Secondary hypertension Exp. induced stenosis of renal artery as a model of renovascular hypertension Arterial blood pressure - definition ■ P = Q x R ■ Analogous to Ohm's law defining voltage ■ Tensor in moving viscous fluid ■ Vessel wall is challenged by its radial member (i.e. pointing towards the endothelium) - Systolic - on the top of the pulse curve - Diastolic - on the bottom of the pulse curve - Pulse - pulse curve amplitude - Mean - average pressure during the cycle 2 Cardiac output ■ Q: is equal to cardiac output (CO) - anatomic shunts CO = SV (stroke volume) x f SV = EDV (enddiastolic volume) - ESV (endsystolic volume) EF [%] = SV/EDV • CO is physiologically equal to venous return (depends on circulating volume) • In very high HR the CO paradoxically decreases (the ventricles are not filled effectively) 0 20 40 60 80 100 120 140 160 180 200 220 240 Srdeční frekvence (/min) Cardiac and venous function curve Renal function curve ■ Provided the renal functions are untouched, the increase in CO or resistance can be compensated by lowering of circulating volume ■ This can be disturbed under pathological conditions - hypervolemia Circulating volume Pulmonary circulation 9 % 450 Heart 7 % 350 Arteries 13 % 650 Arterioles and capillaries 7 % 350 Venules, veins and venous sinuses 64 % 3200 6 Resistance XR [kg.s_1.nr4]: can be obtained from Hagen-Poiseuill law: R = 8xr|xd/7ix r4,where: r| = viscosity d = lenght of the segment r = radius 7 Peripheral resistance ■ The resistance increases inversely to the radius at the power of 4 ■ The decrease in radius is most evident in arterioles ■ The smooth muscle tone in the wall of arterioles changes depending on many factors - this controls peripheral resistance ^resistance arterioles") Vascular smooth muscle Vasodilatation - NO - produced in the endothelium by constitutive (eNOS) and inducible (iNOS) synthase - prostacyclins - histamine - bradykinin - p02, pC02 ,pH - adenosine - catecholamines - cGMP, cAMP Vasoconstriction - endothelin - ATII - ADH - catecholamines - Ca2+ ^Ca+t—s. ^Cyclooxyge ^—I Receptors I- Acetylcholine ATP Adenosine Bradykinin Histamine L-arginine > L-dtrulline NADP+ endothelium j Vessel lumen Arterial wall elasticity (elastic arteries) Elastic arteries Stiff arteries ^ Systolic/pulse pressure * Diastolic flow 7\ Systolic/pulse pressure ^ Diastolic flow ■ Worsens with age ■ Loss of elasticity (arterial stiffness) leads to isolated systolic hypertension Blood pressure regulation ■ Several interconnected systems ■ Regulation of: - heart rate -cardiac contractility - peripheral resistance -circulating volume li Hypertension (BP = CO x R) essential - 90-95% secondary - 5-10% - renal ■ renovascular ■ renoparenchymatous - endocrine ■ adrenal gland *~prim. Hyperaldosteronism *~Cushing syndrome *~feochromocytome ■ others *~Akromegalia *~Hyperthyreosis - Other causes *~Aortic coarctation 12 Adrenal gland adrenal cortex ^■0B-\ Cholesterol f Mineralocorticoids Sex hormones DHEA 17-hydroxylase Aldosteron synthase Aldosterone 11-ß-hydroxylase 14 Adrenal medulla 15 pheochromocytoma Paroxysmal hypertension 90% in the adrenal gland, 10% outside They produce norepinephrine, epinephrine, dopamine Aortic coarctation Stenosis of aortic lumen, usually behind a. subclavia sinistra___ Hypertension od the upper part, hypotension of the lower part Renal functions Regulation of - extracelular volume - tonicity and osmolarity - acid-base equilibrium - nitrogene metabolism - calcium and phosphate homeostasis - hematocrite - lipid metabolism, low molecular weight substances Total flow through the kidneyJs cca 1200 ml/min, which corresponds with -20-25% of cardiac output ■ cortex >>> medulla Renal plasma flow, RPF) -600-700 ml/min - with hematocrite ~0.50 glam. .filtration -20% glomerular filtration rate (GFR) -100-I2(jml/min a v J - ~144 - 170 I daily, but 99% reabsorption -» i.e. 1.5 - 1.7 I urine daily The difference in hemoglobin saturation between arteries and veins is very smalf - given 100% saturation Hb Q? i,n arterial blood, the saturation of Hb in venous Dloocf coming out of following organs is: ■ heart - 35% ■ brain - 50% ■ kidney - 90% - The majn [physiological functionof hiah perfusion through the kidney is thus regulation (see above/ arfdnot nutrition. 17 Blood supply in the kidney ■ a. renalis aa. interlobares aa. arcuates aa. interlobulares afferent arterioles glomerular capillaries efferent arterioles - -> peritubular capillaries (in cortical nephrones) - -> vasa recta (in juxtamedullar nephrones) Two kinds of nephrones Regulation of blood pression in the kidney Systemic blood pressure between 80-160mmHg, RBF is quite stable thanks to the autoregulation - In case of significant decrease of BP, renal perfusion is impaired^ ischemia, necrosis) Autoregulation of RBF (1) myogennic regulation ■ SMC of afferent and efferent arterioles detect the tension and react by their contraction - (2) tubuloglomerular feedback ■ juxtaglomerular apparatus detects eventual changes of NaCI concentration and releases renin ■ activation of local RAS ensures the contraction of efferent arteriole (in higher concentrations of ATII also the afferent arteriole) other paracrinne factors - prostaglandins, adenosine and NO sympaticus noradrenaline from adrenergic terminal endings and circulating adrenaline from adrenal medula lead into vasoconstriction of both afferent and efferent arteriole (al-receptors) ■ Lowering of RBF and GFR noradrenaline stimulates renin release from granular JG-cells (pi-receptors) and subsequent systemic RAS activation noradrenaline increase Na+-reabsorption of prox. tubulus systemic RAS ■o 140 120 I I 000 J = 80 t o 80Ü i ja ^ to J £ 400 C9 - 8 Renal blood flow Y Glomerular filtration rate Urine - A 50 100 150 200 Arterial pressure (mm Hg) ü O 20 Juxtaglomerular apparatus 21 tubular and vascular component - (1) tubular component ■ specialized area of the distal tubule near to afferent and efferent arteriole (macula densa) ■ cells of macula densa are sensitive to NaCI and control the production of renin in juxtaglomerular cells (JG-cells) - increase of tubular salinity -> increase in renin - (2) vascular component ■ afferent and efferent arterioles ■ extra-glomerular mesangium JG-cells (granular cells) are specialized smooth muscle cells that produce and store the renin the cells of macula densa do not have a basal membrane, which enables close contact with JG-cells. JG-cells also contain baroreceptors; when perfusion pression is lower, they start producing renin Both vascular and tubular components are innervated by the sympaticus Glomerulus JGA Ascending thick loop of Merle Descending thin loop of Henle Ascending thin loop of Henle Connecting tubule Distal convoluted tubule Collecting duct Juxtaglomerular apparatus 22 Renin-angiotensin-aldosterone ACE and ACE 2 Angiotensin I (Ang I) can be then transformed into several products Through ACE action, Ang II and Ang III with vasoconstriction effects are formed ACE also degrades bradykinin (pharmacologic inhibition of ACE leads to angioedema) Through the action of ACE 2, angiotensin 1-7 is formed, having vasodilatation and antiproliferation effect on vessel wall (contributing to the decrease of peripheral resistance - Mas receptors 24 angiotensin II receptors and systemic effects of aldosterone Renin ■ K+ ATM JWJ renal Endothelin ■ Aldosterone Heart Interstitial fibrosis Heart failure Kidney I Salt and fluid retention K* secretion Congestion Electrolyte imbalance Other effects (endothelial dysfunction, platelet aggregation) Chymase T Bradykinin tno TPGs Tt-PA(J,PAI-1) Vasodilation Anti proliferation 4. Ang II AT1 Vasoconstriction Hypertrophy Proliferation TNE t Thirst t Na+ retention TPAI-1 (it-PA) T Oxidation inflammation Growth Vasoconstriction Thrombosis Angiotensinogen Ang I AT2 NO Anti proliferation Vasodilation Anti-inflammation Antigrowth Antioxidative AT4 // YV*1 Laminin /I \ MPal-1 TNO I ET 4.TIMP-1 Maintenance of vascular intergrity AT (1-7) J. BP 4. Growth tPGs Tno Source: FusterV, Walsh RAr Harrington Hurst's The Heart, JJth Edition: www .acc££srriedicine .com Copyright i© The McGraw-Hill Companies, Inc. All rights reserved. 25 AT 2 receptors are mostly involved in fetal development Ang III is mostly involved in aldosterone secretion and in the CNS Signal cascade AT II Chohne 26 AT II receptors use 2 secondary messengers: - activation of phospholipase C (PLC) ■ PIP2 is cleaved into IP3 (intracelular Ca mobilization) and DAG ■ DAG activates proteinkinase C (PKC), hydrolyses fosfatidylcholin through the activation of fosfolipase D (PLD) and alkalizes intracelular environment ATII effect on GFR is dose-dependent (biphasic response) glomerulus Local RAAS - paracrine effects of AT II Arterioles Glomerulus Proximal tubule Efferent Distal tubule Afferent 28 Interstitial space angiotensinogen in the kidney is synthethized in the liver and locally in the kidney (proximal tubular cells) - renin is released from JG-cells to afferent arteriole and renal interstitium, where it converts circulating angiotensinogen into AT I, which is further converted into AT II through circulating ACE - parakrine effects ■ mesangial contraction ■ contraction of eferent arteriole ■ Sodium reabsorption in proximal tubule Systemic RAAS Substrate (angiolensinogen) Angiotensin II (octapeptide) Aldosterone Kidney Lüng Kidney Angiotensin I (decapeptide) Adrenal cortex Systemic arteriole / Blood pressure BP/ rises 29 Renal tubu le Localization of AT II receptors and their main effects in the kidney Äcrul arterial circulation GkimŕťLilLtt Tubule ProximaJ lubu I p Curie* @ Arfetml artenole —Conical (o) ihjťk .l-m-miir;, limb of Hen It* Medulla (l),M«iulfarv interstillal cells (7) Vjsj recta 30 1- vazokonstrikce 2- omezeně vazokonstrikce a inhibice tvorby a uvolňování reninu 3- preferenční vazokonstrikce 4- kontrakce 5 a 6-Na+ reabsorpce 7-vazokonstrikce 8 -efekt neznámý Systemic RAAS Brain Thirst Antidiuretic; hormone Afferent arteriole Renin Angioiensinogen I Al -^Ali Autoregulation Angiotensin II Efferent arteriole Arteriolar vasoconstriction Increased bfood pressure y^^v Adrenal gland Aldosterone 31 Goldblatt's model of renovascular hypertension One-kidney, one-clip Two-kidney, one-clip model model ■ 2 kidneys / 1 clip - hypertension (pressure effect of ATII), but maintained regulation of ECV and plasma composition (pressure natriuresis in the contralateral kidney) ■ 1 kidney / 1 clip ( = 2 kidney / 2 clips) - hypertension (pressure effect of ATII, hypervolemia) + dysregulation of ECV and plasmatic composition ■ 1 kidney / 0 clips 32 - normal BP + regulation of ECV and composition Pathophysiology ■ While the hypertension is present in both cases (seethe picture below), they differ in other parameters - in "1 kidneys/1 clip", the plasmatic level of renin is normal or lower and hypervolemia is present (renin dilution) ■ Higher perfusion pressure of the kidney - in "2 kidneys/1 clip", the plasmatic level of renin is high together with normal plasmatic volume (eventual volume expansion is compensated by the other kidney, but there is still the pressure effect of AT II) 33 Renin content of kidney No change Dec rea ses on Inc reases on contralateral side stenotic side Blood pressure Significantly increases Significantly increases Plasma renin activity No change or decreases Significantly increases Plasma volume Increases No change Blood pressurea(lc.r block of angiotensin II No change Decreases Stenosis of the renal artery Early Disease Mild atherosclerosis Left renal artery Aorta Total glomerular filtration rate 100 ml/min Progressive Disease Progressive aortic atherosclerosis and sevBre unilateral renal-artery stenosis Cortical thinning and loss of renal mass Aorta Total glomerular filtration rate 100 ml/min Advanced Disease Atherosclerotic plaque in perirenal aorta and severe bilateral renal-artery stenosis Cortical thinning and loss of renal mass Aorta Total glomerular filtration rate 30 ml/min typical causes of renovascular hypertension: - atherosclerosis ■ Frequent, usually older people ■ Cca 30% of patients with other form of atherosclerosis have also atherosclerosis of renal artery (usually il ^^^k insignificant) ■ ' *-^^^ - fibromuscular hyperplasia ■ younger women Practical ANESTÉZIE i.p. kontrola podvaz a. renalis sin VÝSLEDKY (1) srovnání hmotnosti stenotické kontrolní fedviny a srdce (kontroly vs< model) (2) srovnání charakteru aintenzity exprese reninu ve stenotické a kontrolní ledvině (1) střední laparotomie (2) separace aorty a v, cava inf, (3) inkompletní ligace aorty mezi odstupy a. renalis dx. a sin. (4) uzavření laparotomie ve dvou vrstvách za 3 týdny po podvazu (1) euthanasie predávkovaním anestézie, otevření laparotomie (2) oboustranná nefrektomie + vystřižení srdce (3) zvážení ledvin a srdce (4) histologické zpracování - analýza exprese reninu v JGA 35 Practical - operation