Influence of nicotine on cardiovascular and hormonal effects of cigarette smoking.

To elucidate the importance of nicotine in determining the effects of cigarette smoking, we studied 10 healthy subjects on a research ward who were either smoking their usual brand of cigarettes, smoking high- (HN, 2.5 mg) or low- (LN, 0.4 mg) nicotine research cigarettes, or abstaining. Blood nicotine concentrations were four times as high smoking HN than LN cigarettes. Values while smoking their own brands were intermediate. Cigarette smoking increased mean (24-hr) heart rate (HR), but HR effect did not differ as a function of nicotine exposure. Analysis of the hourly HR pattern showed that smoking increased HR more over the first few hours of the morning, but then followed a circadian pattern similar to that during abstention. HR remained elevated all night even though no cigarettes were smoked. Blood pressures tended to be higher while smoking, but plasma cortisol concentrations throughout the day did not differ while smoking or abstaining. Thus the amount of nicotine consumed when assessed over the whole day has little influence on magnitude of cardiovascular responses to cigarette smoking. Insofar as nicotine contributes to risk, changing nicotine content per se may not alter the risk of sudden adverse cardiac events associated with cigarette smoking.

Cotinine disposition and effects.

Cotinine is the major metabolite of nicotine in man. We studied cotinine disposition kinetics in 28 healthy habitual cigarette smokers. Eight subjects received cotinine fumarate, 4 micrograms base/kg/min IV for 60 min. Mean (+/- SD) metabolic clearance was 60 +/- 12 ml/min and mean renal clearance was 12 +/- 5 ml/min, averaging 17% of total clearance. Steady-state volume of distribution was slightly greater than body weight (mean 88 +/- 17 l). Terminal t 1/2 averaged 15.8 +/- 4.0 hr in these eight subjects and 19.7 +/- 6.5 hr in another 12 subjects who abstained from smoking for 3 days. The effect of urinary acidification and alkalinization on renal clearance of cotinine during cigarette smoking was studied in another group of eight subjects. Compared with baseline (mean urinary pH 5.8, renal clearance 12.3 +/- 5.9 ml/min), renal clearance was increased about 50% by urinary acidification (pH 4.4, clearance 18.6 +/- 10 ml/min), but it was not affected by alkalinization (pH 6.7, clearance 14.0 +/- 10.4 ml/min). Infusion of cotinine to blood concentrations seen in moderately heavy smokers had no effect on heart rate, blood pressure, or skin temperature, measures that are sensitive to effects of nicotine. No spontaneous subjective effects were reported. We conclude that, at levels to which cigarette smokers are generally exposed, cotinine exerts no cardiovascular activity and weak, if any, psychologic activity.

Circadian blood nicotine concentrations during cigarette smoking.

To estimate daily nicotine consumption from the smoking of cigarettes delivering different amounts of nicotine, we studied 12 healthy subjects who smoked 30 cigarettes a day of their usual brand (x = 1.2 mg nicotine) or high- (2.5 mg) or low-nicotine (0.4 mg) research cigarettes. Blood nicotine and carboxyhemoglobin concentrations were measured every 2 hr. Nicotine consumption was estimated by the 24-hr area under the blood concentration-time curve (AUC) and compared across smoking conditions. There was considerable interindividual variation in the nicotine AUC among subjects smoking research cigarettes or while smoking usual brands, even when the latter were normalized on the basis of machine-predicted nicotine delivery. Most subjects smoked the high-nicotine research cigarettes less intensively so that nicotine levels were only modestly higher after smoking high-nicotine cigarettes than after usual brands. Low-nicotine research cigarettes were not smoked more intensively than usual brands and blood nicotine levels were substantially lower than those after smoking a usual brand. Nicotine consumption while smoking usual brands correlated strongly with consumption while smoking high- (r = 0.91) and low-nicotine (r = 0.85) research cigarettes. Circadian studies of blood concentration of nicotine while smoking cigarettes provided a direct estimate of the level of nicotine in the body throughout the day. Results confirm observations by others that levels of nicotine in the body vary widely among individuals even when smoking the same number of identical cigarettes. Thus, neither number of cigarettes smoked nor smoking-machine delivery predict daily nicotine exposure very well.