Department of Physiology, Louisiana State University Health Sciences Center, New Orleans, Louisiana.
Department of Pharmacology & Experimental Therapeutics, Louisiana State University Health Sciences Center, New Orleans, Louisiana.
Am J Physiol Heart Circ Physiol. 2021 Apr 1;320(4):H1526-H1534. doi: 10.1152/ajpheart.00883.2020. Epub 2021 Feb 12.
Use of electronic cigarettes is rapidly increasing among youth and young adults, but little is known regarding the long-term cardiopulmonary health impacts of these nicotine-containing devices. Our group has previously demonstrated that chronic, inhaled nicotine induces pulmonary hypertension (PH) and right ventricular (RV) remodeling in mice. These changes were associated with upregulated RV angiotensin-converting enzyme (ACE). Angiotensin II receptor blockers (ARBs) have been shown to reverse cigarette smoking-induced PH in rats. ACE inhibitor and ARB use in a large retrospective cohort of patients with PH is associated with improved survival. Here, we utilized losartan (an ARB specific for angiotensin II type 1 receptor) to further explore nicotine-induced PH. Male C57BL/6 mice received nicotine vapor for 12 h/day, and exposure was assessed using serum cotinine to achieve levels comparable to human smokers or electronic cigarette users. Mice were exposed to nicotine for 8 wk and a subset was treated with losartan via an osmotic minipump. Cardiac function was assessed using echocardiography and catheterization. Although nicotine exposure increased angiotensin II in the RV and lung, this finding was nonsignificant. Chronic, inhaled nicotine significantly increased RV systolic pressure and RV free wall thickness versus air control. These parameters were significantly lower in mice receiving both nicotine and losartan. Nicotine significantly increased RV internal diameter, with no differences seen between the nicotine and nicotine-losartan group. Neither nicotine nor losartan affected left ventricular structure or function. These findings provide the first evidence that antagonism of the angiotensin II type 1 receptor can ameliorate chronic, inhaled nicotine-induced PH and RV remodeling. Chronic, inhaled nicotine causes pulmonary hypertension and right ventricular remodeling in mice. Treatment with losartan, an angiotensin II type 1 receptor antagonist, ameliorates nicotine-induced pulmonary hypertension and right ventricular remodeling. This novel finding provides preclinical evidence for the use of renin-angiotensin system-based therapies in the treatment of pulmonary hypertension, particularly in patients with a history of tobacco-product use.
电子烟在青少年和年轻人中的使用迅速增加，但人们对这些含尼古丁装置对长期心肺健康的影响知之甚少。我们的研究小组之前已经证明，慢性吸入尼古丁会导致小鼠发生肺动脉高压（PH）和右心室（RV）重构。这些变化与 RV 血管紧张素转换酶（ACE）的上调有关。血管紧张素 II 受体阻滞剂（ARBs）已被证明可逆转大鼠吸烟引起的 PH。在 PH 患者的大型回顾性队列中，ACE 抑制剂和 ARB 的使用与生存率的提高相关。在这里，我们利用氯沙坦（一种针对血管紧张素 II 类型 1 受体的 ARB）进一步探讨尼古丁引起的 PH。雄性 C57BL/6 小鼠每天接受 12 小时尼古丁蒸气暴露，通过血清可替宁来评估暴露情况，以达到与人类吸烟者或电子烟使用者相当的水平。小鼠暴露于尼古丁 8 周，一部分通过渗透微型泵接受氯沙坦治疗。使用超声心动图和心导管术评估心功能。尽管尼古丁暴露增加了 RV 和肺中的血管紧张素 II，但这一发现没有统计学意义。慢性吸入尼古丁会显著增加 RV 收缩压和 RV 游离壁厚度，与空气对照组相比。接受尼古丁和氯沙坦治疗的小鼠这些参数显著降低。尼古丁显著增加 RV 内径，而在尼古丁和尼古丁-氯沙坦组之间未见差异。尼古丁和氯沙坦均未影响左心室结构或功能。这些发现首次提供了证据，表明血管紧张素 II 类型 1 受体拮抗剂可以改善慢性吸入尼古丁引起的 PH 和 RV 重构。慢性吸入尼古丁会导致小鼠发生肺动脉高压和右心室重构。血管紧张素 II 类型 1 受体拮抗剂氯沙坦的治疗可改善尼古丁引起的肺动脉高压和右心室重构。这一新发现为基于肾素-血管紧张素系统的治疗方法在肺动脉高压治疗中的应用提供了临床前证据，特别是在有烟草制品使用史的患者中。
