Angiotensin II Type I Receptor Antagonism Attenuates Nicotine-Induced Cardiac Remodeling, Dysfunction, and Aggravation of Myocardial Ischemia-Reperfusion Injury in Rats

Abstract

Increased exposure to nicotine contributes to the development of cardiac dysfunction by promoting oxidative stress, fibrosis, and inflammation. These deleterious events altogether render cardiac myocytes more susceptible to acute cardiac insults such as ischemia-reperfusion (I/R) injury. This study sought to elucidate the role of angiotensin II type I (AT1) receptors in cardiac injury resulting from prolonged nicotine administration in a rat model. Male Sprague-Dawley rats were given nicotine (0.6 mg/kg ip) for 28 days to induce cardiac dysfunction, alone or in combination with the AT1 receptor antagonist, irbesartan (10 mg/kg, po). Vehicle-treated rats were used as controls. Rat hearts isolated from each experimental group at study endpoint were examined for changes in function, histology, gene expression, and susceptibility against acute I/R injury determined ex vivo. Rats administered nicotine alone exhibited significantly increased cardiac expression of angiotensin II and angiotensin-converting enzyme (ACE) in addition to elevated systolic blood pressure (SBP) and heart rate. Furthermore, nicotine administration markedly reduced left ventricular (LV) performance with concomitant increases in myocardial oxidative stress, fibrosis, and inflammation. Concomitant treatment with irbesartan attenuated these effects, lowering blood pressure, heart rate, oxidative stress, and expression of fibrotic and inflammatory genes. Importantly, the irbesartan-treated group also manifested reduced susceptibility to I/R injury ex vivo. These findings suggest that AT1 receptors play an important role in nicotine-induced cardiac dysfunction, and pharmacological approaches targeting cardiac AT1 receptors may thus benefit patients with sustained exposure to nicotine.

Acute administration of nicotine induces transient elevation of blood pressure and increases myocardial infarct size in rats

“…Although we did not specifically study this mechanism in our current protocol, many studies have demonstrated that nicotine can directly impact cardiac structure and function, promoting inflammation, oxidative stress, cardiomyocyte apoptosis and endothelial dysfunction [42,43,44,45,46,47,48,49,50,51]. In addition, in a recent study by Ramalingam et al, nicotine chronically given for 28 days induced significant increases in blood pressure, heart rate change, cardiac hypertrophy, fibrosis, inflammation, and oxidative stress in myocardial ischemia and reperfusion injury in a rat model, and these effects were partially attenuated by concomitant treatment with irbesartan, an angiotensin II receptor antagonist [52].…”

Targeting mitochondrial reactive oxygen species-mediated oxidative stress attenuates nicotine-induced cardiac remodeling and dysfunction

“…A study conducted in rats has also shown that prolonged administration of nicotine (21–28 days) increases systemic blood pressure and heart rate 5 , accelerates cardiomyocyte inflammation and apoptosis 6 , promotes atherosclerosis 7 , dysregulates blood lipid profile 7 , and causes vascular endothelial dysfunction 5 , 8 . Our recent studies also showed that nicotine administration for 28 days causes cardiac structural remodeling such as hypertrophy and fibrosis, which render the hearts more susceptible to acute insults such as ischemia–reperfusion injury 9 , 10 . We also reported that hearts isolated from nicotine-administered rats exhibited worsened left ventricle (LV) function recovery 9 , 10 .…”

“…Our recent studies also showed that nicotine administration for 28 days causes cardiac structural remodeling such as hypertrophy and fibrosis, which render the hearts more susceptible to acute insults such as ischemia–reperfusion injury 9 , 10 . We also reported that hearts isolated from nicotine-administered rats exhibited worsened left ventricle (LV) function recovery 9 , 10 .…”

Mitochondrial Dysfunction in Diabetic Cardiomyopathy: The Possible Therapeutic Roles of Phenolic Acids

“…Thus, this suggests that cardiomyocytes are more susceptible to diabetes-induced cell death by apoptosis than by necrosis [ 98 , 99 ]. Cardiomyocyte apoptosis leads to cell loss, to decreased cardiac contractile function and ultimately to the promotion of cardiac remodeling [ 100 ].…”