cyclic-gmp and Shock

Methylene blue is used primarily in the treatment of patients with methemoglobinemia. Most recently, methylene blue has been used as a treatment for refractory distributive shock from a variety of causes such as sepsis and anaphylaxis. Many studies suggest that the nitric oxide-cyclic guanosine monophosphate (NO-cGMP) pathway plays a significant role in the pathophysiology of distributive shock. There are some experimental and clinical experiences with the use of methylene blue as a selective inhibitor of the NO-cGMP pathway. Methylene blue may play a role in the treatment of distributive shock when standard treatment fails.

Topics: Anaphylaxis; Animals; Antidotes; Cyclic GMP; Drug Resistance; Endothelium, Vascular; Enzyme Inhibitors; Humans; Isoenzymes; Methylene Blue; Models, Biological; Muscle, Smooth, Vascular; Nitric Oxide; Nitric Oxide Synthase; Second Messenger Systems; Sepsis; Shock; Shock, Cardiogenic; Vascular Resistance

Amlodipine is a potent vasodilator with a long half-life and delayed onset of action that is particularly concerning after an overdose. Vasodilation occurs through stimulation of nitric oxide release with increased cyclic guanosine monophosphate (cGMP) production. Methylene blue inhibits guanylate cyclase. This enzyme is responsible for the production of cGMP. Methylene blue also has the ability to scavenge nitric oxide, as well as inhibit nitric oxide synthase. We report the use of methylene blue for refractory shock in a patient with amlodipine toxicity.

Topics: Adult; Amlodipine; Cyclic GMP; Female; Humans; Methylene Blue; Shock; Vasodilator Agents

Refractory hypotension is a frequent event during reperfusion of a liver graft. Measures that help maintain hemodynamic stability include correction of electrolytes and acid-base abnormalities as well as administration of fluid and/or catecholamines. Vasoplegic syndrome represents the most severe form of hemodynamic instability. Management of this condition is very difficult due primarily to the inadequate response to even very high doses of catecholamines.. A 60-year-old patient presented for liver transplantation due to end stage liver disease. After an initially uneventful hepatic phase, the patient developed excessive tachycardia and refractory hypotension during cross-clamping of the vena cava. The situation rapidly deteriorated despite administration of fluid and extremely high doses of norepinephrine and vasopressin. A transesophageal echocardiogram (TEE) performed at that time failed to demonstrate any cardiac dysfunction or signs of pulmonary emboli. Subsequent blood cultures and imaging studies did not confirm any signs of sepsis. Further investigation revealed an increased preoperative level of cyclic guanosine monophosphate (cGMP). cGMP is the second messenger for nitric oxide, and is responsible for relaxation of vascular smooth muscle with subsequent vasodilatation. This finding suggests a release of nitric oxide in the systemic circulation which could have been a potential cause for vasoplegic shock.. Release of nitric oxide in the systemic circulation can be a potential cause of vasoplegic syndrome. Future investigation will demonstrate whether a patient's preoperative cGMP plasma level can be a potential predictor of intraoperative hemodynamic instability.

Topics: Cyclic GMP; Hemodynamics; Humans; Liver Transplantation; Middle Aged; Nitric Oxide; Preoperative Care; Shock; Vasodilation; Vasoplegia

At present, the clinical management inflammatory vasoplegia associated to sepsis or anaphylaxis is symptomatic. Volume is expanded by means of administration of fluids, and low blood pressure is managed by means of administration of positive inotropes and vasoconstrictors. This therapeutic approach is mainly associated to the cyclic AMP (cAMP) and, many times the circulatory shock is refractory to high amines concentrations. However, beside of cAMP-dependent vasoreactivity mechanisms there are other two known vasoplegia involved mechanisms: cyclic GMP (cGMP) and hyperpolarization that is less clinically considered. Also, it is possible to speculate about 'probable vasopressin deficiency'. Methylene blue (MB) is the most useful and clinically safe cGMP blocker. We propose a decision tree for diagnosis and institution of this therapeutical approach many times underestimate by intensive care and emergency teams.

Topics: Animals; Blood Circulation; Blood Pressure; Catecholamines; Critical Care; Cyclic GMP; Emergency Medicine; Humans; Inflammation; Lactates; Methylene Blue; Models, Biological; Nitric Oxide; Norepinephrine; Shock

Clinical and experimental observations prove that heparin-neutralizing doses of protamine increase pulmonary artery pressures and decrease systemic BP. Protamine also increases myocardial oxygen consumption, cardiac output, and heart rate, and decreases systemic vascular resistance. These cardiovascular effects have clinical consequences that have justified studies in this area. Protamine adverse reactions usually have three different categories: systemic hypotension, anaphylactoid reactions, and catastrophic pulmonary vasoconstriction. The precise mechanism that explains protamine-mediated systemic hypotension is unknown. Four experimental protocols performed at Mayo Clinic, Rochester, MN, studied the intrinsic mechanism of protamine vasodilation. The first study reported in vitro systemic and coronary vasodilation after protamine infusion. The second in vitro study suggested that the pulmonary circulation is extensively involved in the protamine-mediated effects on endothelial function. The third study, carried out in anesthetized dogs, reported the methylene blue and nitric oxide synthase blockers neutralization of the protamine vasodilatatory effects. The fourth study suggested that protamine also causes endothelium-dependent vasodilation in heart microvessels and conductance arteries by different mechanisms including hyperpolarization. Reviewing these experimental results and our clinical experience, we suggest methylene blue as a novel approach to prevent and treat hemodynamic complications caused by the use of protamine after cardiopulmonary bypass. In the absence of prospective clinical trials, a growing body of cumulative clinical evidence suggests that methylene blue may be strongly considered as a therapeutic approach in the treatment of distributive shock.

Topics: Anaphylaxis; Animals; Cyclic GMP; Endothelium, Vascular; Hemodynamics; Humans; Methylene Blue; Nitric Oxide; Protamines; Shock

This work was done on rat tourniquet shock (ToS) model. It was found that reactivity of isolated perfused aortic ring to noradrenaline decreased, while cGMP content of the aortic tissue increased. These changes could be potentiated by perfusion with L-arginine (NO-precursor). On the other side, when the aortic ring was perfused with L-NNA (NO-synthesis inhibitor) or methylene blue (soluble cGMPase inhibitor), the changes could be attenuated. The effect of these drugs are independent of the presence of vascular endothelium. The results suggest that non-endothelium-derived NO-like relaxing factor may be one of the factors causing low vascular reactivity of the ToS animals.

Topics: Animals; Cyclic GMP; Guanylate Cyclase; Male; Methylene Blue; Nitric Oxide; Nitric Oxide Synthase; Nitroarginine; Rats; Rats, Wistar; Shock; Tourniquets; Vasoconstriction

Nitric oxide and atrial natriuretic peptides are the main activators of guanylyl cyclases, which transform GTP into cyclic GMP and thereby contribute to the decrease of vascular tone. To investigate the increase, if any, of plasma cyclic GMP concentrations in human patients with hyperdynamic circulation resulting from acute liver failure and to ascertain whether guanylyl cyclase activation is involved in the decline of systemic vascular resistance that occurs in this pathophysiological condition, we simultaneously recorded hemodynamic data and cyclic GMP levels in patients with fulminant liver failure before and after liver transplantation and in normokinetic patients undergoing abdominal nonseptic surgery. We also compared these data with those recorded in patients with hyperkinetic shock resulting from gram-negative sepsis or nitric oxide-independent vasomotor agent (carbamate) over-dose. In all these patients we simultaneously studied kidney function, platelet counts and atrial natriuretic peptides. Patients with fulminant liver failure had higher cyclic GMP concentrations than did control patients undergoing abdominal surgery (11.02 +/- 1.55 pmol.ml-1 vs. 1.77 +/- 0.18 pmol.ml-1, p < 0.001). At similar heart-loading conditions these concentrations were lower than those in gram-negative septic shock (18.2 +/- 1.35 pmol.ml-1, p < 0.05) but higher than those in carbamate-induced shock (3.6 +/- 0.7 pmol.ml-1, p < 0.01). In addition, cyclic GMP concentrations significantly decreased from the fulminant liver failure period to the posttransplantation period, although atrial natriuretic peptide levels did not change significantly and kidney function worsened.(ABSTRACT TRUNCATED AT 250 WORDS)

Topics: Adolescent; Adult; Atrial Natriuretic Factor; Blood Circulation; Carbamates; Cyclic GMP; Female; Guanylate Cyclase; Hemodynamics; Hepatic Encephalopathy; Humans; Kidney; Liver Failure, Acute; Liver Transplantation; Male; Middle Aged; Platelet Count; Prospective Studies; Shock; Shock, Septic; Vascular Resistance

On tourniquet shock (ToS) rat model, it was found that the reactivity of isolated perfused aortic ring to noradrenaline was decreased, while the cGMP content of the aortic tissue was increased. These ToS-induced changes could be potentiated or attenuated respectively by perfusion with NO-precursor, L-arginine, or NO-synthesis inhibitor L-NNA independent of the presence of vascular endothelium. Guanylate cyclase inhibitor, methylene blue, could also attenuate the aortic reactivity. All these results suggest that the aortic musculature can produce a NO-LRF factor capable of lowering the vascular reactivity of the ToS animals. That L-arginine can ameliorate while L-NNA can exacerbate ToS, suggest that NO-LRF do play an adaptive role in the protective mechanism of the organism during ToS.

Topics: Animals; Aorta; Arginine; Blood Pressure; Cyclic GMP; In Vitro Techniques; Male; Nitric Oxide; Nitroarginine; Rats; Rats, Wistar; Shock; Tourniquets; Vasodilator Agents

Previous studies have shown that when atrial natriuretic peptide (ANF) is given to anaesthetized dogs with hypovolemic acute pancreatitis, it will produce a diuresis and natriuresis but will not elevate the glomerular filtration rate (GFR). When the same dose of peptide is given to dogs equally hypovolemic (hemorrhage) but without pancreatitis, a brisk increment in GFR occurs. GFR will, however, rise in dogs with pancreatitis in response to other peptides, such as glucagon. In these studies we assessed cGMP excretion as a marker for ANF effect in both normal anaesthetized dogs and dogs with acute experimental pancreatitis. In each group, urinary output and sodium excretion increased significantly, but GFR rose only in the control group. Urinary excretion of cGMP rose equally and dramatically in both control and experimental animals. We conclude that GFR is prevented from rising in dogs with experimental pancreatitis following ANF, but this effect does not depend on depressed cGMP generation.

Topics: Acute Disease; Animals; Atrial Natriuretic Factor; Cyclic GMP; Dogs; Female; Glomerular Filtration Rate; Infusions, Intravenous; Male; Pancreatitis; Shock

The effects of dexamethasone sodium phosphate (DSP), 5 mg/kg, administration on the biochemical alterations in hepatic tissue subsequent to the production os splanchnic artery occlusion (SAO) shock was investigated. Following the induction of SAO shock, DSP-treated dogs exhibited a significantly improved cardiovascular status compared to placebo-treated shocked dogs, 2 hr after release of the occlusion, biopsies of the liver were taken and analyzed for beta-glucuronidase (BG), adenosine-3',5'-cyclic monophosphate (cAMP) and guanosine-3',5'-cyclic monophosphate (cGMP) content. SAO shock produced a significant increase in hepatic free BG activity which was reversed by DSP pretreatment. Additionally, SAO shock decreased hepatic cAMP levels, increased cGMP levels and significantly lowered the hepatic ratio of cAMP/cGMP. These changes in cyclic nucleotide levels were reversed by DSP administration and were found to be inversely related to changes in hepatic free BG activity. Thus, the ratio of cellular cAMP/cGMP may function as a regulatory mechanism for lysosomal enzyme release secondary to ischemia and hypoxia. Further, DSP may act to maintain lysosomal integrity in ischemic tissues by preservation of cAMP/cGMP ratios.

Topics: Animals; Cyclic AMP; Cyclic GMP; Dexamethasone; Dogs; Female; Glucuronidase; Liver; Lysosomes; Male; Shock; Time Factors