Hypertensive retinopathy

Hemodynamic mechanism for brain edema formation in patients with hypertensive encephalopathy is unclear. Potential roles of natriuretic peptides in the pathogenesis of hypertensive encephalopathy are discussed. A 32-year-old man presented with slight left hemiparesis. He was slightly confused, and his blood pressure was extremely high. Cranial plain computerized tomography scans revealed diffuse brain edema mainly in the supratentorial white matter region. Blood examination revealed that plasma concentrations of atrial and brain natriuretic peptides were significantly high. His left hemiparesis disappeared within a day, but he tended to be agitated. His altered mental status, however, resolved with control of blood pressure. Serial magnetic resonance imagings demonstrated that the magnitude of brain edema was attenuated in proportion to decline in plasma concentrations of natriuretic peptides. This case suggests that significant elevation of plasma concentrations of natriuretic peptides may contribute to an acute rise in blood pressure, and that these peptides potentially play an important role in development of brain edema in hypertensive encephalopathy. (Neurol Res 2002; 24: 627-630]

Keywords: Atrial and brain natriuretic peptide; brain edema; hypertensive encephalopathy

INTRODUCTION

Hypertensive encephalopathy (HE) is categorized as one of the most fulminant forms of hypertensive crisis1,2. Radiological imagings sometimes reveal diffuse or multifocal brain edema mainly in the subcortical white matter region3,4. Clinical manifestations usually resolve with prompt and adequate treatment of hypertension3,4.

The pathogenesis of brain edema development in HE has been ascribed to a breakthrough of autoregulation with resultant disruption of blood-brain barrier (BBB)3,4. An abrupt and sustained rise in blood pressure is considered to be an initiating step for brain edema formation. The hemodynamic mechanism, however, for an acute elevation of blood pressure remains to be elucidated.

Atrial and brain natriuretic peptides (ANP and BNP) are cardiovascular regulatory hormones mainly of cardiac origin5. Here we report a case of HE that could be followed by magnetic resonance imaging (MRI), simultaneously with serial measurement of plasma concentrations of ANP and BNP. This case suggests a possible involvement of natriuretic peptides in brain edema formation in HE.

CASE REPORT

A 32-year-old obese man was transferred to our hospital complaining of unstable gait on November 18, 1999. He had noticed mild peripheral edema and headache about 2 months before admission. His state of consciousness was slightly confused, and neurological examinations revealed slight left hemiparesis. Blood pressure at admission was 254/145 mmHg, and body temperature was 36.8deg.C. Heart rate was 128 beats per minute with regular sinus rhythm. He had a history of hypertension, which had been left untreated. An ophthalmologic examination revealed severe hypertensive retinopathy, but his visual acuity was normal. Cranial plain computerized tomography scans demonstrated diffuse low density area mainly in the supratentorial white matter, suggestive of edema. No abnormal enhancement was revealed. Findings of cerebrospinal fluid (CSF) examination were within normal ranges, except for an elevated CSF pressure of 290 mmH^sub 2^O. Cerebral angiography demonstrated no apparent abnormalities. Echocardiogram performed at admission demonstrated severe concentric left ventricular hypertrophy (anterior wall thickness: 26 mm). Ejection fraction was 55%, suggestive of modestly lowered cardiac output. The cardiac wall motion was not disturbed. Main laboratory findings at admission were as follows (parenthesis shows the normal range); hematocrit: 0.53 (0.4-0.52), creatinine: 248.0 nmol I^sup -1^ (70.8-115.0), sodium: 138 mmol l^sup -1^ (135-145), potassium: 3.4 mmol l^sup -1^ (3.5-5.0), active renin concentration: 85.6 pg ml-l^sup -1^ (2.5-21.4), aldosterone: 19.7 nmol I^sup -1^ (3.6-24.0), ANP: 102.3 pmol l^sup -1^ (

MRI obtained the next day exhibited extensive hyperintensity in supratentorial white matter region, brainstem, and partial hyperintensity in left cerebellar hemisphere on T2-weighted image (Figure 1). After admission, he was given anti hypertensive medications, and his left hemiparesis disappeared within a day, although he tended to be agitated in the following course. His blood pressure became almost stabilized at the level of approximately 120-140/80-90 mmHg within a few weeks, and an altered mental status resolved with control of hypertension.

Serial MRI scans demonstrated decrease in signal intensity on T2-weighted image (Figure 2). After stabilization of blood pressure, his clinical course was uneventful, and he was discharged on December 28, 1999. MRI scans followed about three months after his discharge confirmed disappearance of edema. Followup plasma concentrations of natriuretic peptides measured on December 2, 1999, December 27, 1999, and March 28, 2000 were 29.5 pmol l^sup -1^, 30.6 pmol I^sup -1^, and 7.2 pmol l^sup -1^, respectively, for ANP, and 252.7 pmol l^sup -1^, 148.4 pmol l^sup -1^, and 45.2 pmol l^sup -1^, respectively, for BNP. These results indicated that plasma concentration of ANP became normalized, while that of BNP remained slightly elevated.

DISCUSSION

There have been a number of previous investigations regarding hemodynamic, renal, and endocrine effects of infused ANP and BNP in patients with essential hypertension or congestive heart failure as well as in normal subjects6-8. These studies commonly indicated that one of the most striking effects of natriuretic peptides is natriuresis and diuresis. An excessive sodium intake with resultant plasma fluid retention leads to an increase in cardiac pre-load, and consequently stimulates production and release of natriuretic peptides from card iomyocytes5,9. ANP and BNP increase sodium and water excretion by enhancing glomerular filtration rate and by inhibition of tubular sodium reabsorption-5-9. In addition, these peptides reportedly attenuate vascular resistance in microcirculations by reducing sympathetic nerve stimuli and counteracting renin-angiotensin system (RAS), and shift intravascular fluid into extravascular compartment by increasing endothelial permeability5,6,8. Hence, in an early stage of hypertension, these functions contribute to a reduction of cardiac preload. However, prolonged sodium and water retention that is often accompanied by secondary renal dysfunction would lead to further increase in plasma volume, and may exacerbate cardiac performance. If the heart is exhausted, cardiac output is lowered, and eventually the heart may fail9. In this case, however, the cardiac contractility was preserved by an increased cardiac wall thickness, which may contribute to further increase in generation and release of natriuretic peptides. This may explain significantly high concentrations of these peptides.

In this case, daily urine volume and sodium excretion were relatively maintained. In addition, presence of peripheral edema, sinus tachycardia, and high hematocrit level suggest contraction in plasma fluid. Therefore, it is speculated that significant levels of ANP and BNP contribute to a reduction of cardiac overload by withdrawing intravascular fluid into urination and extravascular space5,6,8,9.

A sudden and sustained rise in blood pressure is a necessary initiating step for development of hypertensive crisis. Some considerations will be required concerning the initial high blood pressure in this patient, despite a modestly compromised cardiac performance. The patient also was considered to be rather hypovolemic. These evidences mean a critical increase in peripheral vessel resistance. In an established hypertension, increase in peripheral vascular resistance usually is brought by functional and structural alterations of blood vessel walls, mediated by sympathetic nervous activation, actions of vasoconstrictive substances such as angiotensin-II, endothelial dysfunctions, and hypovolemia1,2,10. In this patient, considering the normal urine excretion of VMA, it seems unlikely that sympathetic nerves were excessively activated. Although plasma angiotensin-II concentration was not measured in this case, it would be elevated because of high active renin concentration. As mentioned above, ANP and BNP could contribute to reduction in intravascular volume. Increased interstitial volume and pressure may be another contributor to an augmented peripheral vascular resistance9.

In an established phase of hypertension complicated by lowered cardiac output, redistribution of organ blood flow usually occurs with the brain and heart receiving a higher proportion11. Such a condition may permit a critical elevation of cerebral blood flow caused by an abrupt and sustained rise in blood pressure.

There remain some questions to be discussed. First, in the present case, the magnitude of increase in plasma BNP concentration at admission was much greater than that of plasma ANP. Plasma BNP concentration is usually less than plasma ANP concentration in healthy men12. Plasma BNP level, however, markedly rises in patients with congestive heart failure paralleled to its severity and exceeds the plasma ANP concentration in severe cases12,13. In addition, plasma half-life period of BNP is longer than that of ANP14, which may account for sustained elevation of plasma BNP level. Second, it remains obscure whether natriuretic peptides directly could participate in brain edema formation prior to the clinical manifestation of HE. In this patient, the magnitude of brain edema detected by MRI decreased in proportion to decline in plasma concentrations of natriuretic peptides. ANP and BNP occupy natriuretic A receptor on endothelial cells to increase cyclic guanosine monophosphate (cGMP) generation5. Substantial evidences demonstrated that ANP could affect brain microvessel endothelial functions and that could promote BBB permeability14-19. Synergistic effect of angiotensin-II has been reported on the increase in cGMP evoked by ANP20. Furthermore, ANP has been reported to reduce the large cerebral blood vessel resistance20,21 Taken together, we cannot entirely exclude the possibility that natriuretic peptides directly accelerate BBB permeability. However, given the fact that brain edema rarely develops in patients with congestive heart failure revealing significantly high plasma levels of ANP and BNP, it appears unlikely that BBB disruption is caused primarily by direct effects of natriuretic peptides, and so, brain edema formation is unlikely to precede a critical rise in blood pressure. An acute and sustained rise in blood pressure should be a primary cause for brain edema formation. Third, our case showed diffuse brain edema formation. Previous studies reported that distribution of brain edema is predominant in areas of the posterior circulation 3,4. The exact reason for that remains poorly understood, but a paucity of vascular sympathetic innervation of the posterior circulation may account for such an anatomical predilection 4,22. Taking that natriuretic peptides have a potential role in increase in BBB permeability, the possibility still may exist that significant levels of natriuretic peptides enhance susceptibility to edema development initiated by an acute and continuous blood pressure elevation. This might explain diffuse edema distribution in this patient.

We cannot draw a substantial conclusion only from such a single case evaluation. Natriuretic peptides, however, in conjunction with RAS, potentially play an important role in occurrence and progression of HE. Hemodynamic assessment with collection of more cases will serve to gain more understanding of this entity.

ACKNOWLEDGEMENTS

We greatly thank Dr Hiroshi Nagura, Departnent of Neurology, Tokyo Met;pon Institute of Gerontology, for helpful advice in the diagnosis of his of this case.

REFERENCES

1 Kaplan NM. Systemic hypertension: Mechanisms and diagnosis. In: Braunwald E, ed. Heart Disease. A Textbook of Cardiovascular Medicine, 4th edn, Philadelphia: W.B. Saunders Company, 1992: pp. 817-851

2 Vaughan CJ, Delanty N. Hypertensive emergencies. Lancet 2000; 356:411-417

3 Schwartz RB, Mulkern RV, Gudbjartsson H, jolesz F. Diffusionweighted MR imaging in hypertensive encephalopathy: Clues to pathogenesis. AJNR 1998; 19: 859-962

4 Hinchey J, Chaves C, Appignani B, Breen J, Pao L, Wang A, Pessin MS, Lamy C, Mas JL, Caplan LR. A reversible posterior leukoencepahlopathy sydrome. N Engl J Med 1996; 334: 494-500

5 Levin ER, Gardner DG, Samson WK. Natriuretic peptides. N Engl / Med 1998; 339: 321-328

6 Yoshimura M, Yasue H, Morita E, Sakaino N, Jougasaki M, Kurose M, Mukoyama M, Saito Y, Nakao K, Imura H. Hemodynamic, renal, and hormonal responses to brain natriuretic peptide infusion in patients with congestive heart failure. Circulation 1991; 84: 1581-1588

7 Florkowski CM, Richards AM, Espiner EA, Yandel TG, Frampton C. Renal, endocrine, and hemodynamic interactions of atrial and brain natriuretic peptides in normal men. Am J Physiol 1994; 266: R1244-81250

8 Pidgeon GB, Richards AM, Nicholls MG, Espiner EA, Yandle TG, Frampton C. Differing metabolism and bioactivity of atrial and brain natriuretic peptides in essential hypertension. Hypertension 1996; 27: 906-913

9 Braunwald E. Pathophysiology of heart failure. In: Braunwald E, ed. Heart disease. A Textbook of Cardiovascular Medicine, 4th edn, Philadelphia: W.B. Saunders Company, 1992: pp. 393-418

10 Gibbons GH, Dzau VJ. The emerging concept of vascular remodeling. N Engl I Med 1994; 330: 1431-1438

11 Saxena PR, Schoemaker RG. Organ blood flow protection in hypertension and congestive heart failure. Am J Med 1993; 94(Suppl. 4A): 45-12S

12 Nakagawa 0, Ogawa Y, Itoh H, Suga S, Komatsu Y, Kishimoto I,

Nishino K, Yoshimasa T, Nakao K. Rapid transcriptional activation and early mRNA turnover of brain natriuretic peptide in cardiocyte hypertrophy. Evidence for brain natriuretic peptide as an 'emergency' cardiac hormone against ventricular overload. J Clin Invest 1995; 96: 1280-1287

13 Mukoyama M, Nakao K, Hosoda K, Suga S, Saito Y, Ogawa Y, Shirakami G, Jougasaki M, Obata K, Yasue H, Kambayashi Y, Inoue K, Imura H. Brain natriuretic peptide as a novel cardiac hormone in humans. Evidence for an exquisite dual natriuretic peptide system, atrial natriuretic peptide and brain natriuretic peptide. J Clin Invest 1991; 87: 1402-1412

14 )06 F, Temesvari P, Dux E. Regulation of the macromolecular transport in the brain microvessels: The role of cyclic GMP. Brain Res 1983; 278: 165-174

15 Huxley VH, Tucker VL, Verburg KM, freeman RH. Increased capillary hydraulic conductivity induced by atrial natriuretic peptide. Circ Res 1987; 60: 304-307

16 Homayoun P, Lust WD, Harik SI. Effects of several vasoactive agents on guanylate cyclase activity in isolated rat brain microvessels. Neurosci Lett 1989; 107: 273-278

17 Whitson PA, Huls MH, Sams CF. Characterization of atrial natriuretic peptide receptors in brain microvessel endothelial cells. J Cell Physiol 1991; 146: 43-51

18 Battle Th, Michel JB, Corman B. Effect of atrial natriuretic factor on the water permeability of endothelial cells. Biochem Biophys Res Commun 1992; 185: 386-391

19 Holschermann H, Noll T, Hempel A, Piper HM. Dual role of cGMP in modulation of macromolecule permeability of aortic endothelial cells. Am J Physiol 1997; 271: H91-H98

20 Grammas P, Giacomelli F, Bessert D, Wiener J. Angiotensin II and atrial natriuretic factor receptor interactions at the blood-brain barrier. Brain Res 1991; 562: 93-97

21 Tamaki K, Saku Y, Ogata J. Effects of angiotensin and atrial natriuretic peptide on the cerebral circulation. J Cereb Blood Flow Metab 1992; 12: 318-325

22 Edvinsson L, Owman C, Sjoberg NS. Autonomic nerves, mast cells, and amine receptors in human brain vessels. A histochemical and pharmacological study. Brain Res 1976; 115: 377-393

Kazuhiko Nakagawa*, Takekane Yamaguchi*, Mitsuru Seida*, Youji Tanaka^^ and Maki Yoshino^

*Department of Neurosurgery, ^Department of Internal Medicine, Tokyo Metropolitan Toshima Hospital, Tokyo ^^Department of Neurosurgery, Tokyo Medical and Dental University, Tokyo, Japan

Correspondence and reprint requests to: Kazuhiko Nakagawa, MD, Department of Neurosurgery, Tokyo Metropolitan Toshima Hospital, 33-1, Sakae-Chou, Itabashi-Ku, Tokyo 173-0015, Japan. [nakagawa@toshima-hp.metro.tokyo.jp] Accepted for publication March 2002.

Copyright Forefront Publishing Group Sep 2002
Provided by ProQuest Information and Learning Company. All rights Reserved