Vascular smooth muscle stimulation

A slow intravenous injection of histamine produces marked vasodilation of the arterioles, capillaries, and venules. This causes a fall in blood pressure whose magnitude depends on the concentration of histamine injected, the degree of baroreceptor reflex compensation, and the extent of histamine-induced release of adrenal catecholamines. Vasodilation of cutaneous blood vessels reddens the skin of the face, while a throbbing headache can result from vasodilation of brain arterioles. Vasodilation is mediated through both Hj- and Hj-receptors on vascular smooth muscle. Stimulation of Hj-receptors produces a rapid and short-lived response, whereas stimulation of H2-receptors produces a more sustained response that is slower in onset. Stimulation of Hj-receptors on sympathetic nerve terminals inhibits the release of norepinephrine and its associated vasoconstriction. 

Substitutions in position 8 indicate that the benzene ring of phenylalanine required for pressor activity is not needed for inhibition of uptake. The relative importance of direct and indirect action for vascular smooth-muscle stimulation is not yet known. Indeed, either the pressor response or the vascular contraction in vitro evoked by angiotensin is not blocked by adrenolytic drugs. 

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). 

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. 

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. 

RAO G N and berk b c (1992) Active oxygen species stimulate vascular smooth muscle cell growth and proto-oncogene expression Circulation Research 70, 593-9. 

Endothelin-1, one of the most potent physiologic vasoconstrictors, is an important contributor to HF pathophysiology.9 Endothelin-1 binds to two G-protein coupled receptors, endothelin-A (ET-A) and endothelin-B (ET-B). Endothelin-A receptors mediate vasoconstriction and are prevalent in vascular smooth muscle and cardiac cells. Endothelin-B receptors are expressed on the endothelium and in vascular smooth muscle, and receptor stimulation mediates vasodilation. Levels of ET-1 correlate with HF functional class and mortality. 

Sakurada S, Okamoto H, Takuwa N, Sugimoto N, Takuwa Y. Rho activation in excitatory agonist-stimulated vascular smooth muscle. Am J Physiol Cell Physiol 2001 281(2) C571-578. 

Alpha receptors are the most abundant of the adrenergic receptors. Of the two subtypes, a,-receptors are more widely distributed on the effector tissues these receptors tend to be excitatory. For example, stimulation of aj-receptors causes contraction of vascular smooth muscle, resulting in vasoconstriction. 

Hypertension, or a chronic elevation in blood pressure, is a major risk factor for coronary artery disease congestive heart failure stroke kidney failure and retinopathy. An important cause of hypertension is excessive vascular smooth muscle tone or vasoconstriction. Prazosin, an aradrenergic receptor antagonist, is very effective in management of hypertension. Because oq-receptor stimulation causes vasoconstriction, drugs that block these receptors result in vasodilation and a decrease in blood pressure. 

Beta receptors are also unevenly distributed with P2-receptors the more common subtype on the effector tissues. Beta-two receptors tend to be inhibitory for example, P2-receptor stimulation causes relaxation of vascular smooth muscle and airway smooth muscle, resulting in vasodilation and bronchodilation, respectively. Beta-two receptors have a significantly greater affinity for epinephrine than for norepinephrine. Furthermore, terminations of sympathetic pathways are not found near these receptors, so P2-receptors are stimulated only indirectly by circulating epinephrine instead of by direct sympathetic nervous activity. 

The sympathetic system also innervates vascular smooth muscle and regulates the radius of the blood vessels. All types of blood vessels except capillaries are innervated however, the most densely innervated vessels include arterioles and veins. An increase in sympathetic stimulation of vascular smooth muscle causes vasoconstriction and a decrease in stimulation causes vasodilation. Constriction of arterioles causes an increase in TPR and therefore MAP. Constriction of veins causes an increase in venous return (VR) which increases end-diastolic volume (EDV), SV (Frank-Starling law of the heart), CO, and MAP. 

Because baroreceptors respond to stretch or distension of the blood vessel walls, they are also referred to as stretch receptors. A change in blood pressure will elicit the baroreceptor reflex, which involves negative feedback responses that return blood pressure to normal (see Figure 15.6). For example, an increase in blood pressure causes distension of the aorta and carotid arteries, thus stimulating the baroreceptors. As a result, the number of afferent nerve impulses transmitted to the vasomotor center increases. The vasomotor center processes this information and adjusts the activity of the autonomic nervous system accordingly. Sympathetic stimulation of vascular smooth muscle and the heart is decreased and parasympathetic stimulation of the heart is increased. As a result, venous return, CO, and TPR decrease so that MAP is decreased back toward its normal value. 

Substances released from many cells and tissues in the body, including the endothelium lining blood vessels, endocrine glands, and myocytes in the heart, may affect vascular smooth muscle tone. These substances may stimulate this muscle to cause vasoconstriction or inhibit it to cause vasodilation. As expected, vasoconstriction will increase TPR (and therefore MAP) and vasodilation will decrease TPR (and therefore MAP). 

The major circulating hormones that influence vascular smooth muscle tone are the catecholamines epinephrine and norepinephrine. These hormones are released from the adrenal medulla in response to sympathetic nervous stimulation. In humans, 80% of catecholamine secretion is epinephrine and 20% is norepinephrine. Stimulation of cy-adrenergic receptors causes vasoconstriction. The selective a,-adrenergic receptor antagonist, prazosin, is effective in management of hypertension because it causes arterial and venous smooth muscle to relax. 

Angiotensin II causes vasoconstriction by direct stimulation of ATj receptors on the vascular smooth muscle. It also enhances release of the neurotransmitter norepinephrine from the sympathetic nerve fibers present in the blood vessels. The vasopressor effects of Ag II may be inhibited pharmacologically in order to decrease TPR and treat hypertension. An important class of orally active drugs is the ACE inhibitors, including captopril and enalopril, which prevent formation of Ag II. More recently, angiotensin receptor antagonists have been developed that act at the vascular smooth muscle. These drugs, which include losartin and valsartan, are also orally active. 

Sympathetic stimulation of veins. The smaller, more compliant veins that serve generally as blood reservoirs as well as specific blood reservoirs are densely innervated by the sympathetic system. Stimulation of the vascular smooth muscle in the walls of these vessels causes vasoconstriction and a decrease in venous compliance. Vasoconstriction increases venous pressure in the veins the blood is squeezed out of the veins and, due to the presence of one-way valves, moves toward the heart so that VR increases. A decrease in sympathetic stimulation allows the veins to relax and distend. The vessels become more compliant and capable of holding large volumes of blood at low pressures. In this case, VR decreases. 

A decrease in plasma volume leads to decreased MAP, which is detected by baroreceptors in the carotid sinuses and the arch of the aorta. By way of the vasomotor center, the baroreceptor reflex results in an overall increase in sympathetic nervous activity. This includes stimulation of the heart and vascular smooth muscle, which causes an increase in cardiac output and total peripheral resistance. These changes are responsible for the short-term regulation of blood pressure, which temporarily increases MAP toward normal. 

Cultured rat vascular smooth muscle cells (VSMCs), grown and prepared for respirometry as described in Doeller et al., 2005 [41], were injected into the respirometer chamber to a concentration of between 105 and 106 cells ml 1. Cell viability remained at >90% throughout experiments. Near 4pM 02, H2S production was stimulated by the addition of L-cysteine and PLP (Fig. 8.8). The initial H2S production rate was approximately 20% of the rat aorta homogenate rate. H2S production rate decreased after the initial rise in H2S concentration, perhaps the result of product feedback inhibition. The addition of the CGL inhibitor BCA showed an effect similar to aorta homogenate. 

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