Nitrosyl-cobinamide, a new and direct nitric oxide releasing drug effective in vivo.
A limited number of nitric oxide (NO)-generating drugs are available for clinical use for acute and chronic conditions. Most of these agents are organic nitrates, which do not directly release NO; tolerance to the drugs develops, in part, as a consequence of their conversion to NO. We synthesized nitrosyl-cobinamide (NO-Cbi) from cobinamide, a structural analog of cobalamin (vitamin B12). NO-Cbi is a direct NO-releasing agent that we found was stable in water, but under physiologic conditions, it released NO with a half-life of 30 mins to 1 h. We show in five different biological systems that NO-Cbi is an effective NO-releasing drug. First, in cultured rat vascular smooth muscle cells, NO-Cbi induced phosphorylation of vasodilator-stimulated phosphoprotein, a downstream target of cGMP and cGMP-dependent protein kinase. Second, in isolated Drosophila melanogaster Malpighian tubules, NO-Cbi-stimulated fluid secretion was similar to that stimulated by Deta-NONOate and a cGMP analog. Third, in isolated mouse hearts, NO-Cbi increased coronary flow much more potently than nitroglycerin. Fourth, in contracted mouse aortic rings, NO-Cbi induced relaxation, albeit to a lesser extent than sodium nitroprusside. Fifth, in intact mice, a single NO-Cbi injection rapidly reduced blood pressure, and blood pressure returned to normal after 45 mins; repeated NO-Cbi injections induced the expected fall in blood pressure. These studies indicate that NO-Cbi is a useful NO donor that can be used experimentally in the laboratory; moreover, it could be developed into a vasodilating drug for treating hypertension and potentially other diseases such as angina and congestive heart failure.
Broderick
Kate E
KE
Department of Medicine, University of California, San Diego, 9500 Gilman Drive, La Jolla, CA 92093-0652, USA.
Alvarez
Luis
L
Balasubramanian
Mahesh
M
Belke
Darrell D
DD
Makino
Ayako
A
Chan
Adriano
A
Woods
Virgil L
VL
Dillmann
Wolfgang H
WH
Sharma
Vijay S
VS
Pilz
Renate B
RB
Bigby
Timothy D
TD
Boss
Gerry R
GR
D000787:Angina Pectoris / Q000188:drug therapy / Q000378:metabolism; D000818:Animals; D001011:Aorta / Q000378:metabolism; D001794:Blood Pressure / Q000187:drug effects; D003038:Cobamides / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D003326:Coronary Circulation / Q000187:drug effects; D004331:Drosophila melanogaster; D004353:Drug Evaluation, Preclinical; D006333:Heart Failure / Q000188:drug therapy / Q000378:metabolism; D006973:Hypertension / Q000188:drug therapy / Q000378:metabolism; D008317:Malpighian Tubules / Q000378:metabolism; D051379:Mice; D009126:Muscle Relaxation / Q000187:drug effects; D009131:Muscle, Smooth, Vascular / Q000378:metabolism; D009206:Myocardium / Q000378:metabolism; D009569:Nitric Oxide / Q000378:metabolism*; D020030:Nitric Oxide Donors / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D009603:Nitroso Compounds / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D009924:Organ Culture Techniques; D051381:Rats; D014665:Vasodilator Agents / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*
D003038:Cobamides; D020030:Nitric Oxide Donors; D009603:Nitroso Compounds; D014665:Vasodilator Agents; C017142:cobinamide; D009569:Nitric Oxide