Divergent tolerance to metabolic and cardiovascular effects of nicotine in smokers with low and high levels of cigarette consumption

Cigarette smokers on average weigh less than nonsmokers. However, among smokers, those who smoke the most weigh the most. To better understand the effects of nicotine on body weight, we investigated the pharmacodynamics of intravenous nicotine and cigarette smoking in low-level smokers (10 or fewer cigarettes per day) and high-level smokers (15 to 30 cigarettes per day). Cigarette smoking and intravenous nicotine increased heart rate and energy expenditure in most smokers. The effects of intravenous nicotine and smoking were of similar magnitude, confirming that the effects of smoking are mediated by nicotine. Nicotine produced a slightly greater increase in heart rate in low-level versus high-level smokers, but energy expenditure increased to a much greater extent in low-level versus high-level smokers. The plots of plasma nicotine concentration versus responses suggest development of acute tolerance to both heart rate acceleration and increased energy expenditure in low-level smokers; high-level smokers show a similar pattern of tolerance for heart rate but show only a brief increase in energy expenditure and a hysteresis curve consistent with either rapid development of tolerance or no effect. Thus there is evidence of differential development or rate of loss of tolerance to cardiovascular versus metabolic effects of nicotine in low-level versus high-level smokers. Pharmacodynamic differences between low-level and high-level smokers may explain, at least in part, the unusual relationship between cigarette consumption and body weight.