Nitric oxide and portal hypertension

Jomnal of Hepatology i995, 23 355 356 PHnted m Denmark All right~ re~erved

Copyrzght© Joutnal of Hepatology 1995 Journal of Hepatology ISSN 0168-8278

Editorial

Nitric oxide and portal hypertension Paul A. Cahill and James V. Sitzmann Department o f Surgery, The Johns Hopkms Mechcal Instttutlons, Baltmzol e, Maryland, USA

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ORTAL hypertension (PHT) due to cirrhosis exhibits a circulatory dysfunction characterized by arterial hypotension, reduced peripheral vascular resistance, hypovolemia and high cardiac output (1). The role of nitric oxide (NO) in mediating the arterial vasodilation has attracted much interest since the initial studies of Vatlance & Moncada (2). Several reports, including the recent paper by Michielsen et al., using NO synthesis inhibitors, have demonstrated attenuation of the marked hyporeactivity of PHT vessels to vasoconstrictors in vitro, and reversal of the arterial hypotension m vtvo (3). However, the source and etiology of the enhanced NO production m PHT remain controversial. Since the vascular endothehum and/or the underlying smooth muscle are both potential sites for enhanced NO production, many studies have focused on the possible regulation of nitric oxide synthase (NOS) activity m these cells. Moreover, whether increased NO production represents a primary event in PHT or whether it is secondary to increased hemodynamlc stress is still unresolved. Evidence presented by Michielsen et al. indicates that an extraendothelial production of NO may be involved m the vascular hyporeactlvlty to norepinephrine in PHT since removal of the endothelium does not attenuate the impaired response (4). Furthermore, a secondary role for NO is implied by these authors since the vascular hyporeactivity to norepinephrine is still present despite the absence of a hyperdynamlc circulation in long-term PHT. A possible role for endotoxins and cytokines m triggering the induction of INOS within these vessels has been subsequently proposed (5). However, the lack of immunological 1NOS in PHT vessels despite enhanced NO production may argue

Correspondence James V Sitzmann, M.D., Department of Surgery, Blalock 665, The Johns Hopkins Hospital, 600 North Wolfe Street, Baltimore, Maryland 21287-4665, USA.

against a direct reduction of iNOS in the hyperemic vasculature of PHT (6). An enhanced activity of ECNOS can reduce the response of a-adrenergic vasoconstriction in arterial segments subjected to increased endothelial shear stress (increased blood flow) (7). This exaggerated NO production is regulated at the level of an inhibitory guanine nucleotide regulatory protein (Gia) (8). Therefore, one might expect that the constitutive Ca 2+ dependent ECNOS is regulated in PHT as a direct result of the hemodynamically imposed mechanical forces within the hyperemic vasculature. In thas regard, the hormone-stxmulated ECNOS response is greater in patients with cirrhosis, since at is predominantly ECNOS activity that appears to be enhanced m these vessels (9,10). Receptor-mediated activation of ECNOS by circulating hormones may also be involved. Plasma concentrations of catecholamines are elevated in PHT, where c~2-adrenergic receptor activation is also closely coupled to Gia proteins that produce NO in endothelial cells in response to norepinephrine. An increased Gia protein functional activity within the hyperemic vasculature of PHT animals has recently been demonstrated (11). This may parallel increased Gi functional activity coupled to receptors that are hnked to NO generation and therefore contribute to the regulation of the enhanced ECNOS activity in these vessels. Finally, the fact that, following de-endothehalization, a marked pressor hyporesponsiveness persists in PHT may only highlight a chronic regulatory role for NO in vivo. Namely, following prolonged exposure of the underlying smooth muscle to endothelial NO, vasoconstrictor hormone-responses are modulated at the level of their receptor-transmembrane signalling pathways. Interestingly, recent studies have demonstrated a marked NO-mediated-regulation of vascular angiotensin II receptors in vitro (12). Thus, while the evidence for a role of NO in modu'-'~ng splanchnic and systemic hemodynamics in PHT 355

P. A Cahtll and J V Sttzmann

is strong, the etiology of this altered regulation is at present unknown. Whether the increased vascular NO production is a primary cause or a secondary event in the arterial vasodilation of PHT and whether other endothelial-derived vasoactive substances mediate the hyperemia awaits further investigation.

Acknowledgements The National Institutes of Health; Grant 1RO1 DK47067 and The American Heart Association; Grant 92009340.

References 1. Lebrec D, Batallle C, Bercoff E, Valla D Hemodynamlc changes in patients with venous obstruction Hepatology 1983, 3' 550-3 2. Vallance P, Moncada S. Hyperdynamlc circulation in cirrhosis a role for nitric oxide. Lancet 1991; 237' 776-8 3 Lee F-Y, Colombato LA, Albillos A, Groszmann RJ. N Gnltro-L-arglnme administration corrects peripheral vasodilation and systemic capillary hypotenslon and ameliorates plasma volume expansion and sodium retention in portal hypertensive rats Hepatology 1993; 17 85-90 4 Mlchlelsen PP, Boeckxstaens GE, Herman AG, Pelckmans

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PA. Role of nitric oxide in vascular hyporeactlvlty to noradrenahne of isolated aortic rings in portal hypertensive rats Eur J Pharm (in press) 5 Lopez-Talevera JC, Merrill W, Groszmann RJ. Treatment with anti-tumor necrosis factor-c~ polyclonal antibodies prevents the development of the hyperdynamlc circulation and reduces portal pressure in portal hypertensive rats Hepatology 1993, 18' 140A 6 Cahill PA, Foster C, Redmond EM, Glngalewskl C, Wu Y, Sitzmann JV Enhanced nitric oxide synthase activity In portal hypertensive rabbits Hepatology 1995 (in press) 7 Rubanyl GM, Romero JC, Vanhoutte PM Flow-induced release of endothehum-derlved relaxing factor Am J Physlol 1986; 255 Hl145-9 8 0 h n o M, Gibbons GH, Dzau VJ, Cooke JR Shear stress elevated endothelial cGMR role of potassium channel and Gprotein coupling Circulation 1994, 88 193-7. 9. Cahlll PA, Wu Y, Sitzmann JV Nitric oxide synthase activity an portal hypertension. Hepatology 1993, 18 141A 10. Ros J, Jlmenez W, Lamas S, Clarma J, Arroyo V, Ravera F, Rodes J Nitric oxide production in arterial vessels of cirrhotic rats. Hepatology 1995, 21' 554-60 11 Cahlll PA, Wu Y, SmtzmannJV. Altered adenylyl cyclase activities and G-protein abnormahtles in portal hypertensive rabbits J Chn Invest 1994, 93. 2691-700 12 Cahlll PA, Redmond EM, Foster C, Sltzmann JV Nitric oxide regulates angaotensln II receptors in vascular smooth muscle cells Eur J Pharmacol 1995, 288 219-29