Nitric oxide, myocardial failure and septic shock

ELSEVIER

International Journal of Cardiology 50 (1995) 269-272

Nitric oxide, myocardial failure and septic shock A.J.B. Brady Department

of Cardiology,

Queen Elizabeth

Hospital,

Birmingham

BI5 2TH,

UK

Abstract Septic shock is a major cause of hospital deaths despite modem intensive therapy. Profound hypotension is caused by a collapse of regulatory mechanisms. Recent advances have established that bacterial products and the host inflammatory response together generate uncontrolled production of nitric oxide throughout the vasculature, accounting for this vasodilatation. Progressive heart failure is a further manifestation of established septic shock. Emerging research suggests that overproduction of nitric oxide within the myocardium likewise leads to loss of normal myocardial function. The possibility exists that exciting future therapies will be able to selectively inhibit the overproduction of nitric oxide and aid recovery from this frequently lethal condition. Keywords:

Endotoxic shock; Nitric oxide; Contractility;

1. Introduction

Uncontrolled septicaemia and the accompanying multi-organ failure which characterize the syndrome of septic shock account for a substantial number of hospital deaths. Despite intensive antibiotic and supportive therapy, in the USA alone an estimated 100000 patients die from sepsis in hospital each year [l]. The hallmark of septic shock is profound hypotension caused by a decrease in peripheral vascular resistance, in the presence of bacterial infection. This hypotension is unusually resistant to both volume replacement and vasoconstrictor agents. In the earliest stages

* Corresponding author.

Cardiac myocyte

of septic shock, cardiac output and stroke volume are maintained at a high level; later, ventricular dilatation develops, with a reduction in ventricular ejection fraction [2-41. Recently, important advances have been made in our understanding of the pathophysiology of this frequently lethal condition. Bloodborne infection by Gram-negative bacteria liberates endotoxin, the lipopolysaccharide component of the bacterial cell wall, into the circulation. Gram-negative bacteria account for about 30% of cases of septic shock [5]. Endotoxin and the organisms themselves activate inflammatory mechanisms including the complement, kinin and coagulation cascades, interleukins, tumor necrosis factor (TNF), leukocytes and platelets. These together generate the acute inflammatory

0167-5273/95/$09.50 0 1995 Elsevier ScienceIreland Ltd. AI1 rights reserved SSDI 0167-5273(95)02387-C

270

A.J.B. Brady

/International

Journal

response to bacteraemia. While many inflammatory mediators have vasoactive properties, recent work has shown that much of the hypotension and cardiac depression of septic shock is caused by important changes which take place within the vascular smooth muscle and myocardium. 2. Nitric oxide production

in septic shock

Vascular endothelium tonically produces nitric oxide from the amino acid L-arginine. This reaction is catalysed by a constitutive nitric oxide synthase (cNOS1, and nitric oxide generated by endothelium maintains blood flow and prevents platelet adhesion [6]. Within blood vessels, smooth muscle cells are not a source of nitric oxide in health. In septic shock the presence of bacterial endotoxin, together with the inflammatory response, causes an inducible nitric oxide synthase (iNOS) to be generated in many cell types which do not normally express this enzyme, including hepatocytes, fibroblasts and vascular smooth muscle [6,7]. Nitric oxide is not only a vasodilator, but is also an important free radical produced as part of the inflammatory mechanism of leukocytes. Subsequent production of large quantities of nitric oxide leads not only to haemodynamic instability, but also to widespread production of nitric oxide-based free radicals which can cause considerable damage to tissues. This has been confirmed in clinical studies. Patients with septic shock [S], and cancer patients receiving interleukin-2 chemotherapy [9] induce nitric oxide synthase, and excrete high levels of nitric oxide metabolites. 3. Cardiac failure in septic shock Myocardial failure in patients with endotoxic shock has also been established by clinical studies 12-41. In normal volunteers administration of purified endotoxin causes reversible depression of left ventricular function, in addition to the expected reduction in systemic vascular resistance [lo]. The existence of a specific circulating myocardial depressant substance in septic shock has been postulated, but not proven [4]. Abnormali-

of Cardiology

50 (1995) 269-272

ties of myocardial function are not explained by changes in coronary flow [4]. It is now clear that overproduction of nitric oxide in the peripheral vasculature accounts for a large part of the vasodilatation in septic shock. There is now accumulating evidence that likewise overproduction of nitric oxide within cardiac muscle contributes to its impaired function. 4. Evidence that nitric oxide contributes myocardial depression in septic shock

to

4.1. In vitro studies

In health, cardiac myocytes do not produce appreciable amounts of nitric oxide [11,12]. In experimental endotoxaemia, or following administration of inflammatory cytokines or endotoxin itself to isolated myocytes, the inducible nitric oxide synthase enzyme is expressed within cardiac myocytes [13-171. This activity and the subsequent generation of nitric oxide within the myocytes themselves is accompanied by a loss of contractile function. Nitric oxide generation by myocytes and the impaired contractility can be reversed by inhibitors of the nitric oxide synthase enzyme [13,14]. Pretreatment of animals with high dose corticosteroids prevents the induction of this enzyme and blocks completely the impairment of contraction in vitro [13,14]. Exciting new data has now shown the expression of mRNA for iNOS in rat cardiac myocytes treated with interleukin-1 [IS], and a cDNA for iNOS in human cardiac myocytes [19]. Thus, there appears to be a common mechanism in endotoxic shock contributing to both cardiac and vascular dysfunction. As in the peripheral vasculature, overproduction of nitric oxide within the myocardium, at least in cell models, contributes substantially to the loss of myocardial contractility. 4.2. Animal studies

Unfortunately the success in restoring myocardial contractile function at the cellular level is not matched by the performance of NOS inhibitors in animal models of septic shock. Analogues of the amino acid L-arginine are used to inhibit nitric oxide synthase, but do so in a non-specific man-

A.J.B. Brady

/International

Journal

ner. Both the normal, constitutive NOS and the pathological, inducible NOS are blocked by these modified amino acids. In healthy animals they cause systemic vasoconstriction and a pressor response by inhibiting constitutive nitric oxide production from the endothelium [20-221. In animals with experimental septic shock these NOS inhibitors reverse hypotension, but also cause a sustained increase in systemic vascular resistance and at higher doses a decrease in cardiac output [20,23,24]. In several recent models of septic shock animals treated with nitric oxide, synthesis inhibitors had reduced survival and poorer haemodynamics compared to matched placebo groups [25-271, although in a large study in sheep the esterified version of L-arginine improved haemodynamics without impairment of tissue oxygenation [28]. The action of nitric oxide is mediated intracellularly by soluble guanylate cyclase. This enzyme can be blocked experimentally by the vital stain, methylene blue. Addition of methylene blue to cardiac myocytes from septic animals restores their contractility towards normal [13]. In intact rabbits with septic shock methylene blue also improves haemodynamics [29], although confirmation in further studies is awaited. 4.3. Human studies

Valiance’s group in London have published pioneering work examining the effects of the nonspecific inhibitors of nitric oxide synthase in patients with endotoxic shock [30,31]. Low doses of the modified amino acid NG monomethyl-Larginine increased vascular tone and raised blood pressure in a group of patients in extremis with septic shock. However, cardiac output fell and the possibility existed that tissue perfusion was impaired. Direct measurements of myocardial contractility were not performed during the study. Hepatic failure is also associated with a high output state and excessive nitric oxide production. In a recent report the inhibitor of guanylate cyclase, methylene blue, was given to one such patient, with a short term improvement [321. This has not yet been studied in a randomised prospective manner.

of Cardiology

50 (1995) 269-272

5. Prospects for nitric oxide inhibition shock

271

in septic

One of the principal mechanisms causing cardiovascular depression in septic shock is an excessive production of nitric oxide both in the heart and in the vasculature. Research into the basic mechanisms of disease, in this case septic shock, has led the way to potentially major advances in clinical practice. Non-specific inhibitors of NO synthase are available as experimental tools, but cause widespread inhibition of blood flow. When specific inhibitors of inducible NO synthase are developed we can expect important advances in the management of patients with septic shock. Acknowledgements This work was supported by the Medical Research Council of Great Britain, and by the British Heart Foundation. References HI Parrillo JE, Parker MM, Natanson C, Suffredini AF, Danner RL, Cunnion RE et al. Septic shock in humans. Advances in the understanding of pathogenesis, cardiovascular dysfunction, and therapy. Ann Intern Med 1990, 113: 227-242. 121 MacLean LD, Mulligan WG, McLean APH, Duff JH. Patterns of septic shock in man - a detailed study of 56 patients. Ann Surg 1967; 166: 543-562. 131 Parker MM, Shelhamer JH, Bacharach SL, Green MV, Natanson C, Frederick TM et al. Profound but reversible myocardial depression in patients with septic shock. Ann Intern Med 1984; 100: 483-490. 141 Ellrodt AG, Riedinger MS, Kimchi A, Berman DS, Maddahi J, Swan HJC et al. Left ventricular performance in septic shock: reversible segmental and global abnormalities. Am Heart J 1985; 110: 402-409. [51 Bone RC, Fisher CJ, Clemmer TP, Slotman GJ, Metz CA, Balk RA et al. A controlled clinical trial of high-dose methylprednisolone in the treatment of severe sepsis and septic shock. N Engl J Med 1987; 317: 653-658. [61 Moncada S, Palmer RMJ, Higgs EA. Nitric oxide: physiology, pathophysiology and pharmacology. Pharmacol Rev 1991; 43: 109-142. [71 Nathan C. Nitric oxide as a secretory product of mammalian cells. FASEB J 1992; 6: 3051-3064. WI Ochoa JB, Udekwu AG, Billiar TR, Curran RD, Cerra FB, Simmons RL et al. Nitrogen oxide levels in patients

A.J.B. Brady /International

212

Journal of Cardiology 50 (1995) 269-272

after trauma and during sepsis. Ann Surg 1991; 214: 621-626. [91

Hibbs JB, Westenfelder C, Taintor R, Vavrin Z, Kablitz C, Baranowski RL et al. Evidence for cytokine-inducible nitric oxide synthesis from L-arginine in patients receiving interleukin-2 therapy. J Clin Invest 1992; 89: 867-877.

Suffredini AF, Fromm RE, Parker MM, Brenner M, Kovacs JA, Wesley RA et al. The cardiovascular response of normal humans to the administration of endotoxin. N Engl J Med 1989; 321: 280-287. ml Amrani M, O’Shea J, Allen NJ, Harding SE, Jayakumar J, Pepper JR et al. Role of basal release of nitric oxide on coronary flow and mechanical performance of the isolated rat heart. J Physiol 1992; 456: 681-687. WI Brady AJB, Poole-Wilson PA, Harding SE, Warren JB. Nitric oxide production within cardiac myocytes reduces their contractility in endotoxemia. Am J Physiol 1992; 263: H1963-H1966. 1131 Brady AJB, Warren JB, Poole-Wilson PA, Williams TJ, Harding SE. Nitric oxide attenuates cardiac myocyte contraction. Am J Physiol 1993; 265: H176-H182. [I41 Schulz R, Nava E, Moncada S. Induction and potential biological relevance of a &+-independent nitric oxide synthase in the myocardium. Br J Pharmacol 1992; 105:

[N

575-580.

ml

Balligand J-L, Ungureanu D, Kelly RA et al. Abnormal contractile function due to induction of nitric oxide synthesis in rat cardiac myocytes follows exposure to activated macrophage-conditioned medium. J Clin Invest 1993; 91: 2314-2319. Ml Tao S, McKenna TM. In vitro endotoxin exposure induces contractile dysfunction in adult rat cardiac myocytes. Am J Physiol 1994; 267: H1745-H1752. Shindo T, Ikeda U, Ohkawa F et al. Nitric oxide synthe[I71 sis in rat cardiac myocytes and fibroblasts. Life Sci 1994; 55: 1101-1108. k31 Tsujino M, Hirata Y, Imai T et al. Induction of nitric oxide synthase gene by interleukin-1P in cultured rat cardiocytes. Circulation 1994; 90: 374-383. I191 Luss H, Li R-K, Shapiro RA et al. Cloning of a cDNA for inducible nitric oxide synthase from cytokine-treated human cardiac myocytes. Circulation 1994: 90 (Suppl4): I-193. DO1 Klabunde RE, Ritger RC. NG-monomethyl+arginine (NMA) restores arterial blood pressure but reduces

cardiac output in a canine model of endotoxic shock. Biochem Biophys Res Commun 1991; 178: 1135-1140. La Kilbourn RG, Jubran A Gross SS, Griffith OW, Levi R, Adams J et al. Reversal of endotoxin-mediated shock by NG-methyl+arginine, an inhibitor of nitric oxide synthesis. Biochem Biophys Res Commun 1990; 172: 1132-1138. Lz.21Aisaka K, Gross SS, Griffith OW, Levi R. NG-methylarginine, an inhibitor of endothelium-derived nitric oxide synthesis, is a potent pressor agent in the guinea pig: does nitric oxide regulate blood pressure in vivo. Biochem Biophys Res Commun 1989; 160: 881-886. Dl Nava E, Palmer RMJ, Moncada S. Inhibition of nitric oxide synthesis in septic shock how much is beneficial? Lancet 1991; 338: 1555-1557. [241 Wright CE, Rees DD, Moncada S. Protective and pathological role of nitric oxide in endotoxin shock. Cardiovast Res 1992; 26: 48-57. [251 Statman R, Chang W, Cunningham JH et al. Nitric oxide inhibition in the treatment of the sepsis syndrome is detrimental to tissue oxygenation. J Surg Res 1994; 51: 93-98.

[261 Pastor C, Teisseire B, Vicaut E, Payen D. Effects of L-arginine and L-nitro-arginine treatment on blood pressure and cardiac output in a rabbit endotoxin shock model. Crit Care Med 1994; 22: 465-469. WI Minnard EA, Shou J, Naama H, Cech A, Gallagher H, Daly JM. Inhibition of nitric oxide synthesis is detrimental in endotoxemia. Arch Surg 1994; 9: 142-147. P81 Meyer J, Lentz CW, Stothert JC Jr., Traber LD, Herndon DN, Traber DL. Effects of nitric oxide synthesis inhibition in hyperdynamic endotoxemia. Crit Care Med 1994; 22: 306-303. L2.91Keaney JF Jr., Puyana J-C, Francis S, Loscalzo JF, Stamler JS, Loscalzo J. Methylene blue reverses endotoxin-induced hypotension. Circ Res 1994; 74: 11-15. [301 Petros A, Bennett D, Valiance P. Effect of nitric oxide synthesis inhibitors on hypotension in patients with septic shock. Lancet 1991; 338: 1557-1558. [311 Petros A, Lamb G, Leone A, Moncada S, Bennett D, Valiance P. Effect of a nitric oxide synthesis inhibitor in humans with septic shock. Cardiovasc Res 1994; 28: 34-39.

WI Midgley S, Grant IS, Haynes WG, Webb DJ. Nitric oxide in liver failure. Lancet 1991; 338: 1590.