Renal vein prostaglandins in renovascular hypertensive patients

Prostaglandins, Leukotrienes and Medicine 19: 219-226, 1985

RENAL VEIN

PROSTAGLANDINS IN

RENOVASCULAR HYPERTENSIVE PATIENTS

Y. Tabuchi, T. Ogihara, and Y. Kumahara. Department of Medicine and Geriatrics, Osaka University Medical School, Fukushimaku, Osaka 553, Japan. (reprint requests to T. 0.) ABSTRACT To investigate the role of intrarenal prostaglandins in the pathophysiology of renovascular hypertension, we measured bilateral renal ;&r)prostaglandins (PGE2, 6-keto-PGFla ) and plasma renin activity of nine patients with renovascular hypertension caused by fibromuscular dysplasia. Both PGE2 and PRA on the stenotic side were significantly higher than those on the non-stenotic side. .The difference in 6-keto-PGFlo levels between the stenotic and the nonstenotic sides was not significant. PGE2 ratio of the stenotic and the non-stenotic sides was significantly correlated with PRA ratio of the stenotic and contralateral sides. These results suggest that renal PGE2 plays an important role in the maintenance of renal blood flow through modulation against vasoconstriction in the renal vasculature and that renal PGE2 may be closely associated with renal renin secretion in the renovascular hypertension. INTRODUCTION It is well known that the renin-angiotensin system plays a major role in the development of hypertension caused by renal artery stenosis (1, 2). However, the level of plasma renin activity (PRA) is not always high in this type of hypertension, and an angiotensin II antagonist sometimes fails to reduce the blood pressure of renovascular hypertensive patients. These facts indicate that the activation of the renin-angiotensin system cannot always explain the mechanism of the maintenance of renovascular hypertension, especially in the chronic phase. Increasing sympathetic nervous activity (3), or decreasing the activity of an antihypertensive system, such as the prostaglandin (PG) (4) and kallikrein-kinin system (5) might contribute to the mainteance of hypertension. Renal PGE2 is mainly synthesized in the medulla of the kidney, and PG12 in the cortex. These prostaglandins play a 219

significant function in regulating renal blood flow, sodium excretion and modulation of vasoconstrictive factors, angiotensin II (6) and renal sympathetic nervous activity (7). The protective role of renal prostaglandins has been demonstrated by the acceleration of hypertension and impairment of renal function by indomethacin administration in 2 kidney 1 clip Goldblatt rats (4). It is also reported that renal ischemia causes increases in production of prostaglandins (8). In the present study, we measured the levels of PRA and prostaglandins (PGE2, 6-0-PGFl, ) in renal veins of both the stenotic and contralateral sides of patients with renovascular hypertension to investigate the role of the intra-renal prostaglandins. SUBJECTS AND METHODS All patients were admitted to our hospital and investigated while on a regular sodium and potassium diet (Na : 100 mEq/day, K : 60 mEq/day). Antihypertensive drugs had been discontinued at least two weeks prior to the renal vein sampling study. Nine patients (3 men and 6 women, aged 35 f 4, mean 2 SEM) with renovascular hypertension were studied. Profiles of the subjects are summarized in Table I. The diagnosis was confirmed by renal angiography. All patients had unilateral renal artery stenosis caused by fibromuscular dysplasia. Renal function tests (GFR, blood urea nitrogen, and serum creatinine) were within the normal limits in all patients. [Sarl, Ile8] Angiotensin II (9), showed hypotensive responses in all except one case and the converting enzyme inhibitor, captoril (50 mg, p.o.) decreased BP in all patients. A polyethylane catheter was introduced percutaneously into the right femoral vein by Seldinger's method. Blood samples were taken from the right and left renal veins. The time for switching the catheter between the two renal veins was less than one minute in each case. Blood samples were immediately placed in ice-cooled tubes containing EDTA*2Na (lmg/ml) and aspirin (lmg/ml) for prostaglandin assay and ice-cooled EDTAa2Na (lmg/ml) containing tubes for PRA assay, and immediately centrifuged at 4°C. Plasma was kept at -5O'C until assay and analyzed within 2 weeks. Radioimmunoassay of PGE2 and 6-keto-PGFla was done using specific antiserum after silicic column chromatographic separation by the method described previously (9, lo).. Authentic prostaglandins and antibodies were kindly supplied by Ono Pharmaceucal Company (Osaka, Japan). The cross reactivity of the anti-6-keto-PGFla antibody with known prostaglandins was as follows: PGE2, 1.5 %, TXB2, 0.1 %, 0.1 %. The 13,14-dihydro-6,15-diketo-PGFla, 0.1 %, and PGF2 crossreactivity of anti-PGE2 antibody with other prosiaglandins was as follows: PGA2, 2.1 %, PGBl, 4.7 %, PGB2, 8.4 %, PGEl, 53.3 90, 6-keto-PGFla , 0.1 %, PGF2 , 0.1 %. The intraassay and interassay coefficients of variation were 8.2 and 11.3 % for PGE2, and 8.3 and 10.2 % for 6-keto-PGFl, , respectively. All data are presented as the mean + SEM. Statistical analyses were performed by student's paired t-test.

220

Table

Pt. No.

Sex

Age

Duration of hypertension (years)

1. 2. 3. 4. 5. 6. 7. 8. 9.

Table

Patient number

F F M F F F F M M

21 43 29 25 59 10 30 56 55

II

3 0.5 1 1 3 2 4 4.5 3

I

Profile

Blood pressure on admission (mmBg)

each

patient

Serum creatinine

Basal PRA

(mg/dl)

(ng/ml/h)(ng/dl)

1.0 0.9 0.9 0.8 1.5 1.3 1.1 1.0 1.2

190/l 10 194/124 2201126 170/110 180/118 174/114 200/130 2121126 194/110

Plasma aldosterone concentration

8.4 6.0 5.2 5.7 2.5 2.7 6.7 1.5 2.4

19.4 37.2 14.2 16.0 10.6 11.6 19.7 8.3 10.4

Renal vein PRA, PGE2, and 6-keto-PGFlu of non-stenotic sides, and ratio of stenotic stenotic (N) value

Renal

vein

PRA

Renal

vein

stenotic and (S) to non-

PGE2

Renal vein 6-keto-PGFlu (pg/ml)

(ng/ml/hr) (pg/ml) -~__------__-------_-------___~~~~~~---_~~~~----~~~~------_-. S

N

ratio

S

N

ratio

s

s

ratio

1. 2. 3. 4. 5. 6. 7. 8. 9.

5.7 10.0 5.3 17.5 3.0 4.5 9.1 1.9 2.2

2.8 8.8 3.0 9.7 2.4 2.6 6.8 1.5 1.8

2.04 1.14 1.77 1.80 1.25 1.73 1.34 1.27 1.22

313 162 91 107 264 266 94 57 133

213 127 46 70 194 154 91 47 119

1.47 1.28 1.98 1.53 1.36 1.73 1.03 1.21 1.12

38 30 41 53 23 32 43 25 78

53 49 54 44 23 30 26 74 46

0.72 0.61 0.76 1.20 1.00 1.07 1.65 0.34 1.70

mean

6.6

4.4

1.51

165

118

1.41

40

44

1 .Ol

SEM

1.7

1.1

0.11

30

20

0.10

5.1

5.4

0.15

221

PROST.

of

B

RESULTS Results of each patient are summarized in Table II. PRA of renal vein on the stenotic side was significantly higher than that of the nonstenotic side (p < 0.05) and the mean stenotic to non-stenotic ratio was 1.51 f 0.11 (Fig. 1). The renal vein PGE2 on the stenotic side was also elevated significantly compared with the non-stenotic side (p< 0.01) and the mean stenotic to non-stenotic ratio was 1.41 + 0.10. The renal vein 6-keto-PGFla showed no consistent difference between stenotic and non-stenotic sides and the mean stenotic to non-stenotic ratio was 1.01+0.15 (Fig. 1). Fig. 2 shows the relationship between PRA and PGE2 ratios of each patient. The ratio of PRA was significantly correlated with the ratio of PGE2 (r = 0.69, p
RenudVein PRA

Renal PGEz

S/N=1.61f0.11 ns/mWhf

p
1s -

veinw

S/N=%.41 3~0.10

6-kr(o-PGFm SIN-1 .OlfO.lS

pa/ml 300.

\

2003

100

OC

S

Fig.

1

N

OS

Renal vein PRA, PGE2, and 6-keto-PGFla on the stenotic side (S) and the non-stenotic side(N). Hatched columns show mean f SEM.

222

y=o.74x+o.48 r =0.89 peo.05

3 Y

0 0

z ;

is 1.0 1.0 S/N

Fig.

2

ratio of S/N

The relation between ratio in each patient.

the

ii

S/N PRA ratio

and

the S/N PGE2

DISCUSSION The contribution of prostaglandins to the pathophysiology of renovascular hypertension is unclear. Pugsley et al (4) showed that indomethacin accelerated hypertension in 2-kidney l-clip Goldblatt rats and concluded that prostaglandins may play an important role in the maintenance of renal circulation and the control of systemic blood pressure in renovascular hypertension. Some investigators reported comparisons of ischemic and non-ischemic sides of renal tissues, renal veins, and urinary PGs (8, 12-15). It was reported that in the kidney on the ischemic side, prostaglandin production was stimulated more than on the contralateral side (13, 14). Others reported that

223

increased circulating angiotensin II stimulated the renal prostaglandins from the non-affected kidney more than from the affected kidney because prostaglandin production of the latter ki~dneywas potentially poor (12, 15). These controversies may be attributed to differences in the assay methods, subjects, and causes of renovascular disease. In this study, we measured the renal vein prostaglandins by a sensitive radioimmunoassay in patients with renovascular hypertension caused by fibromuscular dysplasia. Our results showed that PGE2 production increased more on the ischemic side than on the non-ischemic side and that the PRA on the affected side was also significantly higher than that on the contralateral side. The relationship between the PRA ratio of the stenotic to non-stenotic side and the PGE2 ratio was significant. In renovascular hypertension, the increase in renin release from the ischemic kidney elevates angiotensin II levels and causes peripheral vasoconstriction. As a result, systemic blood pressure is elevated to maintain the renal blood flow. However, intrarenal angiotensin II On the may cause vasoconstriction of the renal vascular bed. contrary, the production of renal prostaglandins may increase to alternate vasoconstriction by angiotensin II and to maintain the renal blood flow. It was reported that exogenously infused angiotensin II causes an increase in prostaglandin production in in vivo studies (6) or in tissue cultures of renomedullary interstitzl cells (16). Angiotensin II level of the ischemic kidney should be higher than that of the contralateral kidney by the intrarenal activation of the reninangiotensin system. Therefore it is probable that PGE2 production on the ischemic side is elevated more than that that on the nonischemic side. This elevation of PGE2 production may contribute to the control of systemic blood pressure and to maintaining blood circulation against the activation of the renin-angiotensin system. It is also probable that the increased PGE2 production may participate in the stimulation of renin release from the stenotic side of the kidneys of renovascular hypertensive patients. On the other hand, it is unclear whether prostacyclin may play a role in the maintenance of renal circulation and in modulating blood pressure in renovascular hypertension. Acknowledgment We are indebted to the staff of for their cooperation in this study.

the Radiology Department

for

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224

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