Nicotine absorption and cardiovascular effects with smokeless tobacco use: comparison with cigarettes and nicotine gum

Because of recent resurgence in its consumption, the effects and health consequences of smokeless tobacco are of considerable public health interest. We studied the extent and time course of absorption of nicotine and cardiovascular effects of smokeless tobacco (oral snuff and chewing tobacco) and compared it with smoking cigarettes and chewing nicotine gum in 10 healthy volunteers. Maximum levels of nicotine were similar but, because of prolonged absorption, overall nicotine exposure was twice as large after single exposures to smokeless tobacco compared with cigarette smoking. All tobacco use increased heart rate and blood pressure, with a tendency toward a greater overall cardiovascular effect despite evidence of development of some tolerance to effects of nicotine with use of smokeless tobacco. Relatively low levels of nicotine and lesser cardiovascular responses were observed with use of nicotine gum. Adverse health consequences of smoking that are nicotine related would be expected to present a similar hazard with the use of smokeless tobacco.     

Direct comparison of cerebrovascular effects of norepinephrine and dopamine in head-injured patients

OBJECTIVE: To directly compare the cerebrovascular effects of norepinephrine and dopamine in patients with acute traumatic brain injury. DESIGN: Prospective randomized crossover trial. SETTING: Neurosciences critical care unit of a university hospital. PATIENTS: Ten acutely head-injured patients requiring vasoactive drugs to maintain a cerebral perfusion pressure of 65 mm Hg. INTERVENTIONS: Patients were randomized to start the protocol with either norepinephrine or dopamine. Using an infusion of the allocated drug, cerebral perfusion pressure was adjusted to 65 mm Hg. After 20 mins of data collection, cerebral perfusion pressure was increased to 75 mm Hg by increasing the infusion rate of the vasoactive agent. After 20 mins of data collection, cerebral perfusion pressure was increased to 85 mm Hg and again data were collected for 20 mins. Subsequently, the infusion rate of the vasoactive drug was reduced until a cerebral perfusion pressure of 65 mm Hg was reached and the drug was exchanged against the other agent. The protocol was then repeated. MEASUREMENTS AND MAIN RESULTS: Mean arterial pressure and intracranial pressure were monitored and cerebral blood flow was estimated with transcranial Doppler. Norepinephrine led to predictable and significant increases in flow velocity for each step increase in cerebral perfusion pressure (57.5+/-19.9 cm x sec, 61.3+/-22.3 cm x sec, and 68.4+/-24.8 cm x sec at 65, 75, and 85 mm Hg, respectively; p <.05 for all three comparisons), but changes with dopamine were variable and inconsistent. There were no differences between absolute values of flow velocity or intracranial pressure between the two drugs at any cerebral perfusion pressure level. CONCLUSIONS: Norepinephrine may be more predictable and efficient to augment cerebral perfusion in patients with traumatic brain injury.     

Cardiovascular effects of nicotine, chlorisondamine, and mecamylamine in the pigeon

Chlorisondamine and mecamylamine are nicotinic antagonists that produce both ganglionic and central blockade. Chlorisondamine, when administered as a large systemic dose, produces a persistent central block, despite being charged. The present study evaluated the cardiovascular effects of chlorisondamine. Shortly after administration, chlorisondamine (0.10, 1, and 10 mg/kg i.m.) lowered blood pressure significantly and decreased heart rate at the low dose (0.1 mg/kg i.m.) and increased heart rate at the high dose (10 mg/kg i.m.). Mecamylamine (1 and 10 mg/kg i.m.) also lowered blood pressure and heart rate. After both antagonists, heart rate returned to baseline values within 90 min and blood pressure within 24 h. Low doses of nicotine (0.01-0.03 mg/kg i.m.) lowered blood pressure but did not affect heart rate. Higher doses (0.10-3.2 mg/kg i.m.) transiently increased blood pressure and heart rate. Subsequent to antagonist administration, nicotine was administered to determine whether either drug blocked the cardiovascular effects of nicotine. Chlorisondamine (0.1, 1, and 10 mg/kg i.m.) administered 30 min before nicotine blocked the increases in blood pressure and heart rate. Only the high dose (10 mg/kg i.m.) of chlorisondamine administered 24 h before nicotine produced a blockade of nicotine's pressor effect. This block diminished within 3 days. Mecamylamine (1 mg/kg i.m.) antagonized only nicotine's tachycardic effect. Longer pretreatment with mecamylamine (10 mg/kg, 24 h before nicotine challenge) did not antagonize the cardiovascular effects of nicotine. Thus, chlorisondamine produces a longer lasting blockade of nicotine's cardiovascular effects than mecamylamine.     

Acute effects of nicotine on prolactin release in the rat: agonist and antagonist effects of a single injection of nicotine

The effects of nicotine on prolactin release were studied in conscious, unrestrained rats in which an indwelling jugular cannula allowed multiple samplings of blood after i.v. administration of nicotine. Intravenous administration of nicotine bitartrate dihydrate increases plasma prolactin concentrations in a dose-dependent manner with an ED50 of approximately 100 micrograms/kg (200 nmol/kg) and this effect is blocked completely by pretreatment with mecamylamine, indicating that it is mediated by a nicotinic cholinergic receptor. Intracerebral ventricular injection of 1 microgram of nicotine also increases plasma prolactin levels, but i.v. injection of this same amount of nicotine has no effect, indicating that nicotine acts within the brain to release prolactin. A single i.v. injection of nicotine resulted in desensitization of the prolactin response to a subsequent injection of nicotine given 1 to 2 hr later, thus confirming a previous report by Sharp and Beyer (J. Pharmacol. Exp. Ther. 238: 486-491, 1986). The prolactin response to nicotine was restored within 24 hr after a single injection. The acute desensitization after a single injection of nicotine appears to be specific to release of prolactin by nicotine because the prolactin response to morphine was unaffected 1 hr after injection of nicotine. A single injection of nicotine appears to desensitize the prolactin response to a subsequent injection of nicotine with an ED50 of approximately 20 micrograms/kg (40 nmol/kg), indicating that nicotine is even more potent in stimulating desensitization of nicotinic cholinergic receptors than in stimulating prolactin release. These results support the concept that nicotine acts as a time-averaged antagonist.(ABSTRACT TRUNCATED AT 250 WORDS)     

Adenosine potentiates sympathomimetic effects of nicotinic agonists in vivo

We showed previously that circulating adenosine potentiates pressor responses to nicotine in rats, apparently by enhancing the effects of nicotine in sympathetic ganglia. In the present studies, we examined the effects of adenosine (or synthetic adenosine receptor agonists) on a variety of sympathomimetic responses to nicotine (or other nicotinic cholinergic agonists). Indices of sympathetic activity examined were: blood pressure; heart rate; eyelid tension; and vas deferens perfusion pressure. Elevation of arterial plasma adenosine from its basal level (approximately 1.5 microM) to 2 to 3 microM (by i.v. adenosine infusion) had no effect on the basal value of any of these indices, but increased by 2.5 to 4-fold their peak responses to nicotine (40 microgram/kg i.v.). Adenosine also strongly enhanced sympathomimetic responses to inhaled cigarette smoke. The adenosine receptor antagonist caffeine (10 mg/kg) suppressed the ability of adenosine to potentiate these responses to nicotine. Pressor responses to the nicotinic cholinergic receptor agonists dimethylphenylpiperazinium iodide, tetramethylammonium, lobeline and cytisin were also potentiated by adenosine. Low doses (0.25-5 mu/kg) of synthetic adenosine receptor agonists potentiated all four of the tested sympathomimetic responses to nicotine, exhibiting the rank order of potency: N-Cyclopropylcarboxamidoadenosine greater than 2-Chloroadenosine greater than N6-R-Phenylisopropyl adenosine greater than N6-S-Phenylisopropyladenosine. The nonpurinergic vasodilator sodium nitroprusside failed to potentiate responses to nicotine, suggesting that the influence of adenosine on responses to nicotine is not secondary to its direct circulatory effects.(ABSTRACT TRUNCATED AT 250 WORDS)