title: Vascular Endothelium-Dependent and Independent Actions of Oleanolic Acid and Its Synthetic Oleanane Derivatives as Possible Mechanisms for Hypotensive Effects.
abstract: OBJECTIVE
  Plant-derived oleanolic acid (OA) and its related synthetic derivatives (Br-OA and Me-OA) possess antihypertensive effects in experimental animals. The present study investigated possible underlying mechanisms in rat isolated single ventricular myocytes and in vascular smooth muscles superfused at 37°C.
  
  
  METHODS
  Cell shortening was assessed at 1 Hz using a video-based edge-detection system and the L-type Ca2+ current (ICaL) was measured using the whole-cell patch-clamp technique in single ventricular myocytes. Isometric tension was measured using force transducer in isolated aortic rings and in mesenteric arteries. Vascular effects were measured in endothelium-intact and denuded vessels in the presence of various enzyme or channel inhibitors.
  
  
  RESULTS
  OA and its derivatives increased cell shortening in cardiomyocytes isolated from normotensive rats but had no effect in those isolated from hypertensive animals. These triterpenes also caused relaxation in aortic rings and in mesenteric arteries pre-contracted with either phenylephrine or KCl-enriched solution. The relaxation was only partially inhibited by endothelium denudation, and also partly inhibited by the cyclooxygenase (COX) inhibitor indomethacin, with no additional inhibitory effect of the NO synthase inhibitor, N-ω-Nitro-L-arginine. A combination of both ATP-dependent channel inhibition by glibenclaminde and voltage-dependent K+ channel inhibition by 4-aminopyridine was necessary to fully inhibit the relaxation.
  
  
  CONCLUSIONS
  These data indicate that the effects of OA and its derivatives are mediated via both endothelium-dependent and independent mechanisms suggesting the involvement of COX in the endothelium-dependent effects and of vascular muscle K+ channels in the endothelium-independent effects. Finally, our results support the view that the antihypertensive action of OA and its derivatives is due to a decrease of vascular resistance with no negative inotropic effect on the heart.
authors.affiliation: School of Laboratory Medicine & Medical Sciences, College of Health Sciences, University of KwaZulu-Natal, Durban, South Africa.
authors.forename: Hlengiwe P
authors.initials: HP
authors.lastname: Madlala
authors.affiliation: Pole of Pharmacology and Therapeutics, Institute of Experimental and Clinical Research, Université catholique de Louvain, Brussels, Belgium.
authors.forename: Thomas
authors.initials: T
authors.lastname: Metzinger
authors.affiliation: School of Chemistry & Physics, College of Agriculture, Engineering & Science, University of KwaZulu-Natal, Pietermaritzburg, South Africa.
authors.forename: Fanie R
authors.initials: FR
authors.lastname: van Heerden
authors.affiliation: School of Laboratory Medicine & Medical Sciences, College of Health Sciences, University of KwaZulu-Natal, Durban, South Africa.
authors.forename: Cephas T
authors.initials: CT
authors.lastname: Musabayane
authors.affiliation: Department of Cardiovascular Sciences, Katholieke Universiteit Leuven, Leuven, Belgium.
authors.forename: Kanigula
authors.initials: K
authors.lastname: Mubagwa
authors.affiliation: Pole of Pharmacology and Therapeutics, Institute of Experimental and Clinical Research, Université catholique de Louvain, Brussels, Belgium.
authors.forename: Chantal
authors.initials: C
authors.lastname: Dessy
mesh_terms: D000818:Animals; D000959:Antihypertensive Agents / Q000494:pharmacology*; D004730:Endothelium, Vascular / Q000187:drug effects*; D006973:Hypertension / Q000188:drug therapy; D007022:Hypotension / Q000139:chemically induced; D007213:Indomethacin / Q000494:pharmacology; D008297:Male; D032342:Muscle Cells / Q000187:drug effects; D009131:Muscle, Smooth, Vascular / Q000187:drug effects; D019335:Nitroarginine / Q000494:pharmacology; D009828:Oleanolic Acid / Q000031:analogs & derivatives* / Q000494:pharmacology*; D010656:Phenylephrine / Q000494:pharmacology; D015221:Potassium Channels / Q000187:drug effects / Q000502:physiology; D011189:Potassium Chloride / Q000494:pharmacology; D011451:Prostaglandin-Endoperoxide Synthases / Q000187:drug effects / Q000502:physiology; D051381:Rats; D020303:Rats, Inbred Dahl; D017208:Rats, Wistar
chemical_list: D000959:Antihypertensive Agents; D015221:Potassium Channels; D010656:Phenylephrine; D019335:Nitroarginine; D011189:Potassium Chloride; D009828:Oleanolic Acid; D011451:Prostaglandin-Endoperoxide Synthases; D007213:Indomethacin