Role of the iNOS isoform in the cardiovascular dysfunctions of male rats with 6-OHDA-induced Parkinsonism.

Autor: de Jager L; Departamento de Ciências Fisiológicas, Universidade Estadual de Londrina - UEL, Londrina, PR, Brazil., Vidigal CB; Departamento de Ciências Fisiológicas, Universidade Estadual de Londrina - UEL, Londrina, PR, Brazil., de Campos BH; Departamento de Ciências Fisiológicas, Universidade Estadual de Londrina - UEL, Londrina, PR, Brazil., Reginato GS; Departamento de Ciências Fisiológicas, Universidade Estadual de Londrina - UEL, Londrina, PR, Brazil., Fernandes LM; Departamento de Ciências Fisiológicas, Universidade Estadual de Londrina - UEL, Londrina, PR, Brazil., Ariza D; Departamento de Ciências Fisiológicas, Universidade Estadual de Londrina - UEL, Londrina, PR, Brazil., Higashi-Mckeown CM; Departamento de Ciências Fisiológicas, Universidade Estadual de Londrina - UEL, Londrina, PR, Brazil., Bertozzi MM; Departamento de Ciências Patológicas, Universidade Estadual de Londrina - UEL, Londrina, PR, Brazil., Rasquel de Oliveira FS; Departamento de Ciências Patológicas, Universidade Estadual de Londrina - UEL, Londrina, PR, Brazil., Verri WA Jr; Departamento de Ciências Patológicas, Universidade Estadual de Londrina - UEL, Londrina, PR, Brazil., Ceravolo GS; Departamento de Ciências Fisiológicas, Universidade Estadual de Londrina - UEL, Londrina, PR, Brazil., Crestani CC; Faculdade de Ciências Farmacêuticas de Araraquara, Departamento de Princípios Ativos Naturais e Toxicologia, Universidade Estadual Paulista - UNESP, Araraquara, Brazil., Pinge-Filho P; Departamento de Ciências Patológicas, Universidade Estadual de Londrina - UEL, Londrina, PR, Brazil., Martins-Pinge MC; Departamento de Ciências Fisiológicas, Universidade Estadual de Londrina - UEL, Londrina, PR, Brazil. Electronic address: martinspinge@uel.br.
Jazyk: angličtina
Zdroj: Nitric oxide : biology and chemistry [Nitric Oxide] 2023 May 01; Vol. 134-135, pp. 49-60. Date of Electronic Publication: 2023 Apr 11.
DOI: 10.1016/j.niox.2023.04.003
Abstrakt: Introduction: Available studies have shown the involvement of nitric oxide (NO) in the processes that lead to neurodegeneration in Parkinson's disease (PD). Also, the use of inhibitors of the inducible isoform of NO-synthase (iNOS) promotes neuroprotection and attenuates dopamine (DA) loss in experimental models of Parkinsonism. In addition, NO also appears to be involved in cardiovascular changes in 6-hydroxydopamine (6-OHDA)-induced Parkinsonism. The current study aimed to evaluate the effects of iNOS inhibition on cardiovascular and autonomic function in animals that were subjected to Parkinsonism by the administration of 6-OHDA.
Materials and Methods: The animals underwent stereotaxic surgery for bilateral microinfusion of the neurotoxin 6-OHDA (6 mg/mL in 0.2% ascorbic acid in sterile saline solution) or vehicle solution for the Sham group. From the day of stereotaxis until the day of femoral artery catheterization, the animals were treated with the iNOS inhibitor, S-methylisothiourea (SMT; 10 mg/kg; i. p.) or saline solution (0.9%; i. p.) for 7 days. The animals were divided into four groups: Sham-Saline, Sham-SMT, 6-OHDA-Saline, and 6-OHDA-SMT. Subsequent analyses were performed on these four groups. After 6 days, they underwent catheterization of the femoral artery, and 24 h later, mean arterial pressure (MAP) and heart rate (HR) were recorded. Another group of animals (the 6-OHDA and Sham groups) was assessed for aortic vascular reactivity after 7 days of bilateral infusion of 6-OHDA or vehicle, in which cumulative concentration-effect curves (CCEC) were made for phenylephrine (Phenyl), acetylcholine and sodium nitroprusside (NPS). Also, CCEC in the presence of Nw-nitro-arginine-methyl-ester (l-NAME) (10-5 M), SMT (10-6 M), and indomethacin (10-5 M) blockers were made.
Results: The effectiveness of the 6-OHDA lesion was confirmed with the reduction of DA in 6-OHDA animals. However, treatment with SMT could not reverse the loss of DA. Concerning the baseline parameters, SBP and MAP values were lower in 6-OHDA animals compared to their Sham control, with no effect of treatment with SMT. In the analysis of SBP variability, a decrease in variance, the VLFabs component, and the LFabs component were observed in the 6-OHDA groups when compared to their controls, regardless of treatment with SMT. It was also observed that intravenous injections of SMT resulted in an increase in BP and a decrease in HR. However, the response was not different between the Sham and 6-OHDA groups. In vascular function, there was a hyporeactivity to Phenyl in the 6-OHDA group, and when investigating the mechanisms of this hyporeactivity, it was seen that the Rmax to Phenyl increased with incubation with SMT, indicating that iNOS could be involved in the vascular hyporeactivity of animals with Parkinsonism.
Conclusion: Thus, the set of results presented in this study suggests that part of the cardiovascular dysfunction in animals subjected to 6-OHDA Parkinsonism may be peripheral and involve the participation of endothelial iNOS.
Competing Interests: Declaration of competing interest The authors declare no potential conflicts of interest.
(Copyright © 2023 Elsevier Inc. All rights reserved.)
Databáze: MEDLINE
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