ANS Control of Blood Pressure II 2024 PDF

ANS control of blood pressure II BPS 337 11/25/2024 Richard T. Clements PhD Assistant Professor Biomedical and Pharmaceutical Sciences Office 495P/ Lab 470 [email protected] Outline Chronic control of blood pressure Review of previous lecture and acute control SNS...

ANS control of blood pressure II BPS 337 11/25/2024 Richard T. Clements PhD Assistant Professor Biomedical and Pharmaceutical Sciences Office 495P/ Lab 470 [email protected] Outline Chronic control of blood pressure Review of previous lecture and acute control SNS/ANS control of RAAS system Ang II production and effects Kidney Vasculature Aldosterone effects to increase blood pressure Mineralocorticoid receptor Anti-diuretic hormone/ Arginine-Vasopressin Effects in kidney to increase blood volume Natriuretic peptides and natriuresis Vasodilation Kidney effects SNS interaction Some examples of SNS/adrenergic control of BP.  Summary of previous lecture ANS modulates blood pressure through SNS system Increases vessel resistance Constriction a-AR receptors Arterioles (increases resistance) and veins (increases preload and CO) Increases HR Activation of b1-AR on SA node. Increased Na or funny current Increases cardiac contraction Activation of b1-AR Increased Ca++ signaling/cycling Signaling via nAchR at preganglion, NE at heart and vessels, epinephrine from adrenal medulla. Summary of previous lecture ANS modulates blood pressure through PNS system decreases HR Activation of mAchR in atria/SA node. CV center in brain decreases SNS output when PNS is activated Causes reduced SNS activity and dilation m3AchR activation on endothelial cells can cause dilation (although PNS does not innervate blood vessels. System involves nAcR at ganglion and mAchR at heart Summary: SNS Control of Blood Vessels SNS stimulation of most peripheral arteries alpha receptor actions predominate leading to vasoconstriction SNS stimulation of muscle and lung arteries (mostly EPI and NE from adrenal gland). beta receptor actions predominate leading to vasodilation. SNS stimulation of veins. alpha receptor actions predominate leading to decreased venous capacitance, increased cardiac return, increased cardiac stroke volume and cardiac output (leading to slight increase in pulse pressure). Very Little PNS Innervation of Most Blood Vessels  Baroreceptors and control of blood pressure Decreases in blood pressure are sensed by the baroreceptor which signals to increase blood pressure. Increases SNS activity: b1 in heart to increase HR (SA node) and cardiac contractility Alpha receptors in arteries/arterioles to increase vasoconstriction and raise resistance Alpha receptors in veins to decrease venous compliance and increase preload/CO SNS will also increase epinephrine release from adrenal glands Decreases PNS signals from brain Increases in blood pressure sensed by baroreceptors cause the opposite effect. Increases PNS activity Activates M2AchR receptors in the SA node to slow HR Decreases SNS activity to vessels and heart  SNS and PNS control of BP Baroreceptor signals produce activation of SNS or PNS depending on signal Causes opposite changes in SNS activation and PNS activation SNS increases CO via effects on hearts and veins and increases SVR to maintain pressure PNS has major effects on heart to decrease CO Long Term BP control/regulation Several physiologic mechanisms regulate blood pressure in the long-term. This control is aimed at regulating blood volume. Three major systems: RAAS: renin-angiotensin-aldosterone system ADH: Anti-diuretic hormone (vasopressin) NP: natriuretic peptides (BNP, ANP) Short and long term response to low BP or blood volume  RAAS system Renin Angiotensin Aldosterone System Renin produced by the kidney Angiotensinogen cleaved to Ang I Angiotensin converting enzyme (ACE) Highly expressed on lung and renal endothelium Ang I – Ang II  THE SNS activates RAAS as part of response to maintain blood pressure and perfusion SNS efferents to heart and vessels we covered last lecture SNS also has afferent/efferent nerves to kidney Juxtaglomerular cells in nephron (B1) Parts of a nephron  ANS Control of Kidneys and Blood Juxtaglomerular Pressure cells are smooth muscle-like cells of the blood vessels of the juxtaglomerular apparatus. They express β1- AR and they synthesize and release the enzyme, renin, in response to activation of these β1-AR. Juxtaglomerular cells release renin Juxtaglomerula in response to r cells sympathetic stimulation.  Juxtaglomerular cells and renin release: b1-AR activation in juxtaglomerular cells has signaling similar to vessel contraction cAMP/PKA However different than heart and vessels: PKA activates a transcription factor CREB cAMP Response Element Binding protein CREB promotes production of Renin in these cells.  Angiotensin II has some direct effects on the kidney and Na + resorption Increases Na+ transporters in the proximal tubule Increases ENaC in cortical collecting duct (similar to MR) AGT : angiotensinogen. NHE3: Na channel, AT1R: angiotensin receptor, ENaC: epithelial Na channel  AngII and vasoconstriction Ang II is a potent vasoconstrictor. Effects mediated by activation of AT1R (GPCR): Ca++ channels and Phospholipase C (PLC) to activate IP3 receptor and increase Ca++/MLCK Rho GTPase cascades to inhibit Myosin phosphatase (MYPT) Increases I.V. Ang II MLC phosphorylation infusio n  Angiotensin II Stimulates Release of Aldosterone from Adrenal Cortex Cells of the adrenal cortex express AT1 receptors. They may be activated by angiotensin II to stimulate release of aldosterone.  Ang II stimulates release of ADH Angiotensin II also has receptors on the hypothalamus. Ang II binds AT1-R which causes stimulation of the pituitary to make anti-diuretic hormone (ADH) ADH, AVP (arginine vasopressin), and vasopressin are the same thing Posterior pituitary also makes oxytocin in response to nerve signals Oxytocin: emotional responses, uterine contractions, lactation, sexual stimulation ADH has direct effects on the kidneys and blood vessels to increase blood volume and pressure. Angiotensin II effects : Kidney and more  Ang II and SNS summary In response to chronic low blood pressure: Elevated continuous signaling by the SNS will stimulate release of renin via Beta1-AR on juxtaglomerular smooth muscle cells in kidney blood vessels: Renin generates Ang I from angiotensinogen ACE: on endothelium makes Ang II (renal and lung endothelium) Ang II goes on for numerous direct effects to increase BP Increase Na+ reabsorption in kidney: increases blood volume Increases aldosterone release: Adrenal cortex Increases AVP/ADH release: Pituitary Directly causes vasoconstriction CO* SVR = P  SNS Maria Luisa S. Sequeira-Lopez. Circulation Research. Renin Cells, the Kidney, and Hypertension, Volume: 128, Issue: 7, Pages: 887- 907, DOI: (10.1161/CIRCRESAHA.121.318064) © 2021 American Heart Association, Inc.  Aldosterone and blood pressure regulation Aldosterone is produced by the adrenal cortex in response to Ang II and SNS stimulation Aldosterone activates a transcription factor/nuclear receptor known as the mineralocorticoid receptor (MR) MR exerts its effects by increasing Na+ reabsorption and (H2O) Parts of a nephron Aldosterone acts in the cortical collecting duct  ACEi and aldosterone “escape” Aldosterone and ACEi are often used together to modulate blood pressure Aldosterone can be produced by pathways in addition to Ang II Also additional mechanisms to activate MR Thus ACEi and aldosterone blocking drugs: MR antagonists (MRA) are often used together. Cortical Collecting Duct: Additional water and Na+ reabsorption to concentrate urine Major site of Aldosterone: mineralocorticoid receptor. Initiates a coordinated response to increase Na+ channel (ENAC) expression and transport, Na+/K ATPase expression and transport (more later) Vasopressin (ADH) upregulates aquaporin H2O channels.  MR is activated by aldosterone and initiates a coordinated response to: 1. Increase ENaC expression and trafficking 2. Increase Na/K ATPase and trafficking 3. Alter intracellular permeability (increases fluid absorption) and energy production (not shown)  Aldosterone and vasculature MR is present in the vasculature Not directly involved in vasoregulation Modulates transcriptional responses related to inflammation, fibrosis and other cascades. May contribute to vascular stiffness over time.  Summary: Mechanism of Aldosterone to increase BP Aldosterone increases blood volume Na reabsorption ( increase in water retention) Activates MR Increase Na Channel expression, stability and trafficking (membrane) Increases Na/K ATPase expression, stability and trafficking (membrane) Increased blood volume increases preload on the heart Blood returning to heart fills ventricle more Increases SV and CO Increase in CO increases pressure CO * SVR = P  Angiotensin II Stimulates Release of ADH (Vasopressin) from Posterior Pituitary Angiotensin II also stimulates the release of antidiuretic hormone (ADH), also called vasopressin or arginine vasopressin (AVP) from the posterior pituitary. SNS activation also increase ADH ADH acts on distal tubules and collecting ducts to increase Na and water reabsorption.  Vasopressin/AVP/ADH Produced in pituitary Produced in response to numerous stimuli: low volume and low BP, AngII, SNS Vasopressin acts on two major receptors: V1 receptor: highly expressed in blood vessels and promotes constriction of blood vessels V2 receptors: found in kidney and regulate fluid reabsorption/water retention. Parts of a nephron AVP/ADH acts in the collecting duct  Mechanism of AVP in Kidney to retain H20 These pictures show the same mechanism V2 receptors activate AC, produce cAMP and activate PKA PKA promotes movement of AQP2 to the membrane AQP2 increases water flow from urine to blood (osmotically driven)  Vasopressin signaling and vasoconstriction Vasopressin V1 receptor increases constriction in the vasculature: G proteins activate Ca++ channels and Phospholipase C (PLC) to activate IP3 receptor and increase Ca++/MLCK Rho GTPase cascades to inhibit Myosin phosphatase (MYPT) Increases MLC phosphorylation Summary: ADH and Blood pressure regulation ADH is made by pituitary in response to AngII and SNS activation In the kidney ADH activates V2 receptors to stimulate cAMP/PKA dependent movement of AQP2 channels to kidney lumen surface AQP2 is a water channel and water flows down osmotic gradient from nephron lumen to interstitium In the vasculature : AVP/ADH activates V1 receptors to increase vasoconstriction. Mobilization of intracellular calcium resulting in MLC phosphorylation ADH increase blood pressure by increasing blood volume and thus CO (preload) as well as increasing resistance via vasoconstriction CO* SVR = P RAAS and BP regulation: Summary RAAS system and blood pressure regulation SNS increases renin release: AngII and aldosterone produced RAAS increases Na+ reabsorption (proximal tubule and collecting duct) and vasoconstriction to increase pressure. Aldosterone produced by the adrenal cortex also increases Na+ reabsorption in collecting duct. ADH/AVP produced in pituitary increases H2O reabsorption in collecting duct via AQP2 channels. Increases blood volume and constriction to increase CO and increase resistance. Blood pressure maintained. RAAS and long-term control of BP What about decreasing blood volume/pressure? Natriuretic peptides: Atrial : ANP Made in the atria of the heart Brain : BNP Made in the ventricles and atria of the heart C-type natriuretic peptide Made in the vasculature  Natriuretic Peptides Produced in response to stretch of the heart Volume is too much Increased pressure and stress – afterload. The purpose of NP’s is to reduce volume Reduces volume by removing Na Natriuresis is excretion of Na  NP receptors and vessels NPRA and B: Have a guanylate cyclase built into the receptor Make cGMP Activates PKG Promotes vasodilation Molecular Basis of VSMC Dilation In endothelial cells: Receptor activated signaling cascades activate nitric oxide synthase (eNOS) NO diffuses to VSMC In VSMC NO activates soluble guanylate cyclase (sGC) sGC makes cyclic-GMP cGMP activates PKG KCa PKG has a coordinated response to limit VSMC contraction: K Decrease Ca++ influx/release + Decrease MLC phosphorylation via active MYPT Increase K+ efflux: keeps the cell membrane negative so limited Ca++ release NP’s can cause vasodilation independent of NO through their built- in guanylate cyclase NPR’s and cGMP activates PKG signaling PKG activation counteracts vessel constriction through a coordinated response.  NP effects on kidney Increases kidney filtering at the glomerulus via vasoactive effects Afferent dilation Efferent constriction Antagonizes pathways that promote Na+ reabsorption Direct and indirect effects on kidney (ex decrease ADH and aldosterone production) Increase Na+ excretion (natriuresis) Decreases blood volume CNG channel: cyclic nucleotide gated ion channel. TRPV4 and P2: transient receptor potential - nonselective cation channels  NPs, SNS, and RAAS NPs antagonize RAAS and SNS NPs reduce SNS signaling to kidney and vessels Effect in CNS Negative feedback regulation between RAAS and NPs  NP effects and blood pressure regulation NPs : Produced by heart in response to stretch Decrease Na+ reabsorption Decrease blood volume : decrease preload and CO Directly cause vasodilation, decrease SVR Blocks SNS Blocks Renin production  Summary of NPs and ANS and blood pressure Natriuretic Peptides ANP, BNP and CNP (Focus on ANP and BNP) Effects mediated by receptors NPRA and NPRB, NPRC (clearance) Effects mediated by receptor guanylate cyclase domain Direct effects to cause vasodilation Direct effects to increase Na+ excretion in kidney Reduces SNS activity RAAS activation Reduces Renin release Aldosterone release Decreases blood volume and increases vasodilation to decrease CO and resistance and decrease pressure. CO * SVR = P  BP regulation: Response if BP low Acute responses: Baroreceptor: modulates SNS and PNS activity to : Increase vasoconstriction (SNS, NE) Increase HR (SNS, NE) Release epinephrine from adrenal medulla Chronic or long term responses: SNS activates Renin production in juxtaglomerular cells: Ang II causes vasoconstriction Release of Aldosterone (adrenal cortex) and ADH (pituitary) Increases blood volume and CO  Responses if BP high Acute responses: Baroreceptor: modulates SNS/PNS activity to : Decrease SNS/Increase PNS stimulation of heart: Decreases HR (direct innervation of SA node) and thus CO Increased M2 mAchR / decreased B1 stimulation. Decrease SNS vasoconstriction, Ach can dilate vessels directly (not innervated), so increased PNS signaling does not alter vasoconstriction Chronic or long term responses: Stretch on the heart (volume overload): Increase in ANP, BNP Increase Na+ excretion in kidney Reduces SNS activity Reduces RAAS production and signaling CNS and ANS Integration of Cardiovascular Function ANS integration of Cardiovascular Function occurs largely with the goal of compensating for changes in arterial blood pressure. i.e. keeping pressure at the carotid artery and aortic arch relatively stable.  Important Example of CNS Control of ANS BAROREFLEX and Integration of Cardiovascular Function M2 b1 > b1 a1, a2 (constricts) OTHER REFLEX b1 INPUTS b2 (dilates) Example of ANS control of acute blood pressure regulation. When going from a reclined position to standing: Blood pools in the extremities and blood pressure acutely drops Preload is decreased and CO lowers. Baroreceptors sense pressure drop and send signals to increases SNS activity SNS causes : Increase in HR (b1): increases CO Increase in cardiac contractility (b1): increases CO Increase arterial vasoconstriction: increase pressure (a1) Increase veinous constriction, decreases compliance, and increases preload (a1)  Orthostatic/Postural Hypotension: Failure of the Baroreflex Orthostatic/Postural hypotension, or dizzy spell due to low blood flow to the brain (syncope), is a form of low blood pressure in which a person's blood pressure falls when suddenly standing up. defined as a fall in systolic blood pressure of at least 20 mm Hg or diastolic blood pressure of at least 10 mm Hg when a person assumes a standing position. Caused by blood pooling in the lower extremities upon a change in body position. Normally this is taken care of by the baroreflex and SNS stimulation: however the system can be perturbed to where it does not work as efficiently Nerve, vessel, and/or heart effects Common and can occur briefly in anyone, although it is prevalent in the elderly, and those with low blood pressure. Orthostatic/Postural Hypotension and Reflex Tachycardia often produced pharmacologically by many classes of drugs.  SNS activity is not all or nothing: tone Example of acute baroreflex response Sympathetic nerves are signaling pretty much continuously Signal frequency is increased or decreased in response to SNS activation The frequency of SNS activity is referred to as sympathetic tone.  a and b adrenergic receptors Receptor Tissue expression Actions Type Alpha1: – located in the Alpha1 Most vascular smooth Contracts (increases vascular blood vessels and muscle resistance) promotes constriction Pupillary dilator (radial) Contracts (mydriasis) muscle Pilomotor (piloerector) Contracts (erects hair) Beta1: muscle Located on the heart Alpha2 Adrenergic, and some Inhibits neurotransmitter release and promotes other nerve terminals increases in heart rate and contractility Most vascular smooth Contracts Increases coronary muscle dilation Pancreatic beta cells Inhibits insulin release Fat cells Inhibits lipolysis Beta2 :promotes Beta1 Heart Increases heart rate and increased heart rate and contractility (chronotropy, vasodilation (including ionotropy, lusitropy) coronary) Juxtaglomerular cells Stimulates Renin release Fat cells Stimulates lipolysis Beta2 Respiratory, uterine and Relaxes b-agonists and their selectivity  Norepinephrine infusion NE is a strong B1 and a1 agonist Increases vasoconstriction due to a1 receptor activation Increase in b1 activation will increase HR transiently HR reduced due to baroreceptor activation and vagal stimulation of SA node. Baroreceptor will return to normal pressures over minutes If no baroreceptor, pressure increases continue much longer until NE metabolized  Epinephrine infusion and blood pressure What happens when you infuse epinephrine? At low dose is a b1 and b2 agonist (not alpha). Increases dilation (b2- AR) Increases HR and contractility (b1- AR) Overall increase CO, lower mean pressure, and increase HR. Baroreceptor response will decrease HR and promote dilation. Higher doses of Epi will activate a1 and have response similar to NE (activation of a1 will constrict regardless of b2 activation) Example of Phenylephrine infusion Pure alpha agonist. Increase in BP causes a significant decrease in HR due to baroreceptor activation and PNS signals If the nerve signal is blocked can have a lot less phenylephrine to have the same response. Also no compensatory decrease in HR. If same dose was used in example to right BP increase would last a lot longer. SNS activity is controlled by AR signaling Alpha and beta receptors: Alpha1 and 2 are on the vasculature to cause constriction Beta1 are in the heart to increase HR and contractility Kidney Juxtaglomerular cells – renin release Beta2 are in the vasculature and mediate vasodilation Norepinephrine and epinephrine are made in response to SNS Norepinephrine: a1 and b1 stimulation Epinephrine b1=b2. alpha stimulation at high concentrations Phenylephrine: (not endogenous : alpha specific agonist)  Summary / Things to Know: Understand SNS dependent activation of RAAS Angiotensin II’s mechanism to increase CO and blood pressure Aldosterone signaling and mechanism to increase BP ADH/AVP signaling and mechanism to increase BP NPs signaling and mechanism to decrease BP