Per Bergman Swedish physician. Robert Tigerstedt Finnisch pyhsician

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1 Regulation of Cardiovascular functions Goals: Maintain normal blood pressure (heart pump + vascular resistance + blood volume) Adaptation of blood pressure to special circumstances (redistribution) Maintains the blood flow to the heart and brain (hemorrhage) Increase blood supply to active tissues Increase or decrease heat loss from the body Robert Tigerstedt Finnisch pyhsician Per Bergman Swedish physician Robert Tigerstedt and Per Bergman: Niere und Kreislauf. Arch. Physiol. 8: , The discovery of RENIN Page 1

2 Robert W. Furchgott Louis J. Ignarro Ferid Murad Discovery the role of nitric oxide in the vascular system 1998: Nobel-prize Types of regulation Local Autoregulation: flow independence from blood pressure Metabolic, humoral, mechanical, thermal factors Systemic Hormones Neural regulation by transmitters Page 2

3 Local factors Tissue pressure Myogenic mechanism Metabolic factors (Vasodilators): low level of O 2 (except lung vessels), high level of CO 2 (except lung vessels), ph decrease, high level of K +, adenosine (heart) Humoral factors: Endothel-related vasoactive factors: NO, Endothelin Kinins, Serotonin, Histamine, Eicosanoids, CO, H 2 S, Purines Vasoactive peptides (VIP, SP, CGRP, CCK, NPY, cytokines, etc,) Page 3

4 Locations of the action of metabolites Autoregulation of blood flow during blood pressure changes: myogenic theory (Bayliss effect) Page 4

5 Blood flow Reactive hyperemia in the hind limb of the dog after 15-, 30-, and 60- second occlusions of the femoral artery. Time (min) Active hyperemia during physical work in the muscle. Purine: ATP Cotransmitter with NE, GABA, Dopamine, Ach, histamine Receptors: P2Y: metabotropic P2X: ionotropic Role: vasoconstriction, vasodilation, pain, sensory transmission Page 5

6 ATP Vasoconstriction Vasodilation Adenosine Tissue cell ATP Na + A A A A Caffeine Inozin S-adenozylhomocisteine A2 camp Smooth muscle cell Vasodilation Page 6

7 Blood flow Ach, Na Calcium Histamine NITRIC OXIDE (NO) ENDOTHEL CELL NOS Serotonin Bradykinin SP, CGRP Cytokines L-ARGININE CITRULLINE Hypoxia Hypercapnia Smooth muscle GUANYLATE CYCLASE cgmp PKG Decreased Ca-level VASODILATION Action mechanism of NO in smooth muscle cells PKG decreases the permeability of calcium channels => IC calcium => relaxation Activation of potassium channels => hyperpolarisation => relaxation Activation the myosin light chain phosphatase => dephosphorilation => relaxation Increased calcium uptake into the SR Page 7

8 NOS-1 (nnos) neural Types of NOS NOS-2 (inos) induced phagocyte (cytokine-induced NOS) NOS-3 (cnos) constitutional endothel cell Page 8

9 THE MOST POTENT EDRF: NITRIC OXIDE Receptor G q α Calmodulin Arg NOS PLC IP3 Ca Citrulline + NO NO GTP PKG Ca decrease Guanylylcyclase cgmp Phosphodiesterase Inactivation Sildenafil citrate RELAXATION Endothelial cell Smooth muscle Eicosanoids Cortisol Histamine Bradykinin phsopholipides Leukotriens vasoconstriction Arachidonic acid Lypoxigenase Endoperoxidase (COX1, COX2) ASPIRIN endoperoxides TROMBOXANE A2 vasoconstriction Produced by platelets Prostacycline (PGI2) Vasodilation (produced by endothelial cells PGE2 (D) PGD (C) PGF (C) PGH (C) Page 9

10 Prostaglandin receptors Metabotropic DP (PGD) camp EP1 (PGE) IP3/DAG EP2 (PGE) camp EP3 (PGE) camp EP4 (PGE) camp FP (PGF) IP3/DAG IP (prostacycline) camp TP (tromboxane) IP3/DAG EICOSANOIDS IN CIRCULATION Eicosanoids are general inter- and intracellular signal molecules that can be produced by each cell. Circulation: 1. Endothelial PGI2: continuous vasodilator tone in arteries. It inhibits aggregation of platelets. 2. PGE2: putative mediator of metabolically induced vasodilation. 3. TXA2: vasoconstrictor released from platelets. ASPIRIN can prevent coagulation/thrombosis Page 10

11 Kinins (bradykinin bradykinin, lysyl-bradykinin bradykinin) Prekallikrein (plasma) HMW/ LMW kininogen (alfa2 globulin) (Source: plasma, tissue) Kallikrein (plasma, sweatgland, salivary glands, pancreas, prostate, intestine, kidney Bradikinin Inactive 9 aminoacids metabolite Lysyl-bradykinin (kallidin) Kininase I Kininase II (ACE) ROLE OF KININS Receptors: B1receptor: PLC (inflammation) B2 receptor: PLC/PLA2 (constitutive) 1. MEDIATORS OF INFLAMMATION Vasodilation (NO release) Increased capillary permeability Pain 2. REGULATION OF BLOOD FLOW IN EXOCRIN GLANDS 3. Contraction of visceral smooth muscle Page 11

12 Serotonin Source: platelets, enterochromaffin cells Effects: Local vasoconstriction (mainly veins: 5HT 1-2 ) Pulmonary vasoconstriction (5HT 2 ) Systemic vasodilation (NO release: 5HT 7 ) Serotonin receptors 5-HT1 camp (vasoconstriction) 5-HT2 IP3/DAG (platelet aggregation, smooth muscle contraction, endothel cell activation) Page 12

13 Histamine 1. Source: mast cell, basophil granulocyte 2. Effects (metabotropic receptors): H-1 receptor (IP3/DAG, PLA2 ): a. Indirect vasodilation (NO/PGs release) b. Direct vasoconstriction c. Increased permeability d. Pain, itching e. Visceral muscle constriction f. Bronchoconstriction H2-receptor (camp ): gascric acid secretion, (smooth muscle relaxation: lung) H3-receptor (presynaptic; camp ): : inhibition of neurotransmitter release H4 (e.g. white blood cells, CNS): camp ; IP3/DAG, : inflammation Tissue damage Immune reaction HN Histidine N Histamine NH 2 HISTAMINE Histamine H1-R (IP3/Ca) HISTAMINE IS ONE OF THE MOST IMPORTANT INFLAMMATORY MEDIATOR. H2-R (camp) INFLAMMATION: Vasodilation Increased permeability Itching/pain Page 13

14 Vasoactive peptides ENDOTHELIN Paracrine vasoconstrictor peptide (21 AA) produced by endothelial cells. ET1, ET2, ET3. Circulation: ET1. ET1 is the currently known, most potent vasoconstrictor. Receptors (metabotropic): ET-A (IP3/Ca) : vascular smooth muscle: constriction ET-B: (IP3/Ca) vascular smooth muscle: constriction (endothelial cells: NO release=> vasodilation) Stimulus: angiotensin, catecholamine, hypoxia, thrombin Page 14

15 Vasoactive peptides Locally acting vasoactive peptides originated from sensory and/or autonomic nerves Vasodilators: VIP CGRP SP CCK Vasoconstrictor: NPY Neural/hormonal factors Catecholamines (norepinephrine, epinephrine, dopamine) Acetylcholine; ATP Renin-Angiotensin Vasopressine/Antidiuretic hormone (ADH) Atrial natriuretic peptide/hormone (ANP/ANH) Glucocorticoids, Mineralocorticoids Thyroxine, Triiodothyronine Page 15

16 EFFECTS OF CATECHOLAMINES ON CIRCULATION Source: 1. Sympathetic postganglionic neurons: noradrenaline (NA) 2. Adrenal medulla: 80 % adrenaline (A), 20 % Na, dopamine Receptors: α1: NA>A α 2: NA>A β1: NA=A β2: A>NA α1 (Gq IP3/DAG Ca 2+ ): arteriolar and veins: contraction α2 (Gi camp ): (few in arteriolar smooth muscle: contraction) - autoreceptors on sympathetic terminals: inhibition of NA release - NAergic neurons in the CNS: inhibition, drop in blood pressure - Endothelial cells: NO release β1 (Gs camp ): heart: positive chronotropy, inotropy etc. β2 (Gs camp ): arteriolar smooth muscle (skeletal muscle): relaxation Effect of sympathetic activation: 1. Increase in heart function (+ effects) 2. Peripheral vasoconstriction (except liver and skeletal muscle in special cases) 3. Venoconstriction SOURCE OF CIRCULATING CATECHOLAMINES Sympathetic postganglionic fibers Adrenal cortex Adrenal medulla (nerve tissue) Steroid hormones DOPA Dopamine Noradrenaline Adrenaline Aromatic aminoacid decarboxylase Dopamineβhidroxylase (norepinephrine) (epinephrine) Phenylethanolamine N-methyltransferase 20 % 80 % Page 16

17 Dopamine Source: adrenal medulla Receptors (metabotropic): D1,D5: camp ; pulmonary/kidney arteries: vasodilation D2, D3, D4: camp DOPAMINE RECEPTORS EFFECTS OF CATECHOLAMINES ON CIRCULATION NA/A β-1 Stimulation of the heart α-1 Contraction of veins Increased venous return α-1 Contraction of arteries, arterioles α-1 / β-2 Less strong contraction of arterioles in skeletal muscle Increased cardiac output x Increased TPR INCREASED BLOOD PRESSURE Page 17

18 Effect of noradrenaline on local circulation Acetylcholine Source: Postganglionic parasympathetic nerves Some postganglionic sympathetic nerves (10%) Enteric nervous system Effects: HEART: M 2 receptor camp : Heart rate conductivity Endothel cells: M 1 receptor: IP3/DAG=> Ca 2+ => NO release => vasodilation (Vascular smooth muscle: M 3 receptor: IP3/DAG=> Ca 2+ => vasoconstriction) Page 18

19 Acetylcholine effects Acetylcholine Acetylcholine Vascular smooth muscle (endothelial cells are removed) Endothelial lining is intact Contraction Relaxation Renin-angiotensin System Renin (protease) Source: juxtaglomerular apparatus A Renal corpuscle B Proximal tubule C Distal convoluted tubule D Juxtaglomerular apparatus 1. Basement membrane (Basal lamina) 2. Bowman's capsule parietal layer 3. Bowman's capsule visceral layer 3a. Pedicels (Foot processes from podocytes) 3b. Podocyte 4. Bowman's space (urinary space) 5a. Mesangium Intraglomerular cell 5b. Mesangium Extraglomerular cell 6. Granular cells (Juxtaglomerular cells: Renin secretion) 7. Macula densa 8. Myocytes (smooth muscle) 9. Afferent arteriole 10. Glomerulus Capillaries 11. Efferent arteriole Page 19

20 Renin-releasing factors Decreased blood pressure in the afferent arterioles Decreased tubular sodium concentrations Sympathetic activation (beta1-receptor) Effect: protease activity: angiotensinogen => angiotensin I (10 aminoacids) Angiotensinogen I Angiotensin I Angiotensin II (8 aminoacid) Inactivation: Angiotensin II (8 aminoacid) Angiotensin III (7 AA) Angiotensin IV (6 AA) Page 20

21 Effects of Angiotensin II Receptors (metabotropic): AT 1 : PLC (IP3/DAG ), camp blood vessels: vasoconstriction Adrenal cortex: aldosterone secretion Hypothalamus: ADH secretion Hypothalamus: thirst sensation Kidney: renin release Kidney: sodium and water reabsorption Hypothalamus: thirst sensation AT 2 : Vasodilation Antiproliferation Kidney: sodium and vater reabsorption Bradykinin release NO release Captopril Angiotensinconvertase (ACE) (Endothelial cells) Salt appetite RENIN-ANGIOTENSIN SYSTEM Losartan Drinking Increased CO Vasopressin secretion x Blood: Angiotensinogen (From liver) Angiotensin I Angiotensin II AT-R1 (IP3 Ca) Increased TPR Renin Kidney JGA Arteriolar vasoconstriction Decreased renal blood flow Stimulation of Aldosterone Na-reabsorbtion = Increased BP β1 stimulation Hyponatremia Saralasin Page 21

22 PROSTAGLANDIN, KININS AND RENIN-ANGIOTENSIN Arachidonic acid PGI2, PGE2 Systemic vasoconstriction to angiotensin is associated with local vasodilation in the arterioles of the kidney. Kininogen Kallikrein Prorenin Angiotensinogen Bradykinin Renin Inactive peptides ACE Kininase II Angiotensin I Angiotensin II LOCAL VASODILATION SYSTEMIC VASOCONSTRICTION Vasopressin/ADH 1. Source: hypothalamus supraoptic and paraventricular nuclei 2. Releasing factors: hyperosmosis (osmoreceptors) hypovolaemia (baroreceptors) angiotensin II hypotension 3. Effects: increased water reabsorption in the kidney (V2 receptors) vasoconstriction: decreased filtration (V1 receptors Page 22

23 Angiotensin II Hyperosmosis VASOPRESSIN Hypothalamus Hypovolemia Hypotension Main effect Kidney: [V2 (camp )] Reabsorption of water Neurohypophysis VASOPRESSIN (ADH) Less important Arterioles: [V1 (IP3 Ca)] Vasoconstriction Increased cardiac output x Increased TPR INCREASED BLOOD PRESSURE Action of ADH in the kidney ADH is absent Collecting duct ADH is present Collecting duct AP2 V2 AP3 camp ADH H 2 O AP2 V2 AP3 H 2 O camp ADH AP2 V2 AP3 camp ADH Page 23

24 Atrial natriuretic peptide (ANP, ANH) 1. Source: heart (right atria) 2. Releasing factor: Increased stretch in the right atria (hypervolaemia) 3. Effects: a. Decreased sodium reabsorption (kidney) b. Vasodilation c. Decreased renin, aldosteron, angiotensin II secretion d. Decreased Norepinephiren release e. Suppression of thirst Summary: TPR, blood volume => MAP ANH RECEPTORS (metabotropic) cgmp ANH Guanylyl cyclase GTP cgmp PKG In smooth muscle, cgmp PKG inhibits intracellular Ca and causes relaxation. Page 24

25 ANP, BNP and CNP ANP (ANH): atrial natriuretic peptide (hormone) (heart, brain): hormone and neurotransmitter BNP: brain natriuretic peptide (heart, brain): hormone and neurotransmitter CNP: C-type natriuretic peptide (brain, hypophysis, kidney): paracrin ANP and BNP acting in the brain as neurotransmitters are decreasing blood pressure. Page 25

26 Glucocorticoid - Cortisol Receptors: intracellular: Steroid type II receptor => gene transcription Permissive effect on alfa 1 -receptors Increased binding of noradrenaline/adrenaline to their receptors Increased bindings of adrenoceptors to G-proteins Increased production of camp by adrenaline Prolongation of effects of noradrenaline/adrenaline in smooth muscles => vasoconstriction => MAP Inhibition of synthesis of prostanoids (inhibition of vasodilation) Permisszive for the synthesis of angiotensinogen in the liver Decreases the sensitivity of angiotensin receptors Permissive for renin and ANP synthesis Permissive for normal GFR Decreases the ADH secretion Ensures normal blood pressure Lack: circulation failure Mineralocorticoid - Aldosterone Receptors: intracellular: Steroid type I receptor => gene transcription Effects: Increased Na + reabsorption (and potassium+ proton secretion) = > blood volume => MAP Lack: circulation failure Page 26

27 Thyroid hormones Thyroxine, triiodothyronine Receptors: intranuclear receptor => gene transcription Effects: Heart contractility => Stroke volume β1-receptor number and sensitivity α MHC (increased ATP-ase activity) SR Ca 2+ -ATP-ase Na + -K + -ATP-ase K+-channels β MHC Na + -Ca 2+ -exchanger Heart rate β1-receptor number and sensitivity Cardiac output Peripheral resistance (release of vasodilator factors in tissues, and effect of heat) vasodilation (mainly in the skin vessels) => increased water and Na + reabsorption) => blood volume Pulse pressure Mean arterial blood pressure: No change Page 27

28 MUSCLE ET-A IP3/Ca TP 5HT2a Endothelin-1 Contraction B1 TXA2 NK2 Serotonin 5HT2a M1 α1 Bradykinin B1 H1 Neurokinin A NK2 NK1 Contraction Acetylcholine M1 α2 Noradrenaline α1 camp A1 Histamine H1 H2 Substance P NK1 CGRP?? VIP? Adenosine Relaxation? A2 camp EP1-4 IP NO PGE2 PGI2 ENDOTHEL IP3/Ca NO Page 28