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Rescue of Pulmonary Hypertension with an Oral Sulfonamide Antibiotic Sulfisoxazole by Endothelin Receptor Antagonistic Actions

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Rescue of Pulmonary Hypertension with an Oral Sulfonamide Antibiotic Sulfisoxazole by Endothelin Receptor Antagonistic Actions 1781 Hypertens Res Vol.31 (2008) No.9 p.1781-1790 Original Article Rescue of Pulmonary Hypertension with an Oral Sulfonamide Antibiotic Sulfisoxazole by Endothelin Receptor Antagonistic Actions Tomoko UCHINO1),2),*, Shamarendra N. SANYAL1),*, Motoko YAMABE1), Toshihiko KAKU1), Satoshi TAKEBAYASHI1), Toru SHIMAOKA1), Tatsuo SHIMADA3), Takayuki NOGUCHI2), and Katsushige ONO1) Pulmonary hypertension (PH) is a disease of unknown etiology that ultimately causes right ventricle heart failure with a lethal outcome. An increase in circulating endothelin (ET)-1 levels may contribute to disease progression. This study aimed to examine the possible effects of an orally active ET receptor antagonist, sulfisoxazole (SFX), for the rescue of PH, right ventricular hypertrophy, and eventual right ventricular failure. PH rats (single injection of monocrotaline [MCT]) were treated with an ET antagonist, SFX, an orally active sulfonamide antibody. Effects of SFX on PH rats were assessed in terms of survival rate, pulmonary artery blood pressure (PABP), autonomic nerve activity, and atrial natriuretic peptide (ANP) concentration in right ventricular myocytes and plasma. SFX did not change systemic blood pressure, however, it significantly suppressed the elevation of PABP. SFX maintained the derangement of autonomic nerve control, blunted an increase in ANP in myocytes and plasma, and significantly improved survival in right heart failure and/ or related organs dysfunction in PH rats. The ET antagonistic action of the antimicrobial agent, SFX, was experimentally confirmed for treatment of PH in rats. (Hypertens Res 2008; 31: 1781–1790) Key Words: pulmonary hypertension, sulfisoxazole, endothelin, atrial natriuremic peptide, heart rate variability increase in local pulmonary ET-1 expression (5), which sug- Introduction gests that this peptide may contribute to the pathogenic pro- cess. A non-specific ET receptor antagonist can prevent acute Pulmonary hypertension (PH) is associated with endothelial and chronic hypoxic PH, and reverse the structural remodel- dysfunction that may mediate or contribute to the disease pro- ing of the pulmonary vasculature (6). Blockade of ET activity cess, including an increase in circulating endothelin (ET)-1 by using the specific ETA-receptor antagonist, FR139317, levels. ET is a potent vasoactive and mitogenic peptide that is ameliorates RVH in PH in the monocrotaline (MCT)-induced formed from the corresponding big ETs through the action of rat PH model (7). It has been reported that several mecha- ET converting enzymes in endothelial cells and released nisms involved in the pathophysiology of PH may contribute toward the vascular smooth muscle consistent with a para- to severely increased circulating atrial natriuretic peptide crine role (1, 2). Circulating ET-1 levels are increased in (ANP) levels, which suggests that ANP secretion is activated humans who have primary and secondary PH (3, 4) with an in response to hemodynamic impairment in severe PH (8). From the 1)Department of Cardiovascular Science, 2)Department of Anesthesiology, and 3)Department of Health Science, Oita University School of Med- icine, Yufu, Japan. *These two authors equally contributed to this study. Address for Reprints: Katsushige Ono, M.D., Ph.D., Department of Cardiovascular Science, Oita University School of Medicine, 1–1 Idaigaoka, Hasama, Yufu 879–5593, Japan. E-mail: [email protected] Received April 4, 2008; Accepted in revised form June 6, 2008. 1782 Hypertens Res Vol. 31, No. 9 (2008) Sulfisoxazole (SFX), 4-amino-N-(3,4-dimethyl-5-isooxazol- ment of their SFX consumption in the food. yl) benzenesulfonamide, is an orally active drug of the sul- fonamide group that has a wide range of antimicrobial Recordings of Isometric Contraction activity against both Gram-positive and Gram-negative bacte- ria, and is also recognized as an ETA receptor antagonist (9). Male Wistar rats weighing 300 to 350 g were anesthetized by Additionally, SFX has excellent pharmacological properties an intraperitoneal injection of pentobarbiturate (50 mg/kg), characterized by rapid absorption and excretion (10). We and ventilated via the trachea with a small rodent ventilator demonstrate here the beneficial effects of SFX in an MCT- (Model No. 141; New England Medical Instruments Inc., induced experimental PH model in rats in terms of survival Medway, USA). The heart was removed and placed in Krebs- rate, pulmonary artery blood pressure (PABP), cardiac auto- Henseleit solution (K-H solution) with the following compo- nomic function, and ANP secretion in cardiac myocytes. sition (mmol/L): 119 NaCl, 4.7 KCl, 1 MgCl2, 2.5 CaCl2, 25 NaHCO3, 1.2 KH2PO4, 11 glucose (pH=7.4 with HCl). The Methods main pulmonary artery was dissected and connective tissues were cleaned. The artery was cut into a 2–3 mm–wide ring, and the endothelium was gently removed with a cotton swab. Rats and Housing The functional removal of endothelium was confirmed by the Ten-week-old male Wistar rats weighing 340–370 g were lack of relaxation induced by 3 μmol/L acetylcholine, where used in this study. All rats were purchased from Seac Yoshi- the artery was pre-contracted with 10 μmol/L phenylephrine tomi Ltd. (Tokyo, Japan). The rats were housed in individual (data not shown). One side of the ring was pinned and the cages in a lightproof room (TB181 or TB182; National, other side was connected to a force transducer (TB-612T, Osaka, Japan) with a light-dark cycle (LD 12:12; lights on at Nihon Kohden, Tokyo, Japan) in a 500 μL chamber perfused 08:00 AM), maintained under constant temperature with 95% oxygen–bubbled solution at 37°C. The ring was (22±2°C). This study was conducted in accordance with the mounted in K-H solution for 45 min, and the ring was then Guide for the Care and Use of Laboratory Animals published exposed to high K+ solution (modified K-H solution with 63.7 by the US National Institutes of Health (NIH publication No. mmol/L NaCl, 60 mmol/L KCl). After obtaining the maxi- 85-23, revised 1996) and was approved by the Animal Use mum tension, the rings were washed with K-H solution for 7 Committee of Oita University School of Medicine. min and exposed to one of the following solutions: 1) vehicle (dimethyl sulfoxide [DMSO])+100 nmol/L ET in K-H solu- tion, 2) 0.1 mmol/L SFX+100 nmol/L ET in K-H solution, or Animal Model and Study Design 3) 1.0 mmol/L SFX+100 nmol/L ET in K-H solution. Data Rats were divided into four groups: control (no MCT injec- were collected with a computerized acquisition system tion), MCT (MCT-injected without SFX treatment), SFX0.3 (Power Lab and Chart software; AD Instruments, Sydney, (MCT-injected with 0.3 g/kg/d SFX treatment), and SFX1.0 Australia). The contractile forces of rings by experimental (MCT-injected with 1.0 g/kg/d SFX treatment), respectively. solution were assessed as a ratio to the response obtained in MCT (Sigma Chemical Co., St. Louis, USA), which causes high K+ solution. pulmonary vascular damage leading to PH, right ventricular hypertrophy (RVH), and eventual chronic heart failure (CHF) Measurement of PABP (11), was dissolved in 1 mol/L HCl at a concentration of 40 mg/mL neutralized with 1 mol/L NaOH to a pH of 7.40, Rats were anesthetized (50 mg/kg pentobarbital peritoneal diluted with sterile distilled water, and then injected at a con- injection), and the thoracic cavity was opened for the direct centration of 10 mg/mL. A single dose of 80 mg/kg of MCT insertion of a pressure transducer (model TB-612T; Nihon was injected subcutaneously into the right side of the trunk Kohden) into the pulmonary artery, under the assistance of a region of the rats. Rats received a standard food regimen (CE- ventilator (Model 141; New England Medical Instruments 2; CLER, Tokyo, Japan), 20 g/d with or without SFX. Oral Inc.). administration of SFX was started 7 d after MCT injection. In order to evaluate whether SFX improves long-term survival ECG Recordings and Heart Rate Variability in MCT-induced PH rats, we observed the survival rates in the MCT and SFX groups for 10 weeks after MCT injection. ECG recordings and data analysis were performed as Five weeks after MCT injection, seven rats in each group described previously (12). Briefly, a telemetric ECG radio were measured for their pulmonary artery blood pressure, transmitter (TA11CTA-F40; Data Sciences International, St. were sacrificed, and the hearts were harvested to investigate Paul, USA) was placed in each animal. ECG recording and the RVH index (ratio of right ventricular free wall weight experiments took place after a recovery period of 7 d to avoid [RV] divided by the sum of the septum [S] and left ventricular possible effects of residual anesthetics and surgery. Serial free wall weight [LV] [RV/(LV+S)]). Rats were weighed (daily) acquisition of ECG data was obtained several times a every day and their food intake was measured to allow adjust- day during the light cycle at a sample rate of 5 kHz for 30 min. Uchino et al: Rescue of PH by Oral ET Antagonist 1783 A 20 high wash ET 100 nmol/L K control 15 SFX 0.1 mmol/L SFX 1.0 mmol/L 10 MCT SFX0.3 5 min SFX1.0 Rat Number B 5 3.0 (6) 2.5 0 2.0 12345678910 (6) Follow Up Time (week) 1.5 * (6) Fig. 2. Survival curves for MCT-treated rats with or without 1.0 * SFX administration. Daily application of SFX (0.3 g/kg/d 0.5 and 1.0 g/kg/d) extended survival in MCT-treated PH rats. Fractional Contraction Fractional p<0.001, MCT group vs. SFX1.0 group. n=20 in each group. 0.0 control SFX SFX 0.1 mmol/L 1.0 mmol/L 100CX; Japan Electron Optical Laboratory, Ltd., Tokyo, Fig.
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