Ahmad Ashfaq, Sattar Munavvar A, Azam Maleeha, Khan Safia A, Bhatt Owais, Johns Edward J
School of Pharmaceutical Sciences, Universiti Sains Malaysia, Penang, Malaysia.
Department of Pharmacology and Toxicology, Virginia Commonwealth University, Richmond, Virginia, United States of America.
PLoS One. 2018 Feb 15;13(2):e0189386. doi: 10.1371/journal.pone.0189386. eCollection 2018.
Left ventricular hypertrophy (LVH) is associated with decreased responsiveness of renal α1-adrenoreceptors subtypes to adrenergic agonists. Nitric oxide donors are known to have antihypertrophic effects however their impact on responsiveness of renal α1-adrenoreceptors subtypes is unknown. This study investigated the impact of nitric oxide (NO) and its potential interaction with the responsiveness of renal α1-adrenoreceptors subtypes to adrenergic stimulation in rats with left ventricular hypertrophy (LVH). This study also explored the impact of NO donor on CSE expression in normal and LVH kidney. LVH was induced using isoprenaline and caffeine in drinking water for 2 weeks while NO donor (L-arginine, 1.25g/Lin drinking water) was given for 5 weeks. Intrarenal noradrenaline, phenylephrine and methoxamine responses were determined in the absence and presence of selective α1-adrenoceptor antagonists, 5- methylurapidil (5-MeU), chloroethylclonidine (CeC) and BMY 7378. Renal cortical endothelial nitric oxide synthase mRNA was upregulated 7 fold while that of cystathione γ lyase was unaltered in the NO treated LVH rats (LVH-NO) group compared to LVH group. The responsiveness of renal α1A, α1B and α1D-adrenoceptors in the low dose and high dose phases of 5-MeU, CEC and BMY7378 to adrenergic agonists was increased along with cGMP in the kidney of LVH-NO group. These findings suggest that exogenous NO precursor up-regulated the renal eNOS/NO/cGMP pathway in LVH rats and resulted in augmented α1A, α1B and α1D adrenoreceptors responsiveness to the adrenergic agonists. There is a positive interaction between H2S and NO production in normal animals but this interaction appears absent in LVH animals.
左心室肥厚（LVH）与肾α1 - 肾上腺素能受体亚型对肾上腺素能激动剂的反应性降低有关。已知一氧化氮供体具有抗肥厚作用，但其对肾α1 - 肾上腺素能受体亚型反应性的影响尚不清楚。本研究调查了一氧化氮（NO）及其与左心室肥厚（LVH）大鼠肾α1 - 肾上腺素能受体亚型对肾上腺素能刺激反应性的潜在相互作用。本研究还探讨了NO供体对正常和LVH肾脏中CSE表达的影响。通过在饮用水中使用异丙肾上腺素和咖啡因诱导LVH 2周，同时给予NO供体（L - 精氨酸，1.25g/L于饮用水中）5周。在存在和不存在选择性α1 - 肾上腺素能受体拮抗剂5 - 甲基尿嘧啶（5 - MeU）、氯乙可乐定（CeC）和BMY 7378的情况下，测定肾内去甲肾上腺素、苯肾上腺素和甲氧明的反应。与LVH组相比，在接受NO治疗的LVH大鼠（LVH - NO）组中，肾皮质内皮型一氧化氮合酶mRNA上调了7倍，而胱硫醚γ裂解酶的mRNA未改变。在LVH - NO组肾脏中，5 - MeU、CEC和BMY7378低剂量和高剂量阶段的肾α1A、α1B和α1D - 肾上腺素能受体对肾上腺素能激动剂的反应性以及cGMP均增加。这些发现表明，外源性NO前体上调了LVH大鼠的肾eNOS/NO/cGMP途径，并导致α1A、α1B和α1D肾上腺素能受体对肾上腺素能激动剂的反应性增强。在正常动物中，H2S和NO产生之间存在正性相互作用，但在LVH动物中这种相互作用似乎不存在。
