Blood pressure control

Rok Humar, PhDDepartment of Research

Mean arterial blood pressure

Blood volume Cardiac output Peripheral resistance

Bloodcapacitance

is determined by

determined by determined by determined by determined by

Fluid intake Fluid loss Heart rate Stroke vol. Diameter of arterioles

Number of capillaries

Diameter of veins

Resistance of the system to blood flow

Storage of blood volume

Also site where most ofthe blood volume is foundand where regional blood

volume is regulated

Cardiac output

The cardiac output is determined by stroke volume or heart rate or both

Cardiac output = Stroke Volume X number of heart beats

The maximum percentage that the cardiac output can increase abovenormal is called the cardiac reserve

In the normal young adult the cardiac reserve is 300 to 400 percent(trained athletes >600%, weak elderly ~200%)

For example, running to catch a tramway would cause an increase inoxygen demand which must be balanced by increased blood circulationand blood pressure.

Mean arterial blood pressure

Blood volume Cardiac output Peripheral resistance

Bloodcapacitance

is determined by

determined by determined by determined by determined by

Fluid intake Fluid loss Heart rate Stroke vol. Diameter of arterioles

Number of capillaries

Diameter of veins

Effectiveness of the heart as a pump

Resistance of the system to blood flow

Storage of blood volume

Also site where most ofthe blood volume is foundand where regional blood

volume is regulated

Peripheral resistance

R: resistanceh: viscosityl: length of vesselr: lumen diameter

rule of laminar flow by

Peripheral resistance

Peripheral resistance

Peripheral resistance

Resistance to blood flow/pressure is significant only in arterialvessels with a lumen diameter of <300 µm.Thus, any change in lumen diameter of these resistancevessels or complete loss off will affect blood pressure

left ventricel aorta

arteries

arterioles

capillaries

veinsright ventricel

A.a. pulmonales

capillariesV.v. pulmonales

total peripheral resistance is distributed in

terminal arteries and arterioles: 45-50%capillaries: 23-30%venules: 3-4%veins: 3%

venules

resistance vessels: arteries <300 µm in diameter: capillaries <100µm in diameter

pres

sure

lumen diameter

Cardiac output & Peripheral resistance

Mean arterial blood pressure

Blood volume Cardiac output Peripheral resistance

Bloodcapacitance

is determined by

determined by determined by determined by determined by

Fluid intake Fluid loss Heart rate Stroke vol. Diameter of arterioles Diameter of veins

Effectiveness of the heart as a pump

Resistance of the system to blood flow

Storage of blood volume

Also site where most ofthe blood volume is foundand where regional blood

volume is regulated

Baroreceptor reflex

Number of capillaries

Baroreceptor reflex

The Baroreceptor reflex is a rapidly acting feedback loop.Elevated blood pressure reflexively causes blood pressure to decrease;Decreased blood pressure depresses the baroreflex, causing bloodpressure to rise.Baroreceptors in various organs can detect changes in blood pressure,and adjust the mean arterial pressure by alteringthe force and speed of the heart's contractions (cardiac output) andthe total peripheral resistance.

Baroreceptors are present in the aortic arch, and the carotid sinuses of theleft and right internal carotid arteries.

Baroreceptor reflex

Seidel, H., Herzel, H. & Eckberg, D.L. (1997) Phase dependencies of the human baroreceptorreflex. AmericanJournal of Physiology H2040-H2053

Intrinsic Carotid Sinus Nerve Activity

Baroreceptors are strech-induced mechanoreceptors. Mechanoreceptorsare primary neurons that respond to mechanical stimuli by firing actionpotentials.Active baroreceptors fire action potentials ("spikes") more frequently thaninactive baroreceptors. The greater the stretch, the more rapidlybaroreceptors fire action potentials.The frequency of afferent impulses increases when the pressure is risingduring systole and decreases when the pressure is falling during diastole.

Baroreceptor reflex

BrainBrain

Autonomic nervous system (Sympathicus/Parasympathicus)

Arterial pressureBaroreceptor

Baroreceptor afferent

Vasomotor center

Vagal center

Sympathicus

ArteriolesHeart

low pressure

high pressure

transduction sensing

Parasympathicus

ArteriolesHeart

Parasympathicus:cholinergic fibers from theganglion to the effector organNeurotransmitter=Acetylcholine

Sympathicus:noradregenic fibers from theganglion to the effector organNeurotransmitter=(Nor-)Epinephrine

decreased increased cardiac output

vasoconstriction

β-blockers

ArteriolesHeart

increased cardiac output

vasoconstriction

β1 β2 α1 β2

vasodilation(lung)

Epinephrine stimulates β1-adrenergic receptors of the heart and increases cardiacrhythm and force of contraction, and a1 smooth muscle cell receptors on arteriolesto vasoconstrict (fight-or-flight response)

1st generation β-blockers block β1 and β2

2nd generation β-blockers mainly block β1

3rd generation β-blockers β1 and α1

1st generationNadololPindolol2nd generationAcebutololAtenolol (Atenil®, Cardaxen®,Selobloc®)BisoprololNebivolol (Nebilet ®)3rd generationCarvedilol (Dilatrend®)Labetalol

Mean arterial blood pressure

Blood volume Cardiac output Peripheral resistance

Bloodcapacitance

is determined by

determined by determined by determined by determined by

Fluid intake Fluid loss Heart rate Stroke vol. Diameter of arterioles Diameter of veins

Effectiveness of the heart as a pump

Resistance of the system to blood flow

Storage of blood volume

Also site where most ofthe blood volume is foundand where regional blood

volume is regulated

Aldosterone Renin-angiotensin system (RAS)or

renin-angiotensin-aldosteron system (RAAS)

Number of capillaries

The Renin-Angiotensin-Aldosteron System (RAAS)

Kidney

Renin

BP

Liver

Angiotensinogen Angiotensin I

constitutive

The RAAS begins with the release of renin from specialized kidney tissue, thejuxtaglomerular apparatus, when:

• Blood flow through glomeruli is decreased• Blood pressure as mesured by baroreceptors (Vas afferens) is decreased• Drop in blood volume, that is filtered by glomeruli• Activation of sympathicus

is a hormone system that helps regulate long-term blood pressure and extracellular volume in the body.

Angiotensin Converting Enzyme

Kidney

Renin

BP

Liver

Angiotensinogen Angiotensin I Angiotensin II

Bradykinin

AngiotensinConverting Enzyme

BK degradation

AT1 AT1

AT1

BKR2

SMCarterioles

Adrenal cortex

AT2

PituitaryGland

AT1 CNS

SMC

SMC

AT1 SMCVenules

The Renin-Angiotensin-Aldosteron System (RAAS)

Kidney

Renin

BP

Liver

Angiotensinogen Angiotensin I Angiotensin II

Bradykinin

AngiotensinConverting Enzyme

BK degradation

AT1 AT1

AT1

BKR2

SMCarterioles

Adrenal cortex

Vasoconstriction=decrease in vessel lumen diameter=increase in peripheral resistance BP

AT2

PituitaryGland

AT1 CNS Sympathicus(Norepinephtine)

SMCRemodelingVascular Growth

Hirnanhangdrüse, Hypophyse

SMC VasodilationNO production

AT1 SMCVenules

The Renin-Angiotensin-Aldosteron System (RAAS)

Kidney

Renin

BP

Liver

Angiotensinogen Angiotensin I Angiotensin II

Bradykinin

AngiotensinConverting Enzyme

BK degradation

AT1 AT1

AT1

BKR2

SMCarterioles

Adrenal cortex

Vasoconstriction=decrease in vessel lumen diameter=increase in peripheral resistance BP

Aldosterone

AT2

Transport of Cl- and H2O from urine to bloodNaCl in blood and blood volume (BV) increase

BP

PituitaryGland

ADHAnti Diuretic Hormone/VasopressinRetention of H2O and NaCl -

BV

AT1 CNS Sympathicus

SMCRemodelingVascular Growth

Hirnanhangdrüse, Hypophyse

SMC VasodilationNO production

AT1 SMCVenules

Inhibition of the Renin-Angiotensin-Aldosteron System (RAAS)

Kidney

Renin

BP

Liver

Angiotensinogen Angiotensin I Angiotensin II

Bradykinin

AngiotensinConverting Enzyme

BK degradation

AT1 AT1

AT1

BKR2

SMCarterioles

Adrenal cortex

Vasoconstriction=decrease in vessel lumen diameter=increase in peripheral resistance BP

Aldosterone

AT2

Transport of Cl- and H2O from urine to bloodNaCl in blood and blood volume (BV) increase

BP

PituitaryGland

ADH

BV

AT1 CNS Sympathicus

SMCRemodelingVascular Growth

SMC VasodilationNO production

ACEI

Sulfhydryl-containing ACE inhibitorsCaptopril (Lopirin ®), the first ACE inhibitorDicarboxylate-containing ACE inhibitorsEnalapril(Reniten®)Ramipril (Triatec®/Vesdil®)Quinapril (Accupro®)Perindopril (Coversum®)Lisinopril (Prinil®/Zestril®)Benazepril (Cibacen®)Phosphonate-containing ACE inhibitorsFosinopril (Fositen®),

AT1 SMCVenules

AR1B

The Renin-Angiotensin-Aldosteron System (RAAS)

Kidney

Renin

BP

Liver

Angiotensinogen Angiotensin I Angiotensin II

Bradykinin

AngiotensinConverting Enzyme

BK degradation

AT1 AT1

AT1

BKR2

SMCarterioles

Adrenal cortex

Vasoconstriction=decrease in vessel lumen diameter=increase in peripheral resistance BP

Aldosterone

AT2

Transport of Cl- and H2O from urine to bloodNaCl in blood and blood volume (BV) increase

BP

PituitaryGland

ADH

BV

AT1 CNS Sympathicus

SMCRemodelingVascular Growth

SMC VasodilationNO production

Candesartan (Atacand®, Blopress®)Eprosartan (Teveten®)Irbesartan (Aprovel®)Losartan (Cosaar®)Olmesartan (Votum®, Olmetec®Telmisartan (Micardis®, Kinzal®)Valsartan (Diovan®)

AT1 SMCVenules

The Renin-Angiotensin-Aldosteron System (RAAS)

Kidney

Renin

BP

Liver

Angiotensinogen Angiotensin I Angiotensin II

Bradykinin

AngiotensinConverting Enzyme

BK degradation

AT1 AT1

AT1

BKR2

SMCarterioles

Adrenal cortex

Vasoconstriction=decrease in vessel lumen diameter=increase in peripheral resistance BP

Aldosterone

AT2

Transport of Cl- and H2O from urine to bloodNaCl in blood and blood volume (BV) increase

BP

PituitaryGland

ADH

BV

AT1 CNS Sympathicus

SMCRemodelingVascular Growth

SMC VasodilationNO production

AT1 SMCVenulesRenin-I.

First in class renin inhibitor:Aliskiren (Tekturna®)

Approved by FDA in Feb 2007 forNovartis/Speedel

β-blocker

Mean arterial blood pressure

Blood volume Cardiac output Peripheral resistance

Bloodcapacitance

is determined by

determined by determined by determined by determined by

Fluid intake Fluid loss Heart rate Stroke vol. Diameter of arterioles Diameter of veins

Effectiveness of the heart as a pump

Resistance of the system to blood flow

Storage of blood volume

Also site where most ofthe blood volume is foundand where regional blood

volume is regulated

Number of capillaries

Vascular remodeling

Vascular Remodeling

Endothelial cell tubePericytesBasal lamina

Endothelial cell tubeInternal elastica laminaSmooth muscle cellsBasal laminaExternal elastic lamina

Capillary

Arteriole

Resistance artery remodeling

Intravascular pressure causes an increase in the wall stress, which then stimulates a hypertrophicprocess leading to an increase in wall thickness

Increases in flow lead to increases in diameter and in wall thickness

Hypertrophic processes are also thought to be initiated through growth factors, including angiotensin II(Ang II), or PDGF

Hypertrophic Remodeling

Flow -> vasodilation

pressure Wall stress

Growth factors(Ang IIPDGF)

Essential hypertension is associated with eutrophic remodeling of the small arteries.

Increased neurohumoral activity leads to vasoconstriction and increased blood pressure.

Decrease in diameter (and resulting increase in wall thickness) ensures that the wall stress remainsnormal, thus eliminating a hypertrophic response.

Active vasoconstriction (during essential hypertension) changes to a passive remodeling.

Eutrophic Remodeling

Vasoconstrictors(Ang II

Endothelin) PressureWall stress ~

Passive Remodeling

Resistance artery remodeling

Inhibition of Rho-kinase suppresses angiotensin II-induced cardiovascularhypertrophy in rats in vivo

Higashi et al, Circ Res. 2003 Oct 17;93(8):767-75

Resistance artery remodeling

Microvessel regression causes Hypertension

Bevacizumab (Avastin®) mAB aginst VEGF

side effect grade 3 (severe) hypertension =180/110control group -> 0.5%Avastin group -> 17.5%

Miller et al., Journal of Clinical Oncology, 23 (4) 2005: pp. 792-799

Rarefaction of skin capillaries in normotensive offspring of indiviuals with essential hypertension

Antonios et al., Heart, 2003 Feb; 89(2): 175-8

Capillary rarefaction may be hereditary and predispose to hypertension

Kidney

Renin

BP

Liver

Angiotensinogen Angiotensin I Angiotensin II

Bradykinin

AngiotensinConverting Enzyme

BK degradation

AT1 AT1

AT1

BKR2

SMCarterioles

Adrenal cortex

Vasoconstriction=decrease in vessel lumen diameter=increase in peripheral resistance BP

Aldosterone

AT2

Transport of Cl- and H2O from urine to bloodNaCl in blood and blood volume (BV) increase

BP

PituitaryGland

ADHAnti Diuretic Hormone/VasopressinRetention of H2O and NaCl -

BV

AT1 CNS Sympathicus

SMCRemodelingVascular Growth

Hirnanhangdrüse, Hypophyse

SMC VasodilationNO production

ACEI

AR1B

Longterm antihypertensive treatment & reversal of remodeling

Renin

Liver

Angiotensinogen Angiotensin I Angiotensin II

Bradykinin

AngiotensinConverting Enzyme

BK degradation BKR2

AT2 SMC

SMC VasodilationNO production

ACEI

AR1B

Longterm antihypertensive treatment & capillary rarefaction

Angiogenic Molecules

VEGF; bFGF

Angiogenesis

reversal of capillaryrarefaction

decrease in peripheral resistance and BP

Summary

Blood volume Cardiac output Peripheral resistance

Bloodcapacitance

is determined by

determined by determined by determined by determined by

Fluid intake Fluid loss Heart rate Stroke vol. Diameter of arterioles Diameter of veins

Effectiveness of the heart as a pump

Resistance of the system to blood flow

Storage of blood volume

Also site where most ofthe blood volume is foundand where regional blood

volume is regulated

Number of capillaries

Vascular remodeling

Renin-AngiotensinAldosterone system (RAAS)

Baroreceptorreflex