The Journal of Bone & Joint Surgery

The Journal of Bone & Joint Surgery, Volume 88, Issue suppl 2

Basic Science | November 01, 2006

Femoral Artery Constriction by Norepinephrine Is Enhanced by Methylprednisolone in a Rat Model

Wolf Drescher, MD, PhD; Deike Varoga, MD; Thoralf R. Liebs, MD; Janne Lohse; Thomas Herdegen, MD, PhD; Joachim Hassenpflug, MD, PhD; Thomas Pufe, PhD

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In support of their research for or preparation of this manuscript, one or more of the authors received grants or outside funding from the German Research Foundation (DFG), grants no. DR 449/2-1 and VA 220/2-1. None of the authors received payments or other benefits or a commitment or agreement to provide such benefits from a commercial entity. No commercial entity paid or directed, or agreed to pay or direct, any benefits to any research fund, foundation, educational institution, or other charitable or nonprofit organization with which the authors are affiliated or associated.

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J Bone Joint Surg Am, 2006 Nov 01;88(suppl 2):162-166. doi: 10.2106/JBJS.F.00452

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Abstract

Background: Corticosteroids are associated with femoral head osteonecrosis and arterial hypertension. The patho-mechanism of femoral head osteonecrosis is often attributed to ischemia. The aim of this study was to investigate if corticosteroids directly constrict the femoral artery or if they have a permissive effect on norepinephrine and endothelin-1-induced vasoconstriction.

Methods: Femoral artery segments were harvested from twenty Wistar rats and mounted as ring preparations on a small-vessel myograph for the purpose of making isometric force measurements. For the norepinephrine study, twenty femoral artery segments from ten rats were stimulated cumulatively with norepinephrine before and after incubation with methylprednisolone (5 µg/mL). For the endothelin-1 study, forty femoral artery segments from ten rats were used. The four artery segments from each animal were randomized by pairs to either a corticosteroid treatment group (5 µg/mL methylprednisolone incubation, n = 20) or a control group (placebo incubation, n = 18, as two of the twenty control-group vessels did not meet protocol requirements). Isometric wall tension was plotted and quantified by the EC₅₀ (the plasma concentration of endothelin-1 required for obtaining 50% of maximal constriction in vivo).

Results: In the norepinephrine-stimulated group, incubation with methylprednisolone did not directly induce any vasoconstriction but did enhance norepinephrine-elicited vasoconstriction. The norepinephrine dose-response curve displayed a shift to the left after incubation with methylprednisolone. This shift was reflected by a significantly lower mean EC₅₀ of 9.5 × 10^-7 M ± 5.1 × 10^-7 M after methylprednisolone incubation compared with a mean of 2.5 × 10^-6 M ± 1.1 × 10^-6 M before incubation (p < 0.005). In the endothelin-1-stimulated group, the endothelin-1 dose-response curve displayed a tendency toward stronger contraction in the vessels that were incubated with methylprednisolone, but this tendency did not reach significance.

Conclusions: Incubation with methylprednisolone enhances norepinephrine-mediated contraction of the femoral artery in a rat model.

Clinical Relevance: Vasoconstriction of the vascular bed supplying the femoral head can diminish femoral head blood flow, and this may be a factor in the early pathogenesis of corticosteroid-associated femoral head osteonecrosis.

Figures in this Article

Femoral head osteonecrosis is a disease that severely disables patients who are in their third, fourth, or fifth decade of life¹. The pathomechanism of steroid-associated osteonecrosis of the femoral head is hypothesized to be femoral head ischemia. Corticosteroids have been shown to induce arterial hypertension in rats, and osteonecrosis has frequently been found in hypertensive rats^2-4. To our knowledge, corticosteroid-induced constriction of artery walls supplying the femoral head has not yet been investigated as a mechanism of ischemia. Results from the first study on this topic provide information that is restricted only to the intraosseous part of the vascular bed^5,6. Nothing is known about the influence of corticosteroid treatment on wall tension of the femoral artery⁷.

Blood flow to bone is regulated by the degree of wall tension of the supplying arteries⁸. Constriction increases perfusion pressure and reduces blood flow in bone arteries^8,9. Endothelin-1 is a potent vasoconstrictor that is synthesized and released by vascular endothelial cells. It acts on the microvasculature of bone¹⁰, whereas norepinephrine is the most important vasoconstrictor⁶. Blood flow to the femoral head decreases shortly after methylprednisolone treatment is initiated¹¹. It has also been shown that long-term corticosteroid treatment enhances the constriction of the epiphyseal arteries of the femoral head under the influence of endothelin-1⁵, whereas constriction of these arteries under the influence of norepinephrine was not significantly changed.

This study examines the in vitro effect of corticosteroid treatment on vasoconstriction of femoral arteries in a rat model. The purpose of this study was to investigate changes in isometric wall tension of the femoral artery elicited by methylprednisolone, norepinephrine, and endothelin-1. In addition, we evaluated whether methylprednisolone has a direct or modulatory effect on the femoral artery wall tension elicited by endothelin-1 and norepinephrine.

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Fig. 1: The principle of the Mulvany-Halpern small-vessel myograph is shown. A 2-mm-long arterial segment was threaded onto two 40-µm steel wires, which were fixed on the myograph clamps. Connected to these were the force transducer and the micrometer that registered changes in isometric wall tension. (Reprinted, with permission, from Drescher W, Bünger MH, Weigert K, Bünger C, Hansen ES. Methylprednisolone enhances contraction of porcine femoral head epiphyseal arteries. Clin Orthop Relat Res. 2004;423:114.)

Materials and Methods

Materials and Methods | Results | Discussion | References

Study Design

For the norepinephrine study, twenty femoral artery segments were harvested from ten male Wistar rats (sixty-two to eighty-eight days old and weighing between 254 to 318 g). For the endothelin-1 study, forty femoral artery segments were harvested from ten female Wistar rats (fifty-nine to eighty-eight days old and weighing between 238 to 310 g). All animals were killed with ether in accordance with the rules and regulations of the Institutional Animal Care and Use Committee of the federal state of Schleswig-Holstein, Germany.

Myographic Method

The femoral artery was approached through a medial skin incision, and a segment was cut from the femoral artery and placed in a Petri dish in physiological saline solution at 4°C. Arterial segments, 2 mm in length, were threaded on two stainless steel wires that were each 40 µm in diameter, and these were then mounted as ring preparations on a small-vessel myograph (Fig. 1) for isometric force development¹². The test chamber contained 20 mL of bicarbonate-buffered physiological saline solution, which was heated to 37°C and which bubbled continuously with 95% oxygen and 5% carbon dioxide to give a pH between 7.4 and 7.5. After an initial equilibration time of thirty minutes, the arteries were stretched stepwise to characterize the relationship between the vessel circumference and the passive wall tension. The vessel size was normalized by defining L₁₀₀ as the internal circumference that the vessel would have when relaxed and exposed to a transmural pressure of 100 mm Hg of mercury¹³. The vessels were maintained at 0.9 × L₁₀₀ because this degree of stretch permits development of maximal active force ⁶. Experiments were carried out by adding the vasoactive agents directly to the chamber and recording the isometric force development in the vessel wall. The vasoactive agents used were methylprednisolone (Urbason Soluble; Aventis Pharma, Frankfurt, Germany), norepinephrine, and endothelin-1 (Sigma-Aldrich, St. Louis, Missouri).

All arteries were stimulated three times with 10 µmol of norepinephrine for two minutes at five-minute intervals and then once for five minutes. This standard initial procedure, which was carried out prior to all experiments, served to mobilize the vessel and was used to evaluate smooth-muscle function¹⁴. Vessels with an active force development corresponding to contraction against a pressure of at least 100 mm Hg of mercury were included in the protocol¹³.

For the norepinephrine study, the arteries were stimulated cumulatively with norepinephrine (0.1 to 30 µM in log-unit steps at two-minute intervals) to obtain a dose-response curve and to identify maximal force development. Thereafter, the vessels were incubated with 5 µg/mL of methylpredniso-lone for thirty minutes, and then were once again stimulated with norepinephrine (0.1 to 30 µM in log-unit steps at two-minute intervals).

For the endothelin-1 study, two vessels from each animal were randomized to incubation with methylprednisolone (5 µg/mL for thirty minutes) and the other two vessels were incubated with placebo for thirty minutes. All arteries were then stimulated cumulatively with endothelin-1 (6 to 300 nmol/L in log-unit steps) to obtain a dose-response curve.

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Fig. 2: Graph showing the norepinephrine dose-response curve as increasing concentrations of norepinephrine (1 to 30 µM in log-unit steps) were added to the myograph chamber. Norepinephrine-elicited constriction of the femoral artery was enhanced after methylprednisolone incubation.

Calculations and Statistics

The isometric force exerted by the arterial segment on the force transducer was registered. Agonist sensitivity was expressed as the EC₅₀, defined as the agonist concentration of endothelin-1 (in mol/L = M) resulting in a half maximal effect.

Data are presented as the average (and standard deviation). The normal distribution was documented with use of a univariate quantile-quantile (Q-Q) plotting technique. Homogeneity of variances was checked with use of the Levene test. Comparison of the two experimental groups was done by means of a Student t test. P values of <0.05 (two-tailed) were considered significant.

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Fig. 3: Graph showing the effect of increasing concentrations of endothelin-1 (6 to 300 nmol/L in log-unit steps). Methylprednisolone incubation did not directly change isometric wall tension. After incubation, the endothelin-1 dose-response curve displayed a nonsignificant tendency toward a stronger contraction for the methylprednisolone group, especially as the dose of endothelin-1 was increased, as compared with the placebo (control) group. Control = vessels that received placebo incubation. MP = vessels that received methylprednisolone incubation.

Results

Materials and Methods | Results | Discussion | References

In the norepinephrine study group, the internal diameter of the femoral artery segments at L₁₀₀ was 391 µm ± 93 µm. After the vessels were incubated with methylprednisolone, norepinephrine-elicited constriction of the femoral artery became enhanced and the norepinephrine dose-response curve displayed a shift to the left (Fig. 2). This shift was reflected by a significantly lower mean EC₅₀ of 9.5 × 10^-7 M ± 5.1 × 10^-7 M after methylprednisolone incubation compared with a mean of 2.5 × 10^-6 M ± 1.1 × 10^-6 M before incubation (p < 0.005). With the numbers studied, the maximum contraction force was not significantly different (mean, 8.9 ± 4.3 mN after and 10.2 ± 5.0 mN before corticosteroid treatment).

In the endothelin-1 study group, the internal diameter of the femoral artery segments at L₁₀₀ was 634 µm ± 156 µm in the vessels that were incubated with placebo and 591 µm ± 175 µm in the vessels that were incubated with methylprednisolone. Methylprednisolone incubation did not directly change isometric wall tension (Fig. 3). After the incubation process, the endothelin-1 dose-response curve displayed a tendency toward stronger contraction for the vessels that were incubated with methylprednisolone; however, the EC₅₀ of the methylprednisolone-treated vessels (4.4 × 10^-8 M ± 1.8 × 10^-8 M) was not significantly lower than that of the control vessels (5.9 × 10^-8 M ± 3.4 × 10^-8 M). With the numbers studied, the maximum contraction force was not significantly different between the methylprednisolone-treated vessels and the control vessels (9.2 ± 4.2 mN compared with 8.2 ± 4.1 mN, respectively).

Discussion

Materials and Methods | Results | Discussion | References

This study showed that methylprednisolone did not directly change the vascular tone of the femoral artery. Norepinephrine-induced constriction of the femoral artery was enhanced by corticosteroid incubation. For endothelin-1, this same tendency was observed without reaching significance. This mechanism may cause femoral head ischemia, and consequent osteonecrosis, especially with continuous or high-dose administration of corticosteroid medication.

Femoral artery constriction as a result of norepinephrine administration was stronger after incubation with methylprednisolone. In another study, vascular sensitivity to norepinephrine was enhanced by corticosteroid treatment in the rat hindlimb¹⁵. In contrast, sensitivity to norepinephrine was unchanged in aortic rings from rats after one week of corticosteroid treatment¹⁶. Finally, infused corticosteroids have been shown to induce hypertension in rats and in humans by affecting sodium ion metabolism¹⁷. Thus, methylpredniso-lone appears to enhance norepinephrine-induced vasoconstriction in the femoral artery but not in the femoral-head epiphyseal arteries or centrally in the aorta⁵. This may be a systemic effect, reflecting the pathomechanism of glucocorticoid-induced arterial hypertension as produced in rats¹⁸.

Endothelin-1 has also been shown to be involved in the pathomechanism of hypertension¹⁹, but the vasoconstrictor potential of endothelin-1 was not enhanced in the present study of femoral arteries. In contrast, endothelin-1-induced vasoconstriction has been shown to be enhanced in the lateral epiphy-seal arteries of the femoral head⁵, which provide the major blood supply to the epiphysis of the femoral head in humans^20,21. Enhanced constriction of the lateral epiphyseal arteries to plasma endothelin by methylprednisolone may increase bone perfusion pressure in the femoral head⁸ and decrease blood flow into the vascular bed of the femoral head²², thereby causing local ischemia of the femoral head^11,23.

The endothelins are potent vasoconstrictors that are synthesized in and released by vascular endothelial cells²⁴ and that bind to vascular smooth muscle in bone. Endothelin causes vasoconstriction by increasing the intracellular calcium levels in vascular smooth muscle²⁵. Endothelin-1 is the endothelin with the strongest vasoconstrictive potential; its physiologic effect on canine bone microvasculature has been described¹⁰. Endothelin-1 has been shown to elicit a potent dose-related increase in bone-perfusion pressure in the tibiae of mongrel dogs⁸.

Possible mechanisms of action of methylprednisolone on vasoconstriction have been discussed for tissues other than bone^26,27. It was hypothesized that corticosteroids have a direct effect on the vasculature, mediated by specific glucocorticoid receptors that have been seen in the tunica media of the canine aorta²⁶. Glucocorticoids have been shown to inhibit prostacyclin production in the rabbit carotid artery and aortic rings²⁷. Prostacyclin is a potent vasodilator that is produced by the endothelium and vascular smooth muscle cells, and its production is decreased by glucocorticoids²⁸. Corticosteroids have been shown to increase calcium ion uptake in vascular smooth muscle cells²⁹. Another possible mechanism is a permissive effect of glucocorticoids for vasoconstrictors². Corticosteroids have been shown to down-regulate the expression of endothelial nitrous oxide synthase in rats³⁰. Thus, corticosteroids appear to function as regulators of local blood flow by the modulation of vascular responsiveness to other substances².

The rat was chosen in the current study, as osteonecrosis could be induced with the use of corticosteroids in this model³¹. The dose of methylprednisolone given for incubation in the current study is clinically relevant because it corresponds to the plasma levels of methylprednisolone that were seen in humans during therapy³².

With regard to the limitations of the current study, the effect of methylprednisolone on wall tension of the femoral arteries was investigated in vitro. Earlier myographic studies showed that vessel function still is physiologic after twenty-four hours of hypothermic storage of the isolated vessel⁶, a condition that was fulfilled in all experiments in the current study. It is still uncertain whether these in vitro results can be directly extrapolated to the in vivo situation. Also, these vessels are isolated from the physiologic nerve supply, which is known to play an important role in the regulation of vascular tone. It is not clear whether thirty-minute incubation with methylprednisolone in vitro can fully simulate drug-induced hypercortisolism in vivo.

The pathomechanism of corticosteroid-associated femoral head osteonecrosis is believed to be multifactorial¹. A well-studied pathomechanism is corticosteroid-induced adipogenesis in the pluripotential cells of bone marrow³³. A second well-documented factor is a hypercoagulable state of plasma¹¹ with a wide range of thrombophilic and hypofibrinolytic coagulation abnormalities³⁴.

We conclude that enhanced vasoconstriction of the femoral artery and femoral-head epiphyseal arteries is a new and relevant factor in the pathogenesis of corticosteroid-induced osteonecrosis of the hip. Constriction of both the femoral artery and femoral-head epiphyseal arteries can lead to decreased blood flow and ischemia of the femoral head⁵. Further investigation is needed to define the precise mechanisms involved. ?

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Topics

norepinephrine ; endothelin-1 ; glucocorticoids ; constriction procedure ; femoral artery ; methylprednisolone ; mineralocorticoids

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Wolf Drescher, Deike Varoga, Thoralf R. Liebs, Janne Lohse, Thomas Herdegen, Joachim Hassenpflug, Thomas Pufe; Femoral Artery Constriction by Norepinephrine Is Enhanced by Methylprednisolone in a Rat Model. The Journal of Bone & Joint Surgery. 2006 Nov;88(suppl_2):162-166.

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