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Am J Physiol Heart Circ Physiol 276: H503-H508, 1999;
0363-6135/99 $5.00
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Vol. 276, Issue 2, H503-H508, February 1999

Cytochrome P-450 omega -hydroxylase senses O2 in hamster muscle, but not cheek pouch epithelium, microcirculation

Julian H. Lombard1, Mary Pat Kunert2, Richard J. Roman1, John R. Falck3, David R. Harder1, and William F. Jackson4

1 Department of Physiology, Medical College of Wisconsin, Milwaukee 53226; 2 College of Nursing, Marquette University, Milwaukee, Wisconsin 53202; 3 Department of Biochemistry, University of Texas Southwestern Medical Center, Dallas, Texas 75235; and 4 Department of Biological Sciences, Western Michigan University, Kalamazoo, Michigan 49008


    ABSTRACT
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Abstract
Introduction
Methods
Results
Discussion
References

The goal of this study was to investigate the role of cytochrome P-450 omega -hydroxylase in mediating O2-induced constriction of arterioles in the microcirculation of the hamster. Male Golden hamsters were anesthetized with pentobarbital sodium, and the cremaster muscle or cheek pouch was prepared for observation by intravital microscopy. Arteriolar diameters were measured during elevations of superfusate PO2 from ~5 to 150 mmHg. Arteriolar responses to elevated PO2 were determined in the cremaster muscle, in the retractor muscle where it inserts on the cheek pouch, and in the epithelial portion of the cheek pouch. Elevation of superfusion solution PO2 caused a vigorous constriction of arterioles in the cremaster and retractor muscles and in the epithelial portion of the cheek pouch. Superfusion with 10 µM 17-octadecynoic acid, a suicide substrate inhibitor of cytochrome P-450 omega -hydroxylase, and intravenous infusion of N-methylsulfonyl-12,12-dibromododec-11-enamide, a mechanistically different and highly selective inhibitor of cytochrome P-450 omega -hydroxylase, caused a significant reduction in the magnitude of O2-induced constriction of arterioles in the cremaster and retractor muscles. However, arteriolar constriction in response to elevated PO2 was unaffected by 17-octadecynoic acid or N-methylsulfonyl-12,12-dibromododec-11-enamide in the epithelial portion of the cheek pouch. These data confirm that there are regional differences in the mechanism of action of O2 on the microcirculation and indicate that cytochrome P-450 omega -hydroxylase senses O2 in the microcirculation of hamster skeletal muscle, but not in the cheek pouch epithelium.

arterioles; oxygen; 20-hydroxyeicosatetraenoic acid; 17-octadecynoic acid; vasoconstriction


    INTRODUCTION
Top
Abstract
Introduction
Methods
Results
Discussion
References

ARTERIOLES IN THE peripheral microcirculation constrict in response to elevations in PO2 (6, 17-23). However, the mechanism by which O2 produces this effect is controversial. In vitro studies suggest that changes in the release of prostaglandins from the vascular endothelium may mediate the dilation of isolated resistance arteries in response to reduced tissue PO2 (3, 4, 12, 13, 29) and the constriction of isolated first-order arterioles of the cremaster muscle to elevated PO2 (30). However, other mechanisms appear to mediate arteriolar constriction in response to elevated PO2 in situ (18, 36). Similarly, evidence has been presented for (36) and against (22) nitric oxide as a mediator of O2-mediated changes in vascular tone.

In the hamster cheek pouch, there is considerable evidence that the 5-lipoxygenase senses changes in O2 and that leukotrienes mediate the constriction of arterioles in response to increased O2 availability (20, 21, 23). However, a different mechanism appears to mediate O2-induced constriction of arterioles in the cremaster muscle of the same species (23). Recent studies (17) have suggested that formation of 20-hydroxyeicosatetraenoic acid (20-HETE) by cytochrome P-450 4A omega -hydroxylase may be involved in O2-induced constriction of arterioles in the rat cremaster muscle.

In the present study we tested the hypothesis that cytochrome P-450 omega -hydroxylase senses changes in PO2 and that a product of this pathway mediates O2-induced constriction of hamster skeletal muscle arterioles, but not arterioles in the epithelium of the hamster cheek pouch. To this end, we compared the effects of 17-octadecynoic acid (17-ODYA), a suicide substrate inhibitor of omega -hydroxylases (17, 40), and N-methylsulfonyl-12,12-dibromododec-11-enamide (DDMS), a water-soluble and highly specific inhibitor of cytochrome P-450 omega -hydroxylase that inhibits the formation of 20-HETE without affecting other arachidonic acid metabolites (1, 38), on the changes in the diameter of arterioles in the hamster cremaster muscle, retractor muscle, and cheek pouch epithelium in response to elevations in superfusion solution PO2. The results of these experiments indicate that cytochrome P-450 omega -hydroxylase senses O2 in the hamster skeletal muscle microcirculation, but not in the epithelial portion of the cheek pouch.


    METHODS
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Abstract
Introduction
Methods
Results
Discussion
References

Preparation of tissues for intravital microscopy. Male Golden hamsters were anesthetized with pentobarbital sodium (60 mg/kg ip). The trachea was cannulated with polyethylene tubing to ensure a patent airway, and a femoral vein was cannulated for the administration of small supplemental doses of pentobarbital as necessary to maintain anesthesia. The cremaster muscle or a single-layered cheek pouch was prepared for observation by intravital video microscopy, as described previously (17-23, 26). The animal was placed on the stage of a Leitz microscope, and the preparation was transilluminated and monitored with a closed-circuit television system (17, 26). The diameters of third-order arterioles in the cremaster muscle, the retractor muscle at its insertion onto the proximal surface of the cheek pouch, and the epithelial portion of the cheek pouch were measured with a video micrometer (model IV-550, For-A, Tokyo, Japan). The preparations were superfused at 35°C with physiological salt solution (PSS) equilibrated with a 0% O2-5% CO2-95% N2 gas mixture to ensure that all O2 delivery was via the microcirculation. Under these conditions, the PO2 of the PSS as it flows over the preparation was 3-5 mmHg. The PSS used in these experiments had the following composition (in mM): 131.9 NaCl, 4.7 KCl, 2.0 CaCl2, 1.17 MgSO4, and 20.0 NaHCO3. In each experiment the preparation was allowed to equilibrate for 30-60 min under 0% O2 superfusion before any measurements were performed.

Experimental protocol. After resting tone in the vessels was verified by demonstration of dilation in response to topical application of 10-4 M adenosine solution, the response of third-order arterioles to increased O2 availability was assessed by measuring the constriction of the vessels in response to increases in superfusion solution O2 content produced by switching from a gas mixture containing 0% O2 to one containing 21% O2 (PO2 140-150 mmHg). Arteriolar responses to elevated superfusion solution PO2 were assessed before and after treatment of the preparations with 10 µM 17-ODYA and before and after treatment of the animal with DDMS.

17-ODYA (Biomol, Plymouth Meeting, PA) was dissolved in 375 µl of 99% ethanol to prepare a 10 mM stock solution and then diluted with PSS to prepare 10 ml of the 10 µM 17-ODYA solution. To administer the 17-ODYA, the superfusion solution was stopped for 30 min after recovery from the first exposure to 21% O2 superfusion. The preparation was covered with tissue paper to keep the cremaster muscle or cheek pouch moist and to maintain contact with the inhibitor. PSS containing 17-ODYA was added topically to the preparation with a Pasteur pipette over a 30-min period. In a separate series of experiments the vehicle for 17-ODYA was administered in a similar manner. After the topical application of 17-ODYA or its vehicle was completed, the flow of 0% O2 superfusion solution from the reservoir was restored, and the preparation was allowed to recover for 30 min before the response to 21% O2 superfusion was tested again.

In the DDMS experiments the superfusion solution was equilibrated with a 0% O2-5% CO2-95% N2 gas mixture for a 1-h equilibration period. Control measurements of arteriolar diameter were obtained each minute for 5 min. The superfusion solution was then equilibrated with a 21% O2-5% CO2-74% N2 gas mixture, and arteriolar diameter and mean arterial pressure were measured each minute for 10 min. The superfusion solution was then equilibrated with a 0% O2 mixture. After the control measurements were obtained, DDMS was injected as a bolus (6 mg/kg iv), then at 10 mg/kg over 1 h. After the infusion of DDMS, arteriolar diameter and mean arterial blood pressure were measured each minute for a 5-min control period, and then the superfusion solution was equilibrated with a 21% O2-5% CO2-74% N2 gas mixture. Arteriolar diameter and mean arterial pressure were then measured each minute for 10 min.

Statistics. Values are means ± SE. Comparisons were made using a Student's t-test when two groups were compared or ANOVA with a subsequent Newman-Keuls test when multiple comparisons were made. All comparisons were performed at the 95% confidence level.


    RESULTS
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Abstract
Introduction
Methods
Results
Discussion
References

Response of arterioles to elevated superfusion solution PO2. The constrictor responses of arterioles of the cremaster muscle, retractor muscle, and cheek pouch epithelium to 21% O2 superfusion are summarized in Table 1. During the control period, arterioles of all three regions exhibited a significant constriction in response to elevated superfusion solution PO2.

                              
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  		Table 1.   Arteriolar constriction in response to 21% O2 superfusion in hamster microcirculation

Effect of 17-ODYA on resting diameter and arteriolar responses to elevated superfusion solution PO2 in the cheek pouch and the cremaster muscle. All arterioles studied in these experiments exhibited resting tone, demonstrated by the occurrence of a robust dilation in response to topical addition of 10-4 M adenosine solution. 17-ODYA, the suicide substrate inhibitor of cytochrome P-450 4A omega -hydroxylase, had no effect on resting diameter of arterioles in the cremaster muscle, retractor muscle, or epithelial portion of the cheek pouch (Table 2). However, superfusion with 17-ODYA inhibited O2-induced arteriolar constriction in the cremaster muscle (Fig. 1). In the cheek pouch, 17-ODYA inhibited arteriolar constriction in response to elevated PO2 in the retractor muscle but had no effect on O2-induced constriction of arterioles in the epithelial portion of the cheek pouch (Fig. 1). As previously reported in the rat cremaster muscle (17), 17-ODYA did not prevent norepinephrine (10-7 M)-induced constriction of the arterioles in any of the vascular beds, where the arterioles constricted by 16 ± 2 µm (n = 5) in the epithelial portion of the cheek pouch, 14 ± 1 µm (n = 5) in the retractor muscle, and 15 ± 1 µm in the cremaster muscle (n = 5) after treatment with the inhibitor. O2-induced constriction of arterioles was unaffected by the vehicle for 17-ODYA in any of the tissues (data not shown).

                              
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  		Table 2.   Effect of 17-ODYA and DDMS on resting diameter of arterioles in hamster microcirculation



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  		Fig. 1.   Effect of 17-octadecynoic acid (17-ODYA) on constriction of arterioles in response to elevation of superfusion solution O2 concentration from 0 to 21% in hamster cremaster muscle (n = 9), cheek pouch retractor muscle (n = 5), and epithelial portion of hamster cheek pouch (n = 7). Values (means ± SE) are expressed as mean decrease in diameter from control value measured during superfusion in 0% O2 solution.

Effect of DDMS on resting diameter and arteriolar responses to elevated superfusion solution PO2 in the cheek pouch and cremaster muscle. As with 17-ODYA, DDMS had no effect on the resting diameter of arterioles in the cremaster muscle, retractor muscle, or epithelial portion of the cheek pouch (Table 2). However, consistent with our findings using 17-ODYA, treatment of the animal with DDMS inhibited O2-induced constriction of arterioles in the cremaster and in cheek pouch retractor muscles but had no effect on arteriolar constriction in response to elevated superfusion solution PO2 in the epithelial portion of the cheek pouch (Fig. 2).


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  		Fig. 2.   Effect of N-methylsulfonyl-12,12-dibromododec-11-enamide (DDMS) on constriction of arterioles in response to elevation of superfusion solution O2 concentration from 0 to 21% in hamster cremaster muscle (n = 6), cheek pouch retractor muscle (n = 6), and epithelial portion of hamster cheek pouch (n = 5). Values (means ± SE) are expressed as decrease in diameter from control value measured during superfusion with 0% O2 solution.


    DISCUSSION
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Abstract
Introduction
Methods
Results
Discussion
References

Metabolic autoregulatory mechanisms play a major role in regulating tissue blood flow in the peripheral circulation, and arterioles are highly sensitive to changes in O2 availability (2, 6, 17-23, 25). Most studies of vascular responses to changes in O2 availability have investigated the mechanisms that mediate the relaxation of blood vessels in response to reduced PO2 (3, 4, 9, 10, 12, 13, 28, 29, 32-35). Some investigators have hypothesized that arteriolar dilation and increased blood flow in response to reduced PO2 are mediated by increases in the levels of vasodilator metabolites, e.g., adenosine, H+, K+, and prostaglandins, produced in the parenchymal tissues (2, 16, 25). Other investigators have proposed that the blood vessels are intrinsically sensitive to reduced PO2, independent of parenchymal cell metabolites. In the latter case, vascular relaxation in response to reduced PO2 may be due to the release of vasodilator substances, e.g., cyclooxygenase metabolites (3, 12, 13, 29, 31, 37) or nitric oxide (15) from the endothelial cells, or to an intrinsic sensitivity of the vascular smooth muscle cells to changes in O2 availability (5, 14, 27).

In contrast to the vasodilation that occurs in response to reduced PO2, increasing tissue O2 delivery elicits a vasoconstrictor response in most vascular beds (6, 17-23, 25). Arteriolar constriction in response to elevated PO2 may also be sensed at the level of the parenchymal cells or in the wall of the vessel. However, the mechanisms that mediate O2-induced constriction of arterioles may be different from those that mediate arteriolar dilation in response to reduced PO2. Major questions that remain unanswered are the identity and location of the "sensor" for arteriolar constriction in response to increased PO2 in the microcirculation and the mechanism that couples changes in PO2 to changes in arteriolar diameter.

One widely held version of the metabolic theory of autoregulation holds that O2-induced constriction of arterioles is mediated through a reduction in the tonic level of vasodilator metabolites in the tissue (16, 25). An alternative hypothesis to explain vasoconstriction in response to elevated PO2 is that the blood vessels or the parenchymal cells produce a vasoconstrictor metabolite in response to increased O2 availability. An essential criterion for such a metabolite to be the mediator of O2-induced constriction of arterioles is that its levels must change over a range of PO2 values that are consistent with the changes in PO2 that occur in the tissue during physiological conditions. Until recently, few enzymes had been identified that generate vasoconstrictor substances and have a Michaelis-Menten constant for O2 that lies within the normal physiological range of blood and tissue PO2. As a result, support for the constrictor metabolite hypothesis of O2-induced autoregulatory vasoconstriction has been limited by the lack of candidate metabolites to mediate the response.

Recent studies (17) have demonstrated that the generation of 20-HETE by cytochrome P-450 4A omega -hydroxylase is directly dependent on PO2 in the normal physiological range and that the enzyme that forms 20-HETE is present in rat cremaster muscle homogenates. That study also demonstrated that 20-HETE was made by rat cremaster muscle microsomes and that 17-ODYA inhibits arteriolar constriction in response to increases in superfusion PO2 without affecting resting tone or the vasoconstrictor response to norepinephrine. Taken together, those observations suggested that cytochrome P-450 omega -hydroxylase senses changes in PO2 and that 20-HETE is a likely candidate for the vasoconstrictor substance that mediates the local control of blood flow during increased O2 availability in the rat cremaster muscle.

In the present study we demonstrated that 17-ODYA, a suicide substrate inhibitor of 20-HETE formation (38), also inhibits O2-induced arteriolar constriction in the hamster cremaster and cheek pouch retractor muscles. The blockade of O2-induced constriction after exposure to 17-ODYA does not reflect a nonspecific effect of the inhibitor that impairs the ability of arteriolar smooth muscle cells to contract, since we demonstrated in the present experiments and in our earlier study (17) that norepinephrine-induced constriction of arterioles is unaffected by 10 µM 17-ODYA, whereas O2-induced constriction of the skeletal muscle arterioles was significantly reduced by this inhibitor of cytochrome P-450 omega -hydroxylase. More importantly, in the present study, 10 µM 17-ODYA had no effect on O2-induced constriction of arterioles in the cheek pouch epithelium. Had the effects of the inhibitor been nonspecific, it would likely have affected O2 reactivity in this tissue as well. The effects of 17-ODYA that we observed also cannot be attributed to the vehicle, since the ethanol vehicle at the same concentration used in the 17-ODYA studies did not affect arteriolar O2 responses. A role for cytochrome P-450 omega -hydroxylase in mediating O2-induced constriction of arterioles in the hamster skeletal muscle microcirculation in the present study is further supported by our observation that O2-induced constriction is also blocked by DDMS, a mechanistically different inhibitor of 20-HETE formation that is extremely specific for inhibiting omega -hydroxylation by the cytochrome P-450 system (38).

In the hamster microcirculation, elevation of superfusion solution O2 concentration from 0 to 21% would be expected to increase tissue PO2 from a normal value of ~8-10 mmHg during 0% O2 superfusion to ~40 mmHg during 21% O2 superfusion, and PO2 in arterioles of the branching order used in this study would increase from ~28-30 mmHg during 0% O2 superfusion to 45-50 mmHg during 21% O2 superfusion (8). This PO2 range is much less than the change in superfusion solution PO2 and would span the physiological range of PO2 values where 20-HETE formation by cytochrome P-450 4A omega -hydroxylase is increased by elevated PO2 (17). Thus the present study demonstrates that O2-induced constriction of arterioles is blocked by two different inhibitors of cytochrome P-450 4A omega -hydroxylase in a PO2 range that would be encountered physiologically and that corresponds to the range of PO2 values where 20-HETE formation by this enzyme increases rapidly with elevated PO2 (17).

The finding that inhibition of cytochrome P-450 omega -hydroxylase blocks O2-induced constriction in the microcirculation of hamster skeletal muscle is consistent with the results of our previous studies in rat cremaster muscle (17) and strongly suggests that cytochrome P-450 omega -hydroxylase is the O2 sensor in hamster muscles as well. In contrast, the finding that inhibition of cytochrome P-450 omega -hydroxylase does not block O2-induced constriction of arterioles in the cheek pouch epithelium suggests that mechanisms other than 20-HETE formation by the cytochrome P-450 pathway can also mediate O2-induced constriction in the microcirculation. In the case of the cheek pouch epithelium, this mechanism probably involves the formation of leukotrienes by the lipoxygenase pathway, since Jackson (20, 21, 23) reported that leukotriene antagonists and lipoxygenase inhibitors block O2-induced constriction in the hamster cheek pouch. However, Jackson (23) noted that this mechanism does not appear to mediate O2-induced constriction of microvessels in the hamster cremaster muscle, since the application of 5-lipoxygenase inhibitors or leukotriene antagonists had no effect on O2 reactivity in this vascular bed. The latter finding indicated that there may be regional differences in the mechanisms that mediate O2-induced constriction of arterioles in various vascular beds and suggested that an unknown substance may mediate arteriolar constriction during exposure to elevated PO2 in the hamster cremaster muscle. The current study extends our earlier findings suggesting that 20-HETE may mediate O2-induced constriction in rat cremaster muscle (17) and indicates that the previously unidentified substance that mediates O2-induced constriction in the hamster skeletal muscle microcirculation (23) is a cytochrome P-450 omega -hydroxylase metabolite of arachidonic acid.

Clarification of the mechanisms of O2-induced vasoconstriction in individual vascular beds is crucially important, since the mechanisms of O2-induced changes in vascular tone can differ among vascular beds and even within the same vessel of different species. For example, dilation of the rat middle cerebral artery in response to reduced PO2 is mediated via an endothelium-dependent release of prostacyclin that activates membrane ATP-dependent K+ channels (13), whereas hypoxic dilation of the cat middle cerebral artery is mediated via a direct effect on Ca2+-activated K+ channels in the vascular smooth muscle cells themselves (14). Therefore, it is impossible to make any generalizations regarding the mechanism of O2-induced changes in vascular tone between one vascular bed and another or even in the same vascular bed of different species. In this respect, the identification of distinctly different mechanisms that mediate regional differences in O2 response within the vascular beds of a species (the hamster) that has been widely studied for mechanisms of O2 response in the microcirculation is novel and important.

The observation that superfusion with 17-ODYA and DDMS blocks O2-induced arteriolar constriction in the cremaster and retractor muscles, but not in the cheek pouch epithelium, suggests that the neural or parenchymal cell environment may be an important determinant of the expression of O2-dependent signal transduction pathways that mediate vascular O2 responses. Previous studies have suggested that the mechanisms controlling arteriolar tone differ in the cheek pouch retractor muscle and epithelium. For example, arterioles of the retractor muscle dilate in response to elevated K+ concentration, whereas those in the epithelial portion of the cheek pouch constrict (7). Sympathetic control of vascular tone also differs in the muscles and cheek pouch epithelium, since the cremaster (11, 24) and retractor (39) muscles are innervated by adrenergic nerve fibers, whereas adrenergic influences do not appear to contribute to the regulation of active tone in the epithelial portion of the cheek pouch (24, 26). However, if the neural or parenchymal cell environment influences the expression of O2-related signal transduction pathways, the mechanism by which this occurs remains a matter of speculation.

In summary, we have shown that 17-ODYA and DDMS, which are inhibitors of cytochrome P-450 omega -hydroxylase, inhibit arteriolar O2 reactivity in hamster muscles, but not in the cheek pouch epithelium. These results indicate that cytochrome P-450 omega -hydroxylase senses changes in PO2 in hamster muscles and suggest that an omega -hydroxylase product of arachidonic acid, such as 20-HETE, may mediate the arteriolar constriction in response to increased O2 availability in the hamster cremaster and retractor muscles, but not in the epithelial portion of the cheek pouch.


    ACKNOWLEDGEMENTS

The technical assistance of Joan Cira and Sabina Aggrawal is greatly appreciated.


    FOOTNOTES

This study was supported by National Institutes of Health Grants HL-37374 and HL-29587 to J. H. Lombard, NR-00105 to M. P. Kunert, HL-29587 to R. J. Roman, DK-38226 to J. R. Falck, NS-32321 and HL-59996 to D. R. Harder, and HL-32469 and HL-09290 to W. F. Jackson. D. R. Harder is a career scientist of the Veterans Administration.

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: J. H. Lombard, Dept. of Physiology, Medical College of Wisconsin, 8701 Watertown Plank Rd., Milwaukee, WI 53226.

Received 14 August 1998; accepted in final form 30 September 1998.


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Methods
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Discussion
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Am J Physiol Heart Circ Physiol 276(2):H503-H508
0002-9513/99 $5.00 Copyright © 1999 the American Physiological Society


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