Effects of Chronic Nicotine Inhalation on Systemic and Pulmonary Blood Pressure and Right Ventricular Remodeling in Mice
Authors: Fried Nicholas D. , Morris Tamara M. , Woods David C. , Oakes Joshua M. , Xu Jiaxi , Lazartigues Eric , Gardner Jason D. , Yue Xinping 
Published: April 2020

Cigarette smoking is the single most important risk factor for the development of cardiovascular and pulmonary diseases (CVPD), however, the role of nicotine in the pathogenesis of CVPD is incompletely understood. The purpose of this study was to examine the effects of chronic nicotine inhalation on the development of CVPD with a focus on blood pressure (BP) and cardiac remodeling.

Male C57BL6/J mice were exposed to air (control) or nicotine vapor (daily, 12 h on/12 h off) for 8 weeks. Nicotine exposure was assessed by weekly measurement of serum cotinine levels, which showed a weekly average of 599.0 ± 54.3 ng/ml in nicotine‐exposed mice. Systemic BP was recorded weekly by radio‐telemetry and cardiac remodeling was monitored by echocardiography. At the end of the 8 weeks, mice were subjected to right heart catheterization to measure right ventricular systolic pressure (RVSP).

Nicotine‐exposed mice exhibited elevated systemic BP from weeks 1–3, which then returned to baseline from weeks 4–8, indicating development of tolerance to nicotine. At 8 weeks, significantly increased RVSP was detected in nicotine‐exposed mice (39.6 ± 4.2 mmHg, n=7) compared to the air controls (22.3 ± 1.7 mmHg, n=8, P < 0.01). Echocardiography showed that 8‐week nicotine inhalation resulted in RV hypertrophy with increased RV free wall thickness (0.50 ± 0.02 mm in nicotine group vs. 0.42 ± 0.03 mm in air control group, P < 0.05) and a trend of increase in RV internal diameter (1.92 ± 0.21 mm in nicotine group vs. 1.45 ± 0.08 mm in air control group, P = 0.069). In contrast, there were no significant structural or functional changes in the left ventricle (LV) following nicotine exposure. In the lung, there was a 1.50‐fold increase in the number of muscularized pulmonary arterioles in nicotine‐exposed mice compared to air‐exposed mice (P < 0.001), concomitant with increased pulmonary vascular resistance (1.41 ± 0.22 mmHg·min·ml−1 in nicotine group vs. 0.98 ± 0.09 mmHg·min·ml−1 in air control group, P < 0.05). Mechanistically we observed increased expression of angiotensin converting enzyme (3.87‐fold increase in nicotine‐exposed mice vs. the air controls, P < 0.05) and enhanced activation of mitogen‐activated protein kinase pathways including ERK, p38 and JNK in the RV, but not in the LV, following chronic nicotine inhalation exposure. In addition, mice exposed to nicotine and treated concomitantly with losartan (10 mg/kg/day s.c. for 8 weeks) failed to develop an increased RVSP (24.0 ± 1.3 mmHg, n=12).

We conclude that chronic nicotine inhalation alters both systemic and pulmonary BP with the latter accompanied by RV and pulmonary vascular remodeling, possibly mediated by an enhanced cardiac renin‐angiotensin system leading to progressive and persistent pulmonary hypertension.

Support or Funding Information

National Institutes of Health (R01HL135635 and COBRE P30GM106392) and LSUHSC‐NO Research Enhancement Program.