Division of Cellular and Molecular Cardiology, Sree Chitra Tirunal Institute for Medical Sciences and Technology, Thiruvananthapuram, 695011, India.
Department of Pharmacology and Toxicology, National Institute of Pharmaceutical Education and Research, Hyderabad, 500037, Telangana, India.
Hypertens Res. 2018 Dec;41(12):1023-1035. doi: 10.1038/s41440-018-0109-2. Epub 2018 Oct 11.
The association of histamine with adverse cardiac remodeling in chronic pressure overload has not received much attention. A pilot study in spontaneously hypertensive rats (SHRs) indicated a reduction of left ventricular hypertrophy (LVH) with a histamine-2-receptor (H2R) antagonist (famotidine). This finding prompted a detailed investigation of temporal variation in myocardial histamine and H2R expression and the cardiovascular response to H2R antagonism compared with that of the conventional beta-blocker metoprolol. Reduction of LVH is known to reduce the risk of adverse cardiovascular events. The myocardial histamine content and H2R expression increased with age in SHRs but not in normotensive Wistar rats. The cardiovascular response to famotidine (30 mg kg) was compared with that of metoprolol (50 mg kg) in 6-month-old male SHRs treated for 60 days. The decrease in diastolic blood pressure and improvement in cardiac function induced by famotidine and metoprolol were comparable. Both treatments caused the regression of LVH as assessed from the hypertrophy index, histomorphometry, B type natriuretic peptide (BNP), pro-collagen 1, and hydroxyproline levels. Calcineurin-A expression (marker of pathological remodeling) decreased, and Peroxiredoxin-3 expression (mitochondrial antioxidant) increased in response to the treatments. The myocardial histamine levels decreased with the treatments. The age-dependent increase in myocardial histamine and H2R in the SHRs signifies their association with progressive cardiac remodeling. The regression of LVH and improvement in cardiac function by famotidine further demonstrates the role of histamine in cardiac remodeling. Hypertrophy of cultured cardiac cells upon exposure to histamine and the H2R agonist amthamine substantiates the role of histamine in cardiac remodeling. The cardiovascular response to famotidine is comparable to that of metoprolol, suggesting repurposing of H2R antagonists for the management of hypertensive heart disease.
组胺与慢性压力超负荷引起的不良心脏重构之间的关联尚未引起太多关注。一项自发性高血压大鼠（SHR）的初步研究表明，组胺-2 受体（H2R）拮抗剂（法莫替丁）可减少左心室肥厚（LVH）。这一发现促使我们详细研究心肌组胺和 H2R 表达的时间变化，以及与传统的β受体阻滞剂美托洛尔相比，H2R 拮抗作用对心血管的影响。众所周知，减少 LVH 可降低不良心血管事件的风险。在 SHR 中，心肌组胺含量和 H2R 表达随年龄增长而增加，但在正常血压的 Wistar 大鼠中则不然。在接受 60 天治疗的 6 月龄雄性 SHR 中，比较了法莫替丁（30mg/kg）和美托洛尔（50mg/kg）的心血管反应。法莫替丁和美托洛尔均可降低舒张期血压并改善心功能。两种治疗方法均通过肥大指数、组织形态计量学、B 型利钠肽（BNP）、原胶原 1 和羟脯氨酸水平评估 LVH 消退。钙调神经磷酸酶-A 表达（病理性重构的标志物）下降，而过氧化物还原酶-3 表达（线粒体抗氧化剂）增加。心肌组胺水平随治疗而降低。SHR 心肌组胺和 H2R 的年龄依赖性增加表明它们与进行性心脏重构有关。法莫替丁治疗可使 LVH 消退和心功能改善，进一步证明了组胺在心脏重构中的作用。心肌细胞暴露于组胺和 H2R 激动剂氨甲酰胆碱后发生肥大，证实了组胺在心脏重构中的作用。法莫替丁的心血管反应与美托洛尔相当，提示重新利用 H2R 拮抗剂来治疗高血压性心脏病。
