Nitroprusside nitric oxide released from

NO is also a likely candidate for the NANC messenger of the myenteric plexus of neurons in the gastrointestinal tract, which mediate peristaltic movements. These neurons are rich in NO synthase and inhibitors of this enzyme prevent the nerve-evoked relaxation of the gut [12]. Nitric oxide released from nitroprusside also stimulates ADP ribosylation of glyceradehyde 3-phosphate dehydrogenase [56]. Consequently, there may be a number of enzymes, which are probably Fe-centered, that may be activated by NO. 

A) Nitric oxide is synthesized in vascular endothelium and the brain Nitric oxide is released from storage vesicles by acetylcholine Nitric oxide is released from exogenous molecules, eg, nitrates and nitroprusside Nitric oxide synthase is stimulated by histamine Nitric oxide synthase exists in both inducible and constitutive forms With regard to distribution of a drug from the blood into tissues (A) Blood flow to the tissue is an important determinant... 

The therapeutic effects of sodium nitroprusside depend on release of nitric oxide which relaxes vascular muscle. Sodium nitroprusside is best formulated as a nitrosonium (NO+) complex. Its in vivo activation is probably achieved by reduction to [Fe(CN)5NO]3, which then releases cyanide to give [Fe(CN)4NO]2, which in turn releases nitric oxide and additional CN to yield aquated Fe(II) species and [Fe(CN)6]4 (502). There are problems associated with its use, namely reduced activity due to photolysis (501) and its oxidative breakdown due to the action of an activated immune system (503), both of which release cyanide from the low-spin d6 iron complex. 

Fig. 1. The EDRF/NO pathway in vascular smooth muscle. Vasodilatation by nitrates at a cellular level. Nitrates, nitrites, and nitroprusside-Na are able to release nitric oxide (NO), which stimulates the conversion of GTP into cyclic guanosine monophosphate (cGMP), thus causing vasodilatation. The release of EDRF (=NO) from endothelial cells can be stimulated by various endogenous compounds. Endogenous EDRF (=NO) then causes vasodilatation, similar to the NO released by...

Release of nitric oxide from drug or endothelium Nitroprusside, hydralazine, nitrates,1 histamine, acetylcholine... 

Sodium nitroprusside is used for the short-term control of severe hypertension and can improve cardiac function in patients with left ventricular failure see Chapter 34). Nitroprusside acts by releasing nitric oxide (NO). NO activates the guanylyl cyclase-cyclic GMP-PKG pathway, leading to vasodilation. The mechanism of release of NO likely involves both enzymatic and nonenzymatic pathways. Tolerance does not develop to nitroprusside. Nitroprusside dilates both arterioles and venules the hemodynamic response results from a combination of venous pooling and reduced arterial impedance. In subjects with normal left ventricular function, venous pooling affects cardiac output more than does the reduction of afterload cardiac output thus tends to fall. In patients with severely impaired left ventricular function and diastolic ventricular distention, the reduction of arterial impedance leads to a rise in cardiac output see Chapter 33). Sodium nitroprusside is a nonselective vasodilator, and regional distribution of blood flow is little affected by the drug. In... 

C. Nitroprusside and Diazoxide These parenteral vasodilators are used in hypertensive emergencies. Nitroprusside is a short-acting agent (duration of action is a few minutes) that must be infused continuously. The drug s mechanism of action involves the release of nitric oxide (from the molecule itself, not from the endothelium), which stimulates guanylyl cyclase and increases cGMP concentration in smooth muscle. The toxicity of nitroprusside includes excessive hypotension, tachycardia, and, if infusion is continued over several days, cumulation of cyanide or thiocyanate ions in the blood. 

B. Exogenous Nitric Oxide Donors Nitric oxide is released from several important dmgs, including nitroprusside (Chapter 11), nitrates, (Chapter 12), and nitrites. Release from nitro-prusside occurs spontaneously in the blood in the presence of oxygen, while release from nitrates and nitrites is enzymatic, intracellular, and requires the presence of thiol compounds such tis cysteine. Tolerance may develop to nitrates and nitrites if endogenous thiol compounds are depleted. 

In contrast, drugs that release endogenous nitric oxide and donors of the molecule were in use long before nitric oxide was discovered and continue to be very important in clinical medicine. The cardiovascular applications of nitroprusside (Chapter 11) and the nitrates and nitrites (Chapter 12) have been discussed. The treatments of preeclampsia and of pulmonary hypertension and acute respiratory distress syndrome are currently under clinical investigation. Early results from the pulmonary disease studies appear promising, and one preparation of nitric oxide gas (INOmax) has been approved for use in neonates with hypoxic respiratory failure. 

Nitroprusside and organic nitrites (eg, amyl nitrite) and nitrates (eg, isosorbide dinitrate) contain NO groups that can be released as nitric oxide. Arginine is the normal source of endogenous nitric oxide. Histamine stimulates the production of nitric oxide from arginine. The answer is (C). 

When the effect of nitric oxide donors on cGMP-accumulation is studied, one must take into account the rate of NO-release from the donor compound The diffusion rate of NO is quite high, because of the small size and hpophihcity of this molecule (45), Sodium nitroprusside (SNP) is often used an NO-donor. This compound is inexpensive, which is an important asset. However, the byproduct after NO-release, [Fe(CN)5], is not devoid of pharmacological activity (46) In addition, SNP is light sensitive, although in most cases this property should not rule out use of this compound. In 10-min incubations with brain slices, SNP and the NO-donors S-nitroso-acetyl-penicillamine and streptozotocin were equally effective in raising cGMP levels (unpublished). 

In view of the fact that pharmacological effects of nitroprusside, [Fe(CN)5NO], a widely recognized hypotensive agent (61—65), have been attributed to the release of nitric oxide from its reduced form, i.e., [Fe(CN)5NO], the kinetic and thermodynamic properties of both nitrosyl complexes of pentacyanoferrate-(II) and -(III) have attracted considerable attention in the past two decades (66,67). In this context, the formation of [Fe(CN)5NO] and [Fe(CN)5NO] in the direct reactions of [Fe(CN)5(H20)] and [Fe(CN)5(Fl20)] with nitric oxide, respectively, was subjected to detailed kinetic and mechanistic investigations (68-70). As presented below, the results of these studies allowed to draw valuable conclusions concerning the validity of the mechanism of NO release from nitroprusside postulated in the Hterature. 

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