Development of specific tolerance to nicotine infusions in dogs on chronic nicotine treatment

Chronic smoking in humans and continuous nicotine application in animals do not induce hypertension, although the acute effects of nicotine are sympathoadrenal activation and elevation of blood pressure. In conscious dogs with a carotid artery loop preparation, we studied whether chronic nicotine application induced tolerance to the acute effects of nicotine test infusions. Nicotine was applied as salicylate via subcutaneously implanted osmotic minipumps at a dosage of 1 microgram/kg/min = 1.44 mg/kg/day, corresponding to heavy smoking in humans. Chronic treatment in eight dogs for 5-8 weeks did not modify resting heart rate and plasma levels of free catecholamines, but significantly increased plasma levels of conjugated dopamine by 100%. Mean arterial pressure at rest was elevated in the 2nd week by 6mm Hg, but did not increase further. Sham treatment (n = 8, sodium salicylate in equivalent dosage) was without effect. Acute test-infusions of nicotine (3 and 10 micrograms/kg/min i.v.) caused acute rises in mean arterial pressure (by 12 and 28 mm Hg), heart rate (by 9 and 18 bpm), plasma norepinephrine (by 36 and 68%), plasma epinephrine (by 110 and 180%) and led to plasma nicotine levels of 31 and 95 ng/ml. Chronic nicotine treatment attenuated the hemodynamic and partially abolished the hormonal effects without affecting the nicotine plasma levels obtained with these test infusions, but it did not modify the hemodynamic effects of a norepinephrine test infusion. The data demonstrate the development of a specific, reversible tolerance to the acute sympathoadrenal activation by nicotine.(ABSTRACT TRUNCATED AT 250 WORDS)