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Am J Physiol Heart Circ Physiol 276: H1289-H1294, 1999;
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Vol. 276, Issue 4, H1289-H1294, April 1999

Inhibition of phospholipase A2 attenuates functional hyperemia in the hamster cremaster muscle

Louise C. Nuttle, Alison L. Ligon, Kathryn R. Farrell, and Robert L. Hester

Department of Physiology and Biophysics, University of Mississippi Medical Center, Jackson, Mississippi 39216-4505


    ABSTRACT
TOP
ABSTRACT
INTRODUCTION
MATERIALS AND METHODS
RESULTS
DISCUSSION
REFERENCES

Arachidonic acid (AA) is the common precursor for several vasodilatory factors involved in the local control of blood flow. This study was designed to determine the role of phospholipase A2 (PLA2) and AA release in functional hyperemia in the hamster cremaster muscle. The muscle was prepared for in vivo microscopy and subjected to electrical field stimulation for 1 min. First- and second-order arterioles dilated in response from a mean diameter of 66 ± 5 to 88 ± 7 µm (n = 6). PLA2 was then inhibited with quinacrine (3 × 10-6 M) for 60 min. PLA2 inhibition was verified by an attenuation of thrombin-induced vasodilation (2 U/ml). Quinacrine had no effect on resting arteriolar diameter but completely abolished functional hyperemia. Quinacrine also had no effect on dilation induced by superfusion of the preparation with 3 × 10-6-10-5 M AA, 10-6-10-4 M adenosine, or 10-6-10-4 M sodium nitroprusside, ruling out nonspecific effects of quinacrine on smooth muscle contractility. These results indicate that functional hyperemia in the hamster cremaster muscle is dependent on PLA2 activation and the availability of AA.

microcirculation; arachidonic acid; arteriolar diameter


    INTRODUCTION
TOP
ABSTRACT
INTRODUCTION
MATERIALS AND METHODS
RESULTS
DISCUSSION
REFERENCES

BLOOD FLOW to a contracting skeletal muscle increases proportionately to the metabolic demands of that tissue. A number of factors can contribute to the regulation of skeletal muscle blood flow, including arterial pressure, neural input, circulating humoral factors, and mechanical forces. However, a strong correlation between metabolic activity and vascular resistance within that active tissue suggests that mechanisms triggered by local changes play an important role in the control of blood flow, specifically in arteriolar tone. The cellular mechanisms underlying the regulation of arteriolar tone, or functional vasodilation, are not entirely understood.

A number of arachidonic acid (AA) metabolites have vasoactive properties. Prostaglandins, particularly prostacyclin, have been long recognized as potent vasoactive agents. More recently, products of the cytochrome P-450 epoxygenase and hydroxylase pathways, epoxyeicosatrienoic (EETs) and hydroxyeicosatetraenoic acids (HETEs), respectively, have been determined to be involved in the regulation of blood flow in a variety of microcirculatory beds including cerebral and coronary beds (17).

We (29) have previously demonstrated that inhibition of prostaglandin synthesis using indomethacin, an inhibitor of cyclooxygenase, partially blocks the vasodilation of first- and second-order arterioles in the hamster cremaster microcirculation in response to electrical field stimulation. We (22) have also recently presented similar results using miconazole, an inhibitor of cytochrome P-450 monooxygenase. These observations suggest that AA metabolites of the cyclooxygenase and cytochrome P-450 monooxygenase pathways play a role in the mechanism of functional hyperemia in this tissue. Because liberation of free AA is the rate-limiting step in the production of vasodilatory metabolites (28), we used quinacrine to examine the effect of phospholipase A2 (PLA2) inhibition on functional hyperemia in the cremaster muscle. The goal of the study was to test the hypothesis that PLA2 activity is stimulated during muscle contraction and that this increase in activity is the driving force for the local production of AA-derived vasodilators and the generation of functional hyperemia.


    MATERIALS AND METHODS
TOP
ABSTRACT
INTRODUCTION
MATERIALS AND METHODS
RESULTS
DISCUSSION
REFERENCES

Animal preparation. The experimental protocols for this study were approved by the Institutional Animal Care and Use Committee of the University of Mississippi Medical Center and were carried out according to both the Guide for the Care and Use of Laboratory Animals from the National Institutes of Health and the guidelines of the Animal Welfare Act.

Twenty-nine male golden hamsters (100-170 g, Charles River) were anesthetized with an intraperitoneal injection of pentobarbital sodium (60 mg/kg). The left jugular vein was cannulated for a continual infusion of pentobarbital sodium in 0.9% saline solution (5 mg/ml at 0.01 ml/min). Deep esophageal temperature was maintained at 37-38°C by convective heating. The hamsters used in these experiments had their tracheas intubated, and the animals spontaneously breathed 30% oxygen with balance nitrogen to mimic blood gases typical of conscious animals.

The cremaster muscle was prepared by spreading the muscle over a clear Lucite pedestal and securing the edge of the cremaster muscle with insect pins as previously described (21). During the dissection and experimental period the cremaster muscle was superfused with warm physiological salt solution (PSS), pH 7.35 at 36°C, containing (in mM) 131.9 NaCl, 4.7 KCl, 2.0 CaCl2, 1.2 MgSO4, and 20 NaHCO3. The superfusion solution was equilibrated with 5% CO2 with a balance of N2.

Experimental measurements. The microcirculation of the cremaster muscle was transilluminated and observed with a Leitz Laborlux 12 FS microscope fitted with a ×32 long-working-distance objective (numerical aperture = 0.40). The microscopic image was televised with a Dage closed-circuit television camera and displayed on a Sony monitor. The magnification of the image was ×900 from the tissue to monitor screen. Vessel diameter was measured by using a Colorado Video 321 analyzer modified to function as a video micrometer. With the use of this device, two movable lines were positioned on the inside walls of the vessel, and a DC voltage proportional to the line separation was recorded using a computerized data collecting system. The resolution of this system was ±1 µm.

Electrical stimulation protocol. Two silver-silver chloride electrodes were placed across the narrow proximal portion of the cremaster muscle. The preparation was initially allowed to equilibrate for 30 min at which time the resting arteriolar diameter was measured. Muscle contraction was elicited using a Grass 44 stimulator with a square-wave pulse of 40 µs in duration, at 10 V, and a frequency of 1 Hz. The "poststimulation" arteriolar diameter was measured immediately after cessation of the stimulation.

Pharmacological protocols. Cumulative concentration-response relationships of the effects of adenosine (Ado) and sodium nitroprusside (SNP) and single concentration effects of AA and thrombin on arteriolar diameter were determined. Concentrated stocks were diluted to working concentrations of 10-6-10-4 M Ado, 10-6-10-4 M SNP, 3 × 10-6 and 10-5 M AA, and 2 U/ml thrombin in PSS. To determine the cumulative concentration response to Ado and SNP, the preparation was superfused with increasing concentrations of either Ado or SNP after an initial 30-min equilibration period. Each concentration was applied for 5 min, at which time arteriolar diameter was measured. AA and thrombin were each superfused for 10 min after the equilibration period.

Blockade of PLA2 activity. Topical application of 3 × 10-6 M quinacrine for 60 min was used to inhibit PLA2 activity. This concentration has been demonstrated to inhibit AA release in vitro (5, 31) and in vivo (1). We observed a comparable inhibition of thrombin-induced vasodilation after a 15- to 20-min incubation period with 10-5 M quinacrine (data not shown). A stock solution of 3 × 10-3 M quinacrine was diluted in PSS just before superfusion of the preparation. The maximum arteriolar diameter was determined at the end of the experiment by topical application of either 10-4 M Ado or 10-5 M SNP in the continued presence of quinacrine. An unrelated PLA2 inhibitor, oleyloxyethyl phosphorylcholine (30 µM for 30 min), was also used to inhibit PLA2 activity. However, this agent alone caused vasodilation comparable to that observed in response to thrombin (2 U/ml) alone. Therefore, its ability to inhibit thrombin-induced vasodilation or functional vasodilation could not be further assessed.

Materials. AA, Ado, and human thrombin were purchased from Sigma Chemical (St. Louis, MO); SNP was purchased from Gensia Pharmaceuticals (Irvine, CA); quinacrine was purchased from Research Biochemicals International (Natick, MA); and bovine thrombin was from GenTrac (Middleton, WI).

Analytic and statistical methods. Digital data were collected using a Gateway 486/33 personal computer equipped with a Metrabyte Dash-8 analog-digital converter (Taunton, MA). Data were collected at 1 Hz and stored to a diskette. Statistical significance was determined with either a paired t-test or ANOVA with repeated measures (GB-Stat). All data are means ± SE. Statistical significance was accepted at P < 0.05.


    RESULTS
TOP
ABSTRACT
INTRODUCTION
MATERIALS AND METHODS
RESULTS
DISCUSSION
REFERENCES

Effect of quinacrine on functional hyperemia. Figure 1 illustrates the diameter of first- and second-order arterioles measured at rest and after a 1-min electrical stimulation period. There was no difference in the response of first- and second-order vessels to stimulation. Measurements were made both before and after 60 min of topical superfusion of the preparation with 3 × 10-6 M quinacrine. Under control conditions, a 1-min muscle stimulation period increased arteriolar diameter from a resting diameter of 66 ± 5 to 88 ± 7 µm. Pretreatment with quinacrine had no effect on the resting arteriolar diameter (64 ± 5 µm) but completely abolished the increase in diameter observed after muscle stimulation. Maximal dilation was determined in the continued presence of quinacrine after the application of 10-4 M Ado and was not significantly different from the stimulated control diameter.


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  		Fig. 1.   Effect of quinacrine on functional hyperemia. Arteriolar diameter was measured during rest and after a 1-min electrical stimulation of hamster cremaster muscle. Measurements were repeated after superfusion of muscle for 60 min with 3 × 10-6 M quinacrine. Maximal vasodilation was determined after stimulation of muscle with adenosine (Ado) in continued presence of quinacrine. Data are means ± SE; n = 6 vessels. ++ Significant difference (P < 0.01) compared with control resting diameter. ** Significant difference (P < 0.01) compared with control stimulation.

To verify the inhibition of PLA2 in this preparation using quinacrine we also examined the effect of quinacrine on the ability of thrombin, which stimulates vasodilation through a PLA2-dependent mechanism (14, 32), to induce arteriolar vasodilation in the cremaster muscle (see Fig. 2). Superfusion of the preparation with 2 U/ml of thrombin increased mean arteriolar diameter from a resting value of 67 ± 7 to 80 ± 9 µm. After the preparation was pretreated with 3 × 10-6 M quinacrine, the response to thrombin was significantly attenuated (62 ± 5 to 63 ± 6 µm). There was no difference in the response of the arterioles to human versus bovine thrombin.


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  		Fig. 2.   Effect of quinacrine on thrombin-induced arteriolar dilation. Arteriolar diameter was measured during rest and after superfusion of preparation with 2 U/ml of thrombin for 10 min. Measurements were repeated after superfusion of muscle for 60 min with 3 × 10-6 M quinacrine. Data are means ± SE; n = 6 vessels. + Significant difference (P < 0.05) compared with control resting diameter. ** Significant difference (P < 0.01) compared with thrombin alone.

Effect of quinacrine on Ado-, SNP-, and AA-induced arteriolar dilation. Quinacrine is not a selective inhibitor of PLA2. To characterize the effect of quinacrine in the cremaster muscle, the responsiveness of first- and second-order arterioles to vasodilators, which elicit their responses through PLA2-independent mechanisms, was determined before and after a 60-min incubation period with 3 × 10-6 M quinacrine. Figure 3 summarizes the cumulative concentration effects of Ado (10-6-10-4 M) and SNP (10-6-10-4 M), which elicit their vasodilatory effect on arteriolar diameter through an increase in cAMP (41) and cGMP (35), respectively. Each concentration was applied for 5 min before the measurement of the arteriolar diameter. Mean resting diameter was 69 ± 4 and 69 ± 5 µm in these experiments. A significant increase in arteriolar diameter was observed in response to the addition of each concentration of either Ado (Fig. 3A) or SNP (Fig. 3B). Maximum arteriolar diameters measured in response to these agents were 118 ± 9 and 110 ± 4 µm, respectively. Compared with control values, there was no difference in the arteriolar diameters measured in response to Ado or SNP after quinacrine treatment.


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  		Fig. 3.   Effect of quinacrine on Ado- and sodium nitroprusside (SNP)-induced arteriolar dilation. Arteriolar diameter was measured at rest and after superfusion of the cremaster muscle with cumulative concentrations of Ado (n = 6 vessels, 10-6-10-4 M; A) or SNP (n = 5 vessels, 10-6-10-4 M; B). Measurements were repeated after superfusion of muscle for 60 min with 3 × 10-6 M quinacrine. Data are means ± SE.

To determine whether quinacrine elicits effects through the inhibition of AA metabolism or AA metabolite-induced vasodilation, we examined the effect of quinacrine on arteriolar dilation induced by exogenous AA. These results are summarized in Fig. 4. Arteriolar diameter increased significantly from mean resting diameters of 60 ± 4 and 65 ± 4 µm to maximum diameters of 74 ± 5 and 109 ± 5 µm, respectively, in response to the 10-min superfusion of the preparation with 3 × 10-6 and 10-5 M AA. Pretreatment with quinacrine had no effect on either the resting arteriolar diameter (60 ± 4 and 65 ± 4 µm) or the AA-induced increase in diameter (69 ± 4 and 103 ± 6 µm) at either concentration.


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  		Fig. 4.   Effect of quinacrine on arachidonic acid (AA)-induced arteriolar dilation. Arteriolar diameter was measured during rest and at maximal dilation after superfusion of preparation with AA (n =7 vessels, 3 × 10-6 M A; or n = 6 vessels, 10-5 M B). Measurements were repeated after superfusion of muscle for 60 min with 3 × 10-6 M quinacrine. Data are means ± SE. ++ Significant difference (P < 0.01) compared with control resting diameter.


    DISCUSSION
TOP
ABSTRACT
INTRODUCTION
MATERIALS AND METHODS
RESULTS
DISCUSSION
REFERENCES

This study was designed to test the hypothesis that AA release is a necessary step in the functional vasodilation of first- and second-order arterioles in the hamster cremaster microcirculatory bed. Pretreatment of the cremaster muscle with concentrations of quinacrine, previously shown to inhibit PLA2 and AA release in vitro (31) and in vivo (1), completely abolished the functional vasodilation induced by electrical stimulation of the muscle. Quinacrine also inhibited the arteriolar vasodilation measured in response to thrombin, which induces vasodilation through a receptor-mediated, Ca2+-dependent activation of PLA2 (14, 32). In contrast, quinacrine had no effect on the resting arteriolar diameter or the vasodilation measured in response to Ado or SNP. These vasodilators elicit their effects through PLA2-independent mechanisms involving an increase in smooth muscle cAMP and cGMP levels, respectively, and the activation of cyclic nucleotide-dependent kinases (35, 41). Moreover, quinacrine had no effect on the vasodilation induced by AA, indicating that its inhibitory effect lies upstream of AA metabolism and not, for example, as a result of K+ channel blockade as previously described (8). These data suggest that 1) quinacrine can inhibit functional vasodilation through the inhibition of PLA2 and AA release, and 2) AA and its metabolites do not play a significant role in the regulation of the basal tone of first- and second-order arterioles.

The role of AA metabolites in the local control of blood flow under conditions of increased metabolic demand and hypoxia has been demonstrated in a number of in vivo microvascular models as well as in isolated vessels. Products of the cyclooxygenase pathway, in particular, have been shown to contribute to functional hyperemia as well as hypoxia-induced vasodilation. Both prostacyclin and prostaglandin E2, which are potent vasodilators, are released during skeletal muscle contraction (36, 42, 43), and the inhibition of cyclooxygenase by either aspirin or indomethacin has been shown to significantly reduce functional hyperemia in human studies (9, 25) as well as in the hamster cremaster muscle (38). A reduction in PO2 to levels comparable to tissue and perivenular levels observed in contracting skeletal muscle (26) has been shown to increase the diameter of isolated arterioles (30) as well as larger arteries (6, 13). In all of these examples, hypoxia-induced dilation was inhibited either by indomethacin or by removal of the endothelium.

There is increasing evidence that products of the cytochrome P-450 monooxygenase pathway of AA metabolism are also involved in the determination of basal tone and hypoxia-induced vasodilation. Metabolism of AA along the cytochrome P-450 hydroxylase pathway generates HETEs (17). In the vasculature, 20-HETE is released endogenously in vascular smooth muscle and has been shown to be involved in the vasoconstrictor response to increased levels of O2 (24). Cytochrome P-450 epoxygenase activity, primarily localized to the endothelium, generates EETs which are vasodilatory (18). Although some species appear to have direct effects on vascular smooth muscle, 5,6-EET is further metabolized via a cyclooxygenase pathway to the vasodilatory prostaglandins 5,6-epoxy-PGE1 and 5-hydroxy-PGI1. EETs have been shown to be released in the brain and are thought to play a role in the regulation of cerebral blood flow in response to increase metabolic demand (3) and hypoxia (27). In addition, recent studies from our laboratory indicate that a metabolite of the cytochrome P-450 monooxygenase pathway may account for the cyclooxygenase-independent arteriolar dilation induced by electrical field stimulation in the hamster cremaster muscle (22).

The total inhibition of functional hyperemia observed after pretreatment of the preparation with quinacrine suggests that PLA2 activity represents an important regulatory step in the vasodilatory response to muscle contraction and increased metabolic demand. Liberation of free AA from storage in membrane phospholipids is the rate-limiting step in the production of its metabolites, and the predominant pathway for AA release is through the activity of PLA2. There are currently at least 12 major groups of PLA2 characterized by their intracellular localization, size, Ca2+ requirements, and molecular structure (10). A recent study by Adeagbo and Henzel (2) reported a role for two Ca2+-dependent PLA2 isoforms, 85- and 14-kDa PLA2, in the release of AA and production of endothelium-derived hyperpolarizing factor in the perfused rat mesenteric prearteriolar bed. This study further supports the function of PLA2 as an intracellular effector enzyme that responds to changes in the metabolic state of the tissue. Additional studies of the presence and localization of specific PLA2 isoforms will be useful in determining their role and mechanism of regulation during functional hyperemia in this tissue.

In perspective, the results of the present study, although consistent with the role of the endothelium and endothelium-derived AA metabolites, do not provide any information concerning the location of the PLA2 enzyme involved in the functional dilation or the identity of the trigger for its increased activity. In the hamster cremaster microcirculation and other microvascular beds, first- and second-order arterioles exist in a paired arrangement with venules separated by a distance of <100 µm (19). Several studies have shown that there can be significant diffusion of substances from venules, including vasodilatory factors, which can affect adjacent arterioles (19, 20, 37, 40). In the hamster cremaster microcirculation there appears to be an obligatory role for the venular endothelium and intact venular flow in the feedback mechanism underlying the dilation of its paired arteriole in response to an increase in metabolic demand (37, 39). Disruption of the venular endothelium, for example with the infusion of air into the venule, prevents the increase in arteriolar diameter routinely observed in response to electrical stimulation of the muscle. These observations support the hypothesis that the venular endothelium plays an important role in the local control of blood flow by "sensing" increases in the metabolic needs of the tissue and responds by releasing one or more vasodilatory factors that diffuse and dilate the adjacent arteriole.

One of the potential triggers for an increase in PLA2 activity is a change in venous PO2. Oxygen has long been recognized as a potent regulator of local blood flow (7, 11, 23). During mismatches in oxygen delivery and tissue metabolism there are decreases in oxygen levels of the blood and the tissue (16). Similar decreases have been shown to elicit endothelium-dependent vasodilatory effects in a variety of in vitro models (6, 12, 13, 27, 33, 34) as well as to stimulate PLA2 activity and prostacyclin production in endothelial cells in culture (31). Conversely, increases in PO2 induce vasoconstriction. Harder and colleagues (18) have demonstrated a linear relationship in renal and microvascular tissues between PO2 and the production of 20-HETE, a product of cytochrome P-450 omega -hydroxylase activity and a potent vasoconstrictor. This relationship suggests a role for cytochrome P-450 as an oxygen sensor in the regulation of arteriolar diameter in response to changes in PO2. Although we have preliminary evidence for a role for EETs in the arteriolar vasodilation observed with functional hyperemia, our current data support a model in which both EETs and prostaglandin synthesis are regulated at the level of PLA2 activity and the generation of their common precursor, AA, in response to an increase in metabolic demand.

Several studies argue against a direct effect of PO2 on arteriolar diameter during functional hyperemia. Lash and Bohlen (26) reported that, although tissue and periarteriolar PO2 levels decrease transiently with muscle contraction, venous and perivenular PO2 levels remain significantly below resting levels for the duration of the contraction. Hester and Duling (21) also reported no change in arteriolar hemoglobin saturation during contraction of the hamster cremaster muscle, suggesting that arteriolar PO2 does not change. Consistent with a role for venular endothelium in functional hyperemia, these results suggest that decreased venular PO2 may function as a trigger for the release of vasodilators. The oxygen-dependent regulation of PLA2 and vasodilator release in the venular endothelium and its role in the feedback mechanism for the local control of blood flow remain to be determined.


    ACKNOWLEDGEMENTS

This work was supported by National Heart, Lung, and Blood Institute Grant HL-51971 and an American Heart Association Grant-in-Aid (National and Mississippi Affiliate).


    FOOTNOTES

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: L. C. Nuttle, Dept. of Physiology and Biophysics, Univ. of Mississippi Medical Center, 2500 North State St., Jackson, MS 39216-4505 (E-mail: nuttle{at}ovc.umsmed.edu).

Received 10 June 1998; accepted in final form 4 December 1998.


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ABSTRACT
INTRODUCTION
MATERIALS AND METHODS
RESULTS
DISCUSSION
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Am J Physiol Heart Circ Physiol 276(4):H1289-H1294
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