Endothelium-independent vasorelaxant effect of a Berberis orthobotrys root extract via inhibition of phosphodiesterases in the porcine coronary artery.
BACKGROUND
Berberis orthobotrys Bien ex Aitch. (Berberidaceae) is a plant indigenous of Pakistan that is locally used for the treatment of hypertension.


OBJECTIVE
This study evaluated the vasoactive properties of a Berberis orthobotrys root extract and its fractions, and investigated the role of the endothelium and the underlying mechanism.


METHODS
An aqueous methanolic extract of Berberis orthobotrys roots was prepared and submitted to a multi-step liquid-liquid fractionation with solvents of increasing polarity. Vascular reactivity of the different fractions was assessed using porcine coronary artery rings either with or without endothelium, and in the presence or absence of specific pharmacological tools. The ability of Berberis orthobotrys extracts to affect phosphodiesterase (PDE) activity was evaluated using a radioenzymatic method and purified phosphodiesterases.


RESULTS
The aqueous methanol extract induced similar relaxations in coronary artery rings with and without endothelium, and, amongst the three derived preparations, the butanol fraction (BFBO) was slightly but significantly more effective than the ethyl acetate fraction and the aqueous residue in rings without endothelium. Analysis of the butanol fraction (BFBO) by LC-ELSD-MS indicated the presence of four major isoquinoline alkaloids including berberine. BFBO significantly potentiated the relaxations induced by cyclic GMP- and cyclic AMP-dependent relaxing agonists, and inhibited contractions to KCl, CaCl2, and U46619 in endothelium denuded rings. In contrast, BFBO did not affect relaxations to endothelium-dependent vasodilators. BFBO concentration-dependently inhibited the cyclic GMP-hydrolyzing activity of basal PDE1, calmodulin-activated PDE1 and PDE5, and of cyclic AMP-hydrolyzing activity of PDE3 and PDE4 with IC50 values ranging from 40 to 130µg/ml.


CONCLUSIONS
The butanol fraction of the aqueous methanol extract of Berberis orthobotrys roots induced pronounced endothelium-independent relaxations and inhibited contractile responses by acting directly at the vascular smooth muscle in the coronary artery. Moreover, BFBO potentiated relaxations induced by both cyclic GMP- and cyclic AMP-dependent vasodilators most likely due to its ability to inhibit several vascular PDEs, and in particular PDE4 and PDE5.
UMR CNRS 7213, Laboratory of Biophotonics and Pharmacology, Faculty of Pharmacy, University of Strasbourg, Illkirch, France; Faculty of Pharmacy, University of Sargodha, Pakistan.
Alamgeer
UMR CNRS 7213, Laboratory of Biophotonics and Pharmacology, Faculty of Pharmacy, University of Strasbourg, Illkirch, France.
P
P
Chabert
Faculty of Pharmacy and Alternative Medicine, Islamia University of Bahawalpur, Pakistan.
M S
MS
Akhtar
Faculty of Pharmacy and Alternative Medicine, Islamia University of Bahawalpur, Pakistan.
Q
Q
Jabeen
IBMP, UPR 2357, University of Strasbourg, France.
J
J
Delecolle
IBMP, UPR 2357, University of Strasbourg, France.
D
D
Heintz
Department of Pharmaceutical Sciences, University of Basel, Switzerland.
E
E
Garo
Department of Pharmaceutical Sciences, University of Basel, Switzerland.
M
M
Hamburger
UMR CNRS 7213, Laboratory of Biophotonics and Pharmacology, Faculty of Pharmacy, University of Strasbourg, Illkirch, France.
C
C
Auger
UMR CNRS 7213, Laboratory of Biophotonics and Pharmacology, Faculty of Pharmacy, University of Strasbourg, Illkirch, France.
C
C
Lugnier
College of Pharmacy, Mokpo National University, Muan-gun, Jeollanamdo 534-729, Republic of Korea.
H-J
HJ
Kim
College of Pharmacy, Mokpo National University, Muan-gun, Jeollanamdo 534-729, Republic of Korea.
M-H
MH
Oak
UMR CNRS 7213, Laboratory of Biophotonics and Pharmacology, Faculty of Pharmacy, University of Strasbourg, Illkirch, France. Electronic address: valerie.schini-kerth@unistra.fr.
V B
VB
Schini-Kerth
D000085:Acetates; D000818:Animals; D028142:Berberis / Q000737:chemistry*; D000440:Butanols; D003331:Coronary Vessels / Q000187:drug effects*; D004730:Endothelium, Vascular / Q000187:drug effects*; D066298:In Vitro Techniques; D009126:Muscle Relaxation / Q000187:drug effects*; D009131:Muscle, Smooth, Vascular / Q000187:drug effects; D010726:Phosphodiesterase Inhibitors / Q000494:pharmacology*; D010936:Plant Extracts / Q000494:pharmacology*; D018517:Plant Roots / Q000737:chemistry*; D012997:Solvents; D013552:Swine; D014867:Water
D000085:Acetates; D000440:Butanols; D010726:Phosphodiesterase Inhibitors; D010936:Plant Extracts; D012997:Solvents; D014867:Water; C007650:ethyl acetate
Berberis orthobotrys; Endothelium; Phosphodiesterases; Vasorelaxation