Fenofibrate Attenuates Malignant Hypertension by Suppression of the Renin-angiotensin System: A Study in Cyp1a1-Ren-2 Transgenic Rats

被引：19

作者：

Jichova, Sarka ^{[1
,2
]}

Dolezelova, Sarka ^{[1
]}

Kopkan, Libor ^{[1
]}

Kompanowska-Jezierska, Elzbieta ^{[3
]}

Sadowski, Janusz ^{[3
]}

Cervenka, Ludek ^{[1
,2
]}

机构：

[1] Inst Clin & Expt Med, Ctr Expt Med, 1958-9 Videnska, CZ-14000 Prague 4, Czech Republic

[2] Charles Univ Prague, Dept Pathophysiol, Fac Med 2, Prague, Czech Republic

[3] Polish Acad Sci, Dept Renal & Body Fluid Physiol, Mossakowski Med Res Ctr, Warsaw, Poland

来源：

AMERICAN JOURNAL OF THE MEDICAL SCIENCES | 2016年 / 352卷 / 06期

关键词：

Malignant hypertension; Renin-angiotensin system; Cytochrome P450 metabolites; 20-hydroxyeicosatetraenoic acid; EPOXIDE HYDROLASE INHIBITION; END-ORGAN DAMAGE; EPOXYEICOSATRIENOIC ACID ANALOG; LOWERS BLOOD-PRESSURE; ANG-II; 20-HYDROXYEICOSATETRAENOIC ACID; NITRIC-OXIDE; CARDIOVASCULAR-DISEASE; VASCULAR REACTIVITY; RENAL HEMODYNAMICS;

D O I：

10.1016/j.amjms.2016.09.008

中图分类号：

R5 [内科学];

学科分类号：

1002 ; 100201 ;

摘要：

Background: Malignant hypertension is a life-threatening condition, and its pathophysiology is still poorly understood. The present study was designed to evaluate the role of interaction of the renin-angiotensin system with 20-hydroxyeicosatetraenoic acid (20-HETE), a product of cytochrome P450 (CYP) dependent omega-hydroxylase pathway, in the pathophysiology of angiotensin II (ANG II) dependent malignant hypertension in Cyp1a1-Ren-2 transgenic rats. Methods: Malignant hypertension was induced by 12 days' dietary administration of 0.3 % indole-3-carbinol (I3C), a natural xenobiotic that activates a mouse renin gene. We hypothesized that chronic administration of fenofibrate, 190 mg/kg body weight, a lipid-lowering drug, should increase renal production of 20-HETE, a tubular transport inhibitor; an expected increase in sodium excretion would oppose the development of ANG II dependent malignant hypertension. Blood pressure was monitored by radiotelemetry, and at the end of the experiment rats were prepared for renal functional studies to evaluate in vivo the pressure-natriuresis relationship in response to stepwise reductions in renal arterial pressure (RAP). Results: In I3C-induced rats, the treatment with fenofibrate significantly attenuated hypertension and improved the slope of the pressure-natriuresis relationship. Although fenofibrate treatment increased kidney gene and protein expression of CYP4A1, a major isoform responsible for 20-HETE formation, it did not increase renal 20-HETE concentration. On the contrary, fenofibrate treatment significantly suppressed renin gene expression, plasma renin activity and plasma and kidney ANG II levels. Conclusions: Fenofibrate treatment significantly attenuated the course of malignant hypertension in I3C-induced CYP1a1Ren-2 transgenic rats, and the mechanism responsible for antihypertensive action was fenofibrate-induced suppression of renin-angiotensin system activity.

引用

页码：618 / 630

页数：13

共 67 条

[1] Orally active epoxyeicosatrienoic acid analog does not exhibit antihypertensive and reno- or cardioprotective actions in two-kidney, one-clip Goldblatt hypertensive rats [J].

Alanova, Petra ;

Huskova, Zuzana ;

Kopkan, Libor ;

Sporkova, Alexandra ;

Jichova, Sarka ;

Neckar, Jan ;

Imig, John D. ;

Klevstig, Martina ;

Kolar, Frantisek ;

Reddy, N. Rami ;

Falck, John R. ;

Sadowski, Janusz ;

Nishiyama, Akira ;

Kramer, Herbert J. ;

Melenovsy, Vojtech ;

Cervenkova, Lenka ;

Kujal, Petr ;

Vernerova, Zdenka ;

Cervenka, Ludek .

VASCULAR PHARMACOLOGY, 2015, 73 :45-56

[2] Role of 20-hydroxyeicosatetraenoic acid in the renal and vasoconstrictor actions of angiotensin II [J].

Alonso-Galicia, M ;

Maier, KG ;

Greene, AS ;

Cowley, AW ;

Roman, RJ .

AMERICAN JOURNAL OF PHYSIOLOGY-REGULATORY INTEGRATIVE AND COMPARATIVE PHYSIOLOGY, 2002, 283 (01) :R60-R68

[3] Arachidonic acid monooxygenase: Genetic and biochemical approaches to physiological/pathophysiological relevance [J].

Capdevila, Jorge H. ;

Wang, Wenhui ;

Falck, John R. .

PROSTAGLANDINS & OTHER LIPID MEDIATORS, 2015, 120 :40-49

[4]

Carroll M A, 2001, Med Sci Monit, V7, P567

[5] The roles of intrarenal 20-hydroxyeicosatetraenoic and epoxyeicosatrienoic acids in the regulation of renal function in hypertensive Ren-2 transgenic rats [J].

Certikova Chabova, Vera ;

Kramer, Herbert J. ;

Vaneckova, Ivana ;

Thumova, Monika ;

Skaroupkova, Petra ;

Tesar, Vladimir ;

Falck, John R. ;

Imig, John D. ;

Cervenka, Ludek .

KIDNEY & BLOOD PRESSURE RESEARCH, 2007, 30 (05) :335-346

[6] Combined Suppression of the Intrarenal and Circulating Vasoconstrictor Renin-ACE-ANG II Axis and Augmentation of the Vasodilator ACE2-ANG 1-7-Mas Axis Attenuates the Systemic Hypertension in Ren-2 Transgenic Rats Exposed to Chronic Hypoxia [J].

Cervenka, L. ;

Bibova, J. ;

Huskova, Z. ;

Vanourkova, Z. ;

Kramer, H. J. ;

Herget, J. ;

Jichova, S. ;

Sadowski, J. ;

Hampl, V. .

PHYSIOLOGICAL RESEARCH, 2015, 64 (01) :11-24

[7] Inhibition of soluble epoxide hydrolase counteracts the development of renal dysfunction and progression of congestive heart failure in Ren-2 transgenic hypertensive rats with aorto-caval fistula [J].

Cervenka, Ludek ;

Melenovsky, Vojtech ;

Huskova, Zuzana ;

Skaroupkova, Petra ;

Nishiyama, Akira ;

Sadowski, Janusz .

CLINICAL AND EXPERIMENTAL PHARMACOLOGY AND PHYSIOLOGY, 2015, 42 (07) :795-807

[8] Combined inhibition of 20-hydroxyeicosatetraenoic acid formation and of epoxyeicosatrienoic acids degradation attenuates hypertension and hypertension-induced end-organ damage in Ren-2 transgenic rats [J].

Chabova, Vera Certikova ;

Walkowska, Agnieszka ;

Kompanowska-Jezierska, Elzbieta ;

Sadowski, Janusz ;

Kujal, Petr ;

Vernerova, Zdenka ;

Vanourkova, Zdena ;

Kopkan, Libor ;

Kramer, Herbert J. ;

Falck, John R. ;

Imig, John D. ;

Hammock, Bruce D. ;

Vaneckova, Ivana ;

Cervenka, Ludek .

CLINICAL SCIENCE, 2010, 118 (9-10) :617-632

[9] The role of the renin-angiotensin system in malignant vascular injury affecting the systemic and cerebral circulations [J].

Collidge, TA ;

Lammie, GA ;

Fleming, S ;

Mullins, JJ .

PROGRESS IN BIOPHYSICS & MOLECULAR BIOLOGY, 2004, 84 (2-3) :301-319

[10] The role of the kidney in hypertension [J].

Cowley, AW ;

Roman, RJ .

JAMA-JOURNAL OF THE AMERICAN MEDICAL ASSOCIATION, 1996, 275 (20) :1581-1589

← 1 2 3 4 5 6 7 →