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BKCa Channel Activation Attenuates the Pathophysiological Progression of Monocrotaline-Induced Pulmonary Arterial Hypertension in Wistar Rats

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Abstract

Purpose

In the present study, the therapeutic efficacy of a selective BKCa channel opener (compound X) in the treatment of monocrotaline (MCT)-induced pulmonary arterial hypertension (PAH) was investigated.

Methods

PAH was induced in male Wistar rats by a single injection of MCT. After two weeks, the MCT-treated group was divided into two groups that were either treated with compound X or vehicle. Compound X was administered daily at 28 mg/kg. Electrocardiographic, echocardiographic, and haemodynamic analyses were performed; ex vivo evaluations of pulmonary artery reactivity, right ventricle (RV) and lung histology as well as expression levels of α and β myosin heavy chain, brain natriuretic peptide, and cytokines (TNFα and IL10) in heart tissue were performed.

Results

Pulmonary artery rings of the PAH group showed a lower vasodilatation response to acetylcholine, suggesting endothelial dysfunction. Compound X promoted strong vasodilation in pulmonary artery rings of both control and MCT-induced PAH rats. The untreated hypertensive rats presented remodelling of pulmonary arterioles associated with increased resistance to pulmonary flow; increased systolic pressure, hypertrophy and fibrosis of the RV; prolongation of the QT and Tpeak-Tend intervals (evaluated during electrocardiogram); increased lung and liver weights; and autonomic imbalance with predominance of sympathetic activity. On the other hand, treatment with compound X reduced pulmonary vascular remodelling, pulmonary flow resistance and RV hypertrophy and afterload.

Conclusion

The use of a selective and potent opener to activate the BKCa channels promoted improvement of haemodynamic parameters and consequent prevention of RV maladaptive remodelling in rats with MCT-induced PAH.

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Abbreviations

ACh:

Acetylcholine

ANOVA:

Analysis of Variance

BKCa:

Calcium- and voltage-sensitive potassium channel

BKa:

BKCa channel Opener

BNP:

Brain natriuretic peptide

DAP:

Diastolic arterial pressure

ECG:

Electrocardiogram

ELISA:

Enzyme-linked immunosorbent assay

GAPDH:

Glyceraldehyde-3-phosphate dehydrogenase

HF:

Power density of high frequency

HRV:

Heart rate variability

IL10:

Interleukin-10

LF:

Power density of low frequency

MAP:

Mean arterial pressure

MCT:

Monocrotaline

MHC:

Myosin heavy chain

PAH:

Pulmonary arterial hypertension

PAT:

Pulmonary artery acceleration time

PET:

Pulmonary ejection time

Phe:

Phenylephrine

QTc:

Corrected QT interval

RR:

Time interval between two consecutive R waves

RV:

Right ventricle

RVSP:

RV systolic pressure

RVW:

Right ventricle weight

SAP:

Systolic arterial pressure

SEM:

Standard error of the mean

TNFα:

Tumour necrosis factor-α

Tpeak-Tend:

Time interval between peak and the end of T wave

VSMC:

Vascular smooth muscle cells

VTI:

Velocity–time integral

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Funding

This study was supported by the Department of Science and Technology - Brazilian Ministry of Health (DECIT/SCTIE/MS), the Rio de Janeiro State Research Foundation (FAPERJ), the Brazilian Council for Scientific and Technological Development (CNPq) and the Coordination for the Improvement of Higher Education Personnel (CAPES). JHMN and ACCC are research fellows from CNPq and FAPERJ.

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Authors and Affiliations

  1. Carlos Chagas Filho Institute of Biophysics, Federal University of Rio de Janeiro, Rio de Janeiro, RJ, Brazil

    Ana Paula Ferraz, Fernando A. C. Seara, Emanuelle F. Baptista, Thais S. Barenco, Thais B. B. Sottani, Natalia S. C. Souza, Ainá E. Domingos, Raiana A. Q. Barbosa, Christina M. Takiya, Antonio C. Campos de Carvalho & Jose Hamilton M. Nascimento

  2. Department of Physiological Sciences, Federal Rural University of Rio de Janeiro, Seropedica, RJ, Brazil

    Fernando A. C. Seara

  3. Campus Rio de Janeiro, Federal Institute of Education, Science and Technology of Rio de Janeiro, Rio de Janeiro, RJ, Brazil

    Marcos T. Couto, Gabriel O. Resende & Cristiano G. Ponte

Authors
  1. Ana Paula Ferraz
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  2. Fernando A. C. Seara
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  3. Emanuelle F. Baptista
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  4. Thais S. Barenco
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  5. Thais B. B. Sottani
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  6. Natalia S. C. Souza
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  7. Ainá E. Domingos
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  8. Raiana A. Q. Barbosa
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  14. Jose Hamilton M. Nascimento
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Contributions

APF, FACS, CGP, JHMN conception and design of research study; MTC and GOR synthesized and purified compound X; APF, EFB, FACS, TSB, TBBS, NSCS, AED, RAQB performed experiments; APF, FACS, TSB, RAQB, CMT, analysed the data; APF, FACS, CGP, CMT, ACCC, JHMN interpreted results of experiments; APF, FACS, CGP, JHMN wrote the manuscript; FACS, ACCC, JHMN revised manuscript; All authors read and approved the final manuscript.

Corresponding author

Correspondence to Jose Hamilton M. Nascimento.

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Conflict of Interest

The authors declare no conflict of interest.

Ethics Approval

The study was conducted according to the “Guide for the Care and Use of Laboratory Animals” (NIH Publication No. 85–23, revised in 2010), and the experimental protocols were approved by the Ethics Committee on Animal Use of the Federal University of Rio de Janeiro (protocol 087/15).

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Supplementary Information

Fig. 1.

(a) The vasoconstrictive response of pulmonary artery to the α1-agonist phenylephrine (Phe) in CTL, MCT and MCT + BKa groups (all groups with n = 7). (b) The maximal relaxation elicited by ACh and BKa were compared in CTL (ACh, n = 5; BKa, n = 6), MCT (ACh, n = 5; BKa, n = 4) and MCT + BKa (ACh, n = 5; BKa, n = 5) groups. Data are expressed as mean ± SEM. *p < 0.05 versus CTL. (PNG 26 kb)

High resolution image (TIF 3795 kb)

Fig. 2.

Systemic blood pressure was not affected by BKCa channels activation. Systemic blood pressure was assessed by aortic cannulation in CTL (n = 14), MCT (n = 11) and MCT + BKa (n = 9) groups. Data are expressed as mean ± SEM. (PNG 21 kb)

High resolution image (TIF 3587 kb)

Fig. 3.

Survival analysis. Monocrotaline-injected rats from MCT + BKa group were daily treated with compound X from 14th to the 28th day. CTL (n = 15), MCT (n = 15), and MCT + BKa (n = 14). (PNG 9 kb)

High resolution image (TIF 49023 kb)

Fig. 4.

Right ventricle and systemic hemodynamic properties were not affected by BKCa channels activation in health rats. CTL group (n = 5); MCT group (n = 2–5). Data are expressed as mean ± SEM. (PNG 8 kb)

High resolution image (TIF 15594 kb)

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Ferraz, A.P., Seara, F.A.C., Baptista, E.F. et al. BKCa Channel Activation Attenuates the Pathophysiological Progression of Monocrotaline-Induced Pulmonary Arterial Hypertension in Wistar Rats. Cardiovasc Drugs Ther 35, 719–732 (2021). https://doi.org/10.1007/s10557-020-07115-5

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