Neuronal and Hormonal control of BP_Lucy Privitera_281123.pdf

Neural and Hormonal control of Blood Pressure Dr Lucy Privitera [email protected] Orcid N: 0000-0002-3280-8026 Blood pressure Two systems that regulate BP • Neural- fast acting • Hormonal- slower acting Intended Learning Objectives Neural Control of Blood Pressure • Describe the physi...

Neural and Hormonal control of Blood Pressure Dr Lucy Privitera [email protected] Orcid N: 0000-0002-3280-8026 Blood pressure Two systems that regulate BP • Neural- fast acting • Hormonal- slower acting Intended Learning Objectives Neural Control of Blood Pressure • Describe the physiological sensors and effectors for the neuronal control of arterial blood pressure. • Describe the position and innervation of the aortic and carotid sinus baroreceptors, their central connections and the role of the brainstem in the control of blood pressure. • Describe the role of the vagus nerve and the sympathetic nervous system in the control of blood pressure. Hormonal Control of Blood Pressure • Describe the renin-angiotensin-aldosterone system and explain its role in blood pressure regulation • List common drugs which can be used to control hypertension and explain their mechanism of action Intended Learning Objectives Neural Control of Blood Pressure • Describe the physiological sensors and effectors for the neuronal control of arterial blood pressure. • Describe the position and innervation of the aortic and carotid sinus baroreceptors, their central connections and the role of the brainstem in the control of blood pressure. • Describe the role of the vagus nerve and the sympathetic nervous system in the control of blood pressure. Neural control of blood pressure • The neuronal system provides moment to moment regulation, for example when you go from a lying down to a standing posture it regulates blood pressure: without it you would have postural hypotension. This condition is called orthostatic hypotension • It is also vital for the maintenance of blood pressure after haemorrhage. Neural Control of Blood Pressure: the Baroceptor system. Neural control of Blood pressure is a FAST homeostatic process controlled by negative feedback. All negative feedback systems have sensors to monitor the controlled variable. In the case of blood pressure the sensors are found mainly in the carotid sinus in the internal carotid artery just above the bifurcation of the carotid arteries As well as the carotid sinus there are also baroreceptor in the aortic sinus, at the base of the aortic valve. Arterial baroceptors The mechanotransduction of blood pressure An increase in arterial pressure selectively stretches the sinus wall and thus also the sensory nerve fibres embedded in the wall https://www.science.org/doi/epdf/10.1126/science.aav3495 Negative feedback system Intended Learning Objectives Neuronal Control of Blood Pressure • Describe the physiological sensors and effectors for the neuronal control of arterial blood pressure. • Describe the position and innervation of the aortic and carotid sinus baroreceptors, their central connections and the role of the brainstem in the control of blood pressure. • Describe the role of the vagus nerve and the sympathetic nervous system in the control of blood pressure. The nerve endings in the carotid sinus give rise to the short sinus nerve. This nerve joins the glossopharyngeal nerve and/or the vagus nerve. The afferent fibres from the sinus nerve travel in these cranial nerves and synapse in the brainstem. Nucleus of the solitary tract (NTS) The afferent fibres from the sinus nerve enter the brainstem in the vagus or glossopharyngeal nerve and terminate in the nucleus of the solitary tract (NTS) in the medulla oblongata, (often referred to simply as ‘medulla’), the lowest part of the brainstem. The caudal end of the medulla merges with the rostral end of the spinal cord. See next slide A cross-section of the medulla at the level indicated by the red dashed line in the previous slide The Nucleus of the solitary tract (NTS) lies near the dorsal surface of the medulla The nucleus of the solitary tract (NTS).. The NTS can be regarded as an integrating centre for visceral afferents from mouth, throat and neck. Intended Learning Objectives Neuronal Control of Blood Pressure • Describe the physiological sensors and effectors for the neuronal control of arterial blood pressure. • Describe the position and innervation of the aortic and carotid sinus baroreceptors, their central connections and the role of the brainstem in the control of blood pressure. • Describe the role of the vagus nerve and the sympathetic nervous system in the control of blood pressure. The nucleus of the solitary tract (NTS) connects to the vasomotor centre in the rostral medulla and the nucleus ambiguus in the nearby lateral medulla. The NTS computes whether the information from the sinus nerve matches the blood pressure ‘set point’ and if not activates a corrective output either via the vasomotor centre or the nucleus ambiguus. If blood pressure is too low the NTS activates the vasomotor centre which stimulates sympathetic outflow to the heart via the reticulospinal tract. If blood pressure is too high the NTS activates the nucleus ambiguus which stimulates parasympathetic outflow to the heart via the vagus nerve Vasomotor centre The sympathetic outflow influences the constriction of peripheral arterioles Cardiac Total peripheral x output (CO) resistance (TPR) = Mean arterial pressure (MAP) Increased Sympathetic outflow Cardiac Total peripheral x output (CO) resistance (TPR) Mean arterial = pressure (MAP) The sympathetic outflow also results in an increase in heart rate Heart rate x Stroke volume = Cardiac output (CO) Increased Sympathetic outflow Heart rate x Stroke volume = Cardiac Total peripheral x output (CO) resistance (TPR) Cardiac output (CO) Mean arterial = pressure (MAP) Combined effect Finally, the sympathetic outflow also results in constriction of veins that raises venous return and preload* and thus raised stroke volume and cardiac output. * Ventricular filling due to the initial stretching of cardiac muscle cells prior contraction Heart rate x Stroke volume = Cardiac output Increased Sympathetic outflow causing venoconstriction and increased preload Heart rate x Stroke volume Cardiac Total peripheral x output (CO) resistance (TPR) Cardiac = output Mean arterial = pressure (MAP) If the baroreceptor input is too high, the vasomotor centre is inhibited. Reduction of the sympathetic outflow. Activation of parasympathetic nervous system (via the nucleus ambiguus). Stimulation of the vagus The vagus acts at the sinoatrial node of the heart to slow down the heart and thus reduce cardiac output (CO) Heart rate x Stroke volume = Cardiac output Increased parasympathetic outflow Heart rate x Stroke volume = Cardiac output Cardiac output x Total peripheral resistance (constant) Mean = arterial pressure Schematic diagram of the baroreceptor reflex. Cardiovascular autonomic function in lateral medullary infarction 2013 Neurological Sciences DOI:10.1007/s10072-013-1420-y Carotid massage A carotid massage, or carotid sinus massage (CSM), is a medical manoeuvre that can be used to reduce blood pressure or slow down a dangerously rapid heartbeat or to diagnose certain heart rhythm disturbances. Massaging the sinus in this way increases the rate of firing in the sinus nerve and increases vagal output. To perform a carotid massage, you’ll need to massage the area at the base of the patient’s neck, where the carotid artery enters the head. Please note: An incorrectly performed CSM can cause serious health repercussions, especially in elderly patients and should only be used by experienced health professionals (see URL below) https://www.wikihow.com/Perform-a-Carotid-Massage Baroreflex activation therapy in hypertension https://www.nature.com/articles/jhh2013139 Hormonal Control of Blood Pressure • Describe the renin-angiotensin-aldosterone system and explain its role in blood pressure regulation • List common drugs which can be used to control hypertension and explain their mechanism of action Contents • The juxtaglomerular apparatus • The RAAS system • Drug targets for hypertension (cover during Pharmacology of CVS) • Haemorrhage Contents • The juxtaglomerular apparatus • The RAAS system • Drug targets for hypertension (covered during Pharmacology of CVS) • Haemorrhage Where is the sensor for the hormonal control of blood pressure? • Hormonal control of blood pressure is mediated by blood flow through the kidney • The sensor for the hormonal control of blood pressure is the juxtaglomerular apparatus of the distal tubule. • This organ regulates Glomerular filtrate rate (GFR) by tubuloglomerular feedback • It also regulates blood pressure The juxtaglomerular apparatus (JGA) One part of the distal tubule contacts the point where the afferent and efferent arterials enter the glomerulus forming the juxtaglomerular apparatus (JGA). The three cellular components of the juxtaglomerular apparatus are 1. mesangial cells which lie in between the afferent and efferent arteriole they contain contractile protein (possible function is to shape of the glomerulus and thus its filtration properties). 2. macula densa cells detects sodium in the wall of the distal tubule 3. juxtaglomerular cells around the walls of the afferent and efferent arteriole Distal tubule Mesangial cells Sodium levels in the distal tubule as an index of glomerular filtration rate (GFR) • In the proximal tubule and loop of Henle sodium is removed from the tubular fluid at a constant rate (rate at which the blood is filtered in the kidneys). • If the GFR is low, less sodium enters the proximal tubule per minute • More of this sodium will have been removed by the time the fluid reaches the distal tubule. • Conversely, if the GFR is high, more sodium enters the proximal tubule per minute • less of this sodium will have been removed from the tubular fluid when it reaches the distal tubule. So overall in distal tubule fluid: Low [Na+] = Low GFR (low flow rate means more time for Na+ reabsorption) High [Na+] = High GFR (high flow rate mean less time for Na+ reabsorption) When the sodium concentration in the distal tubular falls below a certain threshold, as well as initiating tubuloglomerular feedback the macula densa cells activate the juxtaglomerular cells to release the enzyme renin into the blood stream Tubuloglomerular feedback • When sodium concentration Distal is low in the distal tubule, in tubule addition to driving renin release, the macula densa cells also activate a local process called tubuloglomerular feedback. • This process acts via local hormones to produce relaxation of the smooth muscle of the afferent arteriole. • This increases the filtration pressure and brings GFR back to normal. Mesangial cells How does afferent relaxation increase Glomerular Filtration Rate? • GFR depends on difference in pressure between afferent arteriole and efferent arteriole; • Dilation of afferent arteriole will increase in the pressure in it and thus filtration pressure and thus increase GFR. efferent filtrate afferent Contents • The juxtaglomerular apparatus • The RAAS system • Renin-angiotensin-aldosterone system • Drug targets for hypertension • Heamorrhage Stimulus of Renin release Remember, renin is released (from the juxtaglomerular cells) when the GFR is too low. Distal tubule Mesangial cells The role of Renin • The renin enzyme passes into the venous blood, where it meets a globular protein angiotensinogen secreted by the liver. • Renin enzymically cleaves angiotensinogen into Angiotensin I, a 10-amino acid peptide. • When angiotensin I passes through the lungs it is further cleaved in the lungs by endothelial-bound angiotensin-converting enzyme (ACE) into an octapeptide angiotensin II (ACE is also found in smaller amounts in heart muscle) Angiotensin II is a potent constrictor of the smooth muscle of systemic arterioles. Thus it raises afterload, and thus, assuming a constant cardiac output, blood pressure. The Role of Renin • One way to look at the renin-angiotensin system is that it is a way for the kidney to control GFR. • By releasing renin the kidney will raise blood pressure in the afferent arteriole and thus increase filtration pressure to restore a low GFR back to normal. • The kidney ‘selfishly’ controls blood pressure everywhere in the body just so it can have a constant GFR!!! • In support of this idea, Angiotensin II causes constriction of smooth muscle in the efferent arteriole but not the afferent arteriole (thus increasing filtration pressure) • Species and concentration dependent effect • Angiotensin II is more potent at efferent arteriole constriction Role of Angiotensin II • Angiotensin II acts on angiotensin II receptors on the luminal surface of endothelium lining blood vessels. • There are two different subtypes of angiotensin II receptors; the main one is AT1. • G-protein coupled receptor • Increases [calcium] in smooth muscle • Causes constriction • AT1 receptors also stimulate noradrenaline release from sympathetic nerve terminals. • rise in blood pressure (SNS) • AT1 receptors in the heart may cause cardiac hypertrophy • The other angiotensin receptor is AT2. The functions of the AT2 receptor are a subject of intense current research; • involved in apoptosis (programmed cell death) • growth and development of neurones • vasoldilation Renin and the sympathetic nervous system Activity in the renal nerve (a sympathetic efferent) increases renin release via stimulation of beta receptors on the juxtaglomerular cells Angiotensin in steroid secretion • AT1 receptors are also found on cells in the adrenal cortex. • These cells secrete the mineralocorticoid steroid hormone aldosterone Adrenal cortex Aldosterone Is a mineralocorticoid produced in the zona Glomerulosa of the adrenal cortex • Aldosterone acts on epithelial sodium channels (ENaC) in the distal convoluted tubule. • These channels increase reabsorption of sodium. • The increased sodium reabsorption increases water reabsorption by osmosis, so the net result is a decrease in urinary loss of sodium and water. • This causes an increase in circulating blood volume, and an increase in blood pressure. Counter-regulatory hormone: Atrial Natriuretic peptide • ANP is released when • atrial wall is stretched, via atrial volume receptors • Increased sympathetic stimulation of β-adrenoceptors • Increased sodium concentration (hypernatremia) • Atrial natriuretic hormone decreases sodium reabsorption (& decreases blood volume) • Aldosterone increases sodium reabsorption (& increases blood volume) Overall summary diagram Note that Renin affects both • blood pressure control system by the effect of AGII on systemic arterioles • blood volume control system by the effect of aldosterone on kidney tubules Contents • The juxtaglomerular apparatus • The RAAS system • Drug targets for hypertension • Haemorrhage Drug targets for primary hypertension One way to reduce primary hypertension (no identifiable secondary cause) is by means of angiotensin or renin blocking drugs; Two main types 1) ACE inhibitors: (captopril) Block angiotensin converting enzyme and thus prevent formation of Angiotensin II. 2) Angiotensin receptor antagonists (ARBs) (losartan) Block AT1 receptors The effect of homeostasis on ACE inhibition • The renin-angiotensin system is a controlled system. • The excess renin in a hypertensive individual is being released for a reason. • If you give a drug that blocks the actions of angiotensin you may reduce blood pressure • you do not cure the primary problem which may be poor renal perfusion. • The kidney may respond to ACE inhibitors by increasing renin output • May have to keep giving greater and greater doses of the drug to have the same antihypertensive effect Millar’s simple guide to Antihypertensive Drug actions & their main side effects 1) Calcium antagonists-vasodilate S/E- flushing, oedema. 2) ACE inhibitors-inhibit renin/angiotensin/aldosterone system (RAAS)-vasodilate S/E- cough, low BP 3)Angiotensin Receptor Blockers-Block action of angiotensin IIvasodilate S/E- Low BP 4) Thiazides-Salt and water loss S/E- impotence, hypokalaemia 5) Beta blockers-Slow & reduce contractile force of heart, reduce renin secretion S/E –lethargy, bronchospasm Calcium channel blockers (CCBs) • Decrease heart rate • Decrease contractility • Increase coronary artery vasodilation • Decrease total peripheral resistance ACE inhibitors (Ramipril) • ACE inhibitors RAAS system • preventing conversion of (inactive) angiotensin I to (active) angiotensin II • Decrease in BP due to prevention of AngII acting on AT1 to cause vasoconstriction • Concomitant decrease in mortality Angiotensin receptor blockers • Angiotensin II receptor antagonists/AT1 receptor antagonists • AT1 receptors are found in smooth muscle cells of vessels • Blockage of AT1 receptors directly causes vasodilation Thiazide drugs • Chlorothiazide/Hydrochlorothiazide • Inhibit reabsorption of sodium (Na+) and chloride (Cl−) ions from the distal convoluted tubules • Increase in osmotic pressure in collecting duct • Acute: diuresis causes fall in plasma volume and a reduction in cardiac output • Chronic: reduction in blood pressure by lowering peripheral resistance (i.e. vasodilation) Beta blockers • Decrease heart rate • Decrease contractility • Block direct effect on the kidney Decrease cardiac output Propanolol: non-selective β adrenoceptor antagonist Contraindicated in asthmatics/COPD Use β1 preferring antagonist (atenolol) Side Effect Profile: ↑End Diastolic Volume ↑ Ejection time Contents • The juxtaglomerular apparatus • The RAAS system • Drug targets for hypertension • Haemorrhage Control of blood pressure after haemorrhage Compensatory mechanisms • Baroreceptor reflexes • Chemoreceptor reflexes • Circulating vasoconstriction • Renal reabsorption of sodium and water • Activation of thirst mechanisms • Reabsorption of tissue fluids Compensatory mechanisms Redistribution of Cardiac output Blood loss Decreased Arterial pressure Altered Blood Gases Systemic acidosis Baroreceptor Reflex Sympathetic discharge Cardiac Stimulation Systemic Vasoconstriction Flow and Volume Redistribution Chemoreceptor Reflex Humoral compensatory mechanisms Blood loss RAAS Activation Catecholamine Release Vasoconstriction Cardiac Stimulation Increased Volume Vasopressin Release The end… Carotid Sinus afferents may travel in either Glossopharyngeal nerve (IX) or Vagus nerve (X) or both. How can the hormonal system malfunction? • Suppose the renal artery or the afferent arterioles are narrowed due to atheroma formation, or some other factor which reduces blood flow into the kidney. • This will reduce GFR, more sodium will be absorbed, which will lead to a reduced sodium concentration in the distal tubule. • The juxtoglomerular apparatus cells release renin, which is converted into angiotensin, which will raises blood pressure in an effort by the kidney to maintain GFR. • The classic experiment which led to the discovery of renin was where the renal artery was ligated in a dog and it was found that this led to a dramatic increase in blood pressure, not mediated by baroreceptors