Photoactivation of tDodSNO induces localized vasodilation in rats: Metabolically stable S-nitrosothiols can act as targeted nitric oxide donors in vivo

Gregory I Giles; Jeffrey R Erickson; Carol T Bussey

doi:10.1016/j.niox.2022.10.001

Photoactivation of tDodSNO induces localized vasodilation in rats: Metabolically stable S-nitrosothiols can act as targeted nitric oxide donors in vivo

Nitric Oxide. 2022 Dec 1:129:53-62. doi: 10.1016/j.niox.2022.10.001. Epub 2022 Oct 7.

Authors

Gregory I Giles¹, Jeffrey R Erickson², Carol T Bussey³

Affiliations

¹ Department of Pharmacology and Toxicology, School of Biomedical Sciences, University of Otago, Dunedin, New Zealand.
² Department of Physiology and HeartOtago, School of Biomedical Sciences, University of Otago, Dunedin, New Zealand.
³ Department of Physiology and HeartOtago, School of Biomedical Sciences, University of Otago, Dunedin, New Zealand; Manaaki Mānawa Centre for Heart Research, Department of Physiology, Faculty of Medical and Health Sciences, University of Auckland, Auckland, New Zealand. Electronic address: carol.bussey@auckland.ac.nz.

PMID: 36209988
DOI: 10.1016/j.niox.2022.10.001

Abstract

Nitric oxide (NO) is a key vasodilatory signalling molecule and NO releasing molecules (NO donors) are being examined as potential treatments for many pathologies. The photoresponsive NO donor tert-dodecane S-nitrosothiol (tDodSNO) has been designed to be highly resistant to metabolism; in principle photoactivation of tDodSNO should therefore enable the controlled release of NO in situ via light modulation. To investigate the therapeutic utility of tDodSNO, we tested drug efficacy in Sprague Dawley rats to assess systemic and localised hemodynamic responses under photoactivation, and to confirm drug safety. For comparison, drug action was evaluated alongside the existing NO donors sodium nitroprusside (SNP) and S-nitrosoglutathione (GSNO). Across a dosing range (0.1-3.0 mg/kg) tDodSNO exerted markedly reduced systemic hypotensive action compared to these standard NO donors, inducing a slight decrease in mean arterial pressure (maximum 14.2 ± 3.0%) without affecting heart rate. Target limb photoactivation of tDodSNO resulted in a substantial localized vasodilatory response, with increases to mean (26.0 ± 7.3%) and maximum (53.2 ± 10.4%) blood flow and decreases to vascular resistance (27.1 ± 3.9%) that were restricted to light exposed tissue. In comparison GSNO and SNP showed variable peripheral effects and were not responsive to photoactivation. tDodSNO did not induce met-Hb formation in blood, or display any signs of toxicity, and was rapidly cleared from the systemic circulation, with no hemodynamic effects detectable 5 min post administration. These data are the first demonstration that drugs based upon a metabolically stable S-nitrosothiol group can be photoactivated in vivo to release NO, and that such agents cause less systemic side effects than existing NO donors. Our data support the use of S-nitrosothiols to enable the spatiotemporal control of NO for therapeutic applications.

Keywords: Hemodynamic; Nitric oxide; Photoactivation; Phototherapy; S-nitrosothiol.

Publication types

Research Support, Non-U.S. Gov't

MeSH terms

Animals
Nitric Oxide / metabolism
Nitric Oxide Donors* / metabolism
Nitric Oxide Donors* / pharmacology
Nitroprusside / pharmacology
Rats
Rats, Sprague-Dawley
S-Nitrosothiols* / metabolism
S-Nitrosothiols* / pharmacology
Vasodilation

Substances

tert-dodecane S-nitrosothiol
Nitric Oxide Donors
S-Nitrosothiols
Nitroprusside
Nitric Oxide