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.

Figure 1

Effects of a bolus i.v. administration (1 mg kg⁻¹) of selegiline or rasagiline on (a) mean arterial pressure, MAP; (b) carotid blood flow, CBF; and (c) CVR, carotid vascular resistance. N=6 rats in each group.

Figure 2

Effects of a bolus i.v. administration (10 mg kg⁻¹) of selegiline or rasagiline on (a) mean arterial pressure, MAP; (b) carotid blood flow, CBF, and (c) carotid vascular resistance, CVR. ^*P<0.05 compared to basal values in both groups. N=6 rats in each group.

Figure 3

Effects of a bolus i.v. administration of equal doses of selegiline and rasagiline on MAP. Data are expressed as % change from absolute baseline values presented in Figures 1 and 2. The curves representing MAP did not differ between the rats treated with selegiline and rasagiline at 1 mg kg⁻¹ (by two-way ANOVA), but were statistically different at 10 mg kg⁻¹.

Figure 4

Effects of a bolus i.v. administration of equal doses of selegiline and rasagiline on CBF. Data are expressed as % change from absolute baseline values presented in Figures 1 and 2. The curves differed significantly between rats treated with selegiline and rasagiline at both 1 and 10 mg kg⁻¹ (two-way ANOVA).

Figure 5

Effects of a bolus i.v. administration of equal doses of selegiline and rasagiline on CVR. Data are expressed as % change from absolute baseline values presented in Figures 1 and 2. The curves differed significantly between rats treated with selegiline and rasagiline at both 1 and 10 mg kg⁻¹ (two-way ANOVA).

Figure 6

Effects of bolus i.v. administration (1 mg kg⁻¹) of either TVP-136 or TVP-1022 (rasagiline metabolites), or L-methamphetamine, a selegiline metabolite on (a) mean arterial pressure, MAP; (b) carotid blood flow, CBF; and (c) carotid vascular resistance, CVR. ^*P<0.05, compared to basal values. The curves representing MAP, CBF, and CVR differed significantly between the rats treated with L-methamphetamine compared with either TVP-136- or TVP-1022-treated animals (by two-way ANOVA). N=4–6 rats in each group.

Figure 7

Effects of bolus i.v. administration (1 mg kg⁻¹) of either TVP-136 or TVP-1022 (rasagiline metabolites), or L-methamphetamine, a selegiline metabolite on (a) mean arterial pressure, MAP; (b) carotid blood flow, CBF; and (c) carotid vascular resistance, CVR. Data are expressed as % change from absolute baseline values presented in Figure 6. ^*P<0.05, compared to basal values. N=4–6 rats in each group.

Figure 8

Comparison of the cardiovascular effects of oral administration (1 and 10 mg kg⁻¹ day⁻¹) of selegiline or rasagiline. Drugs were administered daily by means of gavage for 21 days. Systolic blood pressure (SBP), diastolic blood pressure (DBP), mean arterial pressure (MAP), and heart rate (HR) were measured in conscious rats by means of the tail cuff technique before (baseline value), and at 5, 10, 14, 18, and 21 days of treatment. Rats treated with a saline vehicle served as controls. ^*P<0.05 and P<0.01 compared with basal values. #, P<0.05 and ^P<0.01 vs selegiline 10 mg kg⁻¹. N=5 rats in each group. The graphs representing SBP, MAP, and DBP, but not HR differed significantly between the selegiline- and rasagiline-treated rats (by two-way ANOVA).