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ORIGINAL RESEARCH ARTICLE

Prophylactic Intravesical Instillation of Epinephrine Prevents Cyclophosphamide-Induced Hemorrhagic Cystitis in Rats

Yung-Chiong Chow^*,,, Stone Yang^,, Chun-Jen Huang^,, Chin-Yuan Tzen^,||, Yu-Hsien Su^,¶ and Paulus S. Wang^*,1

^* Department and Institute of Physiology, National Yang-Ming University, Taipei, Taiwan, R.O.C.; Department of Urology, Mackay Memorial Hospital, Taipei, Taiwan, R.O.C.; Mackay Medicine, Nursing, and Management College, Taipei, Taiwan, R.O.C.; Department of Anesthesiology, Mackay Memorial Hospital, Taipei, Taiwan, R.O.C.; ^|| Department of Pathology, Mackay Memorial Hospital, Taipei, Taiwan, R.O.C.; and ^¶ Department of Medical Research, Mackay Memorial Hospital, Taipei, Taiwan, R.O.C.

¹To whom requests for reprints should be addressed at Department and Institute of Physiology, School of Medicine, National Yang-Ming University, 155 Li-Nong Street, Section 2, Shih-Pai, Taipei, 11221 Taiwan, R.O.C. E-mail: pswang{at}ym.edu.tw

	Abstract

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The objective of this study is to investigate the potential protective effects of intravesical instillation of epinephrine in cyclophosphamide-induced hemorrhagic cystitis. In an earlier study, we have shown that epinephrine promotes hemostasis on established hemorrhagic cystitis induced by cyclophosphamide. Female Sprague-Dawley rats were divided into seven groups as follows: group 1: positive control (150 mg/kg, cyclophosphamide, i.p.), group 2: negative control (10 µ g/ml, epinephrine, intravesical), co-administration of cyclophosphamide (150 mg/kg, i.p.), group 3: saline (intravesical), groups 4–6: epinephrine (2.5, 5, and 10 µ g/ml, intravesical), and group 7: mesna (50 mg/kg, i.p.). Rats were sacrificed on 3 consecutive days and the urinary bladders were removed, weighed, and evaluated. The vesical vascular permeability was determined by wet bladder weight and Evan’s blue dye absorbance. After 24 hours of cyclophosphamide administration, severe hemorrhagic cystitis was induced with marked edema, hemorrhage, and inflammation. In the epinephrine-treated groups, symptoms of hemorrhagic cystitis (such as edema, inflammation, and hemorrhage) were reduced significantly. Intravesical instillation of epinephrine prevents edema, hemorrhage, and inflammation in rats with cyclophosphamide-induced hemorrhagic cystitis.

Key Words: hemorrhagic cystitis • cyclophosphamide • urinary bladder • epinephrine • rat

	Introduction

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Cyclophosphamide (CYP) is an oxazaphosphorine alkylating agent widely used in the treatment of malignant and nonmalignant diseases such as lymphoproliferative disorders, nephritic syndrome, rheumatoid arthritis, systemic lupus erythematosis, solid tumors, and bone marrow transplantation (1). Hemorrhagic cystitis (HC) is a common dose-limiting side effect of cyclophosphamide with a reported incidence of 40%–75% and mortality rate of 4% (2). Acrolein, the urotoxic metabolite of cyclophosphamide, has been proposed as the main inducing factor. Direct contact of acrolein to the urothelium results in vesical edema, erosion, hemorrhage, inflammation, and ulceration (3). Earlier prophylactic strategies for CYP-induced HC include superhydration, intravesical instillation of saline, prostaglandins E₁ (4) and F₂ (1), and hyperbaric oxygen therapy (5). One of the most promising prophylactic agents is the intravenous and oral administration of 2-mercaptoethane sodium sulphonate (mesna) (6). Unfortunately, in mesna-treated patients, a considerable number of HC have been reported. Researchers are now looking for more effective agents of CYP prevention. Recent studies showed that decreased nitric oxide production by antioxidants such as alpha-tocopherol (7), melatonin (7), taurine (8), quercetin, and catechine (9) attenuated CYP-induced HC. Other potential prophylactics against the toxicity of CYP include amifostine (10), keratinocyte growth factor (11), and dexamethasone (12).

Recent works in our laboratory have shown that the intravesical instillation of epinephrine attenuated established CYP-induced HC significantly (13). Although successful as a therapeutic agent against CYP-induced HC, the protective effect of epinephrine (EPI) has not been examined. In severe cases of hemorrhagic cystitis refractory to mesna or other prophylactics, we hypothesize that the intravesical administration of epinephrine may provide an alternative means of prevention against the toxicity of cyclophosphamide. The objective of this study is to investigate the protective effects of intravesical instillation of epinephrine on CYP-induced HC.

	Materials and Methods

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Animals.
The Animal Care Committee of the Mackay Memorial Hospital approved this study. Female Sprague-Dawley rats (250–350 g) were maintained in a 12:12-hr light:dark cycle with free access to water and food.

Drugs.
Cyclophosphamide, epinephrine, mesna, and Evan’s blue dye were obtained from Sigma (St. Louis, MO).

Hemorrhagic Cystitis Model.
Sprague-Dawley rats were intraperitoneally injected with 150 mg/kg cyclophosphamide according to the methods described by Botta et al. (14). Hemorrhagic cystitis was established 24 hours later. The animals were sacrificed and the bladders were removed and evaluated for gross and histological changes.

Epinephrine Instillation Model.
Epinephrine (0.1%) solution was diluted with normal saline to concentrations of 2.5 (1:400,000), 5 (1:200,000), or 10 (1:100,000) µ g/ml. After anesthesia, a PE-10 catheter was inserted into the urethra for bladder evacuation of residual urine and drug administration. The intravesical solutions were retained until the animals voided spontaneously.

Experimental Protocol.
The animals were divided into 7 groups of 15 rats each. On Day 0, group 1 (CYP; positive control) animals were given an intraperitoneal injection of CYP (150 mg/kg), while group 2 (EPI; negative control) animals received a 0.5 ml bolus of epinephrine (10 µ g/ml) intravesically. Rats in groups 3 to 7 underwent intraperitoneal CYP (150 mg/kg) on Day 0. On the same day, groups 3 to 6 were concomitantly given a 0.5 ml intravesical bolus of saline (vehicle), or epinephrine, 2.5, 5, or 10 µ g/ml, respectively; group 7 received a concomitant intraperitoneal injection of mesna, 50 mg/kg.

Gross Evaluation.
Five rats per group were sacrificed for 3 consecutive days (Days 1, 2, and 3). All the bladder specimens were removed at the bladder neck by an urologist (Y.C.C.) and reviewed by a designated pathologist (C.Y.T.), blinded to the study groups. Using the criteria described by Gray et al. (4), gross and histologic changes in the bladder were evaluated with half grades allowed in crossover from mild to severe groups. The gross appearance of the bladders was graded by a bladder damage score: Gross edema: 3—severe (fluid within and external to bladder wall); 2—moderate (fluid confined to internal mucosa); 1—mild (between moderate and normal); 0—none (normal). Gross hemorrhage: 3—severe (intravesical clots); 2—moderate (mucosal hematomas); 1—mild (telangiectasia or dilatation of bladder vessels); 0—none (normal).

Histologic Evaluation.
The bladders were excised, embedded in paraffin, and stained with hematoxylin and eosin. A pathologist reviewed each histologic section using the following scoring system: 0—normal (normal epithelium, no inflammatory cell infiltrate or ulcers); 1—mild (diminished epithelial cells, flattening with submucosal edema, mild hemorrhage, few ulcerations); 2—moderate (mucosal erosion, inflammatory cell infiltrate, fibrin deposition, hemorrhage, and multiple ulcerations); 3—severe (mucosal erosion, inflammatory cell infiltrate, fibrin deposition, multiple ulcerations, and transmural hemorrhage with severe edema).

Measurement of Vesical Edema.
Vesical vascular edema was quantified by wet bladder weight (WBW) and Evan’s blue extravasation (EBE) using different sets of animals. On Day 0, the animals underwent treatment as described above in the experimental protocol. On the following day (Day 1), five animals in each group were sacrificed to examine vesical vascular permeability. Evan’s blue dye (25 mg/kg) was injected into the right femoral vein 1 hour before sacrifice. The bladders were dissected, placed in glass tubes containing 1.5 ml of formamide and incubated at 56° C overnight. The optical density of the extracted dye absorbance was measured at 600 nm on a spectrophotometer and expressed as mean ± SEM Evan’s blue/g of the body weight (15). Wet bladder weights (mg) were reported as mean ± SEM tissue/100 gm animal weight (16).

Statistical Analysis.
The results were expressed as mean ± SEM or as median values (macroscopic and histologic scores). Statistical significance (P < 0.05) was assessed by one-way analysis of variance (ANOVA). For morphologic data, statistical evaluation was performed by Kruskal-Wallis non-parametric analysis of variance followed by the Mann-Whitney U-test.

	Results

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Control Animals.
Grossly, all the bladders in the control group showed severe distention, edema, and hemorrhage with a damage score 3 within 24 hours after cyclophosphamide administration.

Gross Evaluations.
The damage score of edema and hemorrhage in the positive control (CYP) group was significantly higher than the score of 0 in the negative control (EPI) group. In groups 4 to 6 administered with epinephrine, there was a dose-dependent reduction of gross hemorrhage and edema. Mesna showed better outcome in the prevention of edema than 10 µ g/ml epinephrine, while epinephrine yielded a greater hemostatic effect than mesna. Compared to the negative control (EPI) group, both the 10 µ g/ml epinephrine and mesna groups showed equivalent attenuation of CYP toxicity (Table 1).

View larger version (10K): [in this window] [in a new window]   Figure 1. (A) Wet bladder weight (mg; mean ± SEM tissue/100 g animal weight). (B) Evan’s blue dye (g; mean ± SEM Evan’s blue/g of the body weight). CYP, cyclophosphamide (positive control); EPI, epinephrine (negative control); NS, normal saline (vehicle); 2.5, 5, 10 Epi, 2.5, 5, 10 µ g/ml epinephrine, respectively; MES, Mesna. Each bar is the mean ± SEM of 5 animals. Vertical bars represent standard errors of the means. * Significantly different from CYP or positive controls with P < 0.05. ** Significantly different compared with EPI or negative control with P < 0.05.

View larger version (145K): [in this window] [in a new window]   Figure 2. Histological analysis of representative bladder walls in cross-section. (A) EPI (epinephrine or negative control group): Score of 0 with absence of edema, hemorrhage, or inflammation. H&E, x100. (B) CYP (cyclophosphamide or positive control group): severe hemorrhagic cystitis with a score of 3 for severe edema, transmural hemorrhage, mucosal ulceration, and neutrophil infiltration. H&E, x100. (C) 2.5 Epi: 2.5 µ g/ml epinephrine group, score of 2 for mucosal erosion, submucosal edema, and hemorrhage and ulcerations. H&E, x100. (D) 10 Epi: 10 µ g/ml epinephrine group, score of 1 with mild submucosal edema, minimal hemorrhage, few diminished epithelial cells, and no inflammation. H&E, x100. (E) NS: normal saline or vehicle group, score of 3 with severe edema, transmural hemorrhage, mucosal erosion, multiple ulcerations, fibrin deposition, and neutrophil infiltration. H&E, x100. F MES: mesna group, score of 0–1 with diminished epithelial cells, submucosal edema, and hemorrhage. H&E, x100 (SE: submucosal edema; SH: submucosal hemorrhage; TH: transmural hemorrhage; N: neutrophil infiltration; F: fibrin deposition; U: ulceration; ME: mucosal erosion; DE: diminished epithelial cells).

	Discussion

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As mentioned earlier, in many patients undergoing cyclophosphamide therapy, hemorrhagic cystitis persists despite prophylactic measures of mesna. The clinical relevance of this study is that in cases of recurrent hematuria induced by cyclophosphamide toxicity intractable to current forms of hemostasis and prevention, our method provides the clinician with an additional treatment option. In our medical center, we successfully controlled intractable bleeding induced by radiation cystitis in over 20 patients suffering from cervical, bladder, and colon cancer by intravesical instillation of epinephrine.¹ Hence, further studies on the effect of epinephrine on dilemmas such as interstitial cystitis or other forms of hemorrhagic cystitis should also be warranted.

Epinephrine (adrenaline), a catecholamine originating from the adrenal medulla, acts as a vasopressor and vasoconstrictor used in various conditions such as shock, hypotension, arrhythmia, congestive heart failure, local hemostasis, nasal decongestant, asthma, and allergy. Epinephrine has been used successfully for hemostasis in many clinical applications such as gastrointestinal surgery, proctology, radiology, orthopedic surgery, endodontic surgery, and plastic surgery. Vaeusorn et al. injected epinephrine into the renal artery and rapidly controlled an intractable post-biopsy renal bleeding (17). From our earlier works, we postulated that the hemostatic effect of intra-vesical epinephrine is the result of vasoconstriction induced by ₁-adrenergic stimulation. Adrenergic receptors are divided into two types, ( ₁ and ₂) and ß (ß ₁, ß ₂, and ß ₃); in the vascular smooth muscle, only ₁, ₂, and ß ₂ adrenoceptors are found. The ₁ postsynaptic adrenoreceptors are found in smooth muscles in the body, genitourinary system and blood vessels near sympathetic nerves. Located on the presynaptic nerve terminals, the ₂ adrenoreceptors respond to circulating catecholamines. Under the stimulation of epinephrine, ₁ and ₂ adrenoceptors induce smooth muscle vasoconstriction by increasing the intracellular calcium concentration, whereas ß ₂ adrenoceptors cause vasodilatation (18).

In another ongoing preliminary study² using similar procedures as previously described (150 mg/kg cyclophosphamide, intraperitoneal injection), ₁-adrenergic agonist, L-phenylephrine (0.1–1 mg/kg), and ₂-adrenergic agonist, clonidine (0.1–1 mg/kg) induced hemostasis in CYP-induced HC. Severe urine retention and blood clots were noted under high (10–100 mg/kg) doses of both agents, presumably due to their actions on the bladder neck and smooth muscles. Under low doses (0.001 mg/kg), both phenylephrine and clonidine showed poor hemostasis. Alpha-adrenergic antagonists were used to block the vaso-constrictive effects of epinephrine. Concomitant use of epinephrine (10 µ g/ml) and high doses of prazosin (50 mg/kg, ₁-adrenergic blocker) and also yohimbine (100 mg/kg, ₂-adrenergic blocker) yielded severe hemorrhage and edema. However, lowered concentrations (0.01–1 mg/kg) of prazosin and clonidine were unable to block the vasoconstriction and hemostasis produced by epinephrine. Interestingly, relatively low doses of phenoxybenzamine (1 mg/kg, mixed -adrenergic blocker) were required to inhibit the hemostatic effects of epinephrine. Since this is only a preliminary study on the actions of epinephrine, we think that the vasoconstrictive effects of epinephrine are the result of synergistic actions on both ₁ and ₂ adrenergic receptors; however, more extensive studies should be conducted in the near future to determine the exact mechanism.

In this study, significant gross and microscopic edema reduction and prevention of CYP-induced HC was observed in epinephrine-treated rats. Quantified measurements of edema using the wet bladder weight and Evan’s Blue dye extravasation further demonstrated that epinephrine-treated groups contained significantly less fluid contents when compared with the positive control (CYP) groups. Rey and coworkers studied the effects of vasoconstriction induced by epinephrine in rats for skin flap hematoma (19). Contrary to most beliefs, hematoma was not observed after the initial vasoconstrictive effect waned, indicating that the reflex vasodilatation had minimal impact on the flap. The death rates of the rats declined significantly after combining epinephrine with lidocaine. The authors proposed that epinephrine slowed the systemic absorption of lidocaine, a highly toxic substance for rats. In this study, we postulated that epinephrine not only induced vasoconstriction but also slowed acrolein absorption in the bladder resulting in reduced tissue edema, hemorrhage, inflammation, and ulceration.

Since the acrolein contact with the urothelium requires no vascular support to induce cystitis, other effects of epinephrine other than vasoconstriction are postulated. One plausible explanation might be the decrease of inflammation and ulceration involving deep layers of the bladder wall. Hence other important functions of catecholamine stimulation of - and ß-adrenergic receptors might provide us with some insight. These functions include enhanced platelet-neutrophil adhesion and platelet aggregation, decreased neutrophil adherence, chemotaxis, and phagocytic activity. Epinephrine also affects cytokine regulation, such as inhibition of tumor necrosis factor and interleukin (IL)-1, activation of IL-8 and IL-10 production, and enhancement of L-selectin (monocytes) and P-selectin (platelets) expressions (20). Recent studies showed that cytokines such as NO are also released in CYP-induced cystitis (21). During inflammatory states, lipopolysaccharides activate monocytes resulting in the production of interleukin-8 (IL-8), a member of CXC chemokines. IL-8 attracts inflammatory cells to areas of infections (22). Loll and Lowry showed that epinephrine upregulates the LPS-induced IL-8 production by beta-adrenergic receptors. In their study, the effects of epinephrine on IL-8 production were blocked after using propranolol, a beta-adrenergic antagonist. However, they stressed that the effects of epinephrine on cytokines are not solely based on beta-adrenergics (23). The stimulatory effect of epinephrine on IL-8 production does not reflect or support the anti-inflammatory effects of epinephrine, but shows one of the many actions of epinephrine with cytokines.

In our study, histologic evaluations demonstrated that epinephrine reduced neutrophil infiltration. The inhibition of inflammatory cells was also postulated through actions mediated by ₂-adrenoceptors. Nordling et al. discovered that the severity of urethral inflammation in female rats was suppressed by high doses (100 µ g/day) and enhanced by low doses (10µ g/day) of epinephrine. Low-dose epinephrine increases sympathetic post-ganglionic neurotransmission mediated by ß ₂-adrenoceptors, whereas high-dose epinephrine inhibits sympathetic neurotransmission and inflammation through the ₂-adrenoceptors (24). From these points, we can logically deduce that the temporary and transient vasoconstrictor effects of epinephrine are local actions on alpha-adrenergic receptors in the bladder as shown in day 1 results. Long-term (day 3) results and more systemic actions may involve the anti-inflammatory effects of epinephrine in inducing cytokine release or synthesis or blocking these cytokines from arriving to their targets. Intravesical instillation of epinephrine can effectively promote protection against vesical edema, inflammation, and hemorrhage induced by cyclophosphamide in rats.

	Acknowledgments

 
We thank Professor Hsiao-Fung Pu for providing equipment and technical assistance, Professor Eileen Chien for manuscript suggestions, and Dr. Mary Jeanne Buttrey for English revisions during the study.

	Footnotes

 
This work was supported by Mackay Memorial Hospital Grant MMH 9567. Part of this work was presented at the 2005 International Union of Physiological Sciences (IUPS), San Diego, California, April 3, 2005.

¹ Chow Y-C, Hsu J-M, Lin W-C, Chang H-K, Yang Y-C, Yang S. Intravesical instillation of epinephrine in patients with intractable hemorrhagic cystitis. Unpublished study. 2007.

² Chow Y-C, Yang S, Huang C-J, Wang T-Y, Su Y-H, Wang P-S. Unpublished study. 2006.

Received for publication September 3, 2006. Accepted for publication November 27, 2006.

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This Article Abstract Full Text (PDF) Alert me when this article is cited Alert me if a correction is posted Services Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Citing Articles Citing Articles via HighWire Citing Articles via Google Scholar Google Scholar Articles by Chow, Y.-C. Articles by Wang, P. S. Search for Related Content PubMed PubMed Citation Articles by Chow, Y.-C. Articles by Wang, P. S.