neuro-vascular physiology. why? hypertension largest single reason for physician visits in the us...
TRANSCRIPT
Neuro-Vascular Physiology
Why?HYPERTENSION
Largest single reason for physician visits in the US
Large proportion of adult population has HTN Patients can live with treated HTN HTN is asymptomatic HTN is a major risk factor for stroke Increased risk with age for cardiovascular
events greater in patients with HTN
Organs adversely affected by HTN
Kidneys-damage to renal arterioles can cause renal failure
Blood Vessels-damage to cerebral arteries can cause stroke, damage to coronary arteries can cause MI
Heart-myocardium works harder to pump against increased afterload causing
– Cardiac Hypertrophy– Less efficient pumping– Cardiac Failure
HTN Treatment
Organ damage occurs over many years, so it is necessary to treat all patients with HTN, even though they are asymptomatic
Major problem is patient compliance
– “I feel fine, so why should I take medication every day? I don’t like the side effects.”
Hypertension
Etiology
The causes of arterial hypertension appear to be no different for elderly and younger patients.
Essential (primary) hypertension, affecting at least 90% of the 50 million hypertensive persons in the USA, may result from changes in any of the pressor and depressor mechanisms that maintain normal arterial pressure.
Etiology
Secondary hypertension is less common than essential hypertension and may be caused by various conditions, which may also exacerbate existing essential hypertension.
The most common of these conditions are renal disorders, including renal artery stenosis due to atherosclerosis, which is common among the elderly; renal parenchymal disease (eg, chronic glomerulonephritis or pyelonephritis, polycystic renal disease, collagen disease of the kidneys, obstructive uropathy); and renal neoplasms.
HTN Treatment
About 1/3 HTN patients are judged to be inadequately controlled– Patients don’t know it is not adequately controlled
1/3 HTN patients are inadequately treated 1/3 HTN are untreated
– Patients don’t see a reason to seek medical treatment even though they may have knowledge of their HTN
Blood Vessels and HTN
HTN produces hypertrophy and remodeling in blood vessels These proliferative changes increase vascular compliance
and promote atherosclerosis HTN alters the ability of the endothelial cell to release
vasoactive factors HTN increases the constrictor tone of systemic and cerebral
arteries HTN alters cerebral autoregulation
– Chronic HTN shifts the autoregulated range toward higher pressures, rendering the brain more vulnerable to reductions in perfusion pressure
– Increased risk of ischemic brain injury
Vascular Tone
Long Distance Control– Autonomic nervous system– Neurohumoral control
Local Control– Vasoactive factors– Local neurogenic mechanisms
Autonomic Nervous System
The cardiovascular center– Located in the medulla oblongata– Main region for nervous system regulation of heart and blood
vessels– Receives input from
Higher brain centers Proprioceptors Baroreceptors Chemoreceptors
– Sends output to effectors Heart Blood vessels
Input to Cardiovascular Center
Higher Brain Centers such as cerebral cortex, limbic system and hypothalamus send information to CV center in response to emotion, temperature, or other impulses.
Sensory receptors provide input based on joint and muscle movements, pressure changes, blood vessel stretch, and chemical concentrations.
Baroreceptors
When BP falls, baroreceptors are stretched less, and they send nerve impulses at a slower rate and CV center decreases parasympathetic stimulation of heart and increases sympathetic stimulation
Baroreceptors
Two major feedback systems involving baroreceptors– Carotid Sinus Reflex
Maintains normal blood pressure of the brain Initiated by baroreceptors in wall of carotid sinuses Sends impulses to CV center via glossopharyngeal nerves
(Cranial Nerve IX)
– Aortic Reflex Governs general systemic blood pressure Initiated by receptors in wall of ascending aorta and arch of aorta Sends impulses to CV center via sensory fibers of vagus nerve
Chemoreceptors
Located close to the baroreceptors in the carotid sinus and aortic arch in small structures called carotid bodies and aortic bodies
Detect changes in blood levels of O2 , CO2 , and H+
Output from CV center
Flows along sympathetic and parasympathetic fibers of the autonomic nervous system
Sympathetic impulses reach the heart via cardiac accelerator nerves
Parasympathetic stimulation is conveyed along the vagus nerve (cranial nerve X)
CV center also continuously sends impulses to smooth muscle in blood vessel walls via sympathetic fibers called vasomotor nerves
Autonomic Control of Heart and Blood Vessels
Vasomotor Nerves
Autonomic control of blood vessel diameter is mostly via the sympathetic division
Vasomotor nerves exit spinal cord through all thoracic and the first one or two lumbar spinal nerves and then pass into the sympathetic trunk ganglia
From there impulses propagate along sympathetic nerves that innervate blood vessels in viscera and peripheral areas
Responsible for vasomotor tone that sets the resting level of systemic vascular resistance
Humoral Control of Blood Pressure
Renin Angiotensin System Epinephrine and Norepinephrine Antidiuretic Hormone Atrial Natriuretic Peptide
Renin Angiotensin System
Epinephrine and Norepinephrine
Released from adrenal gland Increase CO by increasing rate and force of
contractions Vasoconstrict arterioles Epinephrine vasodilates arterioles in skeletal
muscle
Antidiuretic Hormone (ADH, Vasopressin)
Produced by hypothalamus, released by posterior pituitary
Acts to retain water and increase blood pressure Stimulates insertion of aquaporin-2 containing vesicles
into the apical membranes of principal cells in the kidney
Decreases water lost through sweating and causes constriction of arterioles
Hyposecretion or nonfunctional receptors causes diabetes insipidus
Atrial Natriuretic Peptide
Released by cells in atria of the heart in response to stretch
Lowers BP by causing vasodilatation and by inhibiting reabsorption of Na+ and water in the proximal tubule and collecting duct
Suppresses secretion of aldosterone and ADH
Local Regulation of Blood Pressure
Vasoactive Factors Local Neurogenic Mechanisms
Vasoactive Factors
Produced by several types of cells including smooth muscle fibers, WBCs, platelets, macrophages and endothelial cells– Vasoconstriction
Endothelin Angiotensin II
– Vasorelaxation EDRF (NO) Adenosine PGI2
Vasoactive Factors
In each capillary bed, localized changes can regulate vasomotion
Local factors influence systemic vascular resistance and blood pressure
Vasodilators produce local dilation of arterioles and relaxation of precapillary sphincters increasing blood flow
Vasoconstrictors have opposite effect
Transduction of signals from VEC to VSM
2ATP
cAMP
Unifying model of VSM tonal control
VEC Control of VSM Growth
Local Neurogenic Control
Physical Changes– Warming promotes vasodilatation, cooling causes
vasoconstriction Myogenic Response
– Smooth muscle in arteriole wall contracts more forcefully when it is stretched and relaxes when stretching lessens
– If blood flow decreases, stretch decreases, smooth muscle relaxes to increase blood flow
Treatment of HTN
Drugs that are used to treat hypertension include a wide variety of agents, from which diverse sites of drug action can produce a similar therapeutic response.
– Drugs acting on RAS– Sympatholytic Drugs/CNS– Vasodilators– Calcium Channel Blockers– Beta Blockers– Diuretics
Vascular Remodeling
Vascular Remodeling and Hypertension
Arterial remodeling in hypertension is characterized by hypertrophy (dilation) of the large arteries and inward, eutrophic remodeling of the small resistance arteries and arterioles.
The mechanisms leading to these structural changes are incompletely understood, but mechanical factors of pressure and flow are major contributors.
Vascular Remodeling and Hypertension
Vascular remodeling is considered an adaptive response to elevation of arterial pressure to normalize the wall tension.
In essential hypertension, large artery remodeling is characterized by an increase in media thickness–lumen diameter (M/L) ratio and cross-sectional area (CSA).
Vascular Remodeling and Hypertension
This augmentation of media mass, or hypertrophic remodeling, is explained by changes in size or number of vascular smooth muscle cells (VSMCs) and matrix collagen deposition.
In resistance arteries (diameter <300 µm), essential hypertension is associated with a reduced lumen and increased M/L ratio but without CSA increase, producing a type of remodeling designated as inward eutrophic remodeling.
Vascular Remodeling and Hypertension
As seen during normal development, inflammation, wound healing, and cancer, remodeling likely involves modification of cell–matrix interactions and breakdown of existing extracellular matrix (ECM).
In the ECM, a group of secreted glycoproteins, the matricellular proteins, such as tenascin-C (TN-C) and thrombospondin (TSP), are believed to disrupt cell–matrix interaction by favoring de-adhesion and have been associated with remodeling.
Vascular Remodeling and Hypertension
Indeed, TSP expression is augmented in hypertensive pulmonary arteries, and TN-C is implicated in progressive pulmonary vascular disease, in arterialization of human vein grafts, and in hypertension.
Thus, TN-C and TSP are increased in vascular remodeling associated with cell proliferation, regulate in small artery eutrophic remodeling.
Vascular Remodeling and Hypertension
In large pulmonary arteries, hypertrophic remodeling appears to involve reduced adhesion of cells to the ECM, because several matricellular molecules with reduced adhesion properties, such as TN-C and TSP, are over-expressed.
This could be necessary to allow cells to grow, proliferate, and migrate within the matrix.
TN-C has been shown to be elevated in the aorta and could serve such a function.
Vascular Remodeling and Hypertension
TSP-1 has been shown to stimulate MMP-2 activity.
In large elastic arteries, TN-C abundance appears to parallel that of MMP activity.
Vascular Remodeling and Hypertension
To break down the ECM or simply cell–matrix adhesions, vascular cells produce proteases such as matrix metalloproteinases (MMPs), which are secreted in a latent pro-form and require an enzymatic cleavage for activation.
They can degrade several ECM proteins unless bound to specific tissue inhibitors of metalloproteinases (TIMPs).
Vascular Remodeling and Hypertension
The development of eutrophic remodeling of resistance arteries may involve a complex interplay of ECM enzymes and de-adhesive proteins.
In summary, large arteries dilate with hypertension and resistance artery lumens are reduced.
Thus accounting for the formation of aneurysms in aortas and hypertension and mal-perfusion via resistance arteries.
Vascular Remodeling and Hypertension
In general there is:– an increase in the vascular smooth muscles
(hypertrophy hyperplasia),– rearrangement of VSM orientation– an modification of the ECM (stiffening)– an alteration of vascular endothelial cell
function (reduction of NO release).
Vascular Remodeling and Hypertension
Larger arteries Resistance arteries
VSM
Integrins
Tenascin and Thrombospondin uncouple integrins from ECM
This allows vascular remodeling
We will discuss the Rx agents that modulate the hypertensive state on Wednesday.