Vasodilation

thumb|254x254px|Normal blood vessel (left) vs. vasodilation (right)

Vasodilation, also known as vasorelaxation, is the widening of blood vessels. It results from relaxation of smooth muscle cells within the vessel walls, in particular in the large veins, large arteries, and smaller arterioles. 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 an adventitia over the smooth muscle layers. 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. The response may be intrinsic (due to local processes in the surrounding tissue) or extrinsic (due to hormones or the nervous system). In addition, the response may be localized to a specific organ (depending on the metabolic needs of a particular tissue, as during strenuous exercise), or it may be systemic (seen throughout the entire systemic circulation). Baroreceptors sense blood pressure and allow adaptation via the mechanisms of vasoconstriction or vasodilation to maintain homeostasis. Localized tissues have multiple ways to increase blood flow, including releasing vasodilators, primarily adenosine, into the local interstitial fluid, which diffuses to capillary beds, provoking local vasodilation. Some physiologists have suggested that it is the lack of oxygen itself that causes capillary beds to vasodilate by the smooth muscle hypoxia of the vessels in the region. This latter hypothesis is posited due to the presence of precapillary sphincters in capillary beds. These approaches to the mechanism of vasodilation have not been found to be mutually exclusive.

Immune system

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 of inflammation, which is caused by several factors including presence of a pathogen, injury to tissues or blood vessels, and immune complexes.

Inflammation causes not only vasodilation but also causes increased vascular permeability, allowing neutrophils, complement proteins, and antibodies to reach the site of infection or damage. 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. Immune effector cells can more easily attach to selectins expressed on endothelial cells when blood is flowing slowly, enabling these cells to exit the blood vessel via diapedesis. Anaphylatoxins, specifically complement proteins C3a and C5a, bind to receptors on mast cells and basophils causing degranulation. It is directly related to heart rate, myocardial contractility, and preload, and inversely related with afterload. Vasodilation works to decrease vascular resistance and blood pressure through relaxation of smooth muscle cells in the tunica media layer of large arteries and smaller arterioles. When vasodilation causes systolic blood pressure to fall below 90 mmHg, circulatory shock is observed.

Vascular resistance depends on several factors, including the length of the vessel, the viscosity of blood (determined by hematocrit) and the diameter of the blood vessel. The latter is the most important variable in determining resistance, with the vascular resistance changing by the fourth power of the radius.

Smooth muscle physiology

The tunica media of the walls of arteries, arterioles, and veins is composed of smooth muscle and causes vasodilation and vasoconstriction. Contraction is dependent on concentrations of Ca²⁺ in the cytosol, either via Ca,Mg-ATPase from the sarcoplasmic reticulum or voltage-gated calcium channels from the extracellular matrix. 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.

{| class="wikitable"

|-

! Class

! Description

! Example

|-

| Hyperpolarization-mediated (Calcium channel blocker)

| Changes in the resting membrane potential of the cell affects the level of intracellular calcium through modulation of voltage-sensitive calcium channels in the plasma membrane.

| adenosine

|-

| cAMP-mediated

| Adrenergic stimulation results in elevated levels of cAMP and protein kinase A, which results in increasing calcium removal from the cytoplasm.

| prostacyclin

|-

| cGMP-mediated (Nitrovasodilator)

| Through stimulation of protein kinase G.

| nitric oxide

|}

PDE5 inhibitors and potassium channel openers can also have similar results.

Compounds that mediate the above mechanisms may be grouped as endogenous and exogenous.

Causes

Endogenous

{| class="wikitable"

|-

!Vasodilators

|-

| EDHF ||?

|rowspan=3| hyperpolarization → ↓VDCC → ↓intracellular Ca²⁺

|-

| PKG activity →

• phosphorylation of MLCK → ↓MLCK activity → dephosphorylation of MLC
• ↑SERCA → ↓intracellular Ca²⁺

|-

| NO receptor on endothelium || ↓endothelin synthesis

|-

| epinephrine (adrenaline) (Vasoconstrictor)|| β-2 adrenergic receptor

|rowspan=5| ↑G_s activity → ↑AC activity → ↑cAMP → ↑PKA activity → phosphorylation of MLCK → ↓MLCK activity → dephosphorylation of MLC

|-

| histamine || histamine H2 receptor

|-

| prostacyclin || IP receptor

|-

| prostaglandin D₂ || DP receptor

|-

| prostaglandin E₂ || EP receptor

|-

| VIP || VIP receptor || ↑G_s activity → ↑AC activity → ↑cAMP → ↑PKA activity →

• phosphorylation of MLCK → ↓MLCK activity → dephosphorylation of MLC
• open Ca²⁺-activated and voltage-gated K⁺channels → hyperpolarization → close VDCC → ↓intracellular Ca²⁺

|-

| (extracellular) adenosine || A₁, A_2a and A_2b adenosine receptors || ↑ATP-sensitive K⁺ channel → hyperpolarization → close VDCC → ↓intracellular Ca²⁺

|-

|

• (extracellular) ATP
• (extracellular) ADP

|| ↑P2Y receptor || activate G_q → ↑PLC activity → ↑intracellular Ca²⁺ → ↑NOS activity → ↑NO → (see nitric oxide)

|-

| L-arginine || imidazoline and α-2 receptor? || G_i → ↓cAMP → activation of Na⁺/K⁺-ATPase → ↓intracellular Na⁺ → ↑Na⁺/Ca²⁺ exchanger activity → ↓intracellular Ca²⁺

|-

|bradykinin || bradykinin receptor||

|-

|substance P || ||

|-

|niacin (as nicotinic acid only) || ||

|-

| platelet-activating factor (PAF) || ||

|-

| CO₂ || -

|rowspan=2| ↓interstitial pH → ?

|-

| interstitial lactic acid (probably) || -

|-

| muscle work || - ||

• ↑vasodilators:
• ↑ATP consumption → ↑adenosine
• ↑glucose usage → CO₂
• ↑interstitial K⁺
• ↑(extracellular) ATP
• ↑(extracellular) ADP
• ↑interstitial K⁺
• ↓vasoconstrictors:
• ↑ATP consumption → ↓ ATP (intracellular)
• ↓oxygen → ↓oxidative phosphorylation → ↓ ATP (intracellular)

|-

|

• natriuretic peptides

Autonomic nervous system control

As referenced in the explanation of smooth muscle physiology, smooth muscle within the tunica media is innervated by the autonomic nervous system. The autonomic nervous system (ANS) controls essential involuntary body functions and originates as nerves leaving the brain stem or spinal cord; it contains both sensor and motor nerves. Sympathetic nervous system activity, reduced blood volume or reduced arterial pressure trigger β-adrenergic receptors in select kidney cells

Miscellaneous

• Other suggested vasodilators or vasodilating factors include:
• absence of high levels of environmental noise
• adenosine - adenosine agonist, used primarily as an anti-arrhythmic
• alpha blockers (block the vasoconstricting effect of adrenaline)
• atrial natriuretic peptide (ANP) - a weak vasodilator
• ethanol (alcohol) causes immediate vasodilation followed by increase in blood pressure
• nitric oxide inducers
• l-arginine (a key amino acid)
• citrulline (causes increased levels of L-arginine in the body)
• glyceryl trinitrate (commonly known as nitroglycerin)
• isosorbide mononitrate and isosorbide dinitrate
• pentaerythritol tetranitrate (PETN)
• sodium nitroprusside
• PDE5 inhibitors: these agents indirectly increase the effects of nitric oxide
• sildenafil (Viagra)
• tadalafil (Cialis)
• vardenafil (Levitra)
• tetrahydrocannabinol (THC), the principal psychoactive constituent of cannabis
• theobromine, the principal alkaloid found in Theobroma cacao, specifically in (non-fat) cocoa solids (which are especially concentrated in defatted cocoa and dark chocolate)
• minoxidil
• papaverine an alkaloid found in the opium poppy papaver somniferum
• estrogen

Treatment

Direct vasodilation drugs

These drugs can keep vessels staying opened or help vessels refrain from being narrowed.

• Angiotensin II receptor blockers
• ACE inhibitors
• Calcium channel blockers

Alpha-2A adrenergic receptor agonists

Drugs that appear to work by activating the α_2A receptors in the brain thereby decreasing sympathetic nervous system activity.