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(Hypertension. 1999;34:e4.)
© 1999 American Heart Association, Inc.

Letters to the Editor - Web

Chronic Nitric Oxide Inhibition Model Six Years On

Sheila Margaret Gardiner; William Robert Dunn; Terence Bennett

School of Biomedical Sciences, Queen’s Medical Centre, Nottingham University, U.K.

	Introduction

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To the Editor:

In a recent issue of Hypertension, Zatz and Baylis¹ reviewed the literature concerning the cardiovascular and renal effects of chronic nitric oxide inhibition. They considered this model under several headings, and we would like to comment accordingly. Zatz and Baylis¹ pointed out, correctly, that Rees et al² were the first to demonstrate the acute pressor effects of NOS inhibition in vivo. However, they cited a review³ published in 1997 as a source of information relating to the observations concerned with the marked effects that acute NOS inhibition has on renal hemodynamics. Unfortunately, the review they cited does not give a complete picture since it omits to refer to a paper of ours⁴ published in Hypertension in 1990, which was the first to report the renal (and other regional) vasoconstrictor effects of acute NOS inhibition in conscious, chronically instrumented rats. These observations were confirmed and extended by Baylis et al⁵ in a paper in which they referred to our findings in some detail. It is, therefore, disappointing that, in the recent review, no reference was made to our original work.

While it is true that the publications of Baylis et al⁶ and Ribeiro et al⁷ in 1992 were the first to demonstrate that the administration of L-NAME over a period of weeks caused sustained hypertension, that work was an extension of our (uncited) earlier observations showing L-NAME is orally active and causes persistent hypertension and renal vasoconstriction when given in the drinking water of Brattleboro rats.^{8 9} Once again, Baylis et al⁶ were aware of these observations, since they cited them in their 1992 paper.

Zatz and Baylis¹ also comment that sustained BP elevation requires persistence of elevated cardiac output, increased peripheral resistance, or impaired renal ability to excrete sodium. A reader unfamiliar with the field of hypertension might take from this statement a view that renal dysfunction could cause hypertension in the absence of a change in cardiac output or total peripheral resistance. Clearly, while impaired renal excretion of sodium may be the cause of hypertension, that influence would have to manifest as an increased cardiac output and/or total peripheral resistance in order for blood pressure to be elevated.

The question of the irreversibility of hypertension caused by chronic inhibition of NOS and whether or not organ damage, vascular remodelling, and/or the involvement of other vasoconstrictor systems are functions of the dose or type of NOS inhibitor remain unresolved. However, in our own studies,^{10 11} the acute effects of NOS inhibition do not appear to involve systems that are susceptible to inhibition by captopril, losartan, pentolinium, or a vasopressin antagonist. In the chronic model, when L-NAME is withdrawn from the drinking water, even when it has been administered for periods of up to 6 months, we find blood pressure returns to normal within 48 hours.^{9 12} Furthermore, in our model, detailed examination of mesenteric vascular structure shows no evidence of remodelling.¹³ One interpretation of these findings is that, in those studies reporting the development of irreversible hypertension, together with organ damage and changes in vascular structure in response to chronic NOS inhibition, the phenomena observed are a function of other effects of the substance administered rather than elevation of blood pressure per se.

	References

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1. Zatz R, Baylis C. Chronic nitric oxide inhibition model six years on. Hypertension. 1998;32:958–964.[Free Full Text]
2. Rees DD, Palmer RM, Moncada S. Role of endothelium-derived nitric oxide in the regulation of blood pressure. Proc Natl Acad Sci USA. 1989;86:3375–3378.[Abstract/Free Full Text]
3. Kone BC, Baylis C. Biosynthesis and homeostatic roles of nitric oxide in the kidney. Am J Physiol. 1997;272:F561–F578.[Abstract/Free Full Text]
4. Gardiner SM, Compton AM, Bennett T, Palmer RMJ, Moncada S. Control of regional blood flow by endothelium-derived nitric oxide. Hypertension. 1990;15:486–492.[Abstract/Free Full Text]
5. Baylis C, Harton P, Engels K. Endothelial derived relaxing factor controls renal hemodynamics in the normal rat kidney. J Am Soc Nephrol. 1990;1:875–881.[Abstract]
6. Baylis C, Mitruka B, Deng A. Chronic blockade of nitric oxide synthesis in the rat produces systemic hypertension and glomerular damage. J Clin Invest. 1992;90:278–281.
7. Ribeiro MO, Antunes E, De Nucci G, Lovisolo SM, Zatz R. Chronic inhibition of nitric oxide synthesis: a new model of arterial hypertension. Hypertension. 1992;20:298–303.[Abstract/Free Full Text]
8. Gardiner SM, Compton AM, Bennett T, Palmer RMJ, Moncada S. Regional haemodynamic changes during oral ingestion of N^G-monomethyl-L-arginine or N^G-nitro-L-arginine methyl ester in conscious Brattleboro rats. Br J Pharmacol. 1990;101:10–12.[Medline] [Order article via Infotrieve]
9. Gardiner SM, Kemp PA, Bennett T, Palmer RMJ, Moncada S. Nitric oxide synthase inhibitors cause sustained, but reversible, hypertension and hindquarters vasoconstriction in Brattleboro rats. Eur J Pharmacol. 1992;213:449–451.[Medline] [Order article via Infotrieve]
10. Gardiner SM, Compton AM, Kemp PA, Bennett T. Regional and cardiac haemodynamic responses to glyceryl trinitrate, acetylcholine, bradykinin and endothelin-1 in conscious rats: effects of N^G-nitro-L-arginine methyl ester. Br J Pharmacol. 1990;101:632–639.[Medline] [Order article via Infotrieve]
11. Gardiner SM, Kemp PA, Bennett T. Regional haemodynamic responses to N^G-monomethyl-L-arginine are unaffected by the AT₁-receptor antagonist, losartan, in conscious rats. In: Moncada S, Feelisch M, Busse R, Higgs EA, eds. The Biology of Nitric Oxide. London, England: Portland Press; 1994:171–175..
12. Gardiner SM, Kemp PA, Bennett T. Regional haemodynamics in Brattleboro rats during chronic ingestion of N^G-nitro-L-arginine methyl ester. Blood Press. 1993;2:228–232.[Medline] [Order article via Infotrieve]
13. Dunn WR, Gardiner SM. No evidence for vascular remodelling during hypertension induced by chronic inhibition of nitric oxide synthase in Brattleboro rats. J Hypertens. 1995;13:849–857.[Medline] [Order article via Infotrieve]

Response

Roberto Zatz, MD, PhD; Christine Baylis, PhD

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We regret that we have offended Drs Gardiner, Bennett, and Dunn by not citing some of their work in our recent review article. No offense was intended, and we certainly recognize that these workers have contributed to the field of NO in hypertension research.

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