title: Cardiovascular activity of rasagiline, a selective and potent inhibitor of mitochondrial monoamine oxidase B: comparison with selegiline.
abstract: Selegiline is used for treating Parkinson's disease. Despite its efficacy, the clinical use of selegiline in combination with l-dihydroxphenylalanine in Parkinsonian patients is hampered by cardiovascular complications, such as hypotension. This study was designed to compare in rats the cardiovascular effects of selegiline and rasagiline, their metabolites l-methamphetamine and aminoindan (TVP-136), respectively, and the second rasagiline metabolite non-monoamine oxidase (MAO) inhibitor TVP-1022 (N-propargyl-1S(-)aminoindan). Intravenous (i.v.) administration of selegiline and rasagiline (1 mg kg(-1)) to anaesthetized rats (thiobutabarbital, 100 mg kg(-1), i.p.) did not affect mean arterial pressure (MAP), carotid blood flow (CBF) or carotid vascular resistance (CVR). Selegiline (10 mg kg(-1), i.v.) decreased MAP, CBF and increased CVR. In contrast, rasagiline (10 mg kg(-1), i.v.) caused a small transient decrease in MAP, while CBF and CVR were unchanged. l-methamphetamine (1 mg kg(-1), i.v.) administration provoked a dramatic and long-lasting depressor response, decreased CBF and increased CVR. In contrast, injection of aminoindan or TVP-1022 at a similar dose produced gradual nonsignificant decreases in MAP and CBF. Chronic oral treatment (21 days) of awake rats with selegiline at 10 mg kg(-1) decreased systolic blood pressure (SBP), diastolic blood pressure (DBP), and MAP, whereas heart rate was unaffected. Since the effective MAO-B inhibitory and clinical dose of rasagiline is about one-tenth that of selegiline, administration of 1 mg kg(-1) day(-1) rasagiline resulted in moderate decreases in SBP, DBP, and MAP, which were significantly lower than those caused by the 10 mg kg(-1) day(-1) dose of selegiline. These findings indicate that rasagiline, when given at doses equivalent to selegiline, is less likely to be hypotensive.
authors.affiliation: Department of Physiology and Biophysics, Technion-Rappaport Faculty of Medicine and Rappaport Family Institute for Research in the Medical Sciences, Technion, Haifa, Israel.
authors.forename: Zaid A
authors.initials: ZA
authors.lastname: Abassi
authors.forename: Ofer
authors.initials: O
authors.lastname: Binah
authors.forename: Moussa B H
authors.initials: MB
authors.lastname: Youdim
mesh_terms: D000284:Administration, Oral; D000818:Animals; D001783:Blood Flow Velocity / Q000187:drug effects; D001794:Blood Pressure / Q000187:drug effects; D002320:Cardiovascular Physiological Phenomena / Q000187:drug effects*; D002339:Carotid Arteries / Q000187:drug effects / Q000502:physiology; D007189:Indans / Q000494:pharmacology*; D007275:Injections, Intravenous; D008694:Methamphetamine / Q000494:pharmacology; D008928:Mitochondria / Q000187:drug effects / Q000201:enzymology; D008995:Monoamine Oxidase / Q000378:metabolism*; D008996:Monoamine Oxidase Inhibitors / Q000494:pharmacology*; D051381:Rats; D017207:Rats, Sprague-Dawley; D012642:Selegiline / Q000494:pharmacology; D013997:Time Factors; D014655:Vascular Resistance / Q000187:drug effects
chemical_list: D007189:Indans; D008996:Monoamine Oxidase Inhibitors; C031967:rasagiline; D012642:Selegiline; D008694:Methamphetamine; D008995:Monoamine Oxidase