title: Oxidative stress impairs the haemodynamic activity of cardiovascular agents with antioxidant properties.
abstract: Reactive oxygen species (ROS) are known to be involved in the pathogenesis and progression of various cardiovascular diseases. For some therapeutics like carvedilol and captopril used in the treatment of such diseases antioxidant properties have been proposed to play a role in addition to their haemodynamic activities. It was the aim of the present study to assess whether ROS may affect the molecular integrity and the primary pharmacological actions of compounds with additional antioxidant properties. Accordingly, well-known drugs as mentioned were exposed to ROS, generated by electrolysis and analyzed by means of functional and chemical investigations. For this purpose rat thoracic aortic rings were incubated with either the beta1,2/alpha1-adrenoceptor antagonist carvedilol (100 nM), the alpha1-adrenoceptor antagonist prazosin (5 nM), the thiol-containing ACE-inhibitor captopril (3 microM) or lisinopril (300 nM), an ACE-inhibitor without a thiol moiety. Furthermore, isolated rat left atria were incubated with either carvedilol (14 nM) or with the beta1,2-adrenoceptor antagonist timolol (50 nM). After an incubation period of 15 min, electrolysis was applied to the buffer medium in order to generate ROS. After an additional 15 min, concentration-response curves were constructed for angiotensin I and phenylephrine in thoracic aortic rings incubated with the ACE-inhibitors and the alpha1-adrenoceptor antagonists, respectively. In addition, concentration-response curves were constructed for isoprenaline in presence of the beta1,2-adrenoceptor antagonists in isolated left atria. After exposure to oxidative stress the alpha1- and beta-adrenoceptor blocking activity of carvedilol was significantly impaired, when compared to control conditions. In contrast, the pharmacological effects of prazosin and timolol remained unaffected. The ACE-inhibition by captopril was completely abolished after electrolysis, while the pharmacological action of lisinopril was only slightly reduced. In addition, a complete oxidative degradation of captopril and carvedilol could be demonstrated by using UV/Vis spectroscopy and HPLC/fluorospectroscopy, respectively. From these results we conclude that the haemodynamic therapeutics with additional radical scavenging properties may undergo a chemical modification due to ROS-exposure which results in a loss of pharmacological activity.
authors.affiliation: Department of Pharmacotherapy, Academic Medical Center, University of Amsterdam, Meibergdreef 15, 1105 AZ Amsterdam, The Netherlands. csand_amc@yahoo.com
authors.forename: C
authors.initials: C
authors.lastname: Sand
authors.forename: S L
authors.initials: SL
authors.lastname: Peters
authors.forename: M
authors.initials: M
authors.lastname: Pfaffendorf
authors.forename: P A
authors.initials: PA
authors.lastname: van Zwieten
mesh_terms: D000317:Adrenergic alpha-Antagonists / Q000494:pharmacology*; D000818:Animals; D000975:Antioxidants / Q000494:pharmacology*; D001013:Aorta, Thoracic; D002317:Cardiovascular Agents / Q000494:pharmacology*; D006439:Hemodynamics / Q000187:drug effects*; D008297:Male; D009131:Muscle, Smooth, Vascular / Q000187:drug effects*; D018384:Oxidative Stress; D051381:Rats; D017208:Rats, Wistar; D017382:Reactive Oxygen Species / Q000494:pharmacology
chemical_list: D000317:Adrenergic alpha-Antagonists; D000975:Antioxidants; D002317:Cardiovascular Agents; D017382:Reactive Oxygen Species