Cardiovascular responses to combined treatment with selective monoamine oxidase type B inhibitors and L‐DOPA in the rat

Abstract

Background and purpose: Postural hypotension is a common side-effect of L-DOPA treatment of Parkinson's disease, and may be potentiated when L-DOPA is combined with selegiline, a selective inhibitor of monoamine oxidase B (MAO-B). Rasagiline is a new, potent and selective MAO-B inhibitor, which does not possess the sympathomimetic effects of selegiline. We have studied the effects of these selective MAO inhibitors, L-DOPA and dopamine on the cardiovascular system of the rat. Experimental approach: Blood pressure and heart rate was measured in conscious rats following acute or chronic administration of rasagiline, selegiline and L-DOPA, by comparison with the selective MAO-A inhibitor clorgyline, or the MAO-A/B inhibitor tranylcypromine. Cardiovascular responses, catecholamine release, and modification of pressor response to dopamine were studied in pithed rats. Key results: In conscious rats neither rasagiline nor selegiline caused significant potentiation of the effects of L-DOPA (50, 100, 150 mg.kg À1 ) on blood pressure or heart rate at doses which selectively inhibited MAO-B, but L-DOPA responses were potentiated by clorgyline and tranylcypromine. In rats treated twice daily for 8 days with L-DOPA and carbidopa, selegiline (5 mg.kg À1 ) but not rasagiline (0.2 mg.kg À1 ) caused a significant hypotensive response to L-DOPA and carbidopa, although both drugs caused similar inhibition of MAO-A and MAO-B. In pithed rats, selegiline but not rasagiline increased catecholamine release and heart rate, and potentiated dopamine pressor response at MAO-B selective dose. Conclusions and implications:The different responses to the two MAO-B inhibitors may be explained by the amine releasing effect of amphetamine metabolites formed from selegiline.

MAO-inhibitors in Parkinson's Disease

“…This is in agreement with earlier findings in rats and cats (Finberg et al, 1981; Chen and Swope, 2005; Finberg et al, 2006). …”

“…The main metabolite of rasagiline is aminoindan. Therefore any cardiovascular responses of rasagiline are neglectible as shown in animal studies ( Finberg et al, 2006 ) and in all clinical trials including the TEMPO- ( Parkinson Study Group, 2002 ), PRESTO- ( Parkinson Study Group, 2005 ), LARGO- ( Rascol et al, 2005 ) and ADAGIO-study ( Olanow et al, 2008 ; 2009 ).…”

N-Methyl-N-((1-methyl-5-(3-(1-(2-methylbenzyl)piperidin-4-yl)propoxy)-1H-indol-2-yl)methyl)prop-2-yn-1-amine, a New Cholinesterase and Monoamine Oxidase Dual Inhibitor

“…48 Although MAO-AIs enhance extracellular levels of dopamine produced from L-dopa, irreversible, and selective MAO-AI cannot be used in the PD therapy, because of cardiovascular side effects. 49 Another disadvantage of an irreversible MAO-AI is the hypertensive "cheese effect", 50 due to the predominance of MAO-A in the gut wall to metabolize tyramine in fermented foods such as cheese and beer. Hypertensive crises may be prevented by using reversible rather than irreversible MAO-AI, or tissue-specific inhibitors such as the brain-selective ladostigil.…”

Adjuvant Potential of Selegiline in Attenuating Organ Dysfunction in Septic Rats with Peritonitis

“…It has been shown that amphetamine-like drugs, such as SEL and its major metabolites, L-methamphetamine and L-amphetamine, cause tachycardia [35] , [36] , hypotension [37] , [38] or hypertension [39] . Allard et al report that 3 mg/kg of SEL induces only a transient decrease in blood pressure, which returns to its baseline value after 4 min [40] .…”