title: Mechanism of osthole inhibition of vascular Ca(v)1.2 current.
abstract: Osthole is a coumarin extracted from Cnidium monnieri (L.) Cusson. The medicinal plant is widely used in Vietnamese as well as Chinese traditional medicine as a vasodilating and antihypertensive agent. Here we have tested the proposition that the block of Ca(v)1.2 channels is mainly responsible for its vascular activity. An in-depth analysis of the effect of osthole on Ca(v)1.2 current (I(Ca1.2)) was performed in rat tail artery myocytes using the whole-cell patch-clamp method. Osthole decreased I(Ca1.2) in a concentration- and voltage-dependent manner. At holding potentials of -50 and -80mV, the pIC(50) values were 4.78±0.07 and 4.36±0.08, respectively; the latter corresponded to the drug apparent dissociation constant for resting channels, K(R), of 47.8μM. Osthole speeded up the inactivation kinetics of I(Ca1.2) and shifted the voltage dependence of the inactivation curve to more negative potentials in a concentration-dependent manner, with an apparent dissociation constant for inactivated channels (K(I)) of 6.88μM. Block of I(Ca1.2) was frequency-dependent and the rate of recovery from inactivation was slowed down. In conclusion, osthole is a vascular Ca(v)1.2 channel antagonist stabilizing the channel in its inactivated state. This mechanism may account for the systolic blood pressure reduction induced by the drug in animal models of hypertension and points to osthole as a lead for the development of novel antihypertensive agents.
authors.affiliation: Dipartimento di Neuroscienze, Università degli Studi di Siena, via A. Moro 2, 53100 Siena, Italy. fabio.fusi@unisi.it
authors.forename: Fabio
authors.initials: F
authors.lastname: Fusi
authors.forename: Giampietro
authors.initials: G
authors.lastname: Sgaragli
authors.forename: Le Minh
authors.initials: le M
authors.lastname: Ha
authors.forename: Nguyen Manh
authors.initials: NM
authors.lastname: Cuong
authors.forename: Simona
authors.initials: S
authors.lastname: Saponara
mesh_terms: D000818:Animals; D001158:Arteries / Q000187:drug effects / Q000378:metabolism; D001794:Blood Pressure / Q000187:drug effects; D002118:Calcium / Q000378:metabolism; D002121:Calcium Channel Blockers / Q000494:pharmacology*; D020746:Calcium Channels, L-Type / Q000378:metabolism*; D031048:Cnidium / Q000737:chemistry; D003374:Coumarins / Q000494:pharmacology*; D008297:Male; D008564:Membrane Potentials / Q000187:drug effects*; D009131:Muscle, Smooth, Vascular / Q000187:drug effects* / Q000378:metabolism; D032389:Myocytes, Smooth Muscle / Q000187:drug effects* / Q000378:metabolism; D010936:Plant Extracts / Q000494:pharmacology; D010946:Plants, Medicinal / Q000737:chemistry; D051381:Rats; D017208:Rats, Wistar; D014665:Vasodilator Agents / Q000494:pharmacology
chemical_list: D002121:Calcium Channel Blockers; D020746:Calcium Channels, L-Type; D003374:Coumarins; C419385:L-type calcium channel alpha(1C); D010936:Plant Extracts; D014665:Vasodilator Agents; D002118:Calcium; C046627:osthol