Evaluation of in vivo MRI for detecting midodrine-induced arteritis in rats

Yuta Fujii; Yuka Yoshino; Kazuhiro Chihara; Aya Nakae; Jun-Ichiro Enmi; Yoshichika Yoshioka; Izuru Miyawaki

doi:10.1016/j.toxrep.2023.01.001

Evaluation of in vivo MRI for detecting midodrine-induced arteritis in rats

Toxicol Rep. 2023 Jan 5:10:97-103. doi: 10.1016/j.toxrep.2023.01.001. eCollection 2023.

Authors

Yuta Fujii^{1

2}, Yuka Yoshino^{1

2}, Kazuhiro Chihara¹, Aya Nakae^{2

3}, Jun-Ichiro Enmi^{2

3}, Yoshichika Yoshioka^{2

3}, Izuru Miyawaki¹

Affiliations

¹ Preclinical Research Unit, Sumitomo Pharma Co., Ltd., 3-1-98 Kasugade-naka, Konohana-ku, Osaka 554-0022, Japan.
² Graduate school of Frontier Biosciences, Osaka University, 1-3 Yamadaoka, Suita City, Osaka 565-0871, Japan.
³ Center for Information and Neural Networks (CiNet), Osaka University and National Institute of Information and Communications Technology (NICT), 1-4 Yamadaoka, Suita City, Osaka 565-0871, Japan.

Abstract

There are no specific and sensitive biomarkers for arteritis, and the occurrence of arteritis in nonclinical toxicological studies of a candidate drug makes development of the drug very difficult. However, we showed in a previous study that the high signal intensity region around the artery on magnetic resonance imaging (MRI) could be a candidate biomarker for detection of arteritis. The present study was conducted to clarify the details of midodrine hydrochloride (MH)-induced arteritis lesions and whether arteritis induced by a mechanism other than the vasodilatory effect, which was evaluated in a previous study, could be detected by MRI. MH is a selective peripherally acting alpha-1 adrenergic receptor agonist, known to induce arteritis due to its vasoconstrictor action, but there is not enough information about MH-induced arteritis. Based on the data obtained under multiple dosing conditions, MH was administered subcutaneously to each rat once daily for 2 days at a dose level of 40 mg/kg/day for MRI assessment. The mesenteric arteries were examined using in vivo MRI at 1 day or 7 days after administration of the final dose and examined histopathologically. On the day after the final dose, high signal intensity region around the artery was observed in animals with minimal perivascular lesions confirmed by histopathology and not observed in an animal without histological changes. On the 7th day after the final dose, no abnormality was observed in histopathological examinations and no high signal intensity regions were observed by MRI in any animal. In conclusion, although further investigation is needed to confirm that high signal intensity is a reliable biomarker for humans, it is suggested that high signal intensity around the artery could be a versatile candidate biomarker with high specificity and sensitivity.

Keywords: 0.5% CMC, 0.5 w/v% carboxymethyl cellulose solution; Arteritis; Biomarker; Drug; FLASH, fast low-angle shot; FM, fenoldopam mesylate; FOV, field of view; MH, midodrine hydrochloride; MRI, magnetic resonance imaging; Magnetic resonance imaging; Midodrine hydrochloride; Perivascular edema; RARE, rapid acquisition with relaxation enhancement; TE, echo time; TR, repetition time.