Abstract
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.
Similar content being viewed by others
Article PDF
References
Yanagisawa M, Kurihara H, Kimura S, et al: A novel potent vasoconstrictor peptide produced by vascular endothelial cells. Nature 1988; 332: 411–415.
Opgenorth TJ, Wu-Wong JR, Shiosaki K : Endothelin-converting enzymes. FASEB J 1992; 6: 2653–2659.
Rubens C, Ewert R, Halank M, et al: Big endothelin-1 and endothelin-1 plasma levels are correlated with the severity of primary pulmonary hypertension. Chest 2001; 120: 1562–1569.
Cody RJ, Haas GJ, Binkley PF, Capers Q, Kelley R : Plasma endothelin correlates with the extent of pulmonary hypertension in patients with chronic congestive heart failure. Circulation 1992; 85: 504–509.
Giaid A, Yanagisawa M, Langleben D, et al: Expression of endothelin-1 in the lungs of patients with pulmonary hypertension. N Engl J Med 1993; 328: 1732–1739.
Chen SJ, Chen YF, Meng QC, Durand J, Dicarlo VS, Oparil S : Endothelin-receptor antagonist bosentan prevents and reverses hypoxic pulmonary hypertension in rats. J Appl Physiol 1995; 79: 2122–2131.
Ichikawa K, Hidai C, Okuda C, et al: Endogenous endothelin-1 mediates cardiac hypertrophy and switching of myosin heavy chain gene expression in rat ventricular myocardium. J Am Coll Cardiol 1996; 27: 1286–1291.
Wiedemann R, Ghofrani HA, Weissmann N, et al: Atrial natriuretic peptide in severe primary and nonprimary pulmonary hypertension. J Am Coll Cardiol 2001; 38: 1130–1136.
Chan MF, Okun I, Stavros FL, Hwang E, Wolff ME, Balaji VN : Identification of a new class of ETA selective endothelin antagonists by pharmacophore directed screening. Biochem Biophys Res Commun 1994; 201: 228–234.
Mandell GL, Petri WA Jr : Sulfonamides, trimethoprim-sulfamethoxazole, quinolones, and agents for urinary tract infections, in Hardman JG, Limbird LE, Molinoff PB, Ruddon RW, Gilman AG (eds): Goodman & Gillman's the Pharmacological Basis of Therapeutics, 9th ed. New York, The McGraw-Hill Companies, 1996, pp 1057–1072.
Brown L, Miller J, Dagger A, Sernia C : Cardiac and vascular responses after monocrotaline-induced hypertrophy in rats. J Cardiovasc Pharmacol 1998; 31: 108–115.
Sanyal SN, Ono K : Derangement of autonomic nerve control in rat with right ventricular failure. Pathophysiology 2002; 8: 197–203.
Bellavere F, Balzani I, Masi GD, et al: Power spectral analysis of heart-rate variations improves assessment of diabetic cardiac autonomic neuropathy. Diabetes 1992; 41: 633–640.
Radin MJ, Jenkins JE, McCune SA, Jurin RR, Hamlin RL : Effects of enalapril and clonidine on glomerular structure, function, and atrial natriuretic peptide receptors in SHHF/Mcc-cp rats. J Cardiovasc Pharmacol 1992; 19: 464–472.
Akselrod S, Gordon D, Ubel FA, Shannon DC, Barger AC, Cohen RJ : Power spectrum analysis of heart rate fluctuation: a quantitative probe of beat-to-beat cardiovascular control. Science 1981; 213: 220–222.
Rich S, McLaughlin VV : Endothelin receptor blockers in cardiovascular disease. Circulation 2003; 108: 2184–2190.
Jasmin JF, Lucas M, Cernacek P, Dupuis J : Effectiveness of a nonselective ETA/B and a selective ETA antagonist in rats with monocrotaline-induced pulmonary hypertension. Circulation 2001; 103: 314–318.
Miyauchi T, Yorikane R, Sakai S, et al: Contribution of endogenous endothelin-1 to the progression of cardiopulmonary alterations in rats with monocrotaline-induced pulmonary hypertension. Circ Res 1993; 73: 887–897.
Galie N, Hinderliter AL, Torbicki A, et al: Effects of the oral endothelin-receptor antagonist bosentan on echocardiographic and Doppler measures in patients with pulmonary arterial hypertension. J Am Coll Cardiol 2003; 41: 1380–1386.
Channick RN, Sitbon O, Barst RJ, Manes A, Rubin LJ : Endothelin receptor antagonists in pulmonary arterial hypertension. J Am Coll Cardiol 2004; 43: 62S–67S.
Yuyama H, Fujimori A, Sanagi M, et al: The orally active nonpeptide selective endothelin ETA receptor antagonist YM598 prevents and reverses the development of pulmonary hypertension in monocrotaline-treated rats. Eur J Pharmacol 2004; 496: 129–139.
Wada A, Tsutamoto T, Fukai D, et al: Comparison of the effects of selective endothelin ETA and ETB receptor antagonists in congestive heart failure. J Am Coll Cardiol 1997; 30: 1385–1392.
Ohnishi M, Wada A, Tsutamoto T, et al: Comparison the acute effects of a selective endothelin ETA and a mixed ETA/B receptor antagonist in heart failure. Cardiovasc Res 1998; 39: 617–624.
Yamauchi-Kohno R, Miyauchi T, Hoshino T, et al: Role of endothelin in deterioration of heart failure due to cardiomyopathy in hamsters: increase in endothelin-1 production in the heart and beneficial effect of endothelin-A receptor antagonist on survival and cardiac function. Circulation 1999; 99: 2171–2176.
Torre-Amione G, Young JB, Colucci WS, et al: Hemodynamic and clinical effects of tezosentan, an intravenous dual endothelin receptor antagonist, in patients hospitalized for acute decompensated heart failure. J Am Coll Cardiol 2003; 42: 140–147.
Maltsev VA, Undrovinas AI : A multi-modal composition of the late Na+ current in human ventricular cardiomyocytes. Cardiovasc Res 2006; 69: 116–127.
Kaab S, Dixon J, Duc J, et al: Molecular basis of transient outward potassium current downregulation in human heart failure. Circulation 1998; 98: 1383–1393.
Fauchier L, Babuty D, Melin A, Bonnet P, Cosnay P, Fauchier JP : Heart rate variability in severe right or left heart failure: the role of pulmonary hypertension and resistances. Eur J Heart Fail 2004; 6: 181–185.
Klinger JR, Warburton RR, Pietras LA, Smithies O, Swift R, Hill NS : Genetic disruption of atrial natriuretic peptide causes pulmonary hypertension in normoxic and hypoxic mice. Am J Physiol 1999; 276: L868–L874.
Nagaya N, Nishikimi T, Okano Y, et al: Plasma brain natriuretic peptide levels increase in proportion to the extent of right ventricular dysfunction in pulmonary hypertension. J Am Coll Cardiol 1998; 31: 202–208.
Berman S, Byrns PJ, Bondy J, Smith PJ, Lezotte D : Otitis media-related antibiotic prescribing patterns, outcomes, and expenditures in a pediatric medicaid population. Pediatrics 1997; 100: 585–592.
Author information
Authors and Affiliations
Corresponding author
Rights and permissions
About this article
Cite this article
Uchino, T., Sanyal, S., Yamabe, M. et al. Rescue of Pulmonary Hypertension with an Oral Sulfonamide Antibiotic Sulfisoxazole by Endothelin Receptor Antagonistic Actions. Hypertens Res 31, 1781–1790 (2008). https://doi.org/10.1291/hypres.31.1781
Received:
Accepted:
Issue Date:
DOI: https://doi.org/10.1291/hypres.31.1781