Angiotensin II-induced hypertension contribution of Ras GTPase/mitogen-activated protein kinase and cytochrome P450 metabolites

Mubarack M. Muthalif, Nour A. Karzoun, Lillian Gaber, Zinat Khandekar, Ibrahim F. Benter, Abdelwahab E. Saeed, Jean Hugues Parmentier, Anne Estes, Kafait Malik

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Abstract

We reported that norepinephrine and angiotensin II (Ang II) activate the Ras/mitogen-activated protein (MAP) kinase pathway primarily through the generation of cytochrome P450 (CYP450) metabolites. The purpose of the present study was to determine the contribution of Ras and CYP450 to Ang II-dependent hypertension in rats. Infusion of Ang II (350 ng/min for 6 days) elevated mean arterial blood pressure (MABP) (171±3 mm Hg for Ang II versus 94±5 for vehicle group, P<0.05). Ras is activated on farnesylation by farnesyl protein transferase (FPT). When Ang II was infused in combination with FPT inhibitor FPT III (232 ng/min) or BMS-191563 (578 ng/min), the development of hypertension was attenuated (171±3 mm Hg for Ang II plus vehicle versus 134±5 mm Hg for Ang II plus FPT III and 116±6 mm Hg for Ang II plus BMS-191563, P<0.05). Treatment with the MAP kinase kinase inhibitor PD-98059 (5 mg SC) reduce, d MABP. The CYP450 inhibitor aminobenzotriazole (50 mg/kg) also diminished the development of Ang II-induced hypertension to 113±8 mm Hg. The activities Ras, MAP kinase, and CYP450 measured in the kidney were elevated in hypertensive animals. The infusion of FPT III, BMS-191563, or aminobenzotriazole reduced the elevation in Ras and MAP kinase activity. Morphological studies of the kidney showed that FPT III treatment ameliorated the arterial injury, vascular lesions, fibrinoid necrosis, focal hemorrhage, and hypertrophy of muscle walls observed in hypertensive animals. These data suggest that the activation of Ras and CYP450 contributes to the development of Ang II-dependent hypertension and associated vascular pathology.

Original languageEnglish (US)
Pages (from-to)604-609
Number of pages6
JournalHypertension
Volume36
Issue number4
DOIs
StatePublished - Jan 1 2000

Fingerprint

ras Proteins
Mitogen-Activated Protein Kinases
Angiotensin II
Cytochrome P-450 Enzyme System
Hypertension
Transferases
Arterial Pressure
Proteins
Protein Prenylation
Kidney
Vascular System Injuries
Mitogen-Activated Protein Kinase Kinases
Hypertrophy
Blood Vessels
Norepinephrine
Necrosis
Pathology
Hemorrhage

All Science Journal Classification (ASJC) codes

  • Internal Medicine

Cite this

Angiotensin II-induced hypertension contribution of Ras GTPase/mitogen-activated protein kinase and cytochrome P450 metabolites. / Muthalif, Mubarack M.; Karzoun, Nour A.; Gaber, Lillian; Khandekar, Zinat; Benter, Ibrahim F.; Saeed, Abdelwahab E.; Parmentier, Jean Hugues; Estes, Anne; Malik, Kafait.

In: Hypertension, Vol. 36, No. 4, 01.01.2000, p. 604-609.

Research output: Contribution to journalArticle

Muthalif, MM, Karzoun, NA, Gaber, L, Khandekar, Z, Benter, IF, Saeed, AE, Parmentier, JH, Estes, A & Malik, K 2000, 'Angiotensin II-induced hypertension contribution of Ras GTPase/mitogen-activated protein kinase and cytochrome P450 metabolites', Hypertension, vol. 36, no. 4, pp. 604-609. https://doi.org/10.1161/01.HYP.36.4.604
Muthalif, Mubarack M. ; Karzoun, Nour A. ; Gaber, Lillian ; Khandekar, Zinat ; Benter, Ibrahim F. ; Saeed, Abdelwahab E. ; Parmentier, Jean Hugues ; Estes, Anne ; Malik, Kafait. / Angiotensin II-induced hypertension contribution of Ras GTPase/mitogen-activated protein kinase and cytochrome P450 metabolites. In: Hypertension. 2000 ; Vol. 36, No. 4. pp. 604-609.
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AU - Khandekar, Zinat

AU - Benter, Ibrahim F.

AU - Saeed, Abdelwahab E.

AU - Parmentier, Jean Hugues

AU - Estes, Anne

AU - Malik, Kafait

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