Contribution of cytochrome P450 epoxygenase and hydroxylase pathways to afferent arteriolar autoregulatory responsiveness

John D. Imig, J R Falck, Edward W. Inscho

Research output: Contribution to journalArticle

77 Citations (Scopus)

Abstract

1. Previous studies have demonstrated an important role for the cytochrome P450 (CYT-P450) pathway in afferent arteriole autoregulatory responses but the involvement of specific pathways remains unknown. Experiments were performed to determine the role of CYT-P450 epoxygenase and hydroxylase pathways in pressure mediated preglomerular autoregulatory responses. 2. Afferent arteriolar diameter was measured as renal perfusion pressure was increased from 80-160 mmHg. Afferent arteriolar diameter averaged 19 ± 2 μm at a renal perfusion pressure of 80 mmHg and decreased by 15 ± 2% when pressure was increased to 160 mmHg. 3. Inhibition of the epoxygenase pathway with 6-(2-proparglyloxyphenyl)hexanoic acid (PPOH), enhanced the microvascular response to increasing renal perfusion pressure. In the presence of 50 μM PPOH, afferent arteriolar diameter decreased by 29 ± 4% when pressure was increased from 80-160 mmHg. 4. Likewise, the sulphonimide derivative of PPOH, N-methylsulphonyl-6-(2-proparglyloxyphenyl) hexanamide (MS-PPOH, 50 μM), enhanced the afferent arteriolar response to increasing renal perfusion pressure. 5. In contrast, the selective CYT-P450 hydroxylase inhibitor, N-methylsulphonyl-12,12-dibromododec-11-enamide (DDMS) attenuated the vascular response to increasing renal perfusion pressure. In the pressure of 25 μM DDMS, afferent arteriolar diameter decreased by 4 ± 2% when pressure was increased from 80-160 mmHg. 6. These results suggest that CYT-P450 metabolites of the epoxygenase pathway alter afferent arteriolar responsiveness and thereby modify the ability of the preglomerular vasculature to autoregulate renal blood flow. Additionally, these results provide further support to the concept that a metabolite of the hydroxylase pathway is an integral component of the afferent arteriolar response to elevations in perfusion pressure.

Original languageEnglish (US)
Pages (from-to)1399-1405
Number of pages7
JournalBritish Journal of Pharmacology
Volume127
Issue number6
DOIs
StatePublished - 1999

Fingerprint

Afferent Pathways
Mixed Function Oxygenases
Cytochrome P-450 Enzyme System
Pressure
Perfusion
Kidney
Renal Circulation
Arterioles
Blood Vessels

Keywords

  • Autoregulation
  • Endothelium-derived hyperpolarizing factor (EDHF)
  • Epoxyeicosatrienoic acids (EETs)
  • Kidney
  • Microcirculation
  • Renal blood flow

ASJC Scopus subject areas

  • Pharmacology

Cite this

Contribution of cytochrome P450 epoxygenase and hydroxylase pathways to afferent arteriolar autoregulatory responsiveness. / Imig, John D.; Falck, J R; Inscho, Edward W.

In: British Journal of Pharmacology, Vol. 127, No. 6, 1999, p. 1399-1405.

Research output: Contribution to journalArticle

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abstract = "1. Previous studies have demonstrated an important role for the cytochrome P450 (CYT-P450) pathway in afferent arteriole autoregulatory responses but the involvement of specific pathways remains unknown. Experiments were performed to determine the role of CYT-P450 epoxygenase and hydroxylase pathways in pressure mediated preglomerular autoregulatory responses. 2. Afferent arteriolar diameter was measured as renal perfusion pressure was increased from 80-160 mmHg. Afferent arteriolar diameter averaged 19 ± 2 μm at a renal perfusion pressure of 80 mmHg and decreased by 15 ± 2{\%} when pressure was increased to 160 mmHg. 3. Inhibition of the epoxygenase pathway with 6-(2-proparglyloxyphenyl)hexanoic acid (PPOH), enhanced the microvascular response to increasing renal perfusion pressure. In the presence of 50 μM PPOH, afferent arteriolar diameter decreased by 29 ± 4{\%} when pressure was increased from 80-160 mmHg. 4. Likewise, the sulphonimide derivative of PPOH, N-methylsulphonyl-6-(2-proparglyloxyphenyl) hexanamide (MS-PPOH, 50 μM), enhanced the afferent arteriolar response to increasing renal perfusion pressure. 5. In contrast, the selective CYT-P450 hydroxylase inhibitor, N-methylsulphonyl-12,12-dibromododec-11-enamide (DDMS) attenuated the vascular response to increasing renal perfusion pressure. In the pressure of 25 μM DDMS, afferent arteriolar diameter decreased by 4 ± 2{\%} when pressure was increased from 80-160 mmHg. 6. These results suggest that CYT-P450 metabolites of the epoxygenase pathway alter afferent arteriolar responsiveness and thereby modify the ability of the preglomerular vasculature to autoregulate renal blood flow. Additionally, these results provide further support to the concept that a metabolite of the hydroxylase pathway is an integral component of the afferent arteriolar response to elevations in perfusion pressure.",
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N2 - 1. Previous studies have demonstrated an important role for the cytochrome P450 (CYT-P450) pathway in afferent arteriole autoregulatory responses but the involvement of specific pathways remains unknown. Experiments were performed to determine the role of CYT-P450 epoxygenase and hydroxylase pathways in pressure mediated preglomerular autoregulatory responses. 2. Afferent arteriolar diameter was measured as renal perfusion pressure was increased from 80-160 mmHg. Afferent arteriolar diameter averaged 19 ± 2 μm at a renal perfusion pressure of 80 mmHg and decreased by 15 ± 2% when pressure was increased to 160 mmHg. 3. Inhibition of the epoxygenase pathway with 6-(2-proparglyloxyphenyl)hexanoic acid (PPOH), enhanced the microvascular response to increasing renal perfusion pressure. In the presence of 50 μM PPOH, afferent arteriolar diameter decreased by 29 ± 4% when pressure was increased from 80-160 mmHg. 4. Likewise, the sulphonimide derivative of PPOH, N-methylsulphonyl-6-(2-proparglyloxyphenyl) hexanamide (MS-PPOH, 50 μM), enhanced the afferent arteriolar response to increasing renal perfusion pressure. 5. In contrast, the selective CYT-P450 hydroxylase inhibitor, N-methylsulphonyl-12,12-dibromododec-11-enamide (DDMS) attenuated the vascular response to increasing renal perfusion pressure. In the pressure of 25 μM DDMS, afferent arteriolar diameter decreased by 4 ± 2% when pressure was increased from 80-160 mmHg. 6. These results suggest that CYT-P450 metabolites of the epoxygenase pathway alter afferent arteriolar responsiveness and thereby modify the ability of the preglomerular vasculature to autoregulate renal blood flow. Additionally, these results provide further support to the concept that a metabolite of the hydroxylase pathway is an integral component of the afferent arteriolar response to elevations in perfusion pressure.

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