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Vasodilation, also known asvasorelaxation, is the widening ofblood vessels.[1] It results from relaxation ofsmooth muscle cells within the vessel walls, in particular in the largeveins, largearteries, and smallerarterioles.[2] Blood vessel walls are composed of endothelial tissue and a basal membrane lining the lumen of the vessel, concentric smooth muscle layers on top of endothelial tissue, and anadventitia over the smooth muscle layers.[3] Relaxation of the smooth muscle layer allows the blood vessel to dilate, as it is held in a semi-constricted state by sympathetic nervous system activity.[2] Vasodilation is the opposite ofvasoconstriction, which is the narrowing of blood vessels.
When blood vesselsdilate, theflow of blood is increased due to a decrease invascular resistance and increase incardiac output[further explanation needed]. Vascular resistance is the amount of force circulating blood must overcome in order to allowperfusion of body tissues. Narrow vessels create more vascular resistance, while dilated vessels decrease vascular resistance. Vasodilation acts to increase cardiac output by decreasingafterload, −one of the four determinants of cardiac output.[4]
By expanding available area for blood to circulate, vasodilation decreasesblood pressure.[5] The response may beintrinsic (due to local processes in the surroundingtissue) orextrinsic (due tohormones or thenervous system). In addition, the response may be localized to a specificorgan (depending on themetabolic needs of a particular tissue, as during strenuous exercise), or it may be systemic (seen throughout the entiresystemic circulation).[2]
Endogenous substances anddrugs that cause vasodilation are termed vasodilators. Many of these substances areneurotransmitters released by perivascular nerves of theautonomic nervous system[6]Baroreceptors sense blood pressure and allow adaptation via the mechanisms of vasoconstriction or vasodilation to maintainhomeostasis.[2]
The primary function of vasodilation is to increase blood flow in the body to tissues that need it most. This is often in response to a localizedneed for oxygen but can occur when the tissue in question is not receiving enoughglucose,lipids, or othernutrients. Vasodilation, both localized and systemic, also facilitates immune response.[7] Localized tissues have multiple ways to increase blood flow, including releasing vasodilators, primarilyadenosine, into the localinterstitial fluid, which diffuses tocapillary beds, provoking local vasodilation.[8][9] Some physiologists have suggested that it is the lack of oxygen itself that causes capillary beds to vasodilate by the smooth musclehypoxia of the vessels in the region. This latter hypothesis is posited due to the presence ofprecapillary sphincters in capillary beds. These approaches to the mechanism of vasodilation have not been found to bemutually exclusive.[10]
Vasodilation plays a major role in immune system function. Wider blood vessels allow more blood containing immune cells and proteins to reach the infection site. Vasodilation occurs as part of the process ofinflammation, which is caused by several factors including presence of a pathogen, injury to tissues or blood vessels, andimmune complexes.[7] In severe cases, inflammation can lead tosepsis or distributive shock.[11] Vasodilation is also a major component ofanaphylaxis.[12]
Inflammation causes not only vasodilation but also causes increasedvascular permeability, allowingneutrophils,complement proteins, andantibodies to reach the site of infection or damage.[7] Elevated vascular permeability can allow excess fluid to leave blood vessels and collect in tissues resulting inedema; vasodilation prevents blood vessels from constricting to adapt to reduced volume in the vessels, causing low blood pressure andseptic shock.[11]
In the case of inflammation, vasodilation is caused bycytokines.[7]Interferon gamma,TNF-a,interleukin 1 beta, andinterleukin 12 are a few examples of some inflammatory cytokines produced by immune cells such asnatural killer cells,B cells,T cells,mast cells andmacrophages.[7] Anti-inflammatory cytokines that regulate inflammation and help prevent negative results such as septic shock are also produced by these immune cells.[7] Vasodilation and increased vascular permeability also allow immuneeffector cells to leave blood vessels and followchemoattractants to the infection site via a process calledleukocyte extravasation.[13] Vasodilation allows the same volume of blood to move more slowly according to the flow rate equation Q = Av, where Q represents flow rate, A represents cross-sectional area, and v represents velocity.[14] Immune effector cells can more easily attach toselectins expressed on endothelial cells when blood is flowing slowly, enabling these cells to exit the blood vessel viadiapedesis.[13]
Anaphylaxis is a severe allergic reaction characterized by elevated vascular permeability, systemic vasodilation, gastrointestinal dysfunction, and respiratory dysfunction.[15]Anaphylatoxins, specificallycomplement proteins C3a and C5a, bind to receptors on mast cells and basophils causingdegranulation.[12] Granules in these cells containhistamine,platelet-activating factor, and other compounds causing clinical manifestation of anaphylaxis- including systemic vasodilation causing dangerously low blood pressure.[12]Immunoglobulin E, an antibody produced byplasma cells, also binds to receptors on mast cells and basophils causing degranulation.[12]
A basic understanding ofcardiac output,vascular resistance, andblood pressure is necessary to understand the causes and impacts of vasodilation. Cardiac output is defined as the amount of blood pumped through the heart over 1 minute, in units of liters per minute, equal toheart rate multiplied bystroke volume.[4] It is directly related toheart rate,myocardial contractility, andpreload, and inversely related withafterload.[4] Elevated vascular resistance due to constricted blood vessels causes in increase in afterload, the amount of force against which the heart must contract.[4] Vasodilation therefore decreases vascular resistance, which decreases afterload, elevating cardiac output and allowing perfusion of tissues. Blood pressure measures how much pressure blood exerts on blood vessel walls;systolic blood pressure measures pressure while the heart contracts (systole), anddiastolic blood pressure reflects pressure between contractions (diastole).Mean arterial pressure (MAP)is a weighted average of systolic and diastolic blood pressures, and is a better measurement of perfusion over the duration of the cardiac cycle.[16] Vasodilation works to decrease vascular resistance and blood pressure through relaxation of smooth muscle cells in thetunica media layer of largearteries and smaller arterioles.[17] When vasodilation causes systolic blood pressure to fall below 90 mmHg,circulatory shock is observed.[11]
Vascular resistance depends on several factors, including the length of the vessel, the viscosity of blood (determined byhematocrit) and the diameter of the blood vessel.[18] The latter is the most important variable in determining resistance, with the vascular resistance changing by the fourth power of the radius.[2] An increase in either of these physiological components (cardiac output or vascular resistance) causes a rise in MAP.Arterioles create the most vascular resistance of any blood vessel type, as they are very narrow and possess concentric layers of smooth muscle unlikevenules andcapillaries.[2]
Vasodilation occurs in superficial blood vessels ofwarm-blooded animals when their ambient environment is hot; this process diverts the flow of heated blood to the skin of the animal, where heat can be more easily released to the environment. The opposite physiological process isvasoconstriction. These processes are naturally modulated by localparacrine agents fromendothelial cells (e.g.,nitric oxide,bradykinin,potassium ions, andadenosine), and by theautonomic nervous system and theadrenal glands, both of which secretecatecholamines, such asnorepinephrine andepinephrine, respectively.[19][20]
Thetunica media of the walls of arteries, arterioles, and veins is composed ofsmooth muscle and causes vasodilation and vasoconstriction.[3] Contraction of smooth muscle cells causes vasoconstriction, and relaxation of smooth muscle causes vasodilation.[1] Smooth muscle is innervated by theautonomic nervous system and is non-striated (does not contain sarcomeres).[21] Contraction is dependent on concentrations of Ca2+ in the cytosol, either via Ca,Mg-ATPase from thesarcoplasmic reticulum or voltage-gated calcium channels from the extracellular matrix.[21] Calcium ions bind withcalmodulin, activatingmyosin light-chain kinase whichphosphorylates the myosin light-chain.[21] Phosphorylated light-chain myosin interacts withactin filaments forming across-bridge, allowing muscle contraction causing vasoconstriction.[21] Vasodilation is caused bymyosin-light-chain phosphatase, whichdephosphorylates the myosin light chain causing muscle relaxation.[21] Smooth muscle cells can remain contracted without use of ATP due to action of the myosin-binding subunit of myosin light-chain phosphatase. Phosphorylation of this subunit byRho-kinase prevents it from binding to and dephosphorylating the myosin light-chain, allowing the cell to remain contracted.[21]
Vasodilation is the result of relaxation insmooth muscle surrounding the blood vessels. This relaxation, in turn, relies on removing the stimulus for contraction, which depends on intracellular calcium ion concentrations and is tightly linked withphosphorylation of the light chain of the contractile proteinmyosin. Thus, vasodilation works mainly either by lowering intracellular calcium concentration or by dephosphorylation (really substitution of ATP for ADP) of myosin.Dephosphorylation bymyosin light-chain phosphatase and induction of calciumsymporters andantiporters that pumpcalcium ions out of the intracellular compartment both contribute to smooth muscle cell relaxation and therefore vasodilation. This is accomplished through reuptake of ions into thesarcoplasmic reticulum via exchangers and expulsion across the plasma membrane.[22] There are three main intracellular stimuli that can result in the vasodilation of blood vessels. The specific mechanisms to accomplish these effects vary from vasodilator to vasodilator.[citation needed]
| Class | Description | Example |
|---|---|---|
| Hyperpolarization-mediated (Calcium channel blocker) | Changes in theresting membrane potential of the cell affects the level of intracellular calcium through modulation ofvoltage-sensitive calcium channels in the plasma membrane. | adenosine |
| cAMP-mediated | Adrenergic stimulation results in elevated levels of cAMP andprotein kinase A, which results in increasing calcium removal from the cytoplasm. | prostacyclin |
| cGMP-mediated (Nitrovasodilator) | Through stimulation ofprotein kinase G. | nitric oxide |
PDE5 inhibitors andpotassium channel openers can also have similar results.
Compounds that mediate the above mechanisms may be grouped asendogenous andexogenous.
| Vasodilators[23] | Receptor (↑ = opens. ↓ = closes)[23] Onvascular smooth muscle cells if not otherwise specified | Transduction (↑ = increases. ↓ = decreases)[23] |
|---|---|---|
| EDHF | ? | hyperpolarization → ↓VDCC → ↓intracellular Ca2+ |
| PKG activity → | ||
| NO receptor onendothelium | ↓endothelin synthesis[24] | |
| epinephrine (adrenaline)(Vasoconstrictor) | β-2 adrenergic receptor | ↑Gs activity → ↑AC activity → ↑cAMP → ↑PKA activity → phosphorylation ofMLCK → ↓MLCK activity → dephosphorylation of MLC |
| histamine | histamine H2 receptor | |
| prostacyclin | IP receptor | |
| prostaglandin D2 | DP receptor | |
| prostaglandin E2 | EP receptor | |
| VIP | VIP receptor | ↑Gs activity → ↑AC activity → ↑cAMP → ↑PKA activity →
|
| (extracellular)adenosine | A1,A2a andA2badenosine receptors | ↑ATP-sensitive K+ channel → hyperpolarization → closeVDCC → ↓intracellular Ca2+ |
| ↑P2Y receptor | activateGq → ↑PLC activity → ↑intracellular Ca2+ → ↑NOS activity → ↑NO → (see nitric oxide) | |
| L-arginine | imidazoline andα-2 receptor? | Gi → ↓cAMP → activation ofNa+/K+-ATPase[25] → ↓intracellularNa+ → ↑Na+/Ca2+ exchanger activity → ↓intracellular Ca2+ |
| bradykinin | bradykinin receptor | |
| substance P | ||
| niacin (as nicotinic acid only) | ||
| platelet-activating factor (PAF) | ||
| CO2 | - | ↓interstitialpH → ?[26] |
| interstitiallactic acid (probably) | - | |
| muscle work | - |
|
| various receptors onendothelium | ↓endothelin synthesis[24] |
The vasodilating action of activation ofbeta-2 receptors (such as by adrenaline) appears to beendothelium-independent.[27]
As referenced in the explanation of smooth muscle physiology, smooth muscle within the tunica media is innervated by the autonomic nervous system. Theautonomic nervous system (ANS) controls essential involuntary body functions and originates as nerves leaving thebrain stem or spinal cord; it contains both sensor and motor nerves.[2] The two divisions of the ANS, thesympathetic nervous system (SNS) and theparasympathetic nervous system (PSNS), impact blood vessels differently.[2] Traditionally we understand that these two divisions work against each other, the SNS producing "fight or flight" and the PSNS producing "rest and digest", but in the case of vascular innervation this line becomes blurred[6] ANS nerves do not directly innervate the vasculature via synapses with muscle cells; instead, they releaseneurotransmitters that reach target cells and effect smooth muscle contraction or relaxation.[6] Physical characteristics of the SNS and PSNS cause the SNS to have a prolonged, systemic impact on blood vessels, while the PSNS causes short-lived, localized change.[2] SNS stimulation causes a base level of vasoconstriction often referred to as basal neural tone, maintaining blood pressure.[2] Often vasodilation is simply the result of insufficient neurotransmitter to maintain basal neural tone, without the presence of a compound directly causing vasodilation.[2]
Neurotransmitters can act by binding directly to smooth muscle cells or by binding to endothelial cells mediating the effects of the neurotransmitter.[6] Below is a table summarizing major neurotransmitters involved in regulation of the vasculature.
| Neurotransmitter | Sympathetic or Parasympathetic | Target Cells and Receptors | Impact on Vasculature |
|---|---|---|---|
| norepinephrine (NE) | sympathetic (mostly) | adrenergic receptors α1, α2, β1, β2 α1- smooth muscle α2- endothelial β1, β2- smooth muscle | α1- increase concentration calcium ions, vasoconstricton[6] α2- inhibit cAMP, release NO, vasodilation[6] β1, β2- possible vasodilation[6] |
| Acetylcholine (Ach) | parasympathetic | nicotonic Ach receptors (nAchRs) muscanaric Ach receptors (mAchRs) - on both endothelial and smooth muscle cells[6] | nAchRs- modulate cytokines, counteract inflammation[6] mAchRs- endothelial M3 AchR release NO, vasodlation smooth muscle M2 and M3 AchRs reduce release NO, vasoconstriction Note: Ach is quickly broken down, diffused, or undergoes reuptake, impacts are brief and localized[2] |
| Adenosine triphosphate (ATP) | sympathetic | purinergic receptors on smooth muscle and endothelial cells[6] | smooth muscle- increase calcium ion concentration, vasoconstriction[6] endothelium- possible role as mediator of hyperpolarization of smooth muscle cells[6] co-released with norepinephrine[2] |
| Neuropeptide Y (NPY) | sympathetic | receptors on endothelial cells | causes vasoconstriction when co-released with norepinephrine[6] |
| CGRP | ? | CGRP1, CGRP2 receptors in endothelium[6] | vasodilation, role in vascular dysfunction if levels are abnormal[6] |
Also worthy of mention when discussing neural control of vasodilation is the renin-angiotensin-aldosterone system, or RAAS.[2] The kidneys retain water by reabsorbing sodium ions, or eliminate water by eliminating sodium ions.[28] Sympathetic nervous system activity, reduced blood volume or reduced arterial pressure trigger β-adrenergic receptors in select kidney cells[2] to releaserenin, which converts facilitates formation of angiotensin II from its substrateangiotensin.[28] Angiotensin II triggersadrenal glands to secretealdosterone, a potent vasoconstrictor.[28]
Epinephrine, either exogenous or endogenous, is another vasoconstrictor released by the adrenal glands in response to stress.[28] It binds to α and β adrenergic receptors likenorepinephrine, causing vasodilation and vasoconstriction in different body parts to redistribute circulation to critical areas.[2]
Cold-induced vasodilation (CIVD) occurs after cold exposure, possibly to reduce the risk of injury. It can take place in several locations in the human body but is observed most often in the extremities. The fingers are especially common because they are exposed most often.[citation needed]
When the fingers are exposed to cold,vasoconstriction occurs first to reduce heat loss, resulting in strong cooling of the fingers. Approximately five to ten minutes after the start of the cold exposure of the hand, the blood vessels in the finger tips will suddenly vasodilate. This is probably caused by a sudden decrease in the release ofneurotransmitters from thesympathetic nerves to the muscular coat of thearteriovenous anastomoses due to local cold. The CIVD increases blood flow and subsequently the temperature of the fingers. This can be painful and is sometimes known as the 'hot aches' which can be painful enough to bring on vomiting.[citation needed]
A new phase of vasoconstriction follows the vasodilation, after which the process repeats itself. This is called theHunting reaction. Experiments have shown that three other vascular responses to immersion of the finger in cold water are possible: a continuous state of vasoconstriction; slow, steady, and continuous rewarming; and a proportional control form in which the blood vessel diameter remains constant after an initial phase of vasoconstriction. However, the vast majority of responses can be classified as the Hunting reaction.[29]
| This sectionneeds morereliable medical references forverification or relies too heavily onprimary sources. Please review the contents of the section andadd the appropriate references if you can. Unsourced or poorly sourced material may be challenged andremoved.Find sources: "Vasodilation" – news ·newspapers ·books ·scholar ·JSTOR(March 2022) | |
These drugs can keep vessels staying opened or help vessels refrain from being narrowed.[47]
Drugs that appear to work by activating theα2A receptors in the brain thereby decreasingsympathetic nervous system activity.[48][47]
Directly relax the muscle in the walls of the blood vessels (especially the arterioles), allowing the vessel to dilate (widen).[47]
Vasodilators are used to treat conditions such ashypertension, wherein the patient has an abnormally high blood pressure, as well asangina,congestive heart failure, anderectile dysfunction, and where maintaining a lower blood pressure reduces the patient's risk of developing other cardiac problems.[17]Flushing may be a physiological response to vasodilators. Somephosphodiesterase inhibitors such assildenafil,vardenafil andtadalafil, work to increase blood flow in the penis through vasodilation. They may also be used to treatpulmonary arterial hypertension (PAH).
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