Angiotensin II (AII), a vasoconstrictor, stimulates aldosterone release from the zona glomerulosa (ZG) cells of the adrenal cortex. Aldosterone regulates sodium and potassium balance and blood pressure. Adrenal blood flow (ABF) is critical to both aldosterone synthesis and action. ABF delivers oxygen, nutrients, cholesterol esters and AII to ZG cells and carries aldosterone to its target tissues. Thus, mechanisms that influence adrenal vascular tone are important to ABF regulation and steroidogenesis. The intra-adrenal regulation of adrenal vascular tone and steroidogenesis by AII and its metabolites is poorly understood. The long-term goal is to understand the intraadrenal regulation of vascular tone, ABF and steroidogenesis and the coupling of ABF and steroidogenesis. ZG cells are in close anatomical proximity to the adrenal arterioles in the adrenal cortex allowing interactions. We have defined the novel mechanism that ZG cells regulate adrenal vascular tone by releasing epoxyeicosatrienoic acids (EETs) that cause vasorelaxation. In pM concentrations, AII relaxes adrenal arteries by two mechanisms. AII relaxes adrenal arteries directly by endothelial release of nitric oxide (NO) and indirectly by ZG cell release of EETs. These findings indicate the central role of ZG cells in regulating both adrenal vascular tone and steroidogenesis. The major ZG cell pathway for AII metabolism is its conversion to angiotensin III (AIII) by aminopeptidase A (APA). AIII has a new role in the adrenal cortex. AIII is 10-fold more potent than AII in stimulating ZG cell-dependent, EET-mediated relaxation. Inhibition of AII metabolism to AIII blocks the ZG cell-mediated relaxation to AII. Thus, AII metabolism to AIII is critical for the regulation of adrenal vascular tone and ABF by AII. Our objective in this proposal is to understand the importance of AII metabolism by ZG cells in regulating adrenal vascular tone, ABF and aldosterone release. The central hypothesis is that AII metabolism to AIII by APA is an obligatory step for ZG cell-mediated vasorelaxation and increases in ABF by AII. This indicates an important role for APA in regulating adrenal vascular tone and ABF. The central hypothesis will be tested with three aims. (1) We will identify the pathways of AII metabolism by isolated ZG cells and the impact of AII metabolism on EET and aldosterone release. Our hypothesis is that ZG cells metabolize AII to AIII and thereby regulate AII stimulation of EET, but not aldosterone, release. (2) We will identify the mechanisms by which AII regulates vascular tone in isolated adrenal cortical arteries. Our hypothesis is that AII metabolism to AIII and APA activity are critical for ZG cell-dependent, EET-mediated vasorelaxation. (3) We will establish the role of AII metabolism and ZG cell-derived EETs in the regulation of ABF in vivo in anesthetized rats. Our hypothesis is that AII metabolism to AIII by APA is essential for AII increases in ABF. These studies will indicate if metabolism of AII to AIII is an obligatory step to the regulation of adrenal vascular tone and ABF by ZG cells. APA may determine whether ZG cell-mediated EET- and/or endothelial-mediated NO mechanisms oppose the constriction by AII and maintain ABF in high renin states.

Public Health Relevance

Grant Narrative The adrenal gland is life sustaining by making the steroid hormone aldosterone that regulates salt and water balance and blood pressure. The intra-adrenal regulation of aldosterone release and adrenal blood flow is important to normal blood pressure control, salt and water balance and contributes to pathological conditions such as hypertension and congestive heart failure. These studies have discovered a new mechanism that controls adrenal blood flow. Knowledge of the regulation of this new control mechanism will help our understanding of normal adaptation and disease.

National Institute of Health (NIH)
National Heart, Lung, and Blood Institute (NHLBI)
Research Project (R01)
Project #
Application #
Study Section
Hypertension and Microcirculation Study Section (HM)
Program Officer
OH, Youngsuk
Project Start
Project End
Budget Start
Budget End
Support Year
Fiscal Year
Total Cost
Indirect Cost
Medical College of Wisconsin
Schools of Medicine
United States
Zip Code
Kopf, Phillip G; Park, Sang-Kyu; Herrnreiter, Anja et al. (2018) Obligatory Metabolism of Angiotensin II to Angiotensin III for Zona Glomerulosa Cell-Mediated Relaxations of Bovine Adrenal Cortical Arteries. Endocrinology 159:238-247
Park, Sang-Kyu; Herrnreiter, Anja; Pfister, Sandra L et al. (2018) GPR40 is a low-affinity epoxyeicosatrienoic acid receptor in vascular cells. J Biol Chem 293:10675-10691
Shah, Abdul J; Kriska, Tamas; Gauthier, Kathryn M et al. (2018) Effect of Angiotensin II and ACTH on Adrenal Blood Flow in the Male Rat Adrenal Gland In Vivo. Endocrinology 159:217-226
Campbell, William B; Imig, John D; Schmitz, James M et al. (2017) Orally Active Epoxyeicosatrienoic Acid Analogs. J Cardiovasc Pharmacol 70:211-224
Khan, Abdul Hye; Falck, John R; Manthati, Vijaya L et al. (2014) Epoxyeicosatrienoic acid analog attenuates angiotensin II hypertension and kidney injury. Front Pharmacol 5:216
Falck, John R; Koduru, Sreenivasulu Reddy; Mohapatra, Seetaram et al. (2014) 14,15-Epoxyeicosa-5,8,11-trienoic Acid (14,15-EET) surrogates: carboxylate modifications. J Med Chem 57:6965-72
Ansurudeen, Ishrath; Kopf, Phillip G; Gauthier, Kathryn M et al. (2014) Aldosterone secretagogues increase adrenal blood flow in male rats. Endocrinology 155:127-32
Nithipatikom, Kasem; Endsley, Michael P; Pfeiffer, Adam W et al. (2014) A novel activity of microsomal epoxide hydrolase: metabolism of the endocannabinoid 2-arachidonoylglycerol. J Lipid Res 55:2093-102
Hye Khan, Md Abdul; Pavlov, Tengis S; Christain, Sarah V et al. (2014) Epoxyeicosatrienoic acid analogue lowers blood pressure through vasodilation and sodium channel inhibition. Clin Sci (Lond) 127:463-74
Oki, Kenji; Kopf, Phillip G; Campbell, William B et al. (2013) Angiotensin II and III metabolism and effects on steroid production in the HAC15 human adrenocortical cell line. Endocrinology 154:214-21

Showing the most recent 10 out of 22 publications