Acute Nicotine Infusion Research Articles

Nitric oxide synthase–dependent responses of the basilar artery during acute infusion of nicotine

Our goals were to determine whether acute exposure to nicotine alters nitric oxide synthase (NOS)-dependent responses of the basilar artery and to identify a potential role for activation of NAD(P)H oxidase in nicotine-induced impairment in NOS-dependent responses of the basilar artery. We measured in vivo diameter of the basilar artery in response to NOS-dependent (acetylcholine) and NOS-independent (nitroglycerin) agonists before and during an acute infusion of nicotine (2 microg/kg/min intravenously for 30 min followed by a maintenance dose of 0.35 microg/kg/min). In addition, we measured superoxide anion production (lucigenin chemiluminescence) by the basilar artery in response to nicotine in the absence or presence of apocynin. We found that NOS-dependent, but not NOS-independent, vasodilation was impaired during infusion of nicotine. In addition, treatment of the basilar artery with apocynin (100 microM, 30 min prior to infusion of nicotine) prevented nicotine-induced impairment in NOS-dependent vasodilation. Further, the production of superoxide anion was increased in the basilar artery by nicotine, and this increase could be inhibited by apocynin. Our findings suggest that acute exposure to nicotine impairs NOS-dependent dilation of the basilar artery by a mechanism that appears to be related to the release of superoxide anion. A possible source of superoxide may be via the activation of NAD(P)H oxidase.

Nicotine Impairs eNOS‐Dependent Responses of the Basilar Artery

Our goals were to determine whether acute exposure to nicotine alters eNOS‐dependent responses of the basilar artery and to identify a potential role for activation of NAD(P)H oxidase. We measured diameter of the basilar artery to eNOS‐dependent (acetylcholine) and ‐independent (nitroglycerin) agonists before and during acute infusion of nicotine in the absence or presence of apocynin. In addition, we measure superoxide production by brain tissue to nicotine. We found that eNOS‐dependent vasodilatation was impaired during treatment with nicotine and that apocynin prevented this impairment. Further, the production of superoxide was increased by nicotine and this increase could be inhibited by apocynin. We suggest that nicotine impairs eNOS‐dependent dilatation of the basilar artery by activation of NAD(P)H oxidase.

Acute infusion of nicotine impairs nNOS-dependent reactivity of cerebral arterioles via an increase in oxidative stress

Our goals were to determine whether acute exposure to nicotine alters neuronal nitric oxide synthase (nNOS)-dependent reactivity of cerebral arterioles and to identify a potential role for oxidative stress in nicotine-induced impairment in nNOS-dependent responses of cerebral arterioles. We measured in vivo diameter of cerebral arterioles to nNOS-dependent (N-methyl-d-aspartate and kainate) and -independent (nitroglycerin) agonists before and during acute treatment with nicotine. We found that nNOS-dependent, but not -independent, vasodilatation was impaired during treatment with nicotine. In addition, treatment of the cerebral microcirculation with tempol (1 h before infusion of nicotine) prevented nicotine-induced impairment in nNOS-dependent vasodilatation. Furthermore, the production of superoxide anion (lucigenin chemiluminescence) was increased in parietal cortex tissue of rats by treatment with nicotine, and this increase in superoxide anion production could be inhibited by tempol. Our findings suggest that acute exposure to nicotine impairs nNOS-dependent dilatation of cerebral arterioles by a mechanism that appears to be related to the formation of superoxide anion.

L‐Arginine prevents impaired endothelium‐dependent cerebral arteriolar dilatation during acute infusion of nicotine

Exogenous treatment with L-arginine has been shown to restore impaired nitric oxide synthase (NOS)-dependent dilatation of peripheral blood vessels during disease states. We have shown that nicotine impairs NOS-dependent arteriolar dilatation in the cerebral circulation. However, the role of L-arginine in impaired responses of cerebral arterioles during infusion of nicotine has not been examined. Thus the goal of the present study was to examine the role of L-arginine in nicotine-induced impairment of cerebral arteriolar reactivity. We measured the diameter of pial arterioles in response to NOS-dependent (5'-adenosine diphosphate [ADP] and acetylcholine) and NOS-independent (nitroglycerin) agonists before and after infusion of vehicle or nicotine (2 microg/kg/min intravenously for 30 min followed by a maintenance dose of 0.35 microg/kg/min) in the absence or presence of L-arginine (10(-3) M). We found that topical application of L-arginine to cerebral microvessels during infusion of nicotine could prevent impaired NOS-dependent vasodilatation. We suggest that exogenous L-arginine may have a beneficial role in preventing cerebral microvascular dysfunction during exposure to nicotine.

Acute and chronic treatment with nicotine impairs reactivity of arterioles in response to activation of potassium channels.

Although acute and chronic treatment with nicotine impairs nitric oxide synthase-dependent responses of large and small blood vessels, the effect of nicotine on other vasodilator pathways remains uncertain. The goal of the current study was to determine effects of nicotine on dilatation of arterioles to activation of ATP-sensitive potassium channels. Reactivity of cheek pouch arterioles ( approximately 50 microm) was measured during acute (1-2 h) and chronic (2-to 3-week) exposure to nicotine in response to aprikalim, cromakalim, and nitroglycerin. Acute treatment with nicotine impaired dilatation of arterioles in response to aprikalim and cromakalim but not nitroglycerin. Aprikalim and cromakalim (1.0 microM) dilated arterioles by 37 +/- 5% and 30 +/- 3%, respectively, before, but by only 21 +/- 4% and 16 +/- 3%, respectively, after infusion of nicotine (p < 0.05). Chronic exposure to nicotine did not alter vasodilatation to nitroglycerin but impaired vasodilatation to aprikalim and cromakalim. In vehicle-treated hamsters, aprikalim and cromakalim (1.0 microM) dilated arterioles by 28 +/- 1% and 32 +/- 3%, respectively. However, in nicotine-treated hamsters aprikalim and cromakalim (1.0 microM) dilated arterioles by only 3 +/- 1% and 13 +/- 1%, respectively. Next, the role of superoxide anion in impaired responses of arterioles to aprikalim and cromakalim during acute infusion of nicotine was examined. Treatment with superoxide dismutase attenuated the effects of nicotine on aprikalim and cromakalim. Thus, acute and chronic exposure to nicotine has profound affects on vasodilatation to activation of ATP-sensitive potassium channels, which may be mediated by superoxide anion.

Nicotine infusion acutely impairs insulin sensitivity in type 2 diabetic patients but not in healthy subjects

The aim of this study was to examine if an acute nicotine infusion alters insulin sensitivity to a similar degree in type 2 diabetic patients as in healthy control subjects. . Double-blind, cross-over, placebo-controlled, randomized experimental study. Nicotine 0.3 microg kg-1 min(-1) or NaCl was infused (2 h) during a euglycaemic hyperinsulinaemic clamp (4 h) to assess insulin sensitivity. University research laboratory. Six male and female type 2 diabetic patients [DM2; age 54 +/- 10 (mean +/- SD) years; body mass index (BMI) 25.6 +/- 2.9 kg m(-2)] treated with diet or one oral hypoglycaemic agent and six age- and BMI-matched control subjects (Ctr). Insulin sensitivity (rate of glucose infusion per kg fat free body mass and minute), nicotine and free fatty acid (FFA) levels, pulse rate and blood pressure. The infusions produced similar nicotine levels in both groups. In the absence of nicotine, DM2 were more insulin resistant than Ctr (6.7 +/- 0.4 vs. 10.9 +/- 0.3 mg kg-1 LBM min(-1), respectively; P < 0.0001). This insulin resistance was further aggravated by the nicotine infusion in DM2 but not in Ctr (4.6 +/- 0.3 vs. 10.9 +/- 0.3 mg kg(-1) LBM min(-1); P < 0.0001). Only minor differences were seen in FFA levels, pulse rates and blood pressure. At this low infusion rate, nicotine aggravated the insulin resistance in DM2 but not in Ctr. This finding may be because of the (dysmetabolic) diabetic state per se or to an increased sensitivity to environmental factors associated with a genetic predisposition for type 2 diabetes. These results show that diabetic subjects are particularly susceptible to the detrimental effects of nicotine.

Agonist-induced release of nitric oxide during acute exposure to nicotine

While we have shown that acute infusion of nicotine impairs agonist-induced dilatation of resistance arterioles (Am.J.Physiol. 272:H2337–H2342, 1997), no studies have examined the release of nitric oxide in response to these agonists before and during treatment with nicotine. Thus, the first goal of the present study was to examine agonist-induced release of nitric oxide by the hamster cheek pouch microcirculation under control conditions and during acute infusion of nicotine. We measured the release of nitric oxide (Sievers NO analyzer) in response to repeated topical application of acetylcholine (1.0 uμM) and 5′-adenosine diphosphate (ADP; 1.0 μM) during infusion of vehicle and during infusion of nicotine (2.0 μg/kg/min iv for 30 minutes followed by a maintenance dose of 0.35 μg/kg/min). In hamsters treated with vehicle, topical application of acetylcholine and ADP elicited reproducible increases in nitric oxide release. In contrast, in hamsters treated with nicotine, there was a marked inhibition of nitric oxide release in response to acetylcholine and ADP. In a previous study (J.Appl.Physiol. 85:1292–1298, 1998) we found that treatment of the hamster cheek pouch microcirculation with superoxide dismutase restored unpaired agonist-induced vasodilatation during acute infusion of nicotine. Thus, our second goal was to examine whether Superoxide dismutase would restore agonist-induced release of nitric oxide during infusion of nicotine. We found that treatment of the hamster cheek pouch microcirculation with superoxide dismutase prior to infusion of nicotine prevented nicotine-induced impairment of nitric oxide release in response to acetylcholine and ADP. We suggest that nicotine alters dilatation of arterioles via an increased release of superoxide anion and subsequent inactivation of nitric oxide.

Acute infusion of nicotine potentiates norepinephrine-induced vasoconstriction in the hamster cheek pouch

Although cigarette smoking and the components of cigarette smoke appear to alter nitric oxide synthase–dependent dilation of blood vessels, the effect of these substances on constrictor responses of resistance arterioles has not been examined. Thus the goal of this study was to examine the effect of a major component of cigarette smoke—that is, nicotine—on constrictor responses of cheek pouch arterioles. The diameter of cheek pouch arterioles (~50 μm in diameter) was measured by using intravital microscopy. We examined the responses of arterioles to angiotensin II, arginine vasopressin, norepinephrine, and the thromboxane analog U-46619 before and after treatment with vehicle (saline solution), NG-monomethyl-L-arginine (L -NMMA; 1.0 μmol/L), or nicotine (2.0 μg/kg/min IV for 30 minutes followed by a maintenance dose of 0.35 μg/kg/min for 30 minutes). Topical application of angiotensin II (0.01 and 0.1 nmol/L), arginine vasopressin (1.0 and 10 pmol/L), norepinephrine (1.0 and 10 nmol/L), and U-46619 (0.01 and 0.1 nmol/L) produced marked reproducible constriction of cheek pouch arterioles in hamsters treated with vehicle. Topical application of L -NMMA potentiated constrictor responses of arterioles to the high dose of arginine vasopressin (28% ± 4% versus 36% ± 4%; P < .05) and to both doses of norepinephrine (14% ± 1% and 24% ± 2% versus 19% ± 1% and 31% ± 3%; P < .05). The infusion of nicotine did not alter responses to angiotensin II, arginine vasopressin, or U-46619 but modestly potentiated vasoconstriction in response to norepinephrine (12% ± 2% and 22% ± 2% versus 14% ± 2% and 26% ± 2%; P < .05). These findings suggest that the synthesis/release of nitric oxide may modulate constrictor responses of cheek pouch resistance arterioles to selected agonists. In addition, nicotine, at levels observed in smokers, may potentiate norepinephrine-induced vasoconstriction. We suggest that preservation/potentiation of vasoconstrictor responses may contribute to the pathogenesis of vascular abnormalities associated with cigarette smoking. (J Lab Clin Med 1999;133:48-54)

Superoxide dismutase restores endothelium-dependent arteriolar dilatation during acute infusion of nicotine.

We previously showed [Am. J. Physiol. 272 (Heart Circ. Physiol. 41): H2337-H2342, 1997] that nicotine impairs endothelium-dependent arteriolar dilatation. However, mechanisms that accounted for the effect of nicotine on endothelium-dependent vasodilatation were not examined. Thus the goal of this study was to examine the role of oxygen radicals in nicotine-induced impairment of arteriolar reactivity. We measured diameter of cheek pouch resistance arterioles (approximately 50 micrometer diameter) in response to endothelium-dependent (ACh and ADP) and -independent (nitroglycerin) agonists before and after infusion of vehicle or nicotine in the absence or presence of superoxide dismutase. ACh, ADP, and nitroglycerin produced dose-related dilatation of cheek pouch arterioles before infusion of vehicle or nicotine. Infusion of vehicle, in the absence or presence of superoxide dismutase (150 U/ml), did not alter endothelium-dependent or -independent arteriolar dilatation. In contrast, infusion of nicotine (2 microgram . kg-1 . min-1) impaired endothelium-dependent, but not -independent, arteriolar dilatation. In addition, the effect of nicotine on endothelium-dependent vasodilatation was reversed by topical application of superoxide dismutase. We suggest that nicotine impairs endothelium-dependent arteriolar dilatation via an increase in the synthesis/release of oxygen-derived free radicals.

Prenatal nicotine exposure impairs the cardiorespiratory response to acute hypoxemia in sleeping lambs. • 1798

Maternal smoking is a major risk factor for SIDS. The mechanism of action may be a nicotine mediated attenuation of the hypoxic defense as evidenced by impaired arousal and blunted ventilatory response to acute hypoxemia in young lambs exposed to an acute nicotine infusion (Hafstrom et al, Pediatr Res 39:386A, 1996). The aim of this study was to determine whether prenatal nicotine exposure alters the cardiorespiratory response to hypoxia after birth.

Effects of nicotine withdrawal on the local cerebral glucose utilization in conscious rats

Chronic infusion of nicotine has been shown to result (1) in an increase in nicotine binding sites in the brain and (2) in a distinct pattern of increases in local cerebral metabolic rate for glucose (CMRglc). The present study addresses two questions: (1) whether a one-day withdrawal of nicotine after a two-week exposure is long enough to restore local CMRglc to the preinfusion values and (2) whether an acute nicotine infusion after one day's withdrawal would influence local CMRglc. Chronic infusion of L-nicotine (12.5 micrograms/kg/min) was performed by osmotic minipumps. Local CMRglc was measured using the quantitative 2-deoxyglucose method in conscious rats. The following results were obtained: (1) a one-day withdrawal of nicotine after a two-week chronic infusion restores local CMRglc to a pattern which is close to the control pattern obtained without any nicotine infusion, and (2) an acute infusion of nicotine after a one-day withdrawal of a chronic nicotine infusion induces distinct increases in local CMRglc of several brain structures; these are essentially identical with structures which are activated during an acute nicotine infusion in otherwise untreated rats (no chronic infusion). The data indicate: (1) The main effects of chronic nicotine infusion on local CMRglc have disappeared after one day of nicotine withdrawal. (2) An acute load of nicotine in such nicotine-withdrawal rats has effects on local CMRglc which resemble those found in previously untreated rats during an acute nicotine infusion. (3) In contrast to most binding studies which have shown persisting increases in nicotine binding sites after one day's withdrawal of chronic nicotine, local CMRglc is restored to control values and can be again activated by an acute nicotine infusion.

The influence of nicotine on local cerebral blood flow in rats

Local cerebral blood flow (LCBF) was measured in conscious rats during an acute nicotine infusion. LCBF was measured using the autoradiographic iodoantipyrine method. LCBF was unchanged in most brain structures during nicotine infusion compared to controls. Significant ( P < 0.05) increases were found in 3 structures (lateral geniculate body, superior colliculus, anteroventral nucleus of the thalamus). These structures have already shown increases in local glucose utilization in a previous study [2]. The observed increases in LCBF are interpreted to be secondary to metabolic activation by nicotine indicating the lack of a direct action of nicotine on cerebral blood vessels.

Local cerebral glucose utilization of the awake rat during chronic administration of nicotine

Local cerebral glucose utilization (LCGU) was measured in 45 regions of the rat brain during chronic nicotine infusion using the quantitative autoradiographic 2-deoxy- d-[1- 14C]glucose method described by Sokoloff et al. [J. Neurochem., 28 (1977) 897–916]. Osmotic minipumps, filled with l-nicotine, were implanted 14 days before the measurement of LCGU. The infused nicotine dose of 12.5 μg/kg/min resulted in a plasma nicotine concentration of 77 ± 17 and a plasma cotinine concentration of 504 ± 137 (mean±S.E.M.) ng/ml plasma. One day before the LCGU experiment was performed, spontaneous locomotor activity was measured and found to be reduced significantly. Measurement of LCGU showed a significant increase in 6 of the 45 brain structures examined, i.e. globus pallidus, septal nucleus, lateral geniculate body, superior colliculus (superficial grey layer), interpeduncular nucleus and optic chiasm. These results are partly congruent with previous data of our group obtained during acute nicotine infusion, insofar as LCGU was increased in the optic chiasm, the lateral geniculate body, the superior colliculus, and the interpeduncular nucleus. On the other hand, the increased LCGU in the globus pallidus and septal nucleus occurred during chronic infusion only; other structures were not affected by chronic infusion although their LCGU had been raised during acute infusion. It is concluded that chronic nicotine infusion has distinct effects on the functional activity of several brain structures which are partly congruent with those affected during acute nicotine infusion and partly divergent from them.

Effects of chronic smoke exposure on the cardiovascular responses to acute nicotine infusion in the rat

Rats were exposed daily to cigarette smoke for 17–22 weeks in order to characterize mean arterial pressure and regional hemodynamic effects of chronic smoke exposure and to determine if cardiovascular reactivity to acute nicotine infusions is altered by chronic smoke exposure. Urethane-anesthetized animals were instrumented with miniaturized pulsed-Doppler flow probes on the iliac and mesenteric vascular beds. Under resting conditions sham-smoked and smoke-exposed animals had similar levels of mean arterial pressure and mesenteric blood flow; however, resting heart rate was lower in the smoke-exposed group, while iliac blood flow was elevated in the smoke-exposed group. Acute nicotine infusion (6.25, 12.5 and 25 μg/kg per min) produced equivalent, dose-dependent pressor effects as well as increases in iliac and mesenteric resistance in sham and smoke-exposed groups. Thus, chronic cigarette smoke-exposure in rats may exert significant cardiovascular effects other than on arterial pressure such as lowered heart rate and elevated blood flow to skeletal muscle beds, while cardiovascular responses to nicotine are not altered by chronic smoke-exposure.

The effect of an acute nicotine infusion on the local cerebral glucose utilization of the awake rat

The effect of acute infusion of nicotine on local cerebral glucose utilization (LCGU) was studied in discrete regions of the central nervous system of the rat by means of the quantitative autoradiographic 2-deoxy- d-[1- 14C]glucose method described by Sokoloff et al. 26. Nicotine was administered in 3 dosages: 0.5 μg/kg/min and 5 μg/kg/min. The resulting plasma concentrations of nicotine were 10/39/114 ng/ml plasma. During the experiment, blood pressure, heart rate, body temperature, hematocrit, acid-base status and plasma glucose concentration showed no — or minor — changes. Nicotine significantly increased LCGU in a dose-dependent manner in the following 9 of 45 examined structures: substantia nigra (compact part), superior colliculus (superficial grey layer), interpeduncular nucleus and cingulate cortex ( P < 0.05); lateral geniculate body, optic chiasm, anteroventral and anteromedial nucleus of thalamus and mamillary body ( P < 0.05). For most of these structures with increased LCGU, other groups have reported a high regional receptor binding of nicotine (exception: mamillary body and optic chiasm). It is concluded that nicotine has distinct effects on the functional activity of localized brain areas.