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ABSTRACT |
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TOP
ABSTRACT
INTRODUCTION
METHODS
RESULTS
DISCUSSION
REFERENCES
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Furosemide pretreatment greatly reduces the severity of an asthmatic response to several types of
bronchoconstrictor challenge. Indirect evidence suggests that furosemide exerts its protective effects
by dilating the airway vasculature during thermal stress. To test the hypothesis that furosemide dilates airway microvessels, the tracheas of anesthetized rats were surgically exposed and continuously
suffused with Krebs Ringer bicarbonate warmed to 37° C. Tracheal adventitial arterioles (13.0 to 41.0 µm initial diameter, n = 47) and venules (50.0 to 99.0 µm initial diameter, n = 46) were visualized
with a videomicroscope, and vessel diameters were measured using videocalipers. When vessels were
preconstricted with 10
4 M phenylephrine, a selective 
1-adrenergic agonist, and then treated with
104 M furosemide, significant (p < 0.05) dilation was observed in both arterioles (from 64.6 to
79.5% of their initial diameter) and venules (from 52.1 to 65.4% of their initial diameter). When vessels were preconstricted with 104 phenylephrine, after pretreatment with the cyclooxygenase inhibitor indomethacin (5.0 mg/kg), 104 M furosemide significantly dilated arterioles (from 77.5 to 93.0% of their initial diameter) and venules (from 58.5 to 80.1% of their initial diameter). In vessels preconstricted with 103 M L-NAME, an inhibitor of nitric oxide synthesis, addition of 104 M furosemide to
the suffusion still caused significant dilation in arterioles, from 77.4 to 88.8% of their initial diameter,
and in venules from 79.5 to 86.7% of their initial diameter. These data confirm that furosemide,
when applied topically, dilates tracheal arterioles and venules by cyclooxygenase- and nitric oxide-
independent mechanisms.
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INTRODUCTION |
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TOP
ABSTRACT
INTRODUCTION
METHODS
RESULTS
DISCUSSION
REFERENCES
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When given as an aerosol pretreatment, furosemide has been shown to significantly reduce the severity of the airway obstruction that occurs in asthmatics in response to a variety of stimuli, including exercise (1, 2), cold air hyperventilation (3), immunologic challenge (4, 5), and nebulized water (6). Inhaled furosemide may also be useful for the treatment of bronchopulmonary dysplasia, a chronic lung disease of premature infants that causes airway obstruction similar to that of asthma (7). The mechanism for this protective effect of furosemide is currently unknown, but it appears to be unrelated to the diuretic actions of this drug (3, 6, 8).
MacFadden and coworkers (9) showed that exercise-induced asthma is related to the thermal gradient that develops between the airway cooling of hyperpnea and the airway rewarming. When this gradient is lessened, the severity of the obstruction response is reduced (10). This same group demonstrated that changes in airway blood flow significantly alters the gradient for intrathoracic heat exchange (11), although this finding is disputed by others (12). Gilbert and associates (10) reported that inhaled furosemide reduced the thermal gradient for rewarming of the airways after hyperpnea and proposed that the action of this agent was consistent with increased blood flow to the airways. Furosemide has been shown to act as a peripheral (13) and pulmonary (14) vasodilator, to inhibit aortic smooth muscle contractility (15), and to reduce pulmonary arterial pressure (16), but to our knowledge, no direct vasodilatory action of this agent has been demonstrated in airway vessels.
In the present study, we used an in vivo rat preparation to determine whether furosemide indeed dilates tracheal microvessels. Some studies attribute the vasodilatory and protective effects of furosemide to production of products of cyclooxygenase metabolism (16, 17). Therefore, we also tested the hypothesis that the vasoactive effects of furosemide are due to a cyclooxygenase-dependent process. Because cultured endothelial cells in vitro release nitric oxide when treated with furosemide (18), the possibility that furosemide-induced dilation occurs by a nitric oxide-dependent mechanism was also examined.
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METHODS |
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ABSTRACT
INTRODUCTION
METHODS
RESULTS
DISCUSSION
REFERENCES
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Surgical Procedures
Retired breeder Sprague-Dawley rats weighing 250 to 550 g were used in this study. Anesthesia was induced initially by intraperitoneal administration of sodium pentobarbital (50 mg/kg). Catheters were placed in the left femoral artery for monitoring blood pressure and in the left femoral vein for supplemental administration of anesthesia. Body temperature was maintained at 36 to 37° C with a heating pad and radiant heat.
The trachea was prepared for in vivo observation of the microvasculature as previously described (19). Briefly, the rats were placed in the supine position and mechanically ventilated through an uncuffed endotracheal tube with a gas mixture of 40% O2 (balance N2). The ventilation gas was humidified by passing it through a gas washer filled with distilled water. The temperature of the inspired gas was approximately 25° C. To reduce movement associated with breathing, pancuronium bromide (2 mg/ml/kg) was administered intravenously at the onset of ventilation. Krebs Ringer bicarbonate, warmed to 37° C and gassed with 95% N2 and 5% CO2, was constantly suffused over the ventral surface of the trachea. The tracheal ventral surface was epiilluminated, and vessels were visualized with a Zeiss ACM videomicroscope. Videocalipers (Microcirculation Research Institute, Texas A&M, College Station, TX) were used to measure microvessel diameters.
Once the anesthetized rats were placed onto the stage of the microscope, the preparation was allowed to stabilize for approximately 60 min before beginning the protocol. The preparation was considered acceptable when (1) mean arterial pressure was 
80 mm Hg
and stable, (2) blood pH was 7.35 to 7.45, and (3) no visible hemorrhages were present in the trachea. If any of these criteria were not achieved and maintained for the duration of the protocol, the experiment was terminated, and the data were omitted from the analysis.
A detailed description of the organization of tracheal adventitial vessels has been previously described (19). Arterioles were defined as vessels where (1) blood subsequently flows into smaller vessels or capillaries, (2) velocity of blood flow is very rapid, and (3) no adherence of leukocytes is observed. Venules were defined as vessels where (1) blood flows into convergent larger vessels, and (2) blood flow velocity is noticeably low. Adherent leukocytes were sometimes, but not always, observed within venules. A previous study where intravascular pressures were measured confirmed these criteria for distinguished arterioles from venules (22).
Experimental Protocols
Initially, tracheal arteriolar and venular diameters were continuously
monitored for a period of about 20 min to insure that vessels were stable. Then, a preconstricting agent (see below) was added to the Krebs
suffusate, and vessel diameters were measured at 5-min intervals for
15 min. At this time, 104 M furosemide was added to the suffusate,
and vessel diameters were measured at 5-min intervals for an additional 10 min. Initial vessel diameter was taken as the diameter immediately prior to addition of the preconstricting agent (t = 0 min).
To test the effect of cyclooxygenase inhibition, one group of rats
was pretreated with indomethacin (5 mg/kg, intraperitoneally) 1 h before surgery. This experimental paradigm has been shown to effectively block the furosemide-induced decrease in pulmonary vascular
resistance in isolated perfused dog lungs (16). The protocol was otherwise identical to that described above except 104 M indomethacin
was present in the suffusate at all times to insure continuous cyclooxygenase inhibition.
Preconstricting agents consisted of either 104 M phenylephrine, a
selective 1-adrenergic agonist, or 103 M L-NAME, an inhibitor of nitric oxide synthase. Time control experiments were performed when
(1) the preconstrictor (in the presence and in the absence of indomethacin), but not furosemide, was added to the suffusate, and (2)
neither preconstrictor nor furosemide was added to the suffusate. The
above time control experiments were otherwise identical to the basic
protocol. One additional time control group was not preconstricted
and received only the furosemide treatment after the 20-min stabilization period. Vessel diameters in this later group were measured every
5 min for 25 min.
Criteria of Acceptability
The experiments were considered acceptable if (1) initial vessel diameter (measured at t = 0 min in absence of preconstrictor) was reduced
by at least 10% after 15 min of suffusion with 104 M phenylephrine
or 103 M L-NAME, and (2) the diameter measured at t = 15 min of
phenylephrine or L-NAME exposure was no more than 15% higher
than that observed at t = 5 min.
Data Analysis
The vessel diameters were measured during the last 15 s of each period. The initial vessel diameter was obtained at the end of the control period. Responses of the vessels to the drugs were expressed as a percentage of the initial diameter: Response = (DX/DIC) × 100, where DX is the diameter measured after drug treatment and DIC is the initial control diameter.
For the purpose of statistical analysis, it was assumed that both actual diameter measurements and percentage change from initial diameter measurements conformed to normality. A dependent t test was used to compare vessel diameters before and after addition of furosemide. Probability p < 0.05 was accepted as the level of statistical significance. All results are expressed as means ± standard error of the mean (SEM).
Solutions and Drugs
The Krebs solution was composed of NaCl, 112.0 mM; KCl, 4.7 mM; CaCl2, 2.5 mM; MgSO4, 2.5 mM; KH2PO4, 1.2 mM; glucose, 11.6 mM; NaHCO3, 25.0 mM. All drugs were purchased from Sigma Chemical Co. (St. Louis, MO). Stock solutions of all drugs were prepared daily.
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RESULTS |
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ABSTRACT
INTRODUCTION
METHODS
RESULTS
DISCUSSION
REFERENCES
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Eighty-nine rats were used in this study. The mean arterial blood pressure in these animals averaged 100 ± 2 mm Hg at the beginning of the experimental protocol and 109 ± 2 mm Hg when the protocol was completed. Responses in 47 arterioles (13.0 to 41.0 µm initial diameter) and 46 venules (50.0 to 99.0 µm initial diameter) were measured. To minimize experimental bias, only one vessel per category was observed in each animal, but sometimes an arteriole and a venule were observed simultaneously in the same animal.
Control Experiments
The efficacy of furosemide in the absence of preconstriction
was evaluated in three arterioles and three venules. Furosemide (104 M) caused no change in either arteriolar or
venular diameter over a 25-min period (Figure 1). The absence of a dilatory response to furosemide was probably due
to the previously reported low level of resting tone in these
vessels (20, 21). We suspect that surgery around the trachea
results in stimulation of sensory afferents and release of inflammatory neuropeptides such as substance P and neurokinin A and B, which could dilate the tracheal vessels. Therefore, to show a dilatory effect of furosemide on rat tracheal vessels, it was necessary to preconstrict the vessels before addition of furosemide.
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In the absence of preconstrictors and furosemide, vessel diameters were stable and did not vary appreciably from the beginning to the end of the experimental time frame (Figures 2,
3, and 4; open circles). When only phenylephrine (104 M) was
added to the suffusate (Figure 2, open squares), a stable constriction occurred that was slightly greater in relative magnitude in venules (to 53.1% of initial diameter after 25 min of
suffusion, n = 7) than in arterioles (to 65.7% of initial diameter after 25 min of suffusion, n = 7). The presence of indomethacin did not substantially affect the constriction response to phenylephrine in either arterioles (to 70.3% of
initial diameter after 25 min of suffusion, n = 6) or venules
(to 61.3% of initial diameter after 25 min of suffusion, n = 6) (Figure 3, open diamonds). When only L-NAME (103 M)
was added to the suffusate, a stable constriction was also observed in arterioles (to 71.8% of initial diameter after 25 min
of suffusion, n = 7) and venules (to 78.5% of initial diameter after 25 min of suffusion, n = 7) (Figure 4, open triangles). This effect of L-NAME on tracheal microvessels was previously documented and attributed to inhibition of nitric oxide
synthase (21).
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Effect of Furosemide in the Presence of Preconstrictors
When furosemide (104 M) was added to the Krebs suffusate
of vessels that were preconstricted with phenylephrine, significant increases in diameter were observed in arterioles (from
64.6 to 79.5% of initial diameter, n = 6) and venules (from
52.1 to 65.4% of initial diameter, n = 7) (Figure 2, closed
squares). These data confirm that furosemide dilates tracheal
arterioles and venules.
Furosemide has been shown to induce prostaglandin and
nitric oxide release from cultured endothelial cells (18). To
test whether the dilatory effect was mediated by vasodilatory
prostaglandins, indomethacin was administered both intraperitoneally (5 mg/kg) before surgery and throughout the protocol in the suffusate (104 M). In the presence of indomethacin, furosemide induced significant dilation in arterioles (from
77.5 to 93.0% of initial diameter, n = 6) and venules (from
58.5 to 80.1% of initial diameter, n = 7) that were preconstricted with phenylephrine (Figure 3, closed diamonds). To
determine if the dilator response to furosemide was mediated
by a nitric-oxide-dependent process, vessels were preconstricted with the nitric oxide synthase inhibitor L-NAME and
then treated with furosemide. Significant dilation was still observed in arterioles (from 77.4 to 88.8% of initial diameter, n = 7) and venules (from 79.5 to 86.7% of initial diameter,
n = 6) (Figure 4, closed triangles). These results suggest that
furosemide mediates dilation of tracheal arterioles and venules
by a nitric oxide- and cyclooxygenase-independent mechanism.
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DISCUSSION |
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TOP
ABSTRACT
INTRODUCTION
METHODS
RESULTS
DISCUSSION
REFERENCES
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Airway rewarming after airway cooling induced by exercise or hyperventilation can produce airway obstruction in asthmatics (23). A previous study has shown that a direct relationship exists between the severity of thermally-induced asthma and the magnitude of the intra-airway thermal gradient (24). Inhaled furosemide causes a diminution in the airway thermal gradient that develops during and after hyperpnea and reduces airway obstruction (10). Noting that airstream temperature changes are reflective of vascular events (11, 24), Gilbert and colleagues (10) suggested that furosemide acts as a vasodilator of the bronchial microcirculation during thermal stress. In the present study, we have shown that furosemide dilates tracheal arterioles and venules by a cyclooxygenase-independent and a nitric oxide-independent mechanism. These data therefore confirm the previous suggestion that this agent acts as a vasodilator of the airway circulation (10). To our knowledge, this study is the first to demonstrate this action of furosemide on airway microvessels in vivo.
Furosemide, a derivative of anthranilic acid, is used therapeutically as a loop diuretic to reduce blood pressure and extracellular fluid volume. The diuretic effects of furosemide occur through inhibition Na+-K+-Cl cotransport in renal
epithelial cells of the ascending limb of the loop of Henle. It is
plausible that the vasodilatory response is somehow linked to
the inhibition of this transporter, which is present and functions in many cell types as a mechanism for intracellular volume regulation (25). For instance, furosemide could block entry of Na+ into smooth muscle cells through inhibition of Na+-K+-Cl cotransport, resulting in a fall intracellular Na+ concentration. The increased transmembrane Na+ gradient would
then favor increased extrusion of Ca2+ from the cytoplasm via
Na+/Ca2+ exchange and promote vessel relaxation. It is interesting that other loop diuretics such as bumetanide and torasemide, which show greater potency for inhibition of Na+-K+-Cl cotransport, are less effective in blocking the asthmatic
response (6, 8). Such results suggest that the protective effects of furosemide in asthma are unrelated to inhibition of Na+-K+-Cl cotransport.
The vasoactive properties of furosemide could be explained by several alternative mechanisms. Furosemide increases the plasma concentration of arachidonic acid (26), increases prostaglandin (E2) production by renal epithelial cells in the thick ascending limb of the loop of Henle (27), and increases prostaglandin (I2) production by pulmonary artery endothelial cells (16). However, the role of eicosanoids in the protective effects of furosemide against asthma is controversial. Although some studies provide evidence that the vasodilatory and protective effects of furosemide are due to the production of prostanoids (16, 17), others suggest that furosemide acts through a cyclooxygenase-independent pathway (28, 29). In the present study, furosemide-induced vasodilation of airway microvessels appears to be cyclooxygenase- independent. Alternatively, the vasodilatory mechanism of furosemide could be due to inhibition of neural pathways. Furosemide has been shown to inhibit the cough response induced by low-chloride aerosols (30), indicating a possible effect on sensory nerves. Because furosemide also inhibits the release of histamine and leukotriene from lung fragments (31), Polosa and coworkers (32) suggested that mast cells are involved in the protective effect of furosemide.
It is unlikely that the effect of furosemide is due to a direct effect on airway smooth muscle contractility (33, 34). Although this agent is capable of dilating airway smooth muscle in vitro (29), inhalation of aerolized furosemide does not appear to affect resting airway smooth muscle tone in normal or asthmatic persons (1, 3, 5, 6, 8). Indeed, inhaled furosemide has no significant protective effect against direct bronchoconstriction induced by histamine (2, 8) and methacholine (3).
In summary, this study has demonstrated that furosemide is a vasodilator of tracheal arterioles and venules. This vasodilatory activity of furosemide in airway microvessels does not appear to be mediated by nitric oxide or by products of cyclooxygenase metabolism. By dilating the airway vasculature, furosemide could increase the delivery of heat to the airways, and the thermal gradient observed in some forms of asthma would be reduced causing an attenuation of the bronchoconstriction. This study provides no direct link between the vasoactive properties of furosemide and its protection against asthma. However, the notion that vasodilator substances may protect against asthma is intriguing. We are hopeful that future studies into the mechanism and localization of the site of action of furosemide will eventually lead to the development of better treatment strategies for asthma, a prevalent and potentially fatal disease.
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Footnotes |
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Supported by Grants HL-07509 and HL-22549 from the National Institutes of Health.
Correspondence and requests for reprints should be addressed to Michel Corboz, Ph.D., Department of Physiology, MSB 3024, University of South Alabama, Mobile, AL 36688.
(Received in original form September 25, 1996 and in revised form February 27, 1997).
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References |
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ABSTRACT
INTRODUCTION
METHODS
RESULTS
DISCUSSION
REFERENCES
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