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Department of Physiology and Biophysics, University of Nebraska Medical Center, Omaha, Nebraska 68198-4575
ABSTRACT
INTRODUCTION
METHODS
RESULTS
DISCUSSION
ACKNOWLEDGEMENTS
FOOTNOTES
REFERENCES
ABSTRACT 
Mayhan, William G., and Glenda M. Sharpe. Effect of
cigarette smoke extract on arteriolar dilatation in vivo.
J. Appl. Physiol. 81(5):
1996-2003, 1996.
The goal of this study was to determine whether
cigarette smoke extract alters dilatation of arterioles in vivo in
response to agonists that produce activation of ATP-sensitive potassium
channels and activation of adenylate cyclase. By using intravital
microscopy, we measured diameter of arterioles contained within the
microcirculation of the hamster cheek pouch during suffusion with
agonists in the absence and presence of cigarette smoke extract (0.1, 0.5, and 1.0%). Before treatment with cigarette smoke extract,
activation of ATP-sensitive potassium channels with aprikalim and
cromakalim produced dose-related dilatation of cheek pouch
arterioles. Similarly, activation of adenylate cyclase
with isoproterenol and forskolin produced dose-related dilatation of
cheek pouch arterioles before treatment with cigarette smoke extract.
Superfusion of 0.1% cigarette smoke extract did not change baseline
diameter of arterioles and did not alter responses of cheek pouch
arterioles to activation of ATP-sensitive potassium channels and
adenylate cyclase. Superfusion of 0.5 and 1.0% cigarette smoke extract
also did not alter baseline diameter of arterioles but did impair
dilatation of arterioles in response to activation of ATP-sensitive
potassium channels and adenylate cyclase. These findings suggest that
cigarette smoke extract impairs dilatation of resistance arterioles in
response to activation of important cellular dilator pathways.
aprikalim; cromakalim; isoproterenol; forskolin; microcirculation; adenosine 5 INTRODUCTION CIGARETTE SMOKING in human subjects produces
diffuse vascular injury in many organ systems (8, 16, 27, 51). Although the morphological and functional effects of cigarette smoke and /or
cigarette smoke extract on isolated blood vessels and endothelial cells
in vitro have been examined, the pathogenesis of cigarette smoking-induced vascular damage in vivo is still unclear.
Morphological abnormalities, i.e., endothelial cell swelling, extensive
subendothelial edema, and subendothelial blebs, and an increased number
of subendothelial macrophages in the arterial wall have been observed
in human subjects exposed to cigarette smoke for prolonged periods of
time (2, 4, 32). Functionally, exposure of animals and endothelial cell
monolayers to cigarette smoke has been shown to increase permeability
to plasma proteins (3, 20, 23, 32) and to decrease nitric oxide
synthase-mediated relaxation of blood vessels from human subjects (17,
18). In addition, recent studies from our laboratory suggest that
cigarette smoke extract potentiates agonist-induced increases in
microvascular permeability (36) and impairs nitric oxide
synthase-mediated dilatation of resistance arterioles in vivo (48).
In addition to activation of guanylate cyclase via the synthesis
and /or release of nitric oxide, relaxation of vascular smooth muscle can be influenced by activation of ATP-sensitive potassium channels and activation of adenylate cyclase. However, no
studies have examined the effects of cigarette smoking on these
important cellular dilator pathways. Thus the goal of this study was to examine the effects of cigarette smoke extract on dilatation of resistance arterioles in vivo in response to activation of
ATP-sensitive potassium channels and in response to activation of
adenylate cyclase.
METHODS 
-triphosphate-sensitive potassium channels; adenylate
cyclase; cheek pouch; hamsters
1 · h1).
A femoral artery was cannulated to measure arterial blood pressure, which remained constant during the experiment (data not shown). At the
end of the experiment, all animals were killed with an intravenous
infusion of anesthesia (60 mg/100 g body wt). All procedures were
carried out after institutional approval and within institutional
guidelines.
70°C
until use. On the day of the experiment, one aliquot of the stock
solution (considered 100% cigarette smoke extract) was thawed and
diluted in buffer to the appropriate concentrations (0.1, 0.5, and
1.0%). In one study, we determined whether freshly made vs. frozen
cigarette smoke extract affected responses of arterioles to the
agonists. It is difficult to precisely determine the
concentration of cigarette smoke products in blood and tissue in
habitual smokers at rest and during cigarette smoking. The
concentrations of cigarette smoke extract that we chose in the present
study are based on previous studies from our laboratory (36, 48) and
studies from other investigators (19, 20, 41) that postulate that concentrations of cigarette smoke products in tissue and /or
blood in habitual smokers are within the range of concentrations used in the present study.
Experimental protocol.
The cheek pouch microcirculation was superfused for 30 min before
responses of arterioles to the agonists were tested. In the first group
of hamsters (n = 7), we initially
examined responses of cheek pouch arterioles to activation of
ATP-sensitive potassium channels by using aprikalim (0.1 and 1.0 µM)
and cromakalim (0.1 and 1.0 µM) and to activation of adenylate
cyclase by using isoproterenol (1.0 and 10 µM) and forskolin (0.1 and
1.0 µM). Then, we suffused cigarette smoke extract (0.1%) over the
cheek pouch microcirculation. Thirty minutes after starting a
continuous superfusion of cigarette smoke extract, we again examined
responses of arterioles to aprikalim, cromakalim, isoproterenol, and
forskolin. In one study, we were able to determine whether freshly made
cigarette smoke extract produced similar effects on reactivity of
arterioles as did frozen cigarette smoke extract. Aprikalim (0.1 and
1.0 µM) dilated arterioles by 21 and 36%, respectively, before and
by 20 and 34%, respectively, after application of freshly made
cigarette smoke extract. Cromakalim (0.1 and 1.0 µM) dilated
arterioles by 23 and 44%, respectively, before and by 20 and 41%,
respectively, after application of freshly made cigarette smoke
extract. Isoproterenol (1.0 and 10 µM) dilated arterioles by 16 and
25%, respectively, before and by 12 and 21%, respectively, after
application of freshly made cigarette smoke extract. Forskolin (0.1 and
1.0 µM) dilated arterioles by 13 and 28%, respectively, before and
by 13 and 27%, respectively, after application of freshly made
cigarette smoke extract. The conclusions drawn from these findings of
studies using freshly made cigarette smoke extract are similar to those
drawn from studies using frozen and thawed cigarette smoke extract
(0.1%).
In a second group of hamsters (n = 8),
a similar protocol was followed with the exception that we examined the
effect of 0.5% cigarette smoke extract. Thus we initially
examined responses of cheek pouch arterioles to activation of
ATP-sensitive potassium channels by using aprikalim (0.1 and 1.0 µM) and cromakalim (0.1 and 1.0 µM) and to activation of adenyl-
ate cyclase by using isoproterenol (1.0 and 10 µM) and
forskolin (0.1 and 1.0 µM). Then, we suffused cigarette smoke extract
(0.5%) over the cheek pouch microcirculation. Thirty minutes after
starting a continuous superfusion of cigarette smoke extract, we again
examined responses of arterioles to aprikalim, cromakalim,
isoproterenol, and forskolin. The concentrations of agonists used in
these studies were based on previous studies (34) that indicated that
these concentrations produced marked dilatation of cheek pouch
resistance arterioles.
In a third group of hamsters (n = 8),
a similar protocol was followed with the exception that we examined the
effect of 1.0% cigarette smoke extract. Thus we initially
examined responses of cheek pouch arterioles to activation of
ATP-sensitive potassium channels by using aprikalim (0.1 and 1.0 µM)
and cromakalim (0.1 and 1.0 µM) and to activation of adenylate
cyclase by using isoproterenol (1.0 and 10 µM) and forskolin (0.1 and
1.0 µM). Then, we suffused cigarette smoke extract (1.0%) over the
cheek pouch microcirculation. Thirty minutes after starting a
continuous superfusion of cigarette smoke extract, we again examined
responses of arterioles to aprikalim, cromakalim, isoproterenol, and
forskolin.
In a fourth group of hamsters (n = 5),
a similar protocol was followed with the exception that we examined the
effect of vehicle on reactivity of arterioles to the
agonists. Thus we initially examined responses of cheek
pouch arterioles to activation of ATP-sensitive potassium channels by
using aprikalim (0.1 and 1.0 µM) and cromakalim (0.1 and 1.0 µM)
and to activation of adenylate cyclase by using isoproterenol (1.0 and
10 µM) and forskolin (0.1 and 1.0 µM). Then, we suffused vehicle
(bicarbonated buffer) over the cheek pouch microcirculation. Thirty
minutes after starting a continuous superfusion of vehicle, we again
examined responses of arterioles to aprikalim, cromakalim,
isoproterenol, and forskolin.
Drugs.
Aprikalim was a gift from Rhone-Poulenc Rorer. Aprikalim was dissolved
in dimethylsulfoxide (DMSO) to make a stock solution of 1.0 mM.
Dilutions from the stock were made in saline on the day of the
experiment. Cromakalim was a gift from SmithKline Beecham Pharmaceutical. Cromakalim was dissolved in ethanol to make a stock
solution of 1.0 mM. Dilutions from the stock were made in saline on the
day of the experiment. Isoproterenol was purchased from Sanofi Winthrop
Pharmaceuticals and mixed in saline on the day of the experiment.
Forskolin was purchased from Calbiochem. Forskolin was dissolved in
DMSO to make a stock solution of 0.1 mM. Dilutions from the stock were
made in saline on the day of the experiment.
Statistical analysis.
Repeated-measures analysis of variance with Student-Newman-Keuls test
was used to compare responses of cheek pouch arterioles with the
agonists before and after exposure to a specific concentration of
cigarette smoke extract. A P value of
<0.05 was considered to be significant. Data are expressed as means ± SE.
RESULTS
Topical application of 0.1% cigarette smoke extract did not alter baseline diameter of cheek pouch arterioles. Diameter of cheek pouch arterioles was 50 ± 2 (SE) µm before application of cigarette smoke extract and 48 ± 2 µm after application of cigarette smoke extract (P > 0.05). Furthermore, application of 0.1% cigarette smoke extract did not alter dilatation of cheek pouch arterioles in response to activation of ATP-sensitive potassium channels and activation of adenylate cyclase (P > 0.05; Fig. 1). Effect of 0.5% cigarette smoke extract. Under control conditions, activation of ATP-sensitive potassium channels by using aprikalim and cromakalim and activation of adenylate cyclase by using isoproterenol and forskolin produced dose-related dilatation of cheek pouch arterioles (Fig. 2; P < 0.05 vs. baseline diameter).
Topical application of 0.5% cigarette smoke extract did not alter baseline diameter of cheek pouch arterioles. Diameter of cheek pouch arterioles was 51 ± 2 (SE) µm before application of cigarette smoke extract and 52 ± 2 µm after application of cigarette smoke extract (P > 0.05). In contrast to the effect observed with 0.1% cigarette smoke extract, application of 0.5% cigarette smoke impaired dilatation of cheek pouch arterioles in response to aprikalim, the high dose (1.0 µM) of cromakalim, the high dose (10 µM) of isoproterenol, and the high dose (1.0 µM) of forskolin (P < 0.05; Fig. 2). Effect of 1.0% cigarette smoke extract. Under control conditions, activation of ATP-sensitive potassium channels by using aprikalim and cromakalim and activation of adenylate cyclase by using isoproterenol and forskolin produced dose-related dilatation of cheek pouch arterioles (Fig. 3; P < 0.05 vs. baseline diameter).
Topical application of 1.0% cigarette smoke extract did not alter baseline diameter of cheek pouch arterioles. Diameter of cheek pouch arterioles was 49 ± 2 (SE) µm before application of cigarette smoke extract and 50 ± 1 µm after application of cigarette smoke extract (P > 0.05). In addition, application of 1.0% cigarette smoke impaired dilatation of cheek pouch arterioles in response to activation of ATP-sensitive potassium channels and activation of adenylate cyclase (P < 0.05; Fig. 3).
DISCUSSION
The present study is the first to examine the effects of cigarette smoke extract dilatation of resistance arterioles in vivo in response to activation of ATP-sensitive potassium channels and adenylate cyclase. There are two new findings of this study. First, a low concentration of cigarette smoke extract (0.1%) did not alter dilatation of cheek pouch arterioles in response to activation of ATP-sensitive potassium channels and adenylate cyclase. Second, higher concentrations of cigarette smoke extract (0.5 and 1.0%) impaired dilatation of cheek pouch in response to activation of ATP-sensitive potassium channels and adenylate cyclase. The findings of the present study suggest that exposure of resistance arterioles to components of cigarette smoke alters important cellular vasodilator pathways.
Consideration of methods. Many previous studies have examined the effects of activation of ATP-sensitive potassium channels on large peripheral and cerebral blood vessels in vitro (26, 28, 33, 38-40, 43) and in vivo (9, 11, 52, 55). In addition, Mayhan (34) and other investigators (52) have examined the effects of activation of ATP-sensitive potassium channels on peripheral resistance arterioles. In general, activation of ATP-sensitive potassium channels with cromakalim, pinacidil, nicorandil, and aprikalim produces marked relaxation and /or dilatation of arteries and arterioles. Relaxation and /or dilatation of arteries and arterioles in response to activation of ATP-sensitive potassium channels in vitro and in vivo appears to be specific because glibenclamide inhibits responses to activation of ATP-sensitive potassium channels (9, 33, 34, 38, 44, 50). Furthermore, Mayhan has shown that dilatation of cheek pouch arterioles in response to activation of ATP-sensitive potassium channels with aprikalim and cromakalim is not related to the synthesis/release of nitric oxide or a nitric oxide-containing compound. The results of the present study support findings of previous studies (9, 11, 34, 55) that suggest an important role for activation of ATP-sensitive potassium channels in dilatation of blood vessels in vivo. In addition, the results of the present experiments extend findings of previous studies by examining responses of resistance arterioles in vivo to activation of ATP-sensitive potassium channels during exposure to cigarette smoke extract. Relaxation of vascular smooth muscle also can occur via activation of adenylate cyclase via stimulation of
-adrenergic receptors and /or direct activation of adenylate cyclase by forskolin
(15, 49). Although many previous studies have examined responses of
arteries and arterioles to isoproterenol and forskolin, a recent study
(21) has examined responses of hamster cheek pouch arterioles to
isoproterenol and forskolin. This previous study (21) found that
isoproterenol and forskolin produced pronounced dose-related dilatation
of cheek pouch arterioles. Surprisingly, dilatation of cheek pouch
arterioles in response to isoproterenol was partially inhibited by
application of glibenclamide (21). This finding suggests a role for
activation of ATP-sensitive potassium channels in isoproterenol-induced
dilatation of cheek pouch arterioles. Dilatation of cheek pouch
arterioles in response to forskolin, however, was not altered by
treatment with glibenclamide. Although we did not examine a specific
role for activation of ATP-sensitive potassium channels in dilatation
of cheek pouch arterioles in response to isoproterenol in the present
study, it is possible that inhibition of isoproterenol-induced
vasodilatation by cigarette smoke is partially related to an effect on
ATP-sensitive potassium channels. However, we also observed that
cigarette smoke extract (0.5 and 1.0%) inhibited vasodilatation in
response to forskolin, which presumably dilates cheek pouch arterioles
independent of the activation of ATP-sensitive potassium channels (21).
Thus it appears that cigarette smoke extract impairs reactivity of arterioles in response to activation of ATP-sensitive potassium channels and in response to activation of adenylate cyclase.
We examined the effects of various concentrations of cigarette smoke
extract on baseline diameter of cheek pouch arterioles. We found that
cigarette smoke extract did not alter baseline diameter of cheek pouch
arterioles. Two other studies examined the effect of cigarette smoke
extract on diameter of arteries in vitro. Holden et al. (19) found that
cigarette smoke extract produced biphasic responses of intrapulmonary
arteries. Relaxation of intrapulmonary arteries occurred at low
concentrations of cigarette smoke extract (0.001-0.01%), and
constriction of arteries occurred at higher concentrations
(0.1-1.0%) of cigarette smoke extract. In other studies,
investigators found that the gaseous phase of cigarette smoke produced
relaxation of coronary arteries in vitro (12). The mechanism of
relaxation appeared to be related to the activation of guanylate
cyclase, presumably by production of nitric oxide. The results of the
present study differ from previous studies (12, 19). We did not find a
direct effect of cigarette smoke extract on baseline diameter of cheek
pouch arterioles. There are, however, significant differences between
the present study and previous studies (12, 19).
We examined responses of small arterioles contained within the hamster
cheek pouch in vivo, and the previous studies examined responses of
large bovine coronary and pulmonary arteries in vitro (12, 19). Thus
the discrepancy between the present study and previous studies may be
related to size of blood vessels studied, the tissue from which the
blood vessels were derived, and /or a species difference in
response to cigarette smoke extract. We examined the effects of topical
application of cigarette smoke extract, made by bubbling cigarette
smoke through a buffer solution, on arteriolar reactivity. There may be
several limitations of this methodology. First, during cigarette
smoking the products of inhaled smoke that interact with the
endothelium and /or vascular smooth muscle are filtered by
the lungs before entering the blood. In the present study, we were not
able to examine the effects of inhaled smoke vs. smoke extract on
reactivity of resistance arterioles, and thus we cannot exclude the
possibility that reactivity of arterioles may be affected differently
by inhaled smoke. Second, there may be complex interactions
between the components of blood and /or vascular wall and
the products produced during cigarette smoking that may attenuate or
exacerbate the effects of cigarette smoke. In the present study we were
not able to examine these potential interactions and thus cannot draw
conclusions with regard to the role of these potentially important
interactions to impaired reactivity of arterioles. Although there may
be limitations to the present study, we suggest that our findings
provide new insights into the potential effects of cigarette smoking on
important cellular vasodilator pathways.
Consideration of previous studies.
No studies have examined the effect of cigarette smoke extract on
dilator responses of arterioles to activation of ATP-sensitive potassium channels and activation of adenylate cyclase. For the most
part, previous studies have concentrated on an examination of the
effects of cigarette smoking on endothelium-dependent, i.e., nitric
oxide synthase-mediated, responses of peripheral blood vessels. Holden
et al. (19) found that reactivity of intrapulmonary arteries in vitro
in response to cigarette smoke extract (0.001-0.01%) could be
inhibited by removal of the endothelium. Thus it appears that the
endothelium may participate in the vascular response of intrapulmonary
arteries during exposure to cigarette smoke. These investigators (19),
however, did not examine whether cigarette smoke extract altered
responses of intrapulmonary arteries to nitric oxide synthase-mediated
agonists. Other studies using human subjects have shown that cigarette
smoking impairs nitric oxide synthase-mediated relaxation of large
peripheral blood vessels (17, 18). However, other studies using human
subjects have shown either no alteration in nitric oxide
synthase-mediated vasorelaxation (22) or increased sensitivity of
vascular smooth to nitric oxide synthase-mediated vasodilators in
smokers (47). Rubinstein et al. (48) have previously examined nitric
oxide synthase-mediated dilatation of cheek pouch arterioles after
exposure to cigarette smoke extract (1.0%). They found that dilatation
of cheek pouch arterioles in vivo in response to acetylcholine was
profoundly impaired after exposure to cigarette smoke extract (48).
Dilatation of arterioles in response to nitroglycerin, however, was not
altered by exposure to cigarette smoke extract, suggesting that the
effects of cigarette smoke extract are specific for nitric oxide
synthase-mediated responses. Although there appears to be some
discrepancy in results concerning the effects of cigarette smoking on
nitric oxide synthase-mediated vasoreactivity, the results from the
previous study of Rubinstein et al. (48) and studies by other
investigators (17, 18) suggest an important effect of cigarette smoking
on nitric oxide synthase-mediated responses of blood vessels.
The present study is the first to examine the effects of cigarette
smoke extract on other important cellular dilator pathways, i.e.,
activation of ATP-sensitive potassium channels and activation of
adenylate cyclase. We found that low concentrations of cigarette smoke
extract do not alter dilatation of arterioles in response to activation
of ATP-sensitive potassium channels and activation of adenylate
cyclase. Modest-to-moderate concentrations of cigarette smoke extract,
however, produced profound impairment in dilatation of cheek pouch
arterioles in response to activation of ATP-sensitive potassium
channels and adenylate cyclase. Thus findings from the present series
of experiments extend previous findings (17, 18, 48) by examining the
effects of cigarette smoke extract on important cellular dilator
pathways of resistance arterioles.
Mechanism of cigarette smoke extract-induced alterations in vascular
reactivity.
The chemical composition of cigarette smoke is complex, and it is
difficult to determine which compound(s) may be involved in cigarette
smoke extract-induced vascular injury. Nicotine, a major component of
cigarette smoke, has been shown to increase the frequency of
endothelial cell death and thus could be considered a mediator of
vascular injury (29, 31). However, several studies failed to
demonstrate consistent and significant functional and /or
pathological alterations in vascular wall properties during exposure to
nicotine (1, 24, 42), and no studies have examined the effects of
nicotine on reactivity of resistance arterioles in response to
activation of ATP-sensitive potassium channels and adenylate cyclase.
Thus we cannot determine whether the impaired reactivity of arterioles
observed in the present study during exposure to cigarette smoke
extract is related to elevations in nicotine.
Cigarette smoke extract contains many toxic substances, in addition to
nicotine, that may contribute to impaired vascular reactivity. Acrolein and acetaldehyde are highly soluble
components of cigarette smoke extract and have been shown to cause
irritation of airway and ocular mucosa in humans, impair mucociliary
clearance in the upper airway, produce pulmonary edema in animals, and
damage epithelial cells (13, 14, 30, 45). In addition, Holden et al.
(20) have shown that cigarette smoke extract increases albumin flux
across cultured porcine pulmonary endothelium, and this effect was
predominantly due to the vapor phase of cigarette smoke. Furthermore,
cigarette smoke extract contains considerable amounts of oxygen
radicals such as superoxide anion and hydrogen peroxide that may
contribute to vascular dysfunction observed in cigarette smokers (41).
Thus, although the precise contribution of the various components of
cigarette smoke extract to vascular reactivity cannot be determined
from the present study, we speculate that it involves complex
interactions between various components of cigarette smoke extract.
Summary and implications.
We found that cigarette smoke extract produced a concentration-related
impairment in dilatation of resistance arterioles in response to
activation of ATP-sensitive potassium channels and activation of
adenylate cyclase. We suggest that these findings may have important
implications for chronic tobacco smokers. Studies have shown that
cigarette smoking contributes to the development of many cardiovascular
abnormalities, including tissue ischemia, atherosclerosis, stroke, and
coronary artery disease (29, 37, 53, 54, 56). Several cellular
mechanisms, including synthesis and /or release of nitric oxide,
synthesis and /or release of endothelium-derived hyperpolarizing
factor to activate ATP-sensitive potassium channels, and /or
synthesis and /or release of prostaglandins to activate of adenylate
cyclase (5, 10, 46), attempt to maintain adequate tissue blood flow
during increases in demand. Although it is clear that cigarette smoking
may alter the nitric oxide synthase-mediated pathway, the findings of
the present study suggest that cigarette smoking also may contribute to
vascular dysfunction, in part, by altering the ability of resistance
arterioles to dilate in response to activation of ATP-sensitive
potassium channels and activation of adenylate cyclase. Thus our
findings provide new insights into the effects of cigarette smoking on important cellular vasodilator pathways.
ACKNOWLEDGEMENTS
This study was supported by National Heart, Lung, and Blood Institute Grant HL-40781; American Heart Association, Nebraska Affiliate, Grant-in-Aid 9307792S; a grant from the American Diabetes Association; and Nebraska Smoking and Cancer Research Foundation Grant 96-47.
FOOTNOTES
Address for reprint requests: W. G. Mayhan, Dept. of Physiology, Univ. of Nebraska Medical Center, 600 S. 42nd St., Omaha, NE 68198-4575.
Received 15 December 1995; accepted in final form 8 July 1996.
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