REGULATION/DYSREGULATION in BLOOD PRESSURE Blood pressure – the most important parameter in cardiovascular system – „high-profile“ parameter •Blood pressure (BP) – pressure of the blood to the wall of the vessels • •Systolic BP, diastolic BP, pulse pressure, mean arterial pressure (MAP) • •BP = CO x R CO – cardiac output, R – resistance • •CO = SV x HR SV – stroke volume, HR – heart rate • ESH AND ESC GUIDELINES 2013 ESH/ESC Guidelines for the management of arterial hypertension The Task Force for the management of arterial hypertension of the European Society of Hypertension (ESH) and of the European Society of Cardiology (ESC) Authors/Task Force Members: Giuseppe Mancia (Chairperson) (Italy) * , Robert Fagard (Chairperson) Classification BP values category Systolic BP Diastolic BP (mmHg) (mmHg) optimal < 120 < 80 normal 120 – 129 80 – 84 high normal pressure 130 – 139 85 – 89 Hypertension - mild 140 – 159 90 – 99 Hypertension - moderate 160 – 179 100 – 109 Hypertension - severe ≥ 180 ≥ 110 Isolated systolic hypertension ≥ 140 < 90 According the Guidelines of European Society of Cardiology 2013 2018 ESC/ESH Guidelines for the management of arterial hypertension The Task Force for the management of arterial hypertension of the European Society of Cardiology (ESC) and the European Society of Hypertension (ESH) Authors/Task Force Members: Bryan Williams* (ESC Chairperson) (UK), Giuseppe Mancia* (ESH Chairperson) (Italy), Wilko Spiering (The Netherlands), Enrico Agabiti Rosei (Italy), Michel Azizi (France), Michel Burnier (Switzerland), Denis L. Clement (Belgium), Antonio Coca (Spain), Giovanni de Simone (Italy), Anna Dominiczak (UK), Thomas Kahan (Sweden), Felix Mahfoud (Germany), Josep Redon (Spain), Luis Ruilope (Spain), Alberto Zanchetti† (Italy), Mary Kerins (Ireland), Sverre E. Kjeldsen (Norway), Reinhold Kreutz (Germany), Stephane Laurent (France), Gregory Y. H. Lip (UK), Richard McManus (UK), Krzysztof Narkiewicz (Poland), Frank Ruschitzka (Switzerland), Roland E. Schmieder (Germany), Evgeny Shlyakhto (Russia), Costas Tsioufis (Greece), Victor Aboyans (France), and Ileana Desormais (France) European Heart Journal (2018) 39, 3021–3104 •Classification of BP •It is recommended that BP be classified as •optimal, normal, high–normal, or grades •1–3 hypertension, according to office BP. •Classification of office blood pressure and definitions of hypertension gradeb • •Category Systolic (mmHg) Diastolic (mmHg) •Optimal <120 and <80 •Normal 120–129 and/or 80–84 •High normal 130–139 and/or 85–89 • •Grade 1 hypertension 140–159 and/or 90–99 •Grade 2 hypertension 160–179 and/or 100–109 üGrade 3 hypertension ≥180 and/or ≥ 110 •Isolated systolic hypertensionb ≥ 140 and <90 • •BP = blood pressure; SBP = systolic blood pressure. •A) BP category is defined according to seated clinic BP and by the highest level of BP, whether systolic or diastolic. •B) Isolated systolic hypertension is graded 1, 2, or 3 according to SBP values in the ranges indicated. •The same classification is used for all ages from 16 years. •Changes in recommendations •2013 •Diagnosis: Office BP is recommended for screening and diagnosis of hypertension. • •2018 •Diagnosis: It is recommended to base the diagnosis of hypertension on: •Repeated office BP measurements; or Out-of-office BP measurement with ABPM and/or HBPM if logistically and economically feasible. •Treatment thresholds •2013 •Highnormal BP (130–139/85–89 mmHg): Unless the necessary •evidence is obtained, it is not recommended to initiate antihypertensive drug therapy at high–normal BP. •2018 •Highnormal BP (130–139/85–89 mmHg): Drug treatment may be •considered when CV risk is very high due to established CVD, especially •CAD. •Definitions of hypertension according to •office, ambulatory, and home blood pressure levels • •Category SBP(mmHg) DBP(mmHg) •Office BP ≥ 140 and/or ≥ 90 • •Ambulatory BP • Daytime (or awake) mean ≥ 135 and/or ≥ 85 • Night-time (or asleep) mean ≥ 120 and/or ≥ 70 • 24 h mean ≥ 130 and/or ≥ 80 •Home BP mean ≥ 135 and/or ≥ 85 • •BP = blood pressure; DBP = diastolic blood pressure; SBP = systolic blood pressure. •. Regulatory mechanisms for blood pressure are targets for therapy in hypertension. Regulation of blood pressure – complex process RAAS ANP/BNP ADH Vasoconstriction: angiotensin II, vasopresin, epineprin (α1), serotonin, PGF/TXA2, endotelin, cofein, NPY sympatikus parasympatikus baroreflex compliance Vasodilatation: NO, adrenalin (β2), adenosin, acidosis, histamin, PGD2/PGE2/PGI2, prostacyclins, VIP, bradykinin Thomas M Coffman, Under pressure: the search for the essential mechanisms of hypertension , Nature Medicine 17, 1402–1409 (2011) let me remark that 400 years ago REGULATION IN CARDIOVASCULAR SYSTEM •Main function: • • keep relatively constantaneous arterial blood pressure •keep perfusion of tissues • Regulation of vessels tone •Tone of the vessels = basic tension of the smooth muscle inside of the wall • (vasoconstriction x vasodilatation) • •Regulation - local autoregulation • - system regulation Autoregulation •Autoregulation – the capacity of tissues to regulate their own blood flow •Myogenic theory – Bayliss phenomenon (as the pressure rises, the blood vessels are distended and the vascular smooth muscle fibres that surround the vessels contract; the wall tension is proportional to the distending pressure times the radius of the vessels – law of Laplace) • Autoregulation •Metabolic theory – vasodilator substances tend to accumulate in active tissue, and these metabolites also contribute to autoregulation •ending products of energetic metabolism – CO2, lactate acid, K+ •effect of hypoxia (circulation: vasodilatation x pulmonary circulation: vasoconstriction) •Adenosin – coronary circulation: vasodilatation • Autoregulation •by substances which releasing from: • endothelium • tissues • •Substances secreted by the ENDOTHELIUM •Vasodilatation: •Nitric oxide (NO) from endothelial cells •(originally called: EDRF) •Prostacyclin is produced by endothelial cells • • •Vazoconstriction: • Endothelins (polypeptids – 21peptides) • three isopeptides: ET 1, ET 2 , ET 3 •Substances secreted by the tissues: •Histamine – primarily tissue hormones. •General affect: vasodilatation - decrease periphery resistence, blood pressure • •KININS: 2 related vasodilated peptides •Bradykinin + lysylbradykinin (kallidin). •Sweat glands, salivary glands •10x strongers than histamine •Relaxation of smooth muscle, decrease blood pressure • Systemic regulation • •By hormones •Catecholamines – epinephrine, norepinephrine - effect as activation of sympathetic system •RAAS - stress situation •ADH - general vasoconstriction •Natriuretic hormones - vasodilatation Neural regulatory mechanism •Autonomic nervous system •Sympathetic: vasoconstriction •All blood vessels except capillaries and venules contain smooth muscle and receive motor nerve fibers from sympathetic division of ANS (noradrenergic fibers) -Regulation of tissue blood flow -Regulation of blood pressure •Parasympathetic part: vasodilatation •Only sacral parasympathetic cholinergic fibres (Ach) inervated arteriols from external sex organs • http://www.studentconsult.com/common/showimage.cfm?mediaISBN=0721632564&FigFile=S23283-015-f004.jpg &size=fullsize Sympathetic nervous system Fight or flight response Energy/store consumption Preganglionic neuron – Spinal cord -Thoraco - lumbar system Ganglia Paravertebral -Truncus sympathicus - Majority Prevertebral -Plexus aorticus Mostly diffuse effect Parasympathetic nervous system Rest and digest response Energy conservation/en. store production Preganglionic neuron – Brain stem and spinal cord – cranio-sacral system Ganglia Close to target organs or intramurally Mostly local effect http://www.studentconsult.com/common/showimage.cfm?mediaISBN=0721632564&FigFile=S23283-015-f004.jpg &size=fullsize Sympathetic nervous system Fight or flight response Energy/store consumption Preganglionic neuron – Spinal cord -Thoraco - lumbar system Ganglia Paravertebral -Truncus sympathicus - Majority Prevertebral -Plexus aorticus Mostly diffuse effect Parasympathetic nervous system Rest and digest response Energy conservation/energy store production Preganglionic neuron – Brain stem and spinal cord – cranio-sacral system Ganglia Close to target organs or intramurally Mostly local effect http://ccn.aacnjournals.org/content/27/1/30/T1.large.jpg INTEGRATION of regulation in cardiovascular system •The regulation of the heart: •Rami cardiaci n. vagi •Cardiac decelerator center - medula oblongata (ncl.dorsalis, ncl. ambiguus) – parasympathetic fibres of nervus vagus • : vagal tone (tonic vagal discharge) • •Negative chronotropic effect (on heart rate) •Negative inotropic effect (on contractility) •Negative dromotropic effect (on conductive tissue) • INTEGRATION of regulation in cardiovascular system •The regulation of the heart: • nn. cardiaci •Cardiac accelerator center – spinal cord, sympathetic ganglia – sympathetic NS • •Positive chronotropic effect (on heart rate) •Positive inotropic effect (on contractility) •Positive dromotropic effect (on conductive tissue) • • INTEGRATION of regulation in cardiovascular system •Vasomotor centre (regulation for function of vessels) •Medula oblongata ü presoric area (rostral and lateral part –vasoconstriction – increase blood pressure ü üdepresoric area (medio-caudalis part – vasodilatation, decrease of blood pressure) • INTEGRATION of regulation in cardiovascular system • • •Influence by central nervous system • cerebral cortex • limbic cortex • hypothalamus Regulation of blood pressure Short - term regulation - baroreflex Middle - term regulation - humorals regulation • sympathetic - catecholamines • RAAS (decrease perfusion pressure in kidney – secretion of renin) • ADH Long – term regulation - kidney regulation • •Baroreflex – in every day life •Orthostatic – clinostatic reaction •Valsalva maneuvre 04 Resetting of baroreflex •During repeated raising of blood pressure - e.g. in chronic hypertension - the force of baroreflex reaction on systemic blood pressure is lower •??? Why???mechanical changes in baroreceptors – decrease sensitivity due to structure changes on the vessels wall OR dysfunction of endotelium OR down-regulation in the brain center due to their increasing frequency of stimulation •Resseting of baroreflex can regulate the changes in blood pressures, but the resseting is unable to go back on „normal“ level •Resetting is a partially reversible – during a short-term influence of raising blood pressure • •Notice: in clinical practice: •!start treatment of hypertension in time! A change of duration of pulse interval (in ms) due to a change of blood pressure by 1 mmHg Laboratory methods: Spontaneous methods: § in frequency-domeain - Sequence analysis - cross-spectral analysis § in time-domain - a-index - neck suction - Valsalva manoever - Phenylephrin aplication E7C22FD0 Furlan R et al. Circulation 2003;108:717-723 842EF7C5 842EF7C5 842EF7C5 msoDBE03 (#TK)$VN"$SV"$PT"$Stř TK SI [ms] STK [mmHg] Middle – term regulation 1 catecholamines •Mediators of sympathetic nerves for baroreceptors and chemoreceptors •Sympathetic nervous system stimulates releasing of epinephrine and norepinephrine from adrenal medulla – main function: vasoconstriction – chronotropic effect – inotropic effect •Its function start during minutes or hours Adrenal medulla – modified sympathetic ganglion – release stress hormon to blood stream ANS Middle – term regulation 2 Renin - angiotensin - aldosteron •System in kidney •+ •extrarenal system (in other tissues – brain, adrenal medulla, gonades, eyes) •+ •Intermediate system – heart, smooth muscles • •Renin – in juxtaglomerular cells in kidney •In liver – glycoprotein angiotensinogen – release angiotensin I (dekapeptid) – due to angiotensin converting ensyme to angiotensin II(oktapeptid) or angiotensin III (aminopeptidase) • •Angiotensin II – other way – chymase – in th heart and arterioles •(it is reason why during treatment by ACE blocatores – the angiotensin level is not reduce) Secretion of renin is modulated by •Sympathetic nervous system – beta 1 receptors activation – main mechanism of secretion of renin •Second way – by special mechanism due to sensitivity on sodium •exists a special intrarenal mechanism – negative sodium billance increase the renin secretion •???? hypothesis – macula densa register of sodium concentration in renal tubular system – this information transports to juxtaglomerular cells where activated renin-angiotensin system (has an influence on secretion of renin – release angiotensin II ); •Increse level of sodium – decrease releasing of renin (mediator – Nitric Oxide) •???Arterial pressure – stretch receptors (baroreceptory) in vas afferens (juxtaglomerular cells) – influence on blood pressure in kidney or also in systemic circulation??? Angiotensin II - Effects (Owerview) •Vasoconstriction •Change in renal hemodynamics – decrease of blood flow in kidney and glomerular filtration •Influence on reabsorption of sodium in renal tubules •It invokes or enhances the presynaptic release of noradrenaline •Stimulates the release of ADH • •Effect of ANGIOTENSIN III •Stimulation of aldosterone secretion from the adrenal cortex Middle – term regulation 3 ADH - vasopressin •During a strong decline of blood pressure • from posterior pituitary – vasoconstriction • •May be: slowly effect – retention of water in distal tubule and proximal part of collecting ducts Long – term regulation •Little is known about how this occurs • •Pressure diuresis regulates the volume in circulation and keep „pressure homeostasis“ •Blood pressure increases longer than 2 hours (persistant increase)– started pressure diuresis, its time duration a lot of days (increase blood pressure – increase excretion of sodium - osmotic activity – increase excretion of water ---decrease extravascular volume and decrease blood pressure) •a single control system which is not subject to adaptation – the action takes as long as the pressure is returned to the original values (or if its action is not reversed by other mechanisms) • With persistent decrease of BP - the opposite effect • • • Long – term system of pressure natriuresis •It is a cascade of regulatory processes: • the mechanical effect of increased blood flow through the kidney ... increased blood flow in the kidney papilla - increased renal interstitial hydrostatic pressure - increased tight junction of epithelial cells of the renal tubules for sodium - increased sodium excretion - increased excretion water - decrease in volume of circulatory fluids - pressure drop in the systemic circulation •System of internal renal baroreceptors ... pressure increase in vas afferens ... restriction of renin production - attenuation of renal sympathetic stimulation - decrease in sodium reabsorption, reduction of fluid volume - pressure drop •Na+- K+ - ATPase inhibitory factor – released from adrenal medulla (steroid-like digitalis - possibly ouabain) •Increased AT2 receptor expression for angiotensin II (may antagonize the effects of inadequate AT1 receptor stimulation, in rat experiments demonstrated - increased sodium and water excretion) •Others: bradykinin, urodilatin, renal natriuretic peptides