Abstract
Background: Stimulated endothelium‐derived relaxing factor‐mediated vasodilation and conduit artery distensibility are impaired in congestive heart failure (CHF). L‐arginine could have a potentially beneficial role in CHF, acting through the nitric oxide (NO)‐L‐arginine pathway or by growth hormone increment.
Hypothesis: This study was undertaken to investigate the effects of L‐arginine on heart rate, hemodynamics, and left ventricular (LV) function in CHF.
Methods: In seven patients (aged 39 ± 8 years) with CHF, we obtained the following parameters using echocardiography and an LV Millar Mikro‐Tip catheter simultaneously under four conditions: basal, during NO inhalation (40 ppm), in basal condition before L‐arginine infusion, and after L‐arginine intravenous infusion (mean dose 30.4 ± 1.9 g).
Results: Nitric oxide inhalation increased pulmonary capillary wedge pressure from 25 ± 9 to 31 ± 7 mmHg (p < 0.05), but did not change echocardiographic variables or LV contractility by elastance determination. L‐arginine decreased heart rate (from 88 ± 15 to 80 ± 16 beats/min, p < 0.005), mean systemic arterial pressure (from 84 ± 17 to 70 ± 18 mmHg, p < 0.007), and systemic vascular resistance (from 24 ± 8 to 15 ± 6 Wood units, p < 0.003). L‐arginine increased right atrial pressure (from 7 ± 2 to 10 ± 3 mmHg, p < 0.04), cardiac output (from 3.4 ± 0.7 to 4.1 ± 0.8 l/min, p < 0.009), and stroke volume (from 40 ± 9 to 54 ± 14 ml, p < 0.008). The ratios of pulmonary vascular resistance to systemic vascular resistance at baseline and during NO inhalation were 0.09 and 0.075, respectively, and with L‐arginine this increased from 0.09 to 0.12.
Conclusion: L‐arginine exerted no effect on contractility; however, by acting on systemic vascular resistance it improved cardiac performance. L‐arginine showed a negative chronotropic effect. The possible beneficial effect of L‐arginine on reversing endothelial dysfunction in CHF without changing LV contractility should be the subject of further investigations.
Keywords: nitric oxide, heart failure, L‐arginine, endothelium‐derived factors, left ventricular function
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References
- 1. Drexler H, Hayoz D, Munzel T, Hornig B, Just H, Brunner HR, Zellis R: Endothelial function in chronic congestive heart failure. Am J Cardiol 1992; 69: 1596–1601 [DOI] [PubMed] [Google Scholar]
- 2. Ramsey MW, Goodfellow J, Jones CJH, Luddington LA, Lewis MJ, Henderson AH: Endothelium control of arterial distensibility is impaired in chronic heart failure. Circulation 1995; 92: 3212–3219 [DOI] [PubMed] [Google Scholar]
- 3. Palmer RM, Ashton DS, Moncada S: Nitric oxide accounts for the biological activity of endothelium‐derived relaxing factor. Nature 1987; 327: 524–526 [DOI] [PubMed] [Google Scholar]
- 4. Frostell C, Fratacci MD, Wain JC, Jones R, Zapol WM: Inhaled nitric oxide: A selective pulmonary vasodilator reversing hypoxic pulmonary vasoconstriction. Circulation 1991; 83: 2038–2047 [DOI] [PubMed] [Google Scholar]
- 5. Loh E, Stamler JS, Joshua MH, Loscalzo J, Colucci WS: Cardiovascular effects of inhaled nitric oxide in patients with left ventricular dysfunction. Circulation 1994; 90: 2780–2785 [DOI] [PubMed] [Google Scholar]
- 6. Bocchi EA, Bacal F, Auler LOC Jr, Carmone MJC, Bellotti G, Pileggi F: Inhaled nitric oxide leading to pulmonary edema in stable severe heart failure, Am J Cardiol 1994; 74: 70–72 [DOI] [PubMed] [Google Scholar]
- 7. Rimar S, Norman G: Selective pulmonary vasodilation by inhaled nitric oxide is due to hemoglobin inactivation. Circulation 1993; 88: 2884–2887 [DOI] [PubMed] [Google Scholar]
- 8. Palmer RM, Ashton DS, Moncada S: Vascular endothelium cells synthetize nitric oxide from L‐arginine. Nature 1988; 333: 664–666 [DOI] [PubMed] [Google Scholar]
- 9. Amezcua JL, Palmer RM, De Souza BM, Moncada S: Nitric oxide synthetized from L‐arginine regulates vascular tone in the coronary circulation of the rabbit. Br J Pharmacol 1989; 97: 1119–1124 [DOI] [PMC free article] [PubMed] [Google Scholar]
- 10. Gold ME, Bush PA, Ignarro LJ: Depletion of arterial L‐arginine causes reversible tolerance to endothelium‐dependent relaxation. Biochem Biophys Res Commun 1989; 164: 714–721 [DOI] [PubMed] [Google Scholar]
- 11. Koifman B, Wollman Y, Bogomolny N, Chernichowsky T, Finkelstein A, Peer G, Scherez J, Blum M, Laniado S, Jaina A, Keren G: Improvement of cardiac performance by intravenous infusion of L‐arginine in patients with moderate congestive heart failure. J Am Coll Cardiol 1995; 26: 1251–1256 [DOI] [PubMed] [Google Scholar]
- 12. Birks EJ, Yacoub MH: The role of nitric oxide and cytokines in heart failure. Coron Art Dis 1997; 8: 389–402 [DOI] [PubMed] [Google Scholar]
- 13. Bellotti G, Moraes A, Bocchi EA, Arie S, Medeiros C, Moreira LF, Stolf N, Jatene A, Pileggi F: Late effects of cardiomyoplasty on left ventricular mechanics and diastolic filling. Circulation 1993; 88 (part 2) 304–308 [PubMed] [Google Scholar]
- 14. Grossman W: Clinical measurement of vascular resistance and assessment of vasodilator drugs In Cardiac Catheterization, Angiography and Intervention (Eds. Grossman W, Baim DS.), p. 143–151. Philadelphia: Lea & Febiger, 1991. [Google Scholar]
- 15. Piva RMV, Moura LA, Moraes AV, Bellotti G, Melo CP: An image storage and data processing system for hemodynamic‐echocardiographic study In MEDINFO 92 (Ed. Lun KC.), p. 808–811. North Holland: Elsevier Science Publishers BV, 1992. [Google Scholar]
- 16. Semigran MJ, Cockrill BA, Kacmarek R, Thompson T, Zapol WM, Dec W, Fifer MA: Hemodynamic effects of inhaled nitric oxide in heart failure. J Am Coll Cardiol 1994; 24: 982–988 [DOI] [PubMed] [Google Scholar]
- 17. Kieler‐Jensen N, Ricksten SE, Stenqvist O: Inhaled nitric oxide in the evaluation of heart transplant candidates with elevated pulmonary vascular resistance. J Heart Transplant 1994; 13: 366–375 [PubMed] [Google Scholar]
- 18. Cody RJ, Haas GJ, Binkley PF, Capers Q, Kelley R: Plasma endothelin correlates with the extent of pulmonary hypertension in patients with chronic heart failure. Circulation 1992; 85: 504–509 [DOI] [PubMed] [Google Scholar]
- 19. McElroy PA, Shroff SG, Weber KT: Pathophysiology of the failing heart. Cardiol Clin 1989; 7: 25–37 [PubMed] [Google Scholar]
- 20. Suga H, Sagawa K: Instantaneous pressure‐volume relationship and their ratio in the excised supported canine left ventricle. Circ Res 1974; 35: 117–126 [DOI] [PubMed] [Google Scholar]
- 21. Drexler H, Fischell TA, Pinto FJ, Chenzbraun A, Botas J, Cooke JP, Alderman EL: Effect of L‐arginine on coronary endothelial function in cardiac transplant recipients. Relation to vessel morphology. Circulation 1994; 89: 1615–1623 [DOI] [PubMed] [Google Scholar]
- 22. Drexler H, Zeiher AM, Meinzer K, Just H: Correction of endothelial dysfunction in coronary microcirculation of hypercholesterolaemic patients by L‐arginine. Lancet 1991; 338: 1546–1550 [DOI] [PubMed] [Google Scholar]
- 23. Mehta S, Stewart DJ, Levy RD: The hypotensive effect of L‐arginine is associated with increased expired nitric oxide in humans. Chest 1996; 109: 1550–1555 [DOI] [PubMed] [Google Scholar]
- 24. Zanzinger J, Czachurski J, Seller H: Inhibition of sympathetic vasoconstriction is a major principle of vasodilation by nitric oxide in vivo. Circ Res 1994; 75: 1073–1077 [DOI] [PubMed] [Google Scholar]
- 25. Hirooka Y, Imaizumi T, Tagawa T, Shiramoto M, Endo T, Ando S, Takeshita A: Effects of L‐arginine on impaired acetylcholine‐induced and ischemic vasodilation of the forearm in patients with heart failure. Circulation 1994; 90: 658–668 [DOI] [PubMed] [Google Scholar]
- 26. Hare JM, Colucci WS: Role of nitric oxide in the regulation of myocardial function. Prog Cardiovasc Dis 1995; 38: 155–166 [DOI] [PubMed] [Google Scholar]
- 27. Hare JM, Keaney JR, Ballingand J‐L, Loscalzo J, Smith TW, Colucci WS: Role of nitric oxide in parasympathetic modulation on b̃‐adrenergic myocardial contractility in normal dogs (abstr). J Clin Invest 1995; 95: 360–366 [DOI] [PMC free article] [PubMed] [Google Scholar]
- 28. Balligand JL, Kelly RA, Marsden PA, Smith TW, Michel T: Control of cardiac muscle function by an endogenous nitric oxide signalling system. Proc Natl Acad Sci, USA 1993; 90: 347–351 [DOI] [PMC free article] [PubMed] [Google Scholar]
- 29. Paulus WJ, Vantrimpont PJ, Shah AM: Acute effects of nitric oxide on left ventricular relaxation and diastolic distensibility in humans. Assessment by bicoronary sodium nitroprusside infusion. Circulation 1994; 89: 2070–2078 [DOI] [PubMed] [Google Scholar]
- 30. Tseng C‐J, Liu HY, Ger L‐P, Tung C‐S, Yen M‐H: Cardiovascular effects of nitric oxide in the brain stem nuclei of rats. Hypertension 1996; 27: 36–42 [DOI] [PubMed] [Google Scholar]
- 31. Birks EJ, Yacoub MH: The role of nitric oxide and cytokines in heart failure. Coron Art Dis 1997; 8: 389–402 [DOI] [PubMed] [Google Scholar]
- 32. Mohan P, Sys SU, Brutsaert DL: Positive inotropic effect of nitric oxide in myocardium. Int J Cardiol 1995; 50: 233–237 [DOI] [PubMed] [Google Scholar]
- 33. Brutsaert DL, Meulemans AL, Sipido KR, Sys SU: Effects of damaging the endocardial surface on the mechanic performance of isolated heart muscle. Circ Res 1988; 62: 358–366 [DOI] [PubMed] [Google Scholar]
- 34. De Belder AJ, Radomski MW, Why HJF, Richardson PJ, Bucknall CA, Salas E, Martin JF, Moncada S: Nitric oxide synthase activities in human myocardium. Lancet 1993; 341: 84–85 [DOI] [PubMed] [Google Scholar]
- 35. Hirooka Y, Egashira K, Imaizumi T, Tagawa T, Kai H, Sugimachi M, Takeshita A: Endothelium‐dependent vasodilator mechanisms differ among vascular beds. J Am Coll Cardiol 1994; 24: 948–955 [DOI] [PubMed] [Google Scholar]
- 36. Tsuchudi MR, Mesaros S, Lusher TF, Malinski T: Direct in situ measurement of nitric oxide in mesenteric resistance arteries—increased decomposition by superoxide in hypertension. Hypertension 1996; 27: 32–35 [DOI] [PubMed] [Google Scholar]
- 37. Brady AJ, Warren JB, Poole‐Wilson PA, Williams TJ, Harding SE: Nitric oxide attenuates cardiac myocyte contraction. Am J Physiol 1993; 265: H176–H182 [DOI] [PubMed] [Google Scholar]
- 38. Weyrich AS, Xin‐Liang M, Buerke M, Murohara T, Armstead VE, Lefer AM, Nicolas JM, Thomas AP, Lefer DJ, Vinten‐Johansen J: Physiologic concentrations of nitric oxide do not elicit an acute negative inotropic effect in unstimulated cardiac muscle. Circ Res 1994; 75: 692–700 [DOI] [PubMed] [Google Scholar]
- 39. Lefer AM, Murohara T: Comparative pharmacology of nitric oxide and nitric oxide generators on cardiac contractility in mammalian species. Int J Cardiol 1995; 50: 239–242 [DOI] [PubMed] [Google Scholar]
- 40. Shah AM, Prendergast BD, Mason‐Grocott R, Lewis MJ, Paulus WJ: The influence of endothelium‐derived nitric oxide on myocardial contractile function. Int J Cardiol 1995; 50: 225–231 [DOI] [PubMed] [Google Scholar]
- 41. Habib F, Dutka D, Crossman D, Oakley CM, Cleland JF: Enhanced basal nitric oxide production in heart failure: Another failed counter‐regulatory mechanism. Lancet 1994; 344: 371–373 [DOI] [PubMed] [Google Scholar]
- 42. Winlaw DS, Smythe GA, Keogh AM, Schyvens CG, Spratt PM, Macdonald P: Increased nitric oxide production in heart failure. Lancet 1994; 344: 373–374 [DOI] [PubMed] [Google Scholar]
- 43. Smith CJ, Sun D, Hoegler C, Roth BS, Zhang X, Zhao G, Xu X‐B, Kobari Y, Pritchard K, Sessa W, Hintze TH: Reduced gene expression of vascular endothelial NO synthase and cyclooxygenase‐1 in heart failure. Circ Res 1996; 78: 58–64 [DOI] [PubMed] [Google Scholar]
- 44. Levine B, Kalman J, Mayer L, Fillit HM, Packer M: Elevated circulating levels of tumour necrosis factor in severe chronic heart failure. N Engl J Med 1990; 323: 236–241 [DOI] [PubMed] [Google Scholar]
- 45. Adrião M, Shiraishi EM, Nunes MT: Efeitos dos aminoácidos sobre a expressão gěnica do hormonio de crescimento in ratos. Estudo em vivo e em vitro (abstr). Arq Bras Endrocrin Metabol 1997; 41: 11 [Google Scholar]
- 46. Matsuoka H, Nakata M, Kohno K, Koga Y, Nomura G, Toshima H, Imaizumi T: Chronic L‐arginine administration attenuates cardiac hypertrophy in spontaneously hypertensive rats. Hypertension 1996; 27: 14–18 [DOI] [PubMed] [Google Scholar]