 7368, 1 Rue Georges Bonnet, 86073 POITIERS Cedex 9, France.
authors: Frédéric
authors: F
authors: Becq
authors: Signalisation et Transports Ioniques Membranaires, Université de Poitiers, CNRS ERL 7368, 1 Rue Georges Bonnet, 86073 POITIERS Cedex 9, France.
authors: Patrick
authors: P
authors: Bois
authors: Superacid Group in "Organic Synthesis" Team, Université de Poitiers, CNRS UMR 7285 IC2MP, 4, avenue Michel Brunet, F-86022 Poitiers Cedex, France.
authors: Sébastien
authors: S
authors: Thibaudeau
authors: Signalisation et Transports Ioniques Membranaires, Université de Poitiers, CNRS ERL 7368, 1 Rue Georges Bonnet, 86073 POITIERS Cedex 9, France.
authors: Clarisse
authors: C
authors: Vandebrouck
authors: Signalisation et Transports Ioniques Membranaires, Université de Poitiers, CNRS ERL 7368, 1 Rue Georges Bonnet, 86073 POITIERS Cedex 9, France. Electronic address: jocelyn.bescond@univ-poitiers.fr.
authors: Jocelyn
authors: J
authors: Bescond
mesh_terms: D000818:Animals; D000959:Antihypertensive Agents / Q000302:isolation & purification / Q000494:pharmacology*; D020746:Calcium Channels, L-Type / Q000378:metabolism*; D006352:Heart Ventricles / Q000187:drug effects* / Q000378:metabolism; D066298:In Vitro Techniques; D028183:Loranthaceae / Q000737:chemistry*; D008297:Male; D016488:Medicine, African Traditional; D008564:Membrane Potentials / Q000187:drug effects; D009200:Myocardial Contraction / Q000187:drug effects*; D032383:Myocytes, Cardiac / Q000187:drug effects / Q000378:metabolism; D018408:Patch-Clamp Techniques; D010636:Phenols / Q000302:isolation & purification / Q000494:pharmacology*; D011753:Pyrones / Q000302:isolation & purification / Q000494:pharmacology*; D051381:Rats; D017208:Rats, Wistar; D017725:Ventricular Pressure / Q000187:drug effects
chemical_list: D000959:Antihypertensive Agents; D020746:Calcium Channels, L-Type; D010636:Phenols; D011753:Pyrones; C000593123:dodoneine
keywords: Calcium channel blocking drugs; Dodoneine; Hypertension; Isolated rat heart; L-type calcium current; Natural substance