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.