guanosine-monophosphate and Hypotension

We previously demonstrated that nitroxyl causes vasodilation, at least in part, by inducing the formation of an intradisulfide bond between C117 and C195 in the high affinity cyclic guanosine monophosphate-binding site of PKGI (cyclic guanosine monophosphate-dependent protein kinase I). The aim of this study was to determine whether nitroxyl donors lower blood pressure via this novel PKGI activation mechanism in vivo.. To determine this, a C195S PKGI knock-in mouse model was generated that ubiquitously and constitutively expresses a mutant kinase resistant to nitroxyl-induced intradisulfide activation.. Knock-in and wild-type littermates did not differ in appearance, body weight, in PKGI protein expression or blood gas content. Organ weight was similar between genotypes apart from the cecum that was significantly enlarged in knock-in animals. Mean arterial pressure and heart rate monitored in vivo over 24 hours by radio-telemetry revealed neither a significant difference between genotypes at baseline nor during angiotensin II-induced hypertension or sepsis. CXL-1020, a clinically relevant nitroxyl donor, did not lower blood pressure in normotensive animals. In contrast, administering CXL-1020 to hypertensive wild-type mice reduced their blood pressure by 10±4 mm Hg (. Oxidation of C195 in PKGI contributes to the antihypertensive effects observed in response to nitroxyl donors, emphasising the potential importance of nitroxyl donors in pathological scenarios when cyclic guanosine monophosphate levels are reduced and insufficient to activate PKGI.

Topics: Animals; Blood Pressure; Cyclic GMP; Cyclic GMP-Dependent Protein Kinase Type I; Cyclic GMP-Dependent Protein Kinases; Guanosine; Guanosine Monophosphate; Hypertension; Hypotension; Mice; Nitrogen Oxides; Protein Kinases

Increasing evidence has demonstrated that nitric oxide (NO) is involved in central cardiovascular regulation. In this study, we directly measured extracellular NO levels, in real-time, in the nucleus tractus solitarius (NTS) of anesthetized cats using Nafion/Porphyrine/o-Phenylenediamine-coated NO sensors. We found that local application of L-arginine (L-Arg) induced NO overflow in NTS and hypotension. These responses were potentiated in the vagotomized animals. Pretreatment with NO synthase (NOS)/guanylate cyclase inhibitor methylene blue, 1H-[1,2,4]oxadiazolo[4,3-a]quinoxalin-1-one or NO scavenger hemoglobin attenuated L-Arg-induced hypotension, suggesting that exogenous supplement of NO suppressed cardiac functions through the NOS/cyclic guanosine monophosphate mechanism. The role of endogenous NO was examined after local application of N(G)-nitro-L-arginine methyl ester (L-NAME). We found that L-NAME suppressed endogenous NO levels in NTS and elicited hypertension and tachycardia. Taken together, our data suggest that NO is tonically released in the NTS to inhibit blood pressure.

Topics: Animals; Arginine; Biosensing Techniques; Blood Pressure; Bradycardia; Cats; Computer Systems; Electrochemistry; Enzyme Inhibitors; Extracellular Space; Female; Guanosine Monophosphate; Guanylate Cyclase; Hemoglobins; Hypertension; Hypotension; Male; Methylene Blue; NG-Nitroarginine Methyl Ester; Nitric Oxide; Nitric Oxide Synthase; Oxadiazoles; Pressoreceptors; Quinoxalines; Reflex; Sensitivity and Specificity; Solitary Nucleus; Tachycardia; Vagotomy