Selective inhibition of the renal angiotensin type 2 receptor increases blood pressure in conscious rats

被引:35
作者
Moore, AF [1 ]
Heiderstadt, NT [1 ]
Huang, E [1 ]
Howell, NL [1 ]
Wang, ZQ [1 ]
Siragy, HM [1 ]
Carey, RM [1 ]
机构
[1] Univ Virginia Hlth Syst, Dept Med, Div Endocrinol & Metab, Charlottesville, VA 22908 USA
关键词
blood pressure; receptors; angiotensin II; hypertension; experimental; kidney; rats;
D O I
10.1161/01.HYP.37.5.1285
中图分类号
R6 [外科学];
学科分类号
1002 ; 100210 ;
摘要
The angiotensin II type 2 (AT(2)) receptor is present in rat kidney; however, its function is Dot well understood. The purpose of this study was to evaluate the role of the AT(2) receptor In blood pressure (BP) regulation. The effects of selective inhibition of the renal AT(2) receptor with phosphorothioated antisense oligodeoxynucleotide (AS-ODN) were examined in conscious uninephrectomized rats. Oligodeoxynucleotides (AS-ODN or scrambled [S-ODN]) were infused directly into the renal interstitial space by using an osmotic pump at 1 muL/h for 7 days. Texas red-labeled AS-ODN was distributed in renal tubules in the infused but not the contralateral, kidney of normal rats. Continuous renal interstitial infusion of the AS-ODN, but not S-ODN, caused a significant (P<0.01) increase in BP 1 to 5 days after the initiation of the infusion. AS-ODN-treated rats experienced an increase in systolic BP from 109<plus/minus>4 to 130 +/-4 mm Hg (n=8, P<0.01), whereas S-ODN-treated (n=8) and vehicle-treated (n=8) rats did not show any significant change in BP. On day 5 of the oligodeoxynucleotide infusion, AS-ODN-treated rats exhibited a greater presser response to systemic angiotensin II infusion (30 ng/kg per hour) than did S-ODN-treated rats (P<0.01). Renal interstitial fluid cGMP decreased from 11.9 +/-0.8 to 3.6 +/-0.5 pmol/mL (P<0.001), and bradykinin decreased from 0.05<plus/minus>0.05 to 0.18 +/-0.03 ng/mL (P<0.001) in response to AS-ODN, but they were not significantly changed in response to S-ODN. To evaluate the effects of AS-ODN and S-ODN on AT(2) receptor expression, Western Blot analysis was performed on treated kidneys. Kidneys treated with AS-ODN had <approximate to>40% less expression of AT(2) receptor than did kidneys treated with S-ODN or vehicle (P<0.05). These results suggest that AS-ODN directed selectively against the renal AT(2) receptor decreased receptor expression and caused an increase in BP. We conclude that the renal AT(2) receptor plays an important role in the regulation of BP via a bradykinin/cGMP vasodilator signaling cascade.
引用
收藏
页码:1285 / 1291
页数:7
相关论文
共 50 条
[1]   Inhibition of TGF-beta 1 expression by antisense oligonucleotides suppressed extracellular matrix accumulation in experimental glomerulonephritis [J].
Akagi, Y ;
Isaka, Y ;
Arai, M ;
Kaneko, T ;
Takenaka, M ;
Moriyama, T ;
Kaneda, Y ;
Ando, A ;
Orita, Y ;
Kamada, T ;
Ueda, N ;
Imai, E .
KIDNEY INTERNATIONAL, 1996, 50 (01) :148-155
[2]   Increased vasoconstrictor response of the mouse lacking angiotensin II type 2 receptor [J].
Akishita, M ;
Yamada, H ;
Dzau, VJ ;
Horiuchi, M .
BIOCHEMICAL AND BIOPHYSICAL RESEARCH COMMUNICATIONS, 1999, 261 (02) :345-349
[3]   Possible role of P-450 metabolite of arachidonic acid in vasodilator mechanism of angiotensin II type 2 receptor in the isolated microperfused rabbit afferent arteriole [J].
Arima, S ;
Endo, Y ;
Yaoita, H ;
Omata, K ;
Ogawa, S ;
Tsunoda, K ;
Abe, M ;
Takeuchi, K ;
Abe, K ;
Ito, S .
JOURNAL OF CLINICAL INVESTIGATION, 1997, 100 (11) :2816-2823
[4]   AT2 receptor stimulation enhances antihypertensive effect of AT1 receptor antagonist in hypertensive rats [J].
Barber, MN ;
Sampey, DB ;
Widdop, RE .
HYPERTENSION, 1999, 34 (05) :1112-1116
[5]   Novel mechanism of hypertension revealed by cell-specific targeting of human angiotensinogen in transgenic mice [J].
Davisson, RL ;
Ding, YM ;
Stec, DE ;
Catterall, JF ;
Sigmund, CD .
PHYSIOLOGICAL GENOMICS, 1999, 1 (01) :3-9
[7]   ICAM-1 antisense oligodesoxynucleotides prevent reperfusion injury and enhance immediate graft function in renal transplantation [J].
Dragun, D ;
Tullius, SG ;
Park, JK ;
Maasch, C ;
Lukitsch, I ;
Lippoldt, A ;
Gross, V ;
Luft, FC ;
Haller, H .
KIDNEY INTERNATIONAL, 1998, 54 (02) :590-602
[8]   NONPEPTIDE ANGIOTENSIN-II RECEPTOR ANTAGONISTS DISCRIMINATE SUBTYPES OF I-125 ANGIOTENSIN-II BINDING-SITES IN THE RAT-BRAIN [J].
GEHLERT, DR ;
GACKENHEIMER, SL ;
REEL, JK ;
LIN, HS ;
STEINBERG, MI .
EUROPEAN JOURNAL OF PHARMACOLOGY, 1990, 187 (01) :123-126
[9]   Drug therapy - Angiotensin receptors and their antagonists [J].
Goodfriend, TL ;
Elliott, ME ;
Catt, KJ .
NEW ENGLAND JOURNAL OF MEDICINE, 1996, 334 (25) :1649-1654
[10]   Growth-dependent induction of angiotensin II type 2 receptor in rat mesangial cells [J].
Goto, M ;
Mukoyama, M ;
Suga, S ;
Matsumoto, T ;
Nakagawa, M ;
Ishibashi, R ;
Kasahara, M ;
Sugawara, A ;
Tanaka, I ;
Nakao, K .
HYPERTENSION, 1997, 30 (03) :358-362