Renal mechanisms contributing to the antihypertensive action of soluble epoxide hydrolase inhibition in Ren-2 transgenic rats with inducible hypertension

Zuzana Honetschlägerová, Zuzana Husková, Zdeňka Vaňourková, Alexandra Sporková, Herbert J. Kramer, Sung Hee Hwang, Hsing Ju Tsai, Bruce D. Hammock, John D. Imig, Luděk Červenka, Libor Kopkan

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Abstract

Non-technical summary: Arachidonic acid metabolites called epoxyeicosatrienoic acids (EETs) influence vascular tone and renal tubular sodium and water transport and thus have been implicated in the control of blood pressure. Inhibition of the enzyme soluble epoxide hydrolase (sEH), which reduces EET degradation to the corresponding diols, leads to substantial attenuation of malignant hypertension in a transgenic rat strain harbouring the mouse renin gene particularly via an improvement of renal function. The observed antihypertensive and renoprotective effects of this novel pharmacological approach provide a potentially new direction in antihypertensive therapy.In the present study, we examined the effects of soluble epoxide hydrolase (sEH) inhibition on the development of angiotensin II-dependent hypertension and on renal function in transgenic rats with inducible expression of the mouse renin gene (strain name Cyp1a1-Ren-2). Hypertension was induced in these rats by indole-3-carbinol (I3C; 0.3% in the diet) for 12 days. The sEH inhibitor cis-4-[4-(3-adamantan-1-yl-ureido)-cyclohexyloxy]-benzoic acid (c-AUCB) was given in two doses (13 or 26 mg l-1) in drinking water. Blood pressure (BP), body weight (BW) and renal excretory parameters were monitored in conscious animals during the experiment. Renal haemodynamics was assessed at the end of treatment in anaesthetized rats. I3C administration resulted in severe hypertension with a rise in systolic BP from 118 ± 2 to 202 ± 3 mmHg, a loss of BW from 266 ± 5 to 228 ± 4 g and a rise in proteinuria from 14 ± 2 to 34 ± 3 mg day-1. Both doses of c-AUCB significantly attenuated the development of hypertension (systolic BP of 181 ± 4 and 176 ± 4 mmHg, respectively), the loss in BW (256 ± 4 and 259 ± 3 g, respectively) and the degree of proteinuria (27 ± 2 and 25 ± 3 mg day-1, respectively) to a similar extent. Moreover, c-AUCB prevented the reduction in renal plasma flow (5.4 ± 0.4 vs. 4.6 ± 0.3 ml min-1 g-1) and significantly increased sodium excretion (0.84 ± 0.16 vs. 0.38 ± 0.08 μmol min-1 g-1) during I3C administration. These data suggest that the oral administration of c-AUCB displays antihypertensive effects in Ren-2 transgenic rats with inducible malignant hypertension via an improvement of renal function.

Original languageEnglish (US)
Pages (from-to)207-219
Number of pages13
JournalJournal of Physiology
Volume589
Issue number1
DOIs
StatePublished - Jan 2011

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Transgenic Rats
Epoxide Hydrolases
Antihypertensive Agents
Blood Pressure
Hypertension
Kidney
Malignant Hypertension
Body Weight
Proteinuria
Renin
Sodium
Renal Plasma Flow
Renal Hypertension
Benzoic Acid
Arachidonic Acid
Angiotensin II
Drinking Water
Genes
Names
Blood Vessels

ASJC Scopus subject areas

  • Physiology

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Renal mechanisms contributing to the antihypertensive action of soluble epoxide hydrolase inhibition in Ren-2 transgenic rats with inducible hypertension. / Honetschlägerová, Zuzana; Husková, Zuzana; Vaňourková, Zdeňka; Sporková, Alexandra; Kramer, Herbert J.; Hwang, Sung Hee; Tsai, Hsing Ju; Hammock, Bruce D.; Imig, John D.; Červenka, Luděk; Kopkan, Libor.

In: Journal of Physiology, Vol. 589, No. 1, 01.2011, p. 207-219.

Research output: Contribution to journalArticle

Honetschlägerová, Z, Husková, Z, Vaňourková, Z, Sporková, A, Kramer, HJ, Hwang, SH, Tsai, HJ, Hammock, BD, Imig, JD, Červenka, L & Kopkan, L 2011, 'Renal mechanisms contributing to the antihypertensive action of soluble epoxide hydrolase inhibition in Ren-2 transgenic rats with inducible hypertension', Journal of Physiology, vol. 589, no. 1, pp. 207-219. https://doi.org/10.1113/jphysiol.2010.199505
Honetschlägerová, Zuzana ; Husková, Zuzana ; Vaňourková, Zdeňka ; Sporková, Alexandra ; Kramer, Herbert J. ; Hwang, Sung Hee ; Tsai, Hsing Ju ; Hammock, Bruce D. ; Imig, John D. ; Červenka, Luděk ; Kopkan, Libor. / Renal mechanisms contributing to the antihypertensive action of soluble epoxide hydrolase inhibition in Ren-2 transgenic rats with inducible hypertension. In: Journal of Physiology. 2011 ; Vol. 589, No. 1. pp. 207-219.
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AU - Vaňourková, Zdeňka

AU - Sporková, Alexandra

AU - Kramer, Herbert J.

AU - Hwang, Sung Hee

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N2 - Non-technical summary: Arachidonic acid metabolites called epoxyeicosatrienoic acids (EETs) influence vascular tone and renal tubular sodium and water transport and thus have been implicated in the control of blood pressure. Inhibition of the enzyme soluble epoxide hydrolase (sEH), which reduces EET degradation to the corresponding diols, leads to substantial attenuation of malignant hypertension in a transgenic rat strain harbouring the mouse renin gene particularly via an improvement of renal function. The observed antihypertensive and renoprotective effects of this novel pharmacological approach provide a potentially new direction in antihypertensive therapy.In the present study, we examined the effects of soluble epoxide hydrolase (sEH) inhibition on the development of angiotensin II-dependent hypertension and on renal function in transgenic rats with inducible expression of the mouse renin gene (strain name Cyp1a1-Ren-2). Hypertension was induced in these rats by indole-3-carbinol (I3C; 0.3% in the diet) for 12 days. The sEH inhibitor cis-4-[4-(3-adamantan-1-yl-ureido)-cyclohexyloxy]-benzoic acid (c-AUCB) was given in two doses (13 or 26 mg l-1) in drinking water. Blood pressure (BP), body weight (BW) and renal excretory parameters were monitored in conscious animals during the experiment. Renal haemodynamics was assessed at the end of treatment in anaesthetized rats. I3C administration resulted in severe hypertension with a rise in systolic BP from 118 ± 2 to 202 ± 3 mmHg, a loss of BW from 266 ± 5 to 228 ± 4 g and a rise in proteinuria from 14 ± 2 to 34 ± 3 mg day-1. Both doses of c-AUCB significantly attenuated the development of hypertension (systolic BP of 181 ± 4 and 176 ± 4 mmHg, respectively), the loss in BW (256 ± 4 and 259 ± 3 g, respectively) and the degree of proteinuria (27 ± 2 and 25 ± 3 mg day-1, respectively) to a similar extent. Moreover, c-AUCB prevented the reduction in renal plasma flow (5.4 ± 0.4 vs. 4.6 ± 0.3 ml min-1 g-1) and significantly increased sodium excretion (0.84 ± 0.16 vs. 0.38 ± 0.08 μmol min-1 g-1) during I3C administration. These data suggest that the oral administration of c-AUCB displays antihypertensive effects in Ren-2 transgenic rats with inducible malignant hypertension via an improvement of renal function.

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