Aldosterone is synthesized by zona glomerulosa (ZG) cells of the adrenal cortex. It regulates sodium and potassium (K) balance and is involved hypertension, cardiac hypertrophy and congestive heart failure. Angiotensin II (All), adrenocorticotropic hormone (ACTH) and potassium (K) are major stimuli for aldosterone release. Blood flow to the adrenal cortex delivers nutrients to ZG cells and carries aldosterone to its target tissues. Thus, understanding the factors regulating adrenal blood flow (ABF) and adrenal vascular tone is important. ACTH dilates the adrenal vasculature and increases ABF in vivo; however, ACTH does not relax isolated adrenal cortical arteries in vitro. We wondered if other cells in the adrenal cortex released a vasodilator that mediates the dilation by ACTH. When ZG cells were co-incubated with the isolated adrenal arteries, ACTH caused relaxation. The ZG cell-dependent relaxations to ACTH were inhibited by high extracellular K, a K channel inhibitor, a cytochrome P450 inhibitor and an epoxyeicosatrienoic acid (EET) antagonist. ZG cells similarly enhanced the relaxation of adrenal arteries to AII. ZG cell conditioned media (ZG-CM) also relaxed adrenal arteries and continued EETs and prostaglandins. These studies indicate that ZG cells release a soluble factor(s) that mediates the relaxations to ACTH and All. This factor(s) may be an EET or related fatty acid metabolite(s). We will test the hypothesis that ZG cells, which are in close anatomical proximity to adrenal arteries in the adrenal cortex, release soluble, transferable factors that cause vasodilation. The proposed studies will investigate the ability of ZG cells and ZG-CM to relax isolated bovine adrenal cortical arteries in vitro and mediate ACTH- and All-induced dilation. Various fatty acids as well as inhibitors of known endogenous dilators will be tested. Parallel studies will be conducted on zona fasciculata (ZF) cells. To maintain the anatomical relationship between ZG cells and adrenal arteries, parallel studies will be conducted with perfused adrenal arteries embedded in slices of the adrenal cortex. The active factor(s) will be isolated and identified from ZG-CM extracts using HPLC and mass spectrometry. The factor(s) will be synthesized and tested for dilator activity. The action of the factor(s) will also be tested on K channel activity and smooth muscle cell membrane potential. We will measure the release of the factor(s) from ZG cells with ACTH and All stimulation. Studies will also be performed in vivo in anesthetized rats to determine the role of the ZG cell factor(s) in regulating ABF. Cortical ABF will be measured by a laser Doppler flowmeter in response to ACTH and All and the effect of inhibitors of endogenous vasodilator pathways determined. The regulation of adrenal vascular tone by ZG cells may have broader implications. This may represent a general pathway for regulation of vascular tone in many endocrine glands. ? ? ?
| 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
