Muscle contraction nitric oxide

The human histamine Hi-receptor is a 487 amino acid protein that is widely distributed within the body. Histamine potently stimulates smooth muscle contraction via Hi-receptors in blood vessels, airways and in the gastrointestinal tract. In vascular endothelial cells, Hi-receptor activation increases vascular permeability and the synthesis and release of prostacyclin, plateletactivating factor, Von Willebrand factor and nitric oxide thus causing inflammation and the characteristic wheal response observed in the skin. Circulating histamine in the bloodstream (from, e.g. exposure to antigens or allergens) can, via the Hi-receptor, release sufficient nitric oxide from endothelial cells to cause a profound vasodilatation and drop in blood pressure (septic and anaphylactic shock). Activation of... 

Many hormones and other blood-borne substances (including drugs) also alter contractile activity of smooth muscle. Some of the more important substances include epinephrine norepinephrine angiotensin II vasopressin oxytocin and histamine. Locally produced substances that may alter contraction in the tissue in which they are synthesized include nitric oxide prostaglandins leukotrienes carbon dioxide and hydrogen ion. 

Like nitric oxide, the discovery of the eicosanoid signalling molecules was a significant event in twentieth century physiology, due largely to research led by Sir John Vane (Nobel Prize 1982). The diverse actions of the eicosanoids include roles in muscle contraction, blood coagulation, salt and fluid homeostasis, inflammatory responses and pain sensitivity. 

Figure 22.4 Injury to endothelial cells can lead to vasospasm. Normal endothelial cells release nitric oxide (NO) which relaxes smooth muscle this is achieved by nitric oxide increasing the concentration of cyclic GMP within smooth muscle fibres and cyclic GMP relaxing the smooth muscle. Injured endothelial cells secrete very little nitric oxide but secrete more endothelin. The latter increases the formation of inositol trisphosphate (IP3), which binds to the sarcoplasmic reticulum (SR) where it stimulates the Ca ion channel. The Ca ion channel in the plasma membrane is also activated. Both effects result in an increase in cytosolic Ca ion concentration, which then stimulates contraction (vasospasm). This reduces the diameter of the lumen of the artery.

Normal endothelial cells produce nitric oxide, which relaxes smooth muscle, whereas damaged cells release less nitric oxide but more of a local hormone, endothelin, which stimulates contraction of smooth muscle (Figure 22.4). 

Activation of endothelial cell muscarinic receptors by acetylcholine (Ach) releases endothelium-derived relaxing factor (nitric oxide), which causes relaxation of vascular smooth muscle precontracted with norepinephrine, 10-8M. Removal of the endothelium by rubbing eliminates the relaxant effect and reveals contraction caused by direct action of Ach on vascular smooth muscle. (NA, noradrenaline [norepinephrine]. Numbers indicate the log concentration applied at the time indicated.)... 

Kinins produce marked vasodilation in several vascular beds, including the heart, kidney, intestine, skeletal muscle, and liver. In this respect, kinins are approximately 10 times more potent on a molar basis than histamine. The vasodilation may result from a direct inhibitory effect of kinins on arteriolar smooth muscle or may be mediated by the release of nitric oxide or vasodilator prostaglandins such as PGE2 and PGI2. In contrast, the predominant effect of kinins on veins is contraction again, this may result from direct stimulation of... 

Endothelins exert widespread actions in the body. In particular, they cause dose-dependent vasoconstriction in most vascular beds. Intravenous administration of ET-1 causes a rapid and transient decrease in arterial blood pressure followed by a prolonged increase. The depressor response results from release of prostacyclin and nitric oxide from the vascular endothelium, whereas the pressor response is due to direct contraction of vascular smooth muscle. Endothelins also exert direct positive inotropic and chronotropic actions on the heart and are potent coronary vasoconstrictors. They act on the kidneys to cause vasoconstriction and decrease glomerular filtration rate and sodium and water excretion. In the respiratory system, they cause potent contraction of tracheal and bronchial smooth muscle. 

Substance P is the most important member of the tachykinin family. It exerts a variety of incompletely understood central actions that implicate the peptide in behavior, anxiety, depression, nausea, and emesis. It is a potent arteriolar vasodilator, producing marked hypotension in humans and several animal species. The vasodilation is mediated by release of nitric oxide from the endothelium. Conversely, substance P causes contraction of venous, intestinal, and bronchial smooth muscle. It also stimulates secretion by the salivary glands and causes diuresis and natriuresis by the kidneys. 

Epidemiologic, experimental, and in vitro mechanistic data indicate that lead exposure elevates blood pressure in susceptible individuals. In populations with environmental or occupational lead exposure, blood lead concentration is linked with increases in systolic and diastolic blood pressure. Studies of middle-aged and elderly men and women have identified relatively low levels of lead exposure sustained by the general population to be an independent risk factor for hypertension. In addition, epidemiologic studies suggest that low to moderate levels of lead exposure are risk factors for increased cardiovascular mortality. Lead can also elevate blood pressure in experimental animals. The pressor effect of lead may be mediated by an interaction with calcium mediated contraction of vascular smooth muscle, as well as generation of oxidative stress and an associated interference in nitric oxide signaling pathways. 

Nearly all cells express kinin receptors that mediate the activities of both bradykinin and kallidin. The activation of these G-protein coupled receptors causes relaxation of venular smooth muscle and hypotension, increased vascular permeability, contraction of smooth muscle of the gut and airway leading to increased airway resistance, stimulation of sensory neurons, alteration of ion secretion of epithelial cells, production of nitric oxide, release of cytokines from leukocytes, and the production of eicosanoids from various cell types [11,12]. Because of this broad spectrum of activity, kinins have been implicated as an important mediator in many pathophysiologies including pain, sepsis, asthma, rheumatoid arthritis, pancreatitis, and a wide variety of other inflammatory diseases. Moreover, a recent report demonstrated that bradykinin B2 receptors on the surface of human fibroblasts were upregulated three-fold beyond normal in patients with Alzheimer s disease, implicating bradykinin as a participant in the peripheral inflammatory processes associated with that disease [13]. 

Figure 10. Scheme illustrating the main locations and functional role of H3 receptors in the vessels. H3 receptors coupled with inhibitory G proteins (Gj) occur as prejunctional receptors in the adrenergic varicosities, where they negatively modulate noradrenaline (NA) release. Moreover, their activation in endothelial cells can induce muscle relaxation, by the release of inhibitory factors, such as nitric oxide (NO) and prostacyclin (PGI2). In some districts, excitatory H3 receptors were found in muscle cells and they mediate muscle contraction. MC = mast cell NOS = NO synthase COX = cyclooxygenase. 

Hydralazine causes direct relaxation of arteriolar smooth muscle. The arteriolar vasodilatation produced by hydralazine requires an intact endothelium. Therefore, one proposed mechanism of action is that hydralazine liberates nitric oxide from the endothelium (similar to the nitrates), which in turn increases cGMP to ultimately prevent the phosphorylation of myosin light chain (which is required for smooth muscle contraction) resulting in arteriolar vasorelaxation. 

Bradykinin and related kinin peptides are produced by leucocytes and act via Gaq to elevate cytosolic Ca2+ and promote nitric oxide (NO) synthesis, smooth muscle contraction, capillary permeability, inflammation and histamine release from mast cells. 

The nitroxyls (a.k.a. nitroxides) are remarkably stable free radicals. Nitroxyls have two major resonance structures, one N-centered and one O-centered the lone electron may also be considered to be in the 7T orbital of an N=0 tt bond. Nitroxyls are thermodynamically stable because dimerization would give a very weak N-N, N-O, or 0-0 bond. TEMPO (2,2,6,6-tetramethylgiperidin-l-oxyl), a commercially available nitroxyl, is further stabilized by steric shielding. Other thermodynamically stable free radicals include the small molecules O2 (a 1,2-diradical, best represented as -0-0-) and nitric oxide ( N=0), a messenger molecule in mammals that mediates smooth muscle contraction. 

Epithelium of the central and peripheral airways have the capacity to produce and release proinflammatory mediators, such as arachidonic acid metabolites, nitric oxide, cytokines, and growth factors, and thereby modulate the progression of airway diseases [15]. In addition, substances released from central airway epithelium can influence the ability of adjacent smooth muscle to contract [16]. 

Higaki Y, Hirshman MF, Fuji N, Goodyear LJ. 2001. Nitric oxide increases glucose uptake through a mechanism that is distinct from the insulin and contraction pathways in rat skeletal muscle. Diabetes 50 241-247. 

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