VASCULAR MECHANISMS OF CYCLOSPORINE-INDUCED HYPERTENSION IN THE RAT

被引:106
作者
ROULLET, JB [1 ]
XUE, H [1 ]
MCCARRON, DA [1 ]
HOLCOMB, S [1 ]
BENNETT, WM [1 ]
机构
[1] OREGON HLTH SCI UNIV,DIV NEPHROL HYPERTENS & CLIN PHARMACOL,PORTLAND,OR 97201
关键词
CYCLOSPORINE A; RESISTANCE VESSELS; EX VIVO; BLOOD PRESSURE; IN VIVO;
D O I
10.1172/JCI117222
中图分类号
R-3 [医学研究方法]; R3 [基础医学];
学科分类号
1001 ;
摘要
Numerous studies have explored the pathogenesis of cyclosporin A (CysA)-induced hypertension; however, none has assessed the impact of CysA treatment on resistance arteries in the setting of elevated blood pressure. Therefore, we studied the chronic effect of CysA on rat mesenteric artery resistance vessels (ex vivo). CysA (25 mg/kg per d for 7 d), but not vehicle, significantly raised systolic blood pressure (13.4 +/- 2.2 mmHg, P < 0.003, n = 9 per group). The resistance vessels from CysA-treated rats showed a small but significant decrease in norepinephrine sensitivity (P < 0.03) and a pronounced decrease in endothelium-dependent and -independent relaxation (P < 0.001) compared to controls. Endothelin-1 sensitivity tended to be diminished (P = 0.07). The direct (in vitro) effect of CysA was subsequently evaluated in resistance vessels from nontreated animals (n = 8) and exposed to CysA(2 mu g/ml) for 24 h. As observed in vivo, CysA significantly decreased endothelium-dependent and -independent relaxations (P < 0.05) and attenuated norepinephrine sensitivity (P = 0.06). Methylene blue, a nitric oxide quencher, significantly inhibited the acetylcholine-induced relaxation in control, but not in CysA vessels, suggesting a selective action of CysA on the nitric oxide pathway. We conclude that CysA-induced hypertension is the consequence of a primary effect on resistance vessel relaxation, not increased vasoconstriction, as previously suggested.
引用
收藏
页码:2244 / 2250
页数:7
相关论文
共 43 条
[1]   SYSTEMIC HYPERTENSION AFTER CARDIAC TRANSPLANTATION - EFFECT OF CYCLOSPORINE ON THE RENIN-ANGIOTENSIN-ALDOSTERONE SYSTEM [J].
BELLET, M ;
CABROL, C ;
SASSANO, P ;
LEGER, P ;
CORVOL, P ;
MENARD, J .
AMERICAN JOURNAL OF CARDIOLOGY, 1985, 56 (15) :927-931
[2]  
BOUDIER HAJS, 1992, J HYPERTENS, V10, pS147
[3]   ON THE VASCULAR INOTROPIC ACTION OF 1,25-(OH)2 VITAMIN-D3 [J].
BUKOSKI, RD ;
XUE, H .
AMERICAN JOURNAL OF HYPERTENSION, 1993, 6 (05) :388-396
[4]  
CHAN BBK, 1992, CIRCULATION, V86, pS295
[5]   HYPERTENSION AFTER RENAL-TRANSPLANTATION - A COMPARISON OF CYCLOSPORINE AND CONVENTIONAL IMMUNOSUPPRESSION [J].
CHAPMAN, JR ;
MARCEN, R ;
ARIAS, M ;
RAINE, AEG ;
DUNNILL, MS ;
MORRIS, PJ .
TRANSPLANTATION, 1987, 43 (06) :860-864
[6]  
DELIMA JJG, 1908, J CARDIOVASC PHARM, V11, P676
[7]   THE OBLIGATORY ROLE OF ENDOTHELIAL-CELLS IN THE RELAXATION OF ARTERIAL SMOOTH-MUSCLE BY ACETYLCHOLINE [J].
FURCHGOTT, RF ;
ZAWADZKI, JV .
NATURE, 1980, 288 (5789) :373-376
[8]   BLOCKADE OF ENDOTHELIUM-DEPENDENT RESPONSES IN CONSCIOUS RATS BY CYCLOSPORINE-A - EFFECT OF L-ARGININE [J].
GALLEGO, MJ ;
FARRE, AL ;
RIESCO, A ;
MONTON, M ;
GRANDES, SM ;
BARAT, A ;
HERNANDO, L ;
CASADO, S ;
CARAMELO, CA .
AMERICAN JOURNAL OF PHYSIOLOGY, 1993, 264 (03) :H708-H714
[9]   CYCLOSPORINE AUGMENTS RENAL BUT NOT SYSTEMIC VASCULAR REACTIVITY [J].
GARR, MD ;
PALLER, MS .
AMERICAN JOURNAL OF PHYSIOLOGY, 1990, 258 (01) :F211-F217
[10]   THE EFFECT OF SALT INTAKE ON CYCLOSPORINE-INDUCED IMPAIRMENT OF RENAL-FUNCTION IN RATS [J].
GERKENS, JF ;
BHAGWANDEEN, SB ;
DOSEN, PJ ;
SMITH, AJ .
TRANSPLANTATION, 1984, 38 (04) :412-417