Biological activity of designed photolabile metal nitrosyls: light-dependent activation of soluble guanylate cyclase and vasorelaxant properties in rat aorta.
The biological and pharmacological utility of nitric oxide (NO) has led to the development of many classes of NO-donor compounds as both research tools and therapeutic agents. Many donors currently in use rely on thermal decomposition or bioactivation for the release of NO. We have developed several photolabile metal-nitrosyl donors that release NO when exposed to either visible or UV light. Herein, we show that these donors are capable of activating the primary "NO receptor", soluble guanylate cyclase (sGC), in a light-dependent fashion leading to increases in cGMP. Moreover, we demonstrate that these donors are capable of eliciting light-dependent increases of cGMP in smooth muscle cells and vasorelaxation of rat aortic smooth muscle tissue, all effects that are attributed to activation of sGC. The potential utility of these compounds as drugs and/or research tools is discussed.
Madhani
Melanie
M
Wolfson Institute for Biomedical Research, University College London, Cruciform Building, Gower Street, London WC1E 6AE, United Kingdom.
Patra
Apurba K
AK
Miller
Thomas W
TW
Eroy-Reveles
Aura A
AA
Hobbs
Adrian J
AJ
Fukuto
Jon M
JM
Mascharak
Pradip K
PK
D000818:Animals; D001011:Aorta / Q000187:drug effects* / Q000502:physiology; D002478:Cells, Cultured; D006152:Cyclic GMP / Q000096:biosynthesis; D004789:Enzyme Activation; D006162:Guanylate Cyclase / Q000737:chemistry* / Q000302:isolation & purification; D066298:In Vitro Techniques; D007501:Iron; D008027:Light; D008345:Manganese; D009131:Muscle, Smooth, Vascular / Q000166:cytology / Q000187:drug effects / Q000502:physiology; D032389:Myocytes, Smooth Muscle / Q000187:drug effects / Q000378:metabolism; D020030:Nitric Oxide Donors / Q000138:chemical synthesis* / Q000494:pharmacology / Q000528:radiation effects; D009942:Organometallic Compounds / Q000138:chemical synthesis* / Q000494:pharmacology / Q000528:radiation effects; D051381:Rats; D018160:Receptors, Cytoplasmic and Nuclear / Q000737:chemistry* / Q000302:isolation & purification; D012428:Ruthenium; D000071756:Soluble Guanylyl Cyclase; D013329:Structure-Activity Relationship; D014664:Vasodilation / Q000187:drug effects; D014665:Vasodilator Agents / Q000138:chemical synthesis* / Q000494:pharmacology / Q000528:radiation effects
D020030:Nitric Oxide Donors; D009942:Organometallic Compounds; D018160:Receptors, Cytoplasmic and Nuclear; D014665:Vasodilator Agents; C517228:nitrosyl(N,N'-bis(2-pyridylmethyl)amine-N-ethyl-2-pyridine-2-carboxamide)manganese(II); C517227:nitrosyl(N,N'-bis(2-pyridylmethyl)amine-N-ethyl-2-pyridine-2-carboxamide)ruthenium(III); D008345:Manganese; D012428:Ruthenium; D007501:Iron; D006162:Guanylate Cyclase; D000071756:Soluble Guanylyl Cyclase; D006152:Cyclic GMP