Cigarette smoking is the single most important risk factor for the development of cardiovascular and pulmonary diseases; however, the role of nicotine in the pathogenesis of these diseases is incompletely understood. The purpose of this study was to examine the effects of chronic nicotine inhalation on the development of cardiovascular and pulmonary disease with a focus on blood pressure and cardiac remodeling. Male C57BL6/J mice were exposed to air (control) or nicotine vapor (daily, 12 hour on/12 hour off) for 8 weeks. Systemic blood pressure 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. Nicotine-exposed mice exhibited elevated systemic blood pressure from weeks 1 to 3, which then returned to baseline from weeks 4 to 8, indicating development of tolerance to nicotine. At 8 weeks, significantly increased right ventricular systolic pressure was detected in nicotine-exposed mice compared with the air controls. Echocardiography showed that 8-week nicotine inhalation resulted in right ventricular (RV) hypertrophy with increased RV free wall thickness and a trend of increase in RV internal diameter. In contrast, there were no significant structural or functional changes in the left ventricle following nicotine exposure. Mechanistically, we observed increased expression of angiotensin-converting enzyme and enhanced activation of mitogen-activated protein kinase pathways in the RV but not in the left ventricle. We conclude that chronic nicotine inhalation alters both systemic and pulmonary blood pressure with the latter accompanied by RV remodeling, possibly leading to progressive and persistent pulmonary hypertension.
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 PH patient cohort 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 hours per 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 weeks and a subset was treated with losartan via osmotic minipump. Cardiac function was assessed using echocardiography and catheterization. Although nicotine exposure increased angiotensin-II in the RV and lung, this finding was non-significant. 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 effect 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.
While smoking is a proven risk factor for stroke and heart attacks, whether it contributes to the development of hypertension is still unclear. Nicotine inhalation is thought to activate the sympathetic nervous system and could contribute to the development of dysautonomia and blood pressure (BP) dysregulation. The purpose of this study was to investigate a possible relationship between chronic nicotine inhalation and the development of hypertension. C57BL/6 mice (male, 8-12 weeks of age) were exposed to air or nicotine vapor (daily, 12 h on/off) for 8 weeks. BP was recorded weekly for 24 h (telemetry). Nicotine exposure was assessed by weekly measurement of serum cotinine levels, which showed an average of 599.0 ±54.3 ng/ml in nicotine-exposed mice. Nicotine exposure induced a time-dependent increase in systolic BP. Notably, 24-h BP recordings showed that by the end of the 7 th week, systolic BP of nicotine-exposed mice was more often in the hypertensive zone (as defined by the area under the curve [AUC] above the 130 mmHg threshold within a 24-h recording) compared to their air-exposed counterparts (AUC: 555 ±299 vs. 112 ±30, P=0.012 , n=12). This hypertensive response was validated in angiotensin-II (Ang-II)-infused mice (450 ng/kg/min, s.c., AUC: 1358 ±939 vs. 112 ±30, P<0.001 , n=5). At the end of nicotine exposure, urinary norepinephrine (NE) showed significant increase in both nicotine (108.9 ±9.8 vs. 79.53 ±5.7 ng/1ng creatinine, P=0.018 , n=9) and Ang-II groups (114.0 ±14 vs. 79.53 ±5.7 ng/1ng creatinine, P=0.016 , n=9), suggesting increased sympathetic activity in those mice. In addition, mice with global deletion of angiotensin converting enzyme type 2 (ACE2) showed a dramatic elevation in urinary NE level after nicotine exposure (157.8 ±8.5 vs. 79.53 ±5.7 ng/1ng creatinine, P<0.001 , n=9). These data suggest that ACE2 might be protective against nicotine inhalation-mediated rise in sympathetic activity. In summary, chronic nicotine inhalation promotes the development of hypertension, and this could be mediated through the elevated activity of sympathetic nervous system. Experiments are ongoing to confirm sympatho-excitation and a possible involvement of the renin-angiotensin system in chronic nicotine inhalation-induced hypertension.
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.
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