Andrade-Franzé G M F, Pereira E D, Yosten G L C, Samson W K, Menani J V, De Luca L A, Andrade C A F
Department of Physiology and Pathology, School of Dentistry, São Paulo State University - UNESP, Araraquara, SP, Brazil.
Department of Pharmacology and Physiology, Saint Louis University School of Medicine, St. Louis, Missouri, USA.
Peptides. 2021 Feb;136:170439. doi: 10.1016/j.peptides.2020.170439. Epub 2020 Nov 7.
Spontaneously hypertensive rats (SHRs) have increased daily or induced sodium intake compared to normotensive rats. In normotensive rats, angiotensin II (ANG II)-induced sodium intake is blocked by the inactivation of p42/44 mitogen-activated protein kinase, also known as extracellular signal-regulated protein kinase1/2 (ERK1/2). Here we investigated if inhibition of ERK1/2 pathway centrally would change sodium appetite and intracerebroventricular (icv) ANG II-induced pressor response in SHRs. SHRs (280-330 g, n = 07-14/group) with stainless steel cannulas implanted in the lateral ventricle (LV) were used. Water and 0.3 M NaCl intake was induced by the treatment with the diuretic furosemide + captopril (angiotensin converting enzyme blocker) subcutaneously or 24 h of water deprivation (WD) followed by 2 h of partial rehydration with only water (PR). The blockade of ERK1/2 activation with icv injections of U0126 (MEK1/2 inhibitor, 2 mM; 2 μl) reduced 0.3 M NaCl intake induced by furosemide + captopril (5.0 ± 1.0, vs. vehicle: 7.3 ± 0.7 mL/120 min) or WD-PR (4.6 ± 1.3, vs. vehicle: 10.3 ± 1.4 mL/120 min). PEP7 (selective inhibitor of AT1 receptor-mediated ERK1/2 activation, 2 nmol/2 μL) icv also reduced WD-PR-induced 0.3 M NaCl (2.8 ± 0.7, vs. vehicle: 6.8 ± 1.4 mL/120 min). WD-PR-induced water intake was also reduced by U0126 or PEP7. In addition, U0126 or PEP7 icv reduced the pressor response to icv ANG II. Therefore, the present results suggest that central AT1 receptor-mediated ERK1/2 activation is part of the mechanisms involved in sodium appetite and ANG II-induced pressor response in SHRs.
与正常血压大鼠相比，自发性高血压大鼠（SHRs）的每日钠摄入量或诱导性钠摄入量增加。在正常血压大鼠中，血管紧张素II（ANG II）诱导的钠摄入可通过p42/44丝裂原活化蛋白激酶（也称为细胞外信号调节蛋白激酶1/2，ERK1/2）的失活而被阻断。在此，我们研究了中枢抑制ERK1/2信号通路是否会改变SHRs的钠食欲以及脑室注射（icv）ANG II诱导的升压反应。使用在侧脑室（LV）植入不锈钢套管的SHRs（280 - 330 g，每组n = 7 - 14）。通过皮下注射利尿剂速尿+卡托普利（血管紧张素转换酶抑制剂）或24小时禁水（WD）后仅用水进行2小时部分补液（PR）来诱导水和0.3 M NaCl的摄入。脑室注射U0126（MEK1/2抑制剂，2 mM；2 μl）阻断ERK1/2激活，可减少速尿+卡托普利诱导的0.3 M NaCl摄入（5.0 ± 1.0，与溶剂对照组：7.3 ± 0.7 mL/120分钟相比）或WD - PR诱导的摄入（4.6 ± 1.3，与溶剂对照组：10.3 ± 1.4 mL/120分钟相比）。脑室注射PEP7（AT1受体介导的ERK1/2激活的选择性抑制剂，2 nmol/2 μL）也可减少WD - PR诱导的0.3 M NaCl摄入（2.8 ± 0.7，与溶剂对照组：6.8 ± 1.4 mL/120分钟相比）。U0126或PEP7也可减少WD - PR诱导的水摄入。此外，脑室注射U0126或PEP7可降低对脑室注射ANG II的升压反应。因此，目前的结果表明，中枢AT1受体介导的ERK1/2激活是参与SHRs钠食欲和ANG II诱导的升压反应机制的一部分。
