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Department of Medicine, University of Illinois at Chicago, and West Side Department of Veterans Affairs Medical Center, Chicago, Illinois 60612
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ABSTRACT |
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 TOP
 ABSTRACT
 INTRODUCTION
METHODS
RESULTS
DISCUSSION
REFERENCES
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The purpose of this study was to determine whether inhibitors of tyrosine kinase attenuate vasodilation elicited by endogenously elaborated and exogenously applied nitric oxide in the in situ peripheral microcirculation. Using intravital microscopy, we found that pretreatment with genistein (1.0 µM) and tyrphostin 25 (10.0 µM), two structurally unrelated tyrosine kinase inhibitors, significantly attenuated acetylcholine-, bradykinin- and nitroglycerin-induced dilation of second-order arterioles (51 ± 1 µm) in the in situ hamster cheek pouch (P < 0.05). Both inhibitors nearly abrogated acetylcholine-induced responses but only partially blocked bradykinin- and nitroglycerin-induced vasodilation. Genistein and tyrphostin 25 alone had no significant effects on resting arteriolar diameter and on adenosine-induced vasodilation in the cheek pouch. On balance, these data indicate that tyrosine kinase inhibitors attenuate endogenously elaborated and exogenously applied nitric oxide-induced vasodilation in the in situ hamster cheek pouch. However, the extent of tyrosine kinase inhibitor-sensitive pathway involvement in this response appears to be agonist dependent.
microcirculation; vasomotor tone; endothelium; proteinase inhibitors; acetylcholine; bradykinin; nitroglycerin; adenosine; nitric oxide
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INTRODUCTION |
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TOP
ABSTRACT
INTRODUCTION
METHODS
RESULTS
DISCUSSION
REFERENCES
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IT IS WELL ESTABLISHED THAT acetylcholine and bradykinin, two potent vasoactive mediators, elicit endothelium-dependent vasodilation in the peripheral microcirculation that is mediated by local elaboration of nitric oxide (NO) (4, 26-30, 32, 34). However, the nature of the downstream intracellular signal transduction pathway(s) activated by NO in vascular smooth muscle that leads to vasorelaxation is uncertain.
To this end, Kitazono et al. (18) showed that vasodilation elicited by bradykinin in the in situ rat basilar artery is mediated by NO-dependent activation of tyrosine kinase, a ubiquitous family of intracellular signaling enzymes thought to play an important role in regulating vascular smooth muscle contractility (2, 3, 9, 17, 31, 33, 35-37). However, Muller et al. (20) showed that tyrosine kinase inhibitors have no significant effects on vasodilation elicited by substance P, a potent proinflammatory neuropeptide that elicits endothelium- and NO-dependent vasodilation, in isolated porcine coronary arterioles. Taken together, these data suggest that the role tyrosine kinase signaling pathway plays in modulating vascular smooth muscle contractility in the peripheral microcirculation is dependent, in part, on the species, microvascular bed and agonist being studied.
Hence, the purpose of this study was to begin to address this issue by determining whether inhibitors of tyrosine kinase attenuate vasodilation elicited by endogenously elaborated and exogenously applied NO in the in situ peripheral microcirculation.
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METHODS |
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TOP
ABSTRACT
INTRODUCTION
METHODS
RESULTS
DISCUSSION
REFERENCES
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Preparation of Animals
The research adhered to the National Institutes of Health (NIH) Guide for the Care and Use of Laboratory Animals [DHEW Publication No. (NIH) 85-23, Revised 1985, Office of Science and Health Reports, DRR/NIH, Bethesda, MD 20892]. Adult, male golden Syrian hamsters (Sasco, Omaha, NE; n = 38) weighing 131 ± 2 g were anesthetized with pentobarbital sodium (6 mg/100 g body wt ip). A tracheostomy was performed to facilitate spontaneous breathing. A femoral vein was cannulated to inject supplemental anesthesia during the experiment (2-4 mg · 100 g body wt
1 · h1). A
femoral artery was cannulated to record systemic arterial blood
pressure and heart rate, which did not change significantly throughout
the experiments. Body temperature was monitored and kept constant
(37-38°C) via a feedback controller and a heating pad during
the experiments.
To visualize the microcirculation of the cheek pouch, we used a method previously described in our laboratory (10-12, 19, 25, 29, 30, 32). Briefly, the left cheek pouch was spread over a plastic baseplate, and an incision was made in the overlying skin to expose the cheek pouch membrane. The avascular connective tissue layer of the membrane was carefully removed, and an upper plastic chamber was positioned over the baseplate. This arrangement forms a triple-layered complex: the baseplate, the upper chamber, and the cheek pouch membrane exposed between the two plates. The chamber contains the suffusion fluid and is connected via a three-way valve to a reservoir that allows continuous suffusion of the cheek pouch with warm (37-38°C) bicarbonate buffer (pH 7.4) bubbled continuously with 95% N2-5% CO2 at a rate of 2 ml/min. The chamber is also connected via a three-way valve to an infusion pump (Sage Instruments, Boston, MA) for controlled administration of drugs into the suffusate.
Determination of Arteriolar Diameter
The cheek pouch microcirculation was visualized with a microscope (long-working-distance objective, ×4; eyepiece, ×10; Nikon, Tokyo, Japan) coupled to a 100-W mercury light source. The microscope image was projected through a low-light television camera (Panasonic TR-124 MA, Matsushita Communication Industrial, Yokohama, Japan) onto a video screen (Panasonic). The inner diameter of second-order arterioles (51 ± 1 µm), which have been shown to regulate vascular resistance in the cheek pouch (5), was determined during the experiment from the video display of the microscope image by using a videomicrometer with resolution of ±0.5 µm (model VIA 100, Boeckler Instruments, Tucson, AZ). This system was calibrated routinely against a precise line-width standard, and the measurements were found to have <1% error. In each animal, the same arteriolar segment was used to measure changes in diameter during the experiment.Experimental Protocols
Effects of tyrosine kinase inhibitors on acetylcholine-induced vasodilation. Acetylcholine has been shown to elicit endothelium- and NO-dependent vasodilation in the cheek pouch (26-29, 32, 34). The purpose of these studies was to determine whether selective tyrosine kinase inhibitors attenuate acetylcholine-induced vasodilation in the cheek pouch. After bicarbonate buffer was suffused for 30 min (equilibration period), two concentrations of acetylcholine (0.1 and 1.0 µM) were suffused for 5 min each in an arbitrary fashion. At least 45 min elapsed between subsequent suffusions of acetylcholine. Arteriolar diameter was determined before, every minute for 5 min during suffusion of acetylcholine, and every 5 min thereafter for 45 min. Once arteriolar diameter returned to baseline, genistein (1.0 µM) or tyrphostin 25 (10.0 µM), two structurally unrelated tyrosine kinase inhibitors (1, 3, 6, 14, 15, 22, 23), was suffused for 30 min before and during repeated suffusions of acetylcholine (0.1 and 1.0 µM). Changes in arteriolar diameter were determined after each intervention. In preliminary studies, we determined that repeated suffusions of acetylcholine (0.1 and 1.0 µM) were associated with reproducible results. In addition, suffusion of genistein (1.0 µM), tyrphostin 25 (10.0 µM), and dimethyl sulfoxide (0.05%), the vehicle of genistein and tyrphostin 25, alone for 35 min had no significant effects on arteriolar diameter. Suffusion of saline (vehicle) for the entire duration of the experiment had no significant effects on arteriolar diameter. The concentrations of acetylcholine, genistein, and tyrphostin 25 used in these studies are based on previous studies in our laboratory and reports in the literature (1, 3, 14, 15, 17, 22, 27, 28, 30).
Effects of tyrosine kinase inhibitors on bradykinin-induced vasodilation. Bradykinin, like acetylcholine, has been shown to evoke endothelium- and NO-dependent vasodilation in the cheek pouch (7, 26-28). The purpose of these studies was to determine whether inhibitors of tyrosine kinases attenuate bradykinin-induced vasodilation in the cheek pouch. After the equilibration period, two concentrations of bradykinin (0.01 and 0.1 µM) were suffused for 5 min each in an arbitrary fashion. At least 45 min elapsed between subsequent suffusions of bradykinin. Once arteriolar diameter returned to baseline, genistein (1.0 µM) or tyrphostin 25 (10.0 µM) was suffused for 30 min before and during repeated suffusions of bradykinin (0.01 and 0.1 µM) as outlined above. Changes in arteriolar diameter were determined after each intervention. In preliminary studies, we determined that repeated suffusions of bradykinin (0.01 and 0.1 µM) were associated with reproducible results. The concentrations of bradykinin used in these studies are based on previous studies in our laboratory and reports in the literature (7, 10, 27, 28).
Effects of tyrosine kinase inhibitors on nitroglycerin-induced vasodilation. The purpose of these studies was to determine whether inhibitors of tyrosine kinase attenuate vasodilation elicited by nitroglycerin, an NO donor, in the cheek pouch. After the equilibration period, two concentrations of nitroglycerin (0.1 and 1.0 µM) were suffused for 5 min each in an arbitrary fashion. At least 45 min elapsed between subsequent suffusions of nitroglycerin. Once arteriolar diameter returned to baseline, genistein (1.0 µM) or tyrphostin 25 (10.0 µM) was suffused for 30 min before and during repeated suffusions of nitroglycerin (0.1 and 1.0 µM). Changes in arteriolar diameter were determined after each intervention. In preliminary studies, we determined that repeated suffusions of nitroglycerin (0.1 and 1.0 µM) were associated with reproducible results. The concentrations of nitroglycerin used in these studies are based on previous studies in our laboratory (19, 30, 32).
Effects of tyrosine kinase inhibitors on adenosine-induced vasodilation. Vasodilation elicited by adenosine in the cheek pouch, unlike that evoked by bradykinin, acetylcholine, and nitroglycerin, has been shown to be NO independent (10, 13, 16, 21, 24, 32). The purpose of these studies was to determine whether selective tyrosine kinase inhibitors attenuate vasodilation elicited by adenosine in the cheek pouch. After the equilibration period, two concentrations of adenosine (0.1 and 1.0 µM) were suffused for 5 min each in an arbitrary fashion. At least 45 min elapsed between subsequent suffusions of nitroglycerin. Once arteriolar diameter returned to baseline, genistein (1.0 µM) or tyrphostin 25 (10.0 µM) was suffused for 30 min before and during repeated suffusions of adenosine (0.1 and 1.0 µM). Changes in arteriolar diameter were determined after each intervention. In preliminary studies, we determined that repeated suffusions of adenosine (0.1 and 1.0 µM) were associated with reproducible results. The concentrations of adenosine used in these experiments are based on previous studies in our laboratory and reports in the literature (10, 13, 16, 21, 24, 32).
Drugs
Acetylcholine, bradykinin, and adenosine were obtained from Sigma Chemical (St. Louis, MO). Nitroglycerin was obtained from American Regent Laboratories (Shirley, NY). Genistein and tyrphostin 25 were obtained from Life Technologies (Gaithersburg, MD). Genistein and tyrphostin 25 were dissolved in dimethyl sulfoxide as a 1 mM stock solution and diluted in saline to the desired concentration. The final concentration of dimethyl sulfoxide in the cheek pouch suffusate was 0.05%. All other drugs were dissolved and diluted in saline to the desired concentrations on the day of the experiment.Data and Statistical Analyses
When a drug was suffused on the cheek pouch, we determined the maximal change in arteriolar diameter and used this value as the response to that drug in each animal. Arteriolar diameter was expressed as the ratio of experimental to control diameter, with control diameter normalized to 100%, to account for intra- and interanimal variability. Data are expressed as means ± SE except for body weights, which are expressed as means ± SD because these data are not used for comparison between experimental groups. Statistical analysis was performed by using repeated-measures analysis of variance with Neuman-Keuls multiple-range post hoc test to detect values that were different from control values. A P value <0.05 was considered statistically significant; n is given as the number of experiments with each experiment representing a separate animal.| |
RESULTS |
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TOP
ABSTRACT
INTRODUCTION
METHODS
RESULTS
DISCUSSION
REFERENCES
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Effects of Tyrosine Kinase Inhibitors on Acetylcholine-Induced Vasodilation
Suffusion of acetylcholine (0.1 and 1.0 µM) elicited significant, concentration-dependent vasodilation (Fig. 1; each group, n = 4 animals; P < 0.05). Arteriolar diameter increased by 12 ± 2 and 26 ± 4% from baseline during suffusion of 0.1 and 1.0 µM acetylcholine, respectively (Fig. 1). Pretreatment with genistein (1.0 µM) significantly attenuated acetylcholine-induced responses (Fig. 1; each group, n = 4 animals; P < 0.05). Arteriolar diameter increased by 1 ± 1 and 3 ± 1% from baseline during suffusion of 0.1 and 1.0 µM acetylcholine and genistein (1.0 µM), respectively (Fig. 1). Similarly, pretreatment with tyrphostin 25 (10.0 µM) significantly attenuated acetylcholine-induced responses (Fig. 1; each group, n = 4 animals; P < 0.05). Arteriolar diameter increased by 4 ± 1 and 3 ± 2% from baseline during suffusion of 0.1 and 1.0 µM acetylcholine and tyrphostin 25 (10.0 µM), respectively (Fig. 1).
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Effects of Tyrosine Kinase Inhibitors on Bradykinin-Induced Vasodilation
Suffusion of bradykinin (0.01 and 0.1 µM) elicited significant, concentration-dependent vasodilation (Fig. 2; each group, n = 4 animals; P < 0.05). Arteriolar diameter increased by 6 ± 1 and 17 ± 1% from baseline during suffusion of 0.01 and 0.1 µM bradykinin, respectively (Fig. 2). Pretreatment with genistein (1.0 µM) significantly attenuated bradykinin-induced responses (Fig. 2; each group, n = 4 animals; P < 0.05). Arteriolar diameter increased by 1 ± 1 and 11 ± 1% from baseline during suffusion of 0.01 and 0.1 µM bradykinin and genistein (1.0 µM), respectively (Fig. 2). Similarly, pretreatment with tyrphostin 25 (10.0 µM) significantly attenuated bradykinin-induced responses (Fig. 2; each group, n = 4 animals; P < 0.05). Arteriolar diameter increased by 1 ± 1 and 5 ± 3% from baseline during suffusion of 0.01 and 0.1 µM bradykinin and tyrphostin 25 (10.0 µM), respectively (Fig. 2).
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Effects of Tyrosine Kinase Inhibitors on Nitroglycerin-Induced Vasodilation
Suffusion of nitroglycerin (0.1 and 1.0 µM) elicited significant, concentration-dependent vasodilation (Fig. 3; each group, n = 4 animals; P < 0.05). Arteriolar diameter increased by 18 ± 2 and 32 ± 4% from baseline during suffusion of 0.1 and 1.0 µM nitroglycerin, respectively (Fig. 3). Genistein (1.0 µM) significantly attenuated nitroglycerin-induced responses (Fig. 3; each group, n = 4 animals; P < 0.05). Arteriolar diameter increased by 7 ± 3 and 10 ± 3% from baseline during suffusion of 0.1 and 1.0 µM nitroglycerin in the presence of genistein (1.0 µM), respectively (Fig. 3; P < 0.05 in comparison to nitroglycerin alone). Tyrphostin 25 (10.0 µM) significantly attenuated only vasodilation elicited by 1.0 µM nitroglycerin (Fig. 3; each group, n = 4 animals; P < 0.05). Arteriolar diameter increased by 15 ± 1 and 16 ± 2% from baseline during suffusion of 0.1 and 1.0 µM nitroglycerin in the presence of tyrphostin 25 (10.0 µM), respectively (Fig. 3).
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Effects of Tyrosine Kinase Inhibitors on Adenosine-Induced Vasodilation
Adenosine elicited significant, concentration-dependent vasodilation (Fig. 4; each group, n = 4 animals; P < 0.05). Pretreatment with genistein (1.0 µM) had no significant effects on adenosine-induced responses (Fig. 4; each group, n = 4 animals). Arteriolar diameter increased by 9 ± 1 and 16 ± 1% from baseline during suffusion of adenosine (0.1 and 1.0 µM, respectively) alone and by 12 ± 2 and 18 ± 3% during suffusion of adenosine (0.1 and 1.0 µM, respectively) and genistein (1.0 µM; Fig. 4). Similarly, pretreatment with tyrphostin 25 (10.0 µM) had no significant effects on adenosine-induced responses (Fig. 4; each group, n = 4 animals). Arteriolar diameter increased by 9 ± 1 and 16 ± 1% from baseline during suffusion of adenosine (0.1 and 1.0 µM, respectively) alone and by 11 ± 1 and 13 ± 3% during suffusion of adenosine (0.1 and 1.0 µM, respectively) and tyrphostin 25 (10.0 µM; Fig. 4).
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DISCUSSION |
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TOP
ABSTRACT
INTRODUCTION
METHODS
RESULTS
DISCUSSION
REFERENCES
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There are several new findings in this study. We found that tyrosine kinase plays a role in modulating NO-induced vasodilation in the in situ hamster cheek pouch because genistein and tyrphostin 25, two structurally unrelated tyrosine kinase inhibitors, significantly attenuated acetylcholine-, bradykinin-, and nitroglycerin-induced vasodilation in this organ. However, the extent of tyrosine kinase inhibitor-sensitive pathway involvement in this process is variable and appears to be agonist dependent because genistein and tyrphostin 25 nearly abrogated acetylcholine-induced vasodilation but only partially blocked bradykinin- and nitroglycerin-induced responses.
The mechanisms underlying the differential effects of genistein and tyrphostin 25 on agonist-induced vasodilation were not elucidated in this study. Nonetheless, they are unrelated to activation of ATP-sensitive potassium channels because genistein and tyrphostin 25 had no significant effects on adenosine-induced vasodilation in the cheek pouch. The latter is mediated, unlike other microvascular beds and species (24, 38), by activation of ATP-sensitive potassium channels (16). The divergent responses to genistein and tyrphostin 25 are not mediated by local elaboration of vasodilator prostaglandins because Rubinstein et al. (30) and Rivers et al. (28) showed that indomethacin, a nonspecific cyclooxygenase inhibitor, has no significant effects on acetylcholine- and bradykinin-induced vasodilation in the cheek pouch, respectively.
Conceivably, the differential effects of genistein and tyrphostin 25 on nitroglycerin- and acetylcholine-induced vasodilation could be related to a larger amount of NO elaborated by nitroglycerin in the cheek pouch as opposed to equimolar concentrations of acetylcholine (6, 8, 10, 12, 18, 19, 25, 26, 30, 32, 34). This notion is supported, in part, by the study of Fleming et al. (8), who showed that maximal production of NO elicited by isometrically contracted rabbit aortic rings is greater than that detected after application of acetylcholine and that this response is partly mediated by a tyrosine kinase inhibitor-sensitive pathway(s). Nonetheless, the effects of tyrosine kinase inhibitors on vascular smooth muscle sensitivity to endothelial-derived NO in the intact cheek pouch microcirculation were not determined in this study. To this end, Gould et al. (14) and Nelson et al. (22) showed that genistein alters Ca2+ pathways in isolated vascular smooth muscle strips and cells, respectively. This, in turn, may modulate to a certain extent NO-dependent vasorelaxation (2, 8, 9, 14, 22). Clearly, additional studies using molecular, biochemical and cell biology techniques are warranted to address these issues.
The hamster cheek pouch is an established model to elucidate mechanisms regulating vasomotor tone, including the role of tyrosine kinase, in the in situ peripheral microcirculation, (3, 5, 10, 16, 17, 19, 21, 25-30, 32, 34). Previous studies showed that NO and/or an NO-containing compound(s) mediates, in part, acetylcholine- and bradykinin-induced vasodilation in this organ (26-28, 34). Importantly, successive suffusions of bradykinin, acetylcholine, adenosine, and nitroglycerin on the cheek pouch at appropriate time intervals have been previously shown to evoke reproducible vasodilation in the absence of tachyphylaxis (10, 16, 17, 19, 27-30, 32, 34). Hence, the effects of these compounds on vasomotor tone can be tested repeatedly in the same cheek pouch so that each animal serves as its own control. This, in turn, reduces the number of animals required per experiment and facilitates data analysis.
Genistein and tyrphostin 25 alone had no significant effects on resting arteriolar diameter in the cheek pouch. These data are consistent with previous studies in other species and microvascular beds, showing that tyrosine kinase inhibitors, whether applied luminally or abluminally, have no significant effects on basal vasomotor tone (18, 20, 23). However, Kim and Durán (17) and Bertuglia and Colantuoni (3) showed that suffusion of tyrosine kinase inhibitors on the cheek pouch, at concentrations similar to those used in this study, elicits either vasodilation or vasoconstriction, respectively. Although the reasons underlying these discrepant results are uncertain, they may be related, in part, to the age of animals used in these studies. Kim and Durán (17) and Bertuglia and Colantuoni (3) studied younger animals than we and Kitazono et al. (18) did. Whether tyrosine kinase regulation of vasomotor tone in the peripheral microcirculation is age dependent and, if so, whether this phenomenon plays a role in the pathogenesis of vasomotor dysfunction observed in certain cardiovascular disorders remain to be determined.
In summary, the results of this study indicate that tyrosine kinase inhibitors attenuate endogenous-elaborated and exogenously applied NO-induced vasodilation in the in situ hamster cheek pouch. However, the extent of tyrosine kinase inhibitor-sensitive pathway involvement in this response appears to be agonist dependent.
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ACKNOWLEDGEMENTS |
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This study was supported, in part, by grants from the National Institute of Dental Research (DE-10347), American Heart Association of Metropolitan Chicago, and Laerdal Foundation for Acute Medicine. I. Rubinstein is a recipient of a Research Career Development Award from the National Institute of Dental Research (DE-00386) and a University of Illinois Scholar Award.
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FOOTNOTES |
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The costs of publication of this article were defrayed in part by the payment of page charges. The article must therefore be hereby marked "advertisement" in accordance with 18 U.S.C. §1734 solely to indicate this fact.
Address for reprint requests and other correspondence: I. Rubinstein, Dept. of Medicine (M/C 787), Univ. of Illinois at Chicago, 840 S. Wood St., Chicago, IL 60612-7323 (E-mail: IRubinst{at}uic.edu).
Received 16 October 1998; accepted in final form 18 November 1999.
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REFERENCES |
|---|
|
TOP
ABSTRACT
INTRODUCTION
METHODS
RESULTS
DISCUSSION
REFERENCES
|
|---|
1.
Akiyama, T.,
J. Ishida,
S. Nakagawa,
H. Ogawara,
S.-I. Watanabe,
N. Itoh,
M. Shibuya,
and
Y. Fukami.
Genistein, a specific inhibitor of tyrosine-specific protein kinases.
J. Biol. Chem.
262:
5592-5595,
1987
2.
Ayajiki, K.,
M. Kindermann,
M. Kecker,
I. Fleming,
and
R. Busse.
Intracellular pH and tyrosine phosphorylation but not calcium determine shear-stress induced nitric oxide production in native endothelial cells.
Circ. Res.
78:
750-758,
1996
3.
Bertuglia, S.,
and
A. Colantuoni.
Insulin-induced arteriolar dilation after tyrosine kinase and nitric oxide synthase inhibition in hamster cheek pouch microcirculation.
J. Vasc. Res.
35:
250-256,
1998[ISI][Medline].
4.
Bhoola, K. D.,
C. D. Figueroa,
and
K. Worthy.
Bioregulation of kinins: kallikreins, kininogens, and kininases.
Pharmacol. Rev.
44:
1-80,
1992[ISI][Medline].
5.
Davis, M. J.,
W. L. Joyner,
and
J. P. Gilmore.
Microvascular pressure distribution and responses of pulmonary allografts and cheek pouch arterioles in the hamster to oxygen.
Circ. Res.
49:
125-132,
1981
6.
Dong, Z.,
X. Qi,
K. Xie,
and
I. J. Fidler.
Protein tyrosine kinase inhibitors decrease induction of nitric oxide synthase activity in lipopolysaccharide-responsive and lipopolysaccharide-nonresponsive murine macrophages.
J. Immunol.
151:
2717-2724,
1993[Abstract].
7.
Feletou, M.,
E. Bonnardel,
and
E. Canet.
Bradykinin and changes in microvascular permeability in the hamster cheek pouch: role of nitric oxide.
Br. J. Pharmacol.
118:
1371-1376,
1996[ISI][Medline].
8.
Fleming, I.,
J. Bauersachs,
A. Schafer,
D. Scholt,
J. Aldershvile,
and
R. Busse.
Isometric contraction induces the Ca+2-independent activation of the endothelial nitric oxide synthase.
Proc. Natl. Acad. Sci. USA
96:
1123-1128,
1999
9.
Fleming, I.,
and
R. Busse.
Tyrosine phosphorylation and bradykinin-induced signaling in endothelial cells.
Am. J. Cardiol.
80:
102A-109A,
1997[Medline].
10.
Gao, X.-P.,
P. Anding,
R. A. Robbins,
S. I. Rennard,
and
I. Rubinstein.
Peptidases modulate bradykinin-induced arteriolar dilatation in the hamster cheek pouch.
Am. J. Physiol. Heart Circ. Physiol.
266:
H93-H98,
1994
11.
Gao, X.-P.,
and
I. Rubinstein.
Methotrexate potentiates bradykinin-induced macromolecular efflux from the hamster oral mucosa.
Am. J. Physiol. Regulatory Integrative Comp. Physiol.
273:
R1254-R1262,
1997.
12.
Gao, X.-P.,
J. K. Vishwanatha,
J. M. Conlon,
C. O. Olopade,
and
I. Rubinstein.
Mechanisms of smokeless tobacco-induced oral mucosa inflammation: role of bradykinin.
J. Immunol.
157:
4624-4633,
1996[Abstract].
13.
Gawlowski, D. M.,
and
W. N. Durán.
Dose-related effects of adenosine and bradykinin on microvascular permeability to macromolecules in the hamster cheek pouch.
Circ. Res.
58:
348-355,
1986
14.
Gould, E. M.,
C. M. Rembold,
and
R. A. Murphy.
Genistein, a tyrosine kinase inhibitor, reduces Ca2+ mobilization in swine carotid media.
Am. J. Physiol. Cell Physiol.
268:
C1425-C1429,
1995
15.
Hawker, J. R., Jr.,
and
H. J. Granger.
Tyrosine kinase inhibitors impair fibroblast growth factor signaling in coronary endothelial cells.
Am. J. Physiol. Heart Circ. Physiol.
266:
H107-H120,
1994
16.
Jackson, W. F.
Arteriolar tone is determined by activity of ATP-sensitive potassium channels.
Am. J. Physiol. Heart Circ. Physiol.
265:
H1797-H1803,
1993
17.
Kim, D.,
and
W. N. Durán.
Platelet-activating factor stimulates protein tyrosine kinase in hamster cheek pouch microcirculation.
Am. J. Physiol. Heart Circ. Physiol.
268:
H399-H403,
1995
18.
Kitazono, T.,
S. Ibayashi,
T. Nagao,
K. Fujii,
T. Kagiyama,
and
M. Fujishima.
Role of tyrosine kinase in dilator responses of rat basilar artery in vivo.
Hypertension
31:
861-865,
1998
19.
Mayhan, W. G.,
and
I. Rubinstein.
Acetylcholine induces vasoconstriction in the microcirculation of cardiomyopathic hamsters: reversal by L-arginine.
Biochem. Biophys. Res. Commun.
184:
1372-1377,
1992[ISI][Medline].
20.
Muller, J. M.,
M. J. Davis,
and
W. M. Chilian.
Coronary arteriolar flow-induced vasodilation signals through tyrosine kinase.
Am. J. Physiol. Heart Circ. Physiol.
270:
H1878-H1884,
1996
21.
Murray, M. A.,
D. D. Heistad,
and
W. G. Mayhan.
Role of protein kinase C in bradykinin-induced increase in microvascular permeability.
Circ. Res.
68:
1340-1348,
1991
22.
Nelson, S. R.,
T. Chien,
and
J. Di Salvo.
Genistein sensitivity of calcium transport pathways in serotonin-activated vascular smooth muscle cells.
Arch. Biochem. Biophys.
345:
65-72,
1997[ISI][Medline].
23.
Ni, Y.,
V. May,
K. Braas,
and
G. Osol.
Pregnancy augments uteroplacental vascular endothelial growth factor gene expression and vasodilator effects.
Am. J. Physiol. Heart Circ. Physiol.
273:
H938-H944,
1997
24.
Olanrewaju, H. A.,
P. T. Hargittai,
E. A. Lieberman,
and
S. J. Mustafa.
Role of endothelium in hyperpolarization of coronary smooth muscle by adenosine and its analogues.
J. Cardiovasc. Pharmacol.
25:
234-239,
1995[ISI][Medline].
25.
Önyüksel, H.,
H. Ikezaki,
M. Patel,
and
I. Rubinstein.
A novel formulation of VIP in sterically stabilized micelles amplifies vasodilation in vivo.
Pharm. Res.
16:
155-160,
1999[ISI][Medline].
26.
Ramírez, M. M.,
S. M. Quardt,
D. Kim,
H. Oshiro,
M. Minnicozzi,
and
W. N. Durán.
Platelet activating factor modulates microvascular permeability through nitric oxide synthesis.
Microvasc. Res.
50:
223-234,
1995[ISI][Medline].
27.
Rivers, R. J.,
and
B. R. Duling.
Dilations induced by selective stimulation of arteriolar endothelium are partially inhibited by arginine analogs (Abstract).
FASEB J.
5:
A386,
1991.
28.
Rivers, R. J.,
A. L. Loeb,
N. J. Izzo, Jr.,
M. J. Peach,
and
B. R. Duling.
Microcirculatory responses to exogenous endothelial cell-derived relaxing factor.
Am. J. Physiol. Heart Circ. Physiol.
258:
H606-H609,
1990
29.
Rubinstein, I.,
and
W. G. Mayhan.
L-Arginine dilates cheek pouch arterioles in hamsters with hereditary cardiomyopathy but not in controls.
J. Lab. Clin. Med.
125:
313-318,
1995[ISI][Medline].
30.
Rubinstein, I.,
T. Yong,
S. I. Rennard,
and
W. G. Mayhan.
Cigarette smoke extract attenuates endothelium-dependent arteriolar dilatation in vivo.
Am. J. Physiol. Heart Circ. Physiol.
261:
H1913-H1918,
1991
31.
Srivastava, A. K.,
and
J. St.-Louis.
Smooth muscle contractility and protein tyrosine phosphorylation.
Mol. Cell. Biochem.
176:
47-51,
1997[ISI][Medline].
32.
Suzuki, H.,
X.-P. Gao,
C. O. Olopade,
H. A. Jaffe,
S. Pakhlevaniants,
and
I. Rubinstein.
Aqueous smokeless tobacco extract impairs endothelium-dependent vasodilation in the oral mucosa.
J. Appl. Physiol.
81:
225-231,
1996
33.
Takahashi, R.,
H. Watanabe,
H. Kakizawa,
X.-X. Zhang,
H. Hayashi,
and
R. Ohno.
Regulation of bradykinin-stimulated cation entry into endothelial cells by tyrosine kinase.
Jpn. Circ. J.
61:
1030-1036,
1997[Medline].
34.
Tang, T.,
and
W. L. Joyner.
Differential role of endothelial function on vasodilator responses in series-arranged arterioles.
Microvasc. Res.
44:
61-72,
1992[ISI][Medline].
35.
Toma, C.,
P. E. Jensen,
D. Prieto,
A. Hughes,
M. J. Mulvany,
and
C. Aalkjaer.
Effects of tyrosine kinase inhibitors on the contractility of rat mesenteric resistance arteries.
Br. J. Pharmacol.
114:
1266-1272,
1995[ISI][Medline].
36.
Venema, V. J.,
H. Ju,
J. Sun,
D. C. Eaton,
M. B. Marrero,
and
R. C. Venema.
Bradykinin stimulates the tyrosine phosphorylation and bradykinin B2 receptor association of phospholipase Cg1 in vascular endothelial cells.
Biochem. Biophys. Res. Commun.
246:
70-75,
1998[ISI][Medline].
37.
Venema, V. J.,
M. B. Marrero,
and
R. C. Venema.
Bradykinin-stimulated protein tyrosine phosphorylation promotes endothelial nitric oxide synthase translocation to the cytoskeleton.
Biochem. Biophys. Res. Commun.
226:
703-710,
1996[ISI][Medline]
38.
Woodley, N.,
and
J. K. Barclay.
Extravascular adenosine influences endothelium-derived nitric oxide release from perfused dog semitendinosus artery.
Can. J. Physiol. Pharmacol.
76:
90-98,
1998[ISI][Medline].
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P < 0.05 compared with
acetylcholine alone.
