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Cardiovascular activity of rasagiline, a selective and potent inhibitor of mitochondrial monoamine oxidase B: comparison with selegiline
Author(s) -
Abassi Zaid A,
Binah Ofer,
Youdim Moussa B H
Publication year - 2004
Publication title -
british journal of pharmacology
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 2.432
H-Index - 211
eISSN - 1476-5381
pISSN - 0007-1188
DOI - 10.1038/sj.bjp.0705962
Subject(s) - selegiline , rasagiline , monoamine oxidase , monoamine oxidase b , pharmacology , monoamine oxidase inhibitor , clorgyline , medicine , tranylcypromine , chemistry , monoamine oxidase a , parkinson's disease , biochemistry , enzyme , disease
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‐1 S (−)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.British Journal of Pharmacology (2004) 143 , 371–378. doi: 10.1038/sj.bjp.0705962