Asymmetric dimethylarginine enables depolarizing spikes and vasospasm in mesenteric and coronary resistance arteries

Hanson Ng, Y. Y. et al. (2024) Asymmetric dimethylarginine enables depolarizing spikes and vasospasm in mesenteric and coronary resistance arteries. Hypertension, 81(4), pp. 764-775. (doi: 10.1161/HYPERTENSIONAHA.123.22454) (PMID:38226470) (PMCID:PMC10956675)

Abstract

BACKGROUND: Increased vasoreactivity due to reduced endothelial NO bioavailability is an underlying feature of cardiovascular disease, including hypertension. In small resistance arteries, declining NO enhances vascular smooth muscle (VSM) reactivity partly by enabling rapid depolarizing Ca2+-based spikes that underlie vasospasm. The endogenous NO synthase inhibitor asymmetric dimethylarginine (ADMA) is metabolized by DDAH1 (dimethylarginine dimethylaminohydrolase 1) and elevated in cardiovascular disease. We hypothesized ADMA might enable VSM spikes and vasospasm by reducing NO bioavailability, which is opposed by DDAH1 activity and L-arginine. METHODS: Rat isolated small mesenteric arteries and myogenic rat-isolated intraseptal coronary arteries (RCA) were studied using myography, VSM intracellular recording, Ca2+ imaging, and DDAH1 immunolabeling. Exogenous ADMA was used to inhibit NO synthase and a selective DDAH1 inhibitor, NG-(2-methoxyethyl) arginine, to assess the functional impact of ADMA metabolism. RESULTS: ADMA enhanced rat-isolated small mesenteric arteries vasoreactivity to the α1-adrenoceptor agonist, phenylephrine by enabling T-type voltage-gated calcium channel-dependent depolarizing spikes. However, some endothelium-dependent NO-vasorelaxation remained, which was sensitive to DDAH1-inhibition with NG-(2-methoxyethyl) arginine. In myogenically active RCA, ADMA alone stimulated depolarizing Ca2+ spikes and marked vasoconstriction, while NO vasorelaxation was abolished. DDAH1 expression was greater in rat-isolated small mesenteric arteries endothelium compared with RCA, but low in VSM of both arteries. L-arginine prevented depolarizing spikes and protected NO-vasorelaxation in rat-isolated small mesenteric artery and RCA. CONCLUSIONS: ADMA increases VSM electrical excitability enhancing vasoreactivity. Endothelial DDAH1 reduces this effect, and low levels of DDAH1 in RCAs may render them susceptible to endothelial dysfunction contributing to vasospasm, changes opposed by L-arginine.

• Item Type: Articles
• Additional Information: This study was funded by BHF for 4-year DPhil Studentship FS/19/61/34900 (Y.Y. Hanson Ng), FS/18/63/34184 (L. Donovan); British Heart Foundation PG/19/36/34396, PG/20/10260, and PG/23/11496 (J. Lin and H.A.L. Lem-mey); Leon and Iris Beghian Scholarship, Magdalen College (L. Wallis); British Heart Foundation infrastructure grant: IG/13/5/30431, British Heart Foundation Centre of Research Excellence: RE/13/1/30181.
• Status: Published
• Refereed: Yes
• Glasgow Author(s) Enlighten ID: Leiper, Dr Fiona and Leiper, Professor James
• Authors: Hanson Ng, Y. Y., Dora, K. A., Lemmey, H. A. L., Lin, J., Alden, J., Wallis, L., Donovan, L., Shorthose, O., Leiper, F. C., Leiper, J., and Garland, C. J.
• College/School: College of Medical Veterinary and Life Sciences > School of Cardiovascular & Metabolic Health
• Journal Name: Hypertension
• Publisher: American Heart Association
• ISSN: 0194-911X
• ISSN (Online): 1524-4563
• Published Online: 16 January 2024
• Copyright Holders: Copyright © 2024 The Authors
• First Published: First published in Hypertension 81(4):764-775
• Publisher Policy: Reproduced under a Creative Commons license