AJH
1991;
4:575S-577S
The Role of Extrarenal Renin in Goldblatt Hypertension
Renin-like activity can be demonstrated in arterial extracts from normal rats and from rats with Goldblatt hypertension. We have found no evidence, however, for elevated arterial renin levels in rela tion to plasma renin activity. Studies of the rever sal of renovascular hypertension indicate that the fall in blood pressure produced by renal artery deconstriction is not renin-dependent. However, mo lecular biological techniques indicate that extrare nal renin gene expression is altered in some tissues,
P
lasma renin activity and concentration are ele vated in the early phases of Goldblatt 2-kidney, 1 -clip hypertension whereas they are normal or reduced in Goldblatt 1-clip, 1-kidney hyper tension. It has been suggested, however, that measure m e n t s ^ circulating renin underestimate the role of the renin-angiotensin system in Goldblatt hypertension. Furthermore, it has been postulated that angiotensin II generation as a result of local tissue renin may maintain blood pressure independently of circulating renin. Sev eral possible mechanisms may be involved, eg, a direct action of angiotensin II upon resistance vessel contrac tion and structure, or an indirect action mediated by the sympathetic nervous system. This article reviews stud ies we have carried out on the putative role of vascular renin in Goldblatt hypertension using an interventional approach in which vascular renin and blood pressure are altered experimentally. 1
2
such as the adrenal gland in Goldblatt hyperten sion, and it is possible therefore that extrarenal renin synthesis is important in blood pressure con trol. This has to be distinguished from renin de rived from plasma uptake. Am J Hypertens 1991;4:575S-577S
KEY WORDS: Goldblatt hypertension, renin, plasma renin activity, angiotensin II.
MEASUREMENT OF VASCULAR RENIN IN GOLDBLATT HYPERTENSION Several groups have demonstrated that homogenates of arterial tissue generate angiotensin I when incubated with angiotensinogen. Increased arterial renin-like activity and angiotensin converting enzyme activity has been reported in experimental Goldblatt hyperten sion. Skeggs et al. have suggested that increased up take of renin may maintain blood pressure in rabbits with 1-kidney, 1-clip hypertension. In previously re ported studies we demonstrated uptake of semi-purified renin by aortic tissue in bilaterally nephrectomised rats. Furthermore, the clearance of this activity was much slower than the clearance of plasma renin, providing a means of distinguishing between the physiological ef fects of the two. However, in steady state situations plasma renin concentration and aortic renin concentra tion were closely correlated, indicating that the diver gence between the two observed after renin injection was a temporary phenomenon produced by acute changes in plasma renin. Thus, aortic renin concentra tion was elevated in the early stages of Goldblatt 2-kid ney, 1-clip hypertension, but had fallen in the chronic phase. 3-5
6,7
8
9
10
From the Department of Medicine, University of Leicester, UK. Address correspondence and reprint requests to Department of Medicine, Clinical Sciences Building, Leicester Royal Infirmary, P.O. Box 65, Leicester LE2 7LX, England.
© 1991 by the American Journal of Hypertension Inc.
10
0895-7061/'91/'$3.50
Downloaded from http://ajh.oxfordjournals.org/ at Penn State University (Paterno Lib) on January 24, 2016
J.D. Swales and N.J. Samani
576S
AJH-OCTOBER
SWALES AND SAMANI
BILATERAL NEPHRECTOMY IN GOLDBLATT HYPERTENSION
1991-VOL
4, NO. 10, PART 2
Removal of the renal artery clip from Goldblatt 2-kid ney, 1-clip hypertensive rats normalizes blood pressure through a reduction in peripheral resistance within 24 h. This fall in blood pressure is accompanied by an equally dramatic fall in plasma renin. The pattern of blood pressure fall is nearly identical in Goldblatt 1- and 2-kidney hypertension despite the marked difference in initial renin and despite the opposite changes in sodium balance which occur during reversal of hypertension. It would seem likely, therefore, that the mechanism of blood pressure fall is the same in the two cases. We have accordingly studied the changes in blood pressure and plasma and aortic renin in Goldblatt 2-kidney, 1-clip hypertensive rats for 24 h after removal of the renal artery clip. Blood pressures were measured in conscious rats continuously through an indwelling ca rotid artery cannula. Blood pressure and plasma renin fell after unclipping. On the other hand, aortic renin concentration, which was raised initially, declined slowly and only reached normal levels at 24 h. In these studies the fall in blood pressure could not be correlated either with the change in plasma renin or with the change in aortic renin and it was concluded that other mechanisms were responsible. To confirm this conclu sion further studies were carried out in which hyperten sion was reversed surgically during inhibition of the renin-angiotensin system.
1-kidney, 1-clip hypertension. This saralasin response is attenuated or lost in the chronic phase of Goldblatt 2-kidney, 1-clip hypertension. In this situation there is a close correlation between the depressor response to saralasin and concurrent plasma renin concentrations. However, angiotensin converting enzyme (ACE) inhibi tion lowers blood pressure in both models and the rela tionship between the blood pressure fall and renin con centration is weaker or absent. This may reflect additional actions of ACE inhibitors or inhibition of a renin-angiotensin system that is independent or par tially independent of the circulating system. We have tested this hypothesis by reversing Goldblatt 2-kidney, 1-clip hypertension in the early and chronic phases dur ing continuous inhibition of the renin-angiotensin sys tem. If the ACE inhibitor used ( C a p t o p r i l ) had access to an independent renin angiotensin system and if this system were important in maintaining blood pressure, it was predicted that ACE inhibition would anticipate the fall in blood pressure produced by renal artery unclip ping, which would consequently be diminished. Accord ingly, rats during the early and chronic phases of Goldblatt 2-kidney, 1-clip hypertension were continuously infused with either saralasin, C a p t o p r i l or dextrose. After 15 h the constricting clip was removed from the renal artery and blood pressure followed for a further 24 h. Captopril produced a slightly greater initial blood pressure lowering response in both models, but blood pressure still remained in the hypertensive range and the pattern of blood pressure fall induced by removal of the renal artery clip was unchanged. In both early and chronic hypertension unclipping had restored blood pressure to normal levels within 12 h. It was concluded that the circulating and vascular renin-angiotensin sys tems made a small contribution to maintaining blood pressure in the chronic phase of Goldblatt 2-kidney hy pertension and a rather greater contribution during the early phase, although a distinct non-renin-dependent mechanism mediated the fall in blood pressure pro duced by renal artery unclipping. Further studies indi cated that this system required an intact renal medulla. In summary, the studies we have carried out in Goldblatt hypertension in the rat indicate arterial renin-like activity derived by uptake from plasma. In steady state conditions wç have found no evidence that this mecha nism of uptake is disturbed in Goldblatt hypertension, although elevated circulating renin levels in the early phases of Goldblatt hypertension induce higher steady state arterial levels. The reversal of renovascular hyper tension is largely attributable to non-renin-dependent mechanisms.
INHIBITION OF THE RENIN-ANGIOTENSIN SYSTEM IN GOLDBLATT HYPERTENSION
VASCULAR RENIN SYNTHESIS IN GOLDBLATT HYPERTENSION
The competitive antagonist of angiotensin II, saralasin, lowers blood pressure in the early stages of Goldblatt 2-kidney, 1-clip hypertension, but not in Goldblatt
Biochemical analysis of renin-like activity is compara tively insensitive and the above studies cannot exclude the synthesis of small but physiologically important
14
11
SURGICAL REVERSAL OF GOLDBLATT HYPERTENSION
12
13
12
14
15
16
Downloaded from http://ajh.oxfordjournals.org/ at Penn State University (Paterno Lib) on January 24, 2016
To examine whether the high levels of aortic renin in the early phase of Goldblatt 2-kidney hypertension were attributable wholly to increased circulating levels, we carried out bilateral nephrectomy in a group of Goldblatt 2-kidney, 1-clip hypertensive rats. Aortic renin concentration was measured at baseline, 1, 2, 6, and 24 h afterwards. Initial aortic renin-like activity was elevated. Within 2 h after bilateral nephrectomy, values were still not significantly different from initial values although plasma renin had fallen to low levels. How ever, between 2 and 24 h after nephrectomy, aortic renin concentration fell progressively, and at the end of 24 h did not differ from values observed in bilaterally nephrectomized rats. The decay curve of aortic renin closely resembled that observed in bilaterally nephrec tomized rats after injections of semipurified renin and indicated that the aortic renin-like activity being mea sured was derived from uptake of plasma renin.
AJH-OCTOBER
1991-VOL
4, NO. 10, PART 2
EXTRARENAL RENIN
and sodium balance. Clin Sei Mol Med 1978;55:261270. 5.
Rosenthal JH, Pfeifle B, Michailov ML, et al: Investiga tions of the components of the renin-angiotensin system in rat vascular tissue. Hypertension 1984;6:383-390.
6.
Garst JB, Koletsky S, Wisenbaugh PE, et al: Arterial wall renin and renal venous renin in the hypertensive rat. Clin Sei 1979;56:41-46.
7.
Okamura T, Miyazaki M, Inagami Τ, Toda Ν: Vascular renin-angiotensin system in two kidney 1 clip hyperten sive rats. Hypertension 1986;8:560-565.
8.
Skeggs LT, Dorer FE, Lentz KE, et al: A new mechanism in one kidney one clip hypertension. Hypertension 1985;7:72-80.
9.
Loudon M, Bing RF, Thurston H, Swales JD: Arterial wall uptake of renal renin and blood pressure control. Hyper tension 1983;5:629-634.
10.
Swales JD, Heagerty AM: Vascular renin-angiotensin system: the unanswered questions. J Hypertens 1987;5(suppl 2),S1-S5.
11.
Thurston H, Swales JD, Bing ED, et al: Vascular reninlike activity and blood pressure maintenance in the rat: studies of the effect of changes in sodium bal ance, hypertension and nephrectomy. Hypertension 1979;1:643-649.
12.
Brice JM, Russell Gl, Bing RF, et al: Surgical reversal of renovascular hypertension in rats: changes in blood pressure, plasma and aortic renin. Clin Sei 1983;65: 33-36.
13.
Godfrey N, Kumar A, Bing RF, et al: Reversal of renovas cular hypertension: a comparison of changes in blood pressure, plasma renin and sodium balance in two models in rats. J Lab Clin Med 1985;105:679-685.
14.
Bing RF, Russell GI, Swales JD, Thurston H: Effect of 12 hour infusions of saralasin or Captopril on blood pressure in hypertensive, conscious rats. J Lab Clin Med 1981;98:302-310.
15.
Russell Gl, Bing RF, Thurston H, Swales JD: Surgical reversal of 2 kidney 1 clip hypertension during inhibi tion of the renin-angiotensin system. Hypertension 1982;4:69-76.
16.
Swales JD, Bing RF, Edmunds ME, Russell GI: Renal vasodepressor mechanism: characterisation by chemical medullectomy. Am J Med Sei 1988;295:241-245.
17.
Samani NJ, Brammar WJ, Swales JD: Renal and extra-re nal levels of renin mRNA in experimental hypertension. Clin Sei 1991;80:339-344.
18.
Samani NJ, Swales JD, Brammar WJ: A widespread ab normality of renin gene expression in the spontaneously hypertensive rat: modulation in some tissues with the development of hypertension. Clin Sei 1989,77:629636.
19.
Mullins JJ, Peters J, Ganten D: Fulminant hypertension in transgenic rats harbouring the mouse REN-2 gene. Nature 1990;344:541-544.
2
17,18
18
19
CONCLUSIONS Biochemical measures of arterial renin in Goldblatt hy pertension indicate activity derived from the uptake of renin from plasma and with a slower clearance than plasma renin. We have found no evidence that inappro priately high vascular renin measured in this way main tains blood pressure in Goldblatt hypertension. It is pos sible that extrarenal synthesis of renin in quantities too small to be detected by classical biochemical analysis of tissue may be important in the pathogenesis of hyper tension. Whereas molecular biological techniques indi cate that extrarenal renin gene expression does take place in arterial and other tissues, the physiological sig nificance of these observations is unknown. REFERENCES 1. Swales JD: Renin-angiotensin system in hypertension. Pharmacol Ther 1979;7:173-201. 2. Dzau V: Significance of the vascular renin-angiotensin pathway. Hypertension 1986;8:553-559. 3.
Gould AB, Skeggs LT, Khan JR: Presence of renin-activity in blood vessel walls. J Exp Med 1964;119:389-399.
4. Barrett JD, Eggena P, Sambhi MP: Partial characterisa tion of aortic renin in the spontaneously hypertensive rat: its relationship with plasma renin, blood pressure
Downloaded from http://ajh.oxfordjournals.org/ at Penn State University (Paterno Lib) on January 24, 2016
amounts of renin by arterial tissue. The capacity of vas cular tissue to release angiotensin II into synthetic media and to synthesise renin in tissue culture has been re ported, although the physiological role of this material is uncertain. Few studies have been carried out in Goldblatt hypertension. However, recently we have exam ined the capacity of renal and extrarenal tissues to ex press the renin gene by measuring renin messenger RNA using an RNase protection technique. These studies have demonstrated increased renin messenger RNA in several extrarenal tissues in spontaneously hy pertensive rats, although not in the aorta. Our studies so far have demonstrated no change in renin gene ex pression in the liver, heart or brain, in animals with either early or chronic Goldblatt 2-kidney, 1-clip hyper tension. So far, aortic tissue has not been examined. However, there was marked elevation in renin messen ger RNA in adrenal gland tissue of animals with chronic Goldblatt 2-kidney hypertension. The role of the pro tein product of this RNA is unknown, but it is interesting that a strain of rats transgenic for the ren-2 mouse gene also showed increased expression of the gene in the adrenal gland with high tissue renin content despite low circulating renin and severe hypertension.
577S
1991;
4:575S-577S
The Role of Extrarenal Renin in Goldblatt Hypertension
Renin-like activity can be demonstrated in arterial extracts from normal rats and from rats with Goldblatt hypertension. We have found no evidence, however, for elevated arterial renin levels in rela tion to plasma renin activity. Studies of the rever sal of renovascular hypertension indicate that the fall in blood pressure produced by renal artery deconstriction is not renin-dependent. However, mo lecular biological techniques indicate that extrare nal renin gene expression is altered in some tissues,
P
lasma renin activity and concentration are ele vated in the early phases of Goldblatt 2-kidney, 1 -clip hypertension whereas they are normal or reduced in Goldblatt 1-clip, 1-kidney hyper tension. It has been suggested, however, that measure m e n t s ^ circulating renin underestimate the role of the renin-angiotensin system in Goldblatt hypertension. Furthermore, it has been postulated that angiotensin II generation as a result of local tissue renin may maintain blood pressure independently of circulating renin. Sev eral possible mechanisms may be involved, eg, a direct action of angiotensin II upon resistance vessel contrac tion and structure, or an indirect action mediated by the sympathetic nervous system. This article reviews stud ies we have carried out on the putative role of vascular renin in Goldblatt hypertension using an interventional approach in which vascular renin and blood pressure are altered experimentally. 1
2
such as the adrenal gland in Goldblatt hyperten sion, and it is possible therefore that extrarenal renin synthesis is important in blood pressure con trol. This has to be distinguished from renin de rived from plasma uptake. Am J Hypertens 1991;4:575S-577S
KEY WORDS: Goldblatt hypertension, renin, plasma renin activity, angiotensin II.
MEASUREMENT OF VASCULAR RENIN IN GOLDBLATT HYPERTENSION Several groups have demonstrated that homogenates of arterial tissue generate angiotensin I when incubated with angiotensinogen. Increased arterial renin-like activity and angiotensin converting enzyme activity has been reported in experimental Goldblatt hyperten sion. Skeggs et al. have suggested that increased up take of renin may maintain blood pressure in rabbits with 1-kidney, 1-clip hypertension. In previously re ported studies we demonstrated uptake of semi-purified renin by aortic tissue in bilaterally nephrectomised rats. Furthermore, the clearance of this activity was much slower than the clearance of plasma renin, providing a means of distinguishing between the physiological ef fects of the two. However, in steady state situations plasma renin concentration and aortic renin concentra tion were closely correlated, indicating that the diver gence between the two observed after renin injection was a temporary phenomenon produced by acute changes in plasma renin. Thus, aortic renin concentra tion was elevated in the early stages of Goldblatt 2-kid ney, 1-clip hypertension, but had fallen in the chronic phase. 3-5
6,7
8
9
10
From the Department of Medicine, University of Leicester, UK. Address correspondence and reprint requests to Department of Medicine, Clinical Sciences Building, Leicester Royal Infirmary, P.O. Box 65, Leicester LE2 7LX, England.
© 1991 by the American Journal of Hypertension Inc.
10
0895-7061/'91/'$3.50
Downloaded from http://ajh.oxfordjournals.org/ at Penn State University (Paterno Lib) on January 24, 2016
J.D. Swales and N.J. Samani
576S
AJH-OCTOBER
SWALES AND SAMANI
BILATERAL NEPHRECTOMY IN GOLDBLATT HYPERTENSION
1991-VOL
4, NO. 10, PART 2
Removal of the renal artery clip from Goldblatt 2-kid ney, 1-clip hypertensive rats normalizes blood pressure through a reduction in peripheral resistance within 24 h. This fall in blood pressure is accompanied by an equally dramatic fall in plasma renin. The pattern of blood pressure fall is nearly identical in Goldblatt 1- and 2-kidney hypertension despite the marked difference in initial renin and despite the opposite changes in sodium balance which occur during reversal of hypertension. It would seem likely, therefore, that the mechanism of blood pressure fall is the same in the two cases. We have accordingly studied the changes in blood pressure and plasma and aortic renin in Goldblatt 2-kidney, 1-clip hypertensive rats for 24 h after removal of the renal artery clip. Blood pressures were measured in conscious rats continuously through an indwelling ca rotid artery cannula. Blood pressure and plasma renin fell after unclipping. On the other hand, aortic renin concentration, which was raised initially, declined slowly and only reached normal levels at 24 h. In these studies the fall in blood pressure could not be correlated either with the change in plasma renin or with the change in aortic renin and it was concluded that other mechanisms were responsible. To confirm this conclu sion further studies were carried out in which hyperten sion was reversed surgically during inhibition of the renin-angiotensin system.
1-kidney, 1-clip hypertension. This saralasin response is attenuated or lost in the chronic phase of Goldblatt 2-kidney, 1-clip hypertension. In this situation there is a close correlation between the depressor response to saralasin and concurrent plasma renin concentrations. However, angiotensin converting enzyme (ACE) inhibi tion lowers blood pressure in both models and the rela tionship between the blood pressure fall and renin con centration is weaker or absent. This may reflect additional actions of ACE inhibitors or inhibition of a renin-angiotensin system that is independent or par tially independent of the circulating system. We have tested this hypothesis by reversing Goldblatt 2-kidney, 1-clip hypertension in the early and chronic phases dur ing continuous inhibition of the renin-angiotensin sys tem. If the ACE inhibitor used ( C a p t o p r i l ) had access to an independent renin angiotensin system and if this system were important in maintaining blood pressure, it was predicted that ACE inhibition would anticipate the fall in blood pressure produced by renal artery unclip ping, which would consequently be diminished. Accord ingly, rats during the early and chronic phases of Goldblatt 2-kidney, 1-clip hypertension were continuously infused with either saralasin, C a p t o p r i l or dextrose. After 15 h the constricting clip was removed from the renal artery and blood pressure followed for a further 24 h. Captopril produced a slightly greater initial blood pressure lowering response in both models, but blood pressure still remained in the hypertensive range and the pattern of blood pressure fall induced by removal of the renal artery clip was unchanged. In both early and chronic hypertension unclipping had restored blood pressure to normal levels within 12 h. It was concluded that the circulating and vascular renin-angiotensin sys tems made a small contribution to maintaining blood pressure in the chronic phase of Goldblatt 2-kidney hy pertension and a rather greater contribution during the early phase, although a distinct non-renin-dependent mechanism mediated the fall in blood pressure pro duced by renal artery unclipping. Further studies indi cated that this system required an intact renal medulla. In summary, the studies we have carried out in Goldblatt hypertension in the rat indicate arterial renin-like activity derived by uptake from plasma. In steady state conditions wç have found no evidence that this mecha nism of uptake is disturbed in Goldblatt hypertension, although elevated circulating renin levels in the early phases of Goldblatt hypertension induce higher steady state arterial levels. The reversal of renovascular hyper tension is largely attributable to non-renin-dependent mechanisms.
INHIBITION OF THE RENIN-ANGIOTENSIN SYSTEM IN GOLDBLATT HYPERTENSION
VASCULAR RENIN SYNTHESIS IN GOLDBLATT HYPERTENSION
The competitive antagonist of angiotensin II, saralasin, lowers blood pressure in the early stages of Goldblatt 2-kidney, 1-clip hypertension, but not in Goldblatt
Biochemical analysis of renin-like activity is compara tively insensitive and the above studies cannot exclude the synthesis of small but physiologically important
14
11
SURGICAL REVERSAL OF GOLDBLATT HYPERTENSION
12
13
12
14
15
16
Downloaded from http://ajh.oxfordjournals.org/ at Penn State University (Paterno Lib) on January 24, 2016
To examine whether the high levels of aortic renin in the early phase of Goldblatt 2-kidney hypertension were attributable wholly to increased circulating levels, we carried out bilateral nephrectomy in a group of Goldblatt 2-kidney, 1-clip hypertensive rats. Aortic renin concentration was measured at baseline, 1, 2, 6, and 24 h afterwards. Initial aortic renin-like activity was elevated. Within 2 h after bilateral nephrectomy, values were still not significantly different from initial values although plasma renin had fallen to low levels. How ever, between 2 and 24 h after nephrectomy, aortic renin concentration fell progressively, and at the end of 24 h did not differ from values observed in bilaterally nephrectomized rats. The decay curve of aortic renin closely resembled that observed in bilaterally nephrec tomized rats after injections of semipurified renin and indicated that the aortic renin-like activity being mea sured was derived from uptake of plasma renin.
AJH-OCTOBER
1991-VOL
4, NO. 10, PART 2
EXTRARENAL RENIN
and sodium balance. Clin Sei Mol Med 1978;55:261270. 5.
Rosenthal JH, Pfeifle B, Michailov ML, et al: Investiga tions of the components of the renin-angiotensin system in rat vascular tissue. Hypertension 1984;6:383-390.
6.
Garst JB, Koletsky S, Wisenbaugh PE, et al: Arterial wall renin and renal venous renin in the hypertensive rat. Clin Sei 1979;56:41-46.
7.
Okamura T, Miyazaki M, Inagami Τ, Toda Ν: Vascular renin-angiotensin system in two kidney 1 clip hyperten sive rats. Hypertension 1986;8:560-565.
8.
Skeggs LT, Dorer FE, Lentz KE, et al: A new mechanism in one kidney one clip hypertension. Hypertension 1985;7:72-80.
9.
Loudon M, Bing RF, Thurston H, Swales JD: Arterial wall uptake of renal renin and blood pressure control. Hyper tension 1983;5:629-634.
10.
Swales JD, Heagerty AM: Vascular renin-angiotensin system: the unanswered questions. J Hypertens 1987;5(suppl 2),S1-S5.
11.
Thurston H, Swales JD, Bing ED, et al: Vascular reninlike activity and blood pressure maintenance in the rat: studies of the effect of changes in sodium bal ance, hypertension and nephrectomy. Hypertension 1979;1:643-649.
12.
Brice JM, Russell Gl, Bing RF, et al: Surgical reversal of renovascular hypertension in rats: changes in blood pressure, plasma and aortic renin. Clin Sei 1983;65: 33-36.
13.
Godfrey N, Kumar A, Bing RF, et al: Reversal of renovas cular hypertension: a comparison of changes in blood pressure, plasma renin and sodium balance in two models in rats. J Lab Clin Med 1985;105:679-685.
14.
Bing RF, Russell GI, Swales JD, Thurston H: Effect of 12 hour infusions of saralasin or Captopril on blood pressure in hypertensive, conscious rats. J Lab Clin Med 1981;98:302-310.
15.
Russell Gl, Bing RF, Thurston H, Swales JD: Surgical reversal of 2 kidney 1 clip hypertension during inhibi tion of the renin-angiotensin system. Hypertension 1982;4:69-76.
16.
Swales JD, Bing RF, Edmunds ME, Russell GI: Renal vasodepressor mechanism: characterisation by chemical medullectomy. Am J Med Sei 1988;295:241-245.
17.
Samani NJ, Brammar WJ, Swales JD: Renal and extra-re nal levels of renin mRNA in experimental hypertension. Clin Sei 1991;80:339-344.
18.
Samani NJ, Swales JD, Brammar WJ: A widespread ab normality of renin gene expression in the spontaneously hypertensive rat: modulation in some tissues with the development of hypertension. Clin Sei 1989,77:629636.
19.
Mullins JJ, Peters J, Ganten D: Fulminant hypertension in transgenic rats harbouring the mouse REN-2 gene. Nature 1990;344:541-544.
2
17,18
18
19
CONCLUSIONS Biochemical measures of arterial renin in Goldblatt hy pertension indicate activity derived from the uptake of renin from plasma and with a slower clearance than plasma renin. We have found no evidence that inappro priately high vascular renin measured in this way main tains blood pressure in Goldblatt hypertension. It is pos sible that extrarenal synthesis of renin in quantities too small to be detected by classical biochemical analysis of tissue may be important in the pathogenesis of hyper tension. Whereas molecular biological techniques indi cate that extrarenal renin gene expression does take place in arterial and other tissues, the physiological sig nificance of these observations is unknown. REFERENCES 1. Swales JD: Renin-angiotensin system in hypertension. Pharmacol Ther 1979;7:173-201. 2. Dzau V: Significance of the vascular renin-angiotensin pathway. Hypertension 1986;8:553-559. 3.
Gould AB, Skeggs LT, Khan JR: Presence of renin-activity in blood vessel walls. J Exp Med 1964;119:389-399.
4. Barrett JD, Eggena P, Sambhi MP: Partial characterisa tion of aortic renin in the spontaneously hypertensive rat: its relationship with plasma renin, blood pressure
Downloaded from http://ajh.oxfordjournals.org/ at Penn State University (Paterno Lib) on January 24, 2016
amounts of renin by arterial tissue. The capacity of vas cular tissue to release angiotensin II into synthetic media and to synthesise renin in tissue culture has been re ported, although the physiological role of this material is uncertain. Few studies have been carried out in Goldblatt hypertension. However, recently we have exam ined the capacity of renal and extrarenal tissues to ex press the renin gene by measuring renin messenger RNA using an RNase protection technique. These studies have demonstrated increased renin messenger RNA in several extrarenal tissues in spontaneously hy pertensive rats, although not in the aorta. Our studies so far have demonstrated no change in renin gene ex pression in the liver, heart or brain, in animals with either early or chronic Goldblatt 2-kidney, 1-clip hyper tension. So far, aortic tissue has not been examined. However, there was marked elevation in renin messen ger RNA in adrenal gland tissue of animals with chronic Goldblatt 2-kidney hypertension. The role of the pro tein product of this RNA is unknown, but it is interesting that a strain of rats transgenic for the ren-2 mouse gene also showed increased expression of the gene in the adrenal gland with high tissue renin content despite low circulating renin and severe hypertension.
577S
