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(Circulation. 1997;95:1108-1110.)
© 1997 American Heart Association, Inc.

Articles

Role of Vasopressin Deficiency in the Vasodilation of Septic Shock

Ian A. Reid, PhD

the Department of Physiology, University of California San Francisco.

Correspondence to Ian A. Reid, PhD, Department of Physiology, University of California San Francisco, San Francisco, CA 94143-0444. E-mail ianreid{at}itsa.ucsf.edu

Key Words: Editorials • shock • vasopressin • blood pressure • vasodilation

	Introduction

Top Introduction Vasopressin Vasopressin and Septic Shock References

 
Septic shock is a form of distributive shock most commonly caused by infection with gram-negative bacteria.^{1 2} The hallmark of septic shock is marked peripheral arteriolar vasodilation, which results in low systemic vascular resistance, high cardiac output, severe hypotension, and inadequate tissue perfusion. Therapy typically includes administration of fluids and vasopressor agents.

The mechanism of the vasodilation of septic shock remains incompletely understood, but considerable evidence implicates abnormalities of vasodilator mechanisms. Much attention has been focused on bacterial lipopolysaccharide or endotoxin, the administration of which reproduces many of the cardiovascular alterations that occur in septic shock.³ Endotoxin stimulates the synthesis of tumor necrosis factor, interleukin 1, and other cytokines, and these substances in turn increase the generation of the vasodilator nitric oxide. Thus, inhibition of nitric oxide synthase reverses endotoxin- or cytokine-induced hypotension in experimental animals^{4 5 6 7} and increases systemic vascular resistance and blood pressure in patients with septic shock who have not responded to conventional therapy.⁸ In addition to increased generation of nitric oxide, there may also be activation of the vascular ATP-sensitive K⁺ channel in septic shock.⁹ Opening of this channel hyperpolarizes vascular smooth muscle and reduces Ca²⁺ entry through voltage-gated Ca²⁺ channels, thereby inducing vasodilation.

There may also be abnormalities in vasoconstrictor mechanisms in septic shock. In this issue, Landry and associates¹⁰ present evidence that deficiency of vasopressin, now recognized as an important vasoconstrictor peptide, contributes to the hypotension of septic shock.

	Vasopressin

Top Introduction Vasopressin Vasopressin and Septic Shock References

 
Vasopressin is a peptide hormone that is synthesized in the supraoptic and paraventricular nuclei of the hypothalamus and transported to the posterior pituitary, where it is stored. It is released into the circulation upon stimulation by increased plasma osmolality or as a baroreflex response to decreases in blood volume or blood pressure.¹¹ Release of vasopressin is also increased by nausea, pain, and other stimuli.

Vasopressin plays a key role in the regulation of body fluid balance through its antidiuretic action. This action is mediated by renal vasopressin V₂-receptors, which are coupled to adenylyl cyclase and the generation of cAMP. Vasopressin is also capable of causing vasoconstriction and increasing blood pressure.¹² This action is mediated by vascular V₁-receptors, which, unlike the renal receptors, are coupled to phospholipase C and increased intracellular Ca²⁺ concentration.

In early studies, it became apparent that larger doses of vasopressin are required to increase blood pressure than to cause maximal antidiuresis. For this reason, it was considered that the pressor action of vasopressin was a pharmacological rather than a physiological one. However, subsequent studies involving cardiovascular measurements in conscious animals revealed that the pressor action of vasopressin significantly underestimates its vasoconstrictor action.¹³ Indeed, it was shown that vasopressin is a more potent vasoconstrictor than angiotensin II or norepinephrine and is capable of increasing systemic vascular resistance in doses less than those required to produce maximum urine concentration.¹²

The reason that vasopressin is a relatively weak pressor agent is that it resets the cardiac baroreflex to a lower pressure. This action, which is apparently mediated by V₁-receptors in the area postrema, a circumventricular organ located in the medulla oblongata, causes a leftward shift of the heart rate–arterial pressure baroreflex curve.^{14 15} This action explains the well-documented phenomenon that for a given increase in blood pressure, vasopressin causes more bradycardia than other vasoconstrictors. Removal of this buffering mechanism by baroreceptor denervation greatly enhances the pressor sensitivity to vasopressin.¹⁶ Pressor sensitivity is also increased in patients with autonomic insufficiency.¹⁷

A major development early in the last decade was the discovery of vasopressin V₁ antagonists, which selectively block the vasoconstrictor action of vasopressin.¹⁸ These drugs proved to be valuable tools for investigating the contribution of vasopressin to cardiovascular regulation, and a role for the peptide in the regulation of blood pressure regulation in hypovolemic states including water deprivation, hemorrhage, and adrenal insufficiency was soon demonstrated.¹² It is now generally accepted that vasopressin, by virtue of its potent vasoconstrictor action, plays an important role in the regulation of arterial pressure.

	Vasopressin and Septic Shock

Top Introduction Vasopressin Vasopressin and Septic Shock References

 
Landry and associates¹⁰ previously observed that some patients with septic shock are very sensitive to the pressor action of vasopressin. This finding suggested to them that vasopressin levels in these patients might be inappropriately low and stimulated the present investigation.

Their study included 19 patients with septic shock and, for comparison, 12 patients with cardiogenic shock. A striking finding was that plasma vasopressin concentration in the patients with septic shock averaged only 3.1 pg/mL despite the accompanying hypotension (systolic pressure, 92 mm Hg), which would normally stimulate vasopressin releases.¹¹ Presumably endotoxin and cytokine levels in these patients were high and would have also tended to stimulate vasopressin release.^{19 20} In patients with cardiogenic shock with a similar degree of hypotension, plasma vasopressin concentration was appropriately increased to 22.7 pg/mL.

The inappropriately low plasma vasopressin concentration in patients with septic shock could have been due to low vasopressin secretion or increased clearance of vasopressin from the circulation. The latter possibility was excluded by showing that infusion of exogenous vasopressin produced the expected increase in plasma vasopressin concentration. Therefore, the authors concluded that vasopressin secretion was low. Further, they considered it likely that the low secretion rate was due to impaired baroreflex-mediated vasopressin secretion rather than to impaired osmotic-mediated stimulation. The apparent impairment of baroreflex-mediated secretion may have resulted from autonomic failure, since sympathetic function has been reported to be impaired in septic shock. Alternatively, excessive secretion of vasopressin in the early stages of septic shock may have depleted pituitary vasopressin stores.

A second major finding in this study was that infusion of exogenous vasopressin in a dose of 0.04 U/min, which does not increase blood pressure in normal subjects, caused a striking increase in systolic pressure from 92 to 146 mm Hg. This increase was due to the vasoconstrictor action of vasopressin, since it occurred in association with a large increase in systemic vascular resistance and a small reduction in cardiac output. In some patients, blood pressure could be maintained with vasopressin alone, without administration of catecholamines that are normally required for blood pressure control in septic shock. When the vasopressin infusion was stopped, blood pressure rapidly decreased. Subsequent administration of a lower dose of vasopressin, 0.01 U/min, which was estimated to increase plasma vasopressin concentration to near the levels measured in cardiogenic shock, rapidly increased systolic pressure from 83 to 115 mm Hg.

The findings of Landry et al¹⁰ provide convincing evidence that there are alterations in vasopressin secretion and action in septic shock. Specifically, they demonstrate that vasopressin secretion is inappropriately low in septic shock, while the pressor sensitivity to vasopressin is enhanced. Nevertheless, important questions remain to be answered. In particular, is the inappropriately low vasopressin secretion specifically due to impaired baroreflex-mediated vasopressin secretion, or is it simply due to depletion of pituitary vasopressin stores? Administration of an osmotic challenge would distinguish between these possibilities because it would increase vasopressin secretion in the former case, but not in the latter. What is the mechanism of the enhanced pressor sensitivity to vasopressin in septic shock? Autonomic dysfunction seems a likely candidate since, as noted above, pressor sensitivity to vasopressin is increased in autonomic insufficiency. The observation that the pressor response to exogenous vasopressin was not accompanied by the normal reflex reduction in heart rate favors this possibility. However, it would be of interest to determine if the increase in sensitivity is specific for vasopressin or if sensitivity to other vasoconstrictors such as angiotensin II is similarly enhanced.

It is worth emphasizing that although the article¹⁰ is titled "Vasopressin deficiency contributes to the vasodilation of septic shock," vasopressin deficiency per se does not cause vasodilation. Thus, V₁-receptor blockade does not decrease systemic vascular resistance or blood pressure when vasopressin levels are not significantly elevated, as in the present study.¹² Rather, vasopressin is secreted in response to hypotension or hypovolemia and helps defend blood pressure by causing vasoconstriction. It is this compensatory response to the vasodilation (presumably caused by cytokines and nitric oxide^{3 4 5 6 7 8} ) that was apparently impaired in septic shock. Thus, the concluding sentence of the abstract, "The deficiency in vasopressin contributes to the hypotension of vasodilatory septic shock," is a more precise expression of the present results. Of course, vasopressin secretion may have been high in the early stages of septic shock and helped defend blood pressure until vasopressin stores were depleted.

Two additional points merit consideration. First, the implications for using vasopressin for the treatment of septic shock are apparent. In this context, it would seem worthwhile to evaluate selective V₁ agonists, such as [Phe²Orn⁸] oxytocin, which have a longer half-life than vasopressin.²¹ Second, although the authors do not specifically comment on it, their finding that plasma vasopressin levels increase markedly in cardiogenic shock suggest an important role for vasopressin in blood pressure control in that situation. Therefore, it would be of interest to test the effect of V₁-receptor blockade in animal models of cardiogenic and other forms of shock. In the meantime, the present findings significantly extend animal studies by showing the importance of vasopressin in cardiovascular regulation in humans.

	Acknowledgments

 
Research in the author's laboratory is supported by National Institutes of Health grant HL-49943.

	Footnotes

 
The opinions expressed in this editorial are not necessarily those of the editors or of the American Heart Association.

	References

Top Introduction Vasopressin Vasopressin and Septic Shock References

 

1. Parrillo JE, Parker MM, Natanson C, Suffredini AF, Danner RL, Cunnion RE, Ognibene FP. Septic shock in humans: advances in the understanding of pathogenesis, cardiovascular dysfunction, and therapy. Ann Intern Med. 1990;13:227-242.
   
2. Glauser MP, Zanetti G, Baumgartner J-D, Cohen J. Septic shock: pathogenesis. Lancet. 1991;338:732-736.[Medline] [Order article via Infotrieve]
   
3. Suffredini AF, Frome WL, Parker NM, Brenner M, Kovacs JA, Wesley RA, Parrillo JE. The cardiovascular response of normal humans to the administration of endotoxin. N Engl J Med. 1989;321:280-287.[Abstract]
   
4. Loscalzo J, Welch G. Nitric oxide and its role in the cardiovascular system. Prog Cardiovasc Dis. 1995;38:87-104.[Medline] [Order article via Infotrieve]
   
5. Kilbourn RG, Gross SS, Jubran A, Adams J, Griffith OW, Levi R, Lodato RF. N^G-methyl-L-arginine inhibits tumor necrosis factor-induced hypotension: implications for the involvement of nitric oxide. Proc Natl Acad Sci U S A. 1990;87:3629-3632.[Abstract/Free Full Text]
   
6. Thiemermann C, Vane JR. Inhibition of nitric oxide synthesis reduces the hypotension induced by bacterial lipopolysaccharides in the rat in vivo. Eur J Pharmacol. 1990;182:591-595.[Medline] [Order article via Infotrieve]
   
7. Kilbourn RG, Jubran A, Gross SS, Griffith OW, Levi R, Adams J, Lodato RF. Reversal of endotoxin-mediated shock by N^G-methyl-L-arginine, an inhibitor of nitric oxide synthesis. Biochem Biophys Res Commun. 1990;72:1132-1138.
   
8. Petros A, Bennett D, Vallance P. Effect of nitric oxide synthase inhibitors on hypotension in patients with septic shock. Lancet. 1991;338:1557-1558.[Medline] [Order article via Infotrieve]
   
9. Landry DW, Oliver JA. The ATP-sensitive K⁺ channel mediates hypotension in endotoxemia and hypoxic lactic acidosis in dog. J Clin Invest. 1992;89:2071-2074.
   
10. Landry DW, Levin HR, Gallant EM, Ashton RC Jr, Seo S, D'Alesandro D, Oz MC, Oliver JA. Vasopressin deficiency contributes to the vasodilation of septic shock. Circulation. 1997;95:1122-1125.[Abstract/Free Full Text]
    
11. Schrier RW, Berl T, Anderson RJ. Osmotic and nonosmotic control of vasopressin release. Am J Physiol. 1979;236:F321-F332.
    
12. Reid IA, Schwartz J. Role of vasopressin in the control of blood pressure. In: Martini L, Ganong WF, eds. Frontiers in Neuroendocrinology. New York, NY: Raven Press; 1984:177-197.
    
13. Montani JP, Liard JF, Schoun J, Mohring J. Hemodynamic effects of exogenous and endogenous vasopressin at low plasma concentrations in conscious dogs. Circ Res. 1980;47:346-355.[Abstract/Free Full Text]
    
14. Undesser KP, Hasser EM, Haywood JR, Johnson AK, Bishop VS. Interactions of vasopressin with the area postrema in arterial baroreflex function in conscious rabbits. Circ Res. 1985;56:410-417.[Abstract/Free Full Text]
    
15. Luk J, Ajaelo I, Wong V, Wong J, Chang D, Chou L, Reid IA. Role of V₁-receptors in the action of vasopressin on the baroreflex control of heart. Am J Physiol. 1993;265:R524-R529.[Abstract/Free Full Text]
    
16. Cowley AW Jr, Monos E, Guyton AC. Interaction of vasopressin and the baroreceptor reflex system in the regulation of arterial blood pressure in the dog. Circ Res. 1974;34:505-514.[Abstract/Free Full Text]
    
17. Mohring J, Glanzer K, Maciel JA Jr, Dusing R, Kramer HJ, Arbogast R, Koch-Weser J. Greatly enhanced pressor response to antidiuretic hormone in patients with impaired cardiovascular reflexes due to idiopathic orthostatic hypotension. J Cardiovasc Pharmacol. 1980;2:367-376.[Medline] [Order article via Infotrieve]
    
18. Manning M, Sawyer WH. Antagonists of vasopressor and antidiuretic responses to arginine vasopressin. Ann Intern Med. 1982;96:520-522.
    
19. Brackett DJ, Schaefer CF, Tompkins P, Fagraeus L, Peters LJ, Wilson MF. Evaluation of cardiac output, total peripheral vascular resistance, and plasma concentrations of vasopressin in the conscious, unrestrained rat during endotoxemia. Circ Shock. 1985;17:273-284.[Medline] [Order article via Infotrieve]
    
20. Raber J, Bloom FE. IL-2 induces vasopressin release from the hypothalamus and the amygdala: role of nitric oxide-mediated signaling. J Neurosci. 1994;14:6187-6195.[Abstract]
    
21. Sawyer WH, Grzonka Z, Manning M. Neurohypophysial peptides: design of tissue-specific agonists and antagonists. Mol Cell Endocrinol. 1981;22:117-134.[Medline] [Order article via Infotrieve]
    

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