Smooth muscle vascular

Nontraditional Hormones. Novel hormones identified ia cardiovascular tissue have profound effects on maintenance of blood pressure and blood volume ia mammals. Atrial natriuretic hormone (ANH) is a polypeptide hormone secreted from the atria of the heart. When the cardiac atrium is stretched by increased blood volume, secretion of ANH is stimulated ANH ia turn increases salt and water excretion and reduces blood pressure (6). Endothelin is a polypeptide hormone secreted by endothehal cells throughout the vasculature. Although endothelin is released into the circulation, it acts locally in a paracrine fashion to constrict adjacent vascular smooth muscle and increase blood pressure (7). 

Lead is toxic to the kidney, cardiovascular system, developiag red blood cells, and the nervous system. The toxicity of lead to the kidney is manifested by chronic nephropathy and appears to result from long-term, relatively high dose exposure to lead. It appears that the toxicity of lead to the kidney results from effects on the cells lining the proximal tubules. Lead inhibits the metaboHc activation of vitamin D in these cells, and induces the formation of dense lead—protein complexes, causing a progressive destmction of the proximal tubules (13). Lead has been impHcated in causing hypertension as a result of a direct action on vascular smooth muscle as well as the toxic effects on the kidneys (12,13). 

ANPs play an important role in the maintenance of cardiovascular homeostasis by counterbalancing the renin—angiotensin (RAS) system. ANP, the main circulating form of the natriuretic peptides, effectively relaxes vascular smooth muscle, promotes the excretion of sodium and water, and in the CNS inhibits vasopressin release and antagonizes AT-II induced thirst. 

Amiodarone dilates arteriolar vascular smooth muscle, especiady coronary arteries, and thus exhibits antianginal effects. Its effects on the peripheral vasculature to decrease resistance leads to a decrease in left ventricular stroke work and a decrease in myocardial oxygen consumption. The dmg rarely produces hypotension that requires discontinuation of the dmg (1,2). 

The precise mechanism of nitrate action is not cleady understood and may be a combination of many factors. The basic pharmacologic action of nitrates is a relaxation of most vascular smooth muscle, eg, vascular, bronchial, gastrointestinal, uretal, uterine, etc. Vascular smooth muscle relaxation is a... 

Calcium and Vascular Smooth Muscle Contraction. Calcium acts on a number of sites associated with the control of the cytoplasmic calcium concentration. Vascular smooth muscle contraction can be initiated by the opening of the slow calcium channel aUowing influx of extraceUular calcium through the sarcolemmal membrane into the cytoplasmic compartment. The iatraceUnlar calcium concentration increases to 1 x 10 Af, a threshold concentration necessary to initiate contraction. 

Nitroprusside. Nitropmsside is a poteat, fast-actiag vasodilator that has to be administered iatravenously by iafusion. It relaxes arterial and venous vascular smooth muscle. Its use is mainly ia hyperteasive crises. Its effects terminate as sooa as iafusioa of the dmg is stopped. 

The resting membrane potential of most excitable cells is around —60 to —80 mV. This gradient is maintained by the activity of various ion channels. When the potassium channels of the cell open, potassium efflux occurs and hyperpolari2ation results. This decreases calcium channel openings, which ia turn preveats the influx of calcium iato the cell lea ding to a decrease ia iatraceUular calcium ia the smooth muscles of the vasculature. The vascular smooth muscles thea relax and the systemic blood pressure faUs. 

Excitation of smooth muscle via alpha-1 receptors (eg, in the utems, vascular smooth muscle) is accompanied by an increase in intraceUular-free calcium, possibly by stimulation of phosphoUpase C which accelerates the breakdown of polyphosphoinositides to form the second messengers inositol triphosphate (IP3) and diacylglycerol (DAG). IP3 releases intracellular calcium, and DAG, by activation of protein kinase C, may also contribute to signal transduction. In addition, it is also thought that alpha-1 adrenergic receptors may be coupled to another second messenger, a pertussis toxin-sensitive G-protein that mediates the translocation of extracellular calcium. 

Vasoconstrictor. A drug that causes a contraction of the vascular smooth muscle, thus increasing the resistance to blood flow. 

The calcification of atherosclerotic plaques may be induced by osteopontin expression, since osteopontin is a protein with a well-characterized role in bone formation and calcification. Vascular smooth muscle cell migration on osteopontin is dq endent on the integrin av 33 and antagonists of av 33 prevent both smooth muscle cell migration and restenosis in some animal model [8]. 

In addition to intracellular heme-containing proteins, big-conductance calcium-dependent K+ (BKCa) channels and calcium-spark activated transient Kca channels in plasma membrane are also tar geted by CO [3]. As well known, nitric oxide (NO) also activates BKca channels in vascular smooth muscle cells. While both NO and CO open BKCa channels, CO mainly acts on alpha subunit of BKCa channels and NO mainly acts on beta subunit of BKca channels in vascular smooth muscle cells. Rather than a redundant machinery, CO and NO provide a coordinated regulation of BKca channel function by acting on different subunits of the same protein complex. Furthermore, pretreatment of vascular smooth muscle... 

Human umbilical vein endothelial cells (HUVEC) express the isoforms ECE-la, -lb, -Id and ECE-2. In these cells, ET-1 is secreted via both a constitutive and a regulated pathway. The ratio of released ET-1 big-ET-1 is 4 1. About 80% of the ET-1 is secreted at the abluminal cell surface of endothelial cells. ECE-isoforms are abundantly expressed on the cell surface of endothelial cells and to a lower level also on vascular smooth muscle cells. In atherosclerotic lesions of vessels, however, ECE expression in smooth muscle cells is upregulated. ECE isoforms expressed in smooth muscle cells contribute significantly to the generation of mature ET in normal and in particular atherosclerotic vessels. 

The ETa receptor activates G proteins of the Gq/n and G12/i3 family. The ETB receptor stimulates G proteins of the G and Gq/11 family. In endothelial cells, activation of the ETB receptor stimulates the release of NO and prostacyclin (PGI2) via pertussis toxin-sensitive G proteins. In smooth muscle cells, the activation of ETA receptors leads to an increase of intracellular calcium via pertussis toxin-insensitive G proteins of the Gq/11 family and to an activation of Rho proteins most likely via G proteins of the Gi2/i3 family. Increase of intracellular calcium results in a calmodulin-dependent activation of the myosin light chain kinase (MLCK, Fig. 2). MLCK phosphorylates the 20 kDa myosin light chain (MLC-20), which then stimulates actin-myosin interaction of vascular smooth muscle cells resulting in vasoconstriction. Since activated Rho... 

ET-1 also stimulates anti-apoptotic signal cascades in fibroblasts, vascular smooth muscles and endothelial cells (via phosphatidylinositol-3-kinase and Akt/pro-tein kinase B). In prostate and ovarian cancer, upregulation of endothelin synthesis and ETA receptors has been associated with a progression of the disease. The inhibiton of ETA receptors results in a reduced tumour growth. In malignant melanoma, ETB receptors are associated with tumour progression. Endothelins can also stimulate apoptosis in stretch-activated vessels via the ETB receptor, which contrasts the above-mentioned effects. The molecular basis for these differential anti- and pro-apoptotic reactions mediated by endothelins remains elusive. 

Sites of endothelin-receptor expression. ETA receptors are expressed in the smooth muscle cells of the vascular medial layer and the airways, in cardiac myocytes, lung parenchyma, bronchiolar epithelial cells and prostate epithelial cells. ETB receptors are expressed in endothelial cells, in bronchiolar smooth muscle cells, vascular smooth muscle cells of certain vessels (e.g. saphenous vein, internal mammary artety), in the renal proximal and distal tubule, the renal collecting duct and in the cells of the atrioventricular conducting system. 

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