The effect of long-term cigarette smoking on beta-adrenoceptor density and catecholamine response was studied in 10 monozygotic male twin-pairs discordant for smoking, with an average discordance time for smoking of 23 years (range, 12-35 years). The density of beta-adrenergic receptors was 40% lower in the lymphocytes of smoking twins compared with their nonsmoking cotwins (beta-receptor density, 6.7 +/- 1.2 and 11.1 +/- 1.8 fmol/10(6) cells, respectively; p less than 0.05). The corresponding apparent Kd values were 31.7 +/- 5.5 and 26.7 +/- 5.4 pM, respectively. Stimulation of the lymphocyte beta-receptors resulted in significantly lower levels of cyclic adenosine monophosphate in the smokers compared with the nonsmokers (16.2 +/- 3.3 vs. 29.2 +/- 6.5 pmol/10(6) cells, p less than 0.05). When subjected to submaximal exercise, the smokers had a lower level of cyclic adenosine monophosphate in plasma (25.9 +/- 1.2 vs. 28.6 +/- 1.0, p less than 0.05) and a net decrease was seen in plasma free fatty acids in the smokers compared with a net increase in the nonsmokers (-15% vs. +19%, p less than 0.01). The total plasma catecholamine level was, in the basal state, significantly higher in smokers compared with nonsmokers (74.8%, p less than 0.05). The intrapair difference in plasma norepinephrine predicted well the intrapair difference in beta-receptor density (r = -0.84, p less than 0.001). We conclude that the autonomic neurohumoral response evoked by cigarette smoking results in downregulation of beta-adrenergic receptors in long-term smokers.