REGLAREA CARDIOVASCULARĂ. A. Reglarea locală (intrinsecă) Intregul = o reţea de relaţii
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1 REGLAREA CARDIOVASCULARĂ A. Reglarea locală (intrinsecă) B. Reglarea sistemică Intregul = o reţea de relaţii
2 Ap.CV 2 AD AS VD VS A- atriu; V-ventricul; D-drept; S-stâng; 1.Circulaţia sistemică, 2. Circulaţia pulmonară; 3. Circulaţia limfatică
3 AD VS R = ΔP F F = πδpr4 8ηl
4 A. Reglarea locală A.1. Reglarea activităţii cardiace A.1.1. Activitatea ţesutului nodal A.1.2.Activitatea miocardului de lucru A. 2. Reglarea microcirculaţiei A.2.1. Reglare pe termen scurt A.2.2. Reglare pe termen lung
5 Ritmicitate... Celule miocardice embrionare izolate în cultură. Imediat după punerea în cultură se observă contracția celulelor individuale, la diferite ritmuri, Dupa 2-3 zile în vitro, miocitele se conectează prin joncțiuni gap, care asigură activarea și contracția lor sincronă.
6 A. Reglarea locală A.1.1. Activitatea ţesutului nodal -Activitatea electrică spontană Specifically, we found that Ryr2 is required for setting normal heart rate, and that deletion of this gene causes general bradycardia. We further found that Ryr2 is required to maintain normal heart rhythm, and that Ryr2 deletion causes intermittent tachycardic arrhythmias Cardiac ryanodine receptors control heart rate and rhythmicity in adult mice. Bround J M et al. Cardiovascular Research (2012)
7 Dong Woo Song D.W et al. Ryanodine receptor assembly: A novel systems biology approach to 3D mapping. Progress in Biophysics and Molecular Biology 105 (2011)
8 Dong Woo Song D.W et al. Ryanodine receptor assembly: A novel systems biology approach to 3D mapping. Progress in Biophysics and Molecular Biology 105 (2011)
9 Abbreviations: CaM, calmodulin; CAMKII, calmodulin-dependent kinase II; CCD, central core disease; cadpr, cyclic ADP ribose; CLIC2, chloride intracellular channel protein 2; co-ip, co-immunoprecipitation; CPVT, catechol-aminergic polymorphic ventricular tachycardia; CSQ, calse-questrin; CRC, Ca2ţ release channel; CY, cytoplasmic; DHPR, dihydropyridine receptor; DR, divergent region; EC coupling, excitationecontraction coupling; EM, electron microscope; ER, endoplasmic reticulum; FKBPs, FK506-binding proteins; FRET, fluorescence resonance energy transfer; GFP, green fluorescence protein; GST, glutathione-s-transferase; HRC, histidinerich Ca2ţ-binding protein; IP3R, inositol trisphosphate receptor; JP, junctophilin; LZ, leucine zipper; MH, malignant hyperthermia; makap, muscle A-kinase anchor protein; NMR, nuclear magnetic resonance; NTD, N-terminal domain; PKA, protein kinase A; PKC, protein kinase C; PKD, protein kinase D; PP, protein phosphatase; PPI, proteineprotein interaction; PPP,phosphoprotein phosphatase; SP, spinophilin; SR, sarcoplasmic reticulum; S100A1, S100 calcium binding protein A1; 3D, three dimensional; TA, transmembrane assembly; TM, transmembrane; T-tubules, transverse tubules.
10 These arrhythmias result from the establishment of a re-entry circuit within the atrio-ventricular node. They are usually episodic in nature, and may result in the patient exhibiting signs and symptoms ranging from tachycardia or palpitations, shortness of breath, chest pain, anxiety, nausea and dizziness to presyncope/syncope as a consequence of reduced cardiac output. Smith GD et al. Cochrane Database Syst.Rev. 2015
11 The arrhythmia is usually transient, and may be precipitated by such factors as cardiac disease, stimulant use, electrolyte imbalance and stress. The use of vagal manoeuvres (Valsalva) also been employed for some time, with demonstrated effectiveness in reverting supraventricular tachycardia of between 12% and 54% Smith GD et al. Effectiveness of the Valsalva Manoeuvre for reversion ofsupra-ventricular tachycardia in the prehospital and emergency medicine settings. Cochrane Database Syst.Rev. 2015
12 Ca 2+ ATPază A. Reglarea locală 1.1 Rolul Ca 2+ Na + /K + ATPază Canale de Ca 2+ Calsequestrin Schimbător Na + /Ca 2+ Reticul sarcoplasmic Ca 2+ ATPază
13 Agenţi inotropi pozitivi - Agonişti adr.prin β 1 R activează prot G: 1. AMPc PKA Canale Na + 2. Canale Ca 2+ (L) - Glicozidele cardiace pompa Na /K - Ca 2+ extracel. - Na + extracel. - Creşterea frecvenţei cardiace - Ca 2+ intracel. Agenţi inotropi negativi -Blocanţi de Ca, -Na + extracel. Ca 2+ extracel. H + intracel.
14 A.2. Reglarea locală a microcirculaţiei A.2.1. Reglare pe termen scurt A.2.2. Reglare pe termen lung
15 A.2. Reglarea locală a microcirculaţiei A.2.1. Reglare pe termen scurt
16 P=100 mmhg Reglarea locală a microcirculaţiei Q Pr 4 8 l Φ = 1; Q=1ml/min Φ = 2; Q=16ml/min Φ = 4; Q=256ml/min
17 A. Reglarea locală 2. Reglarea microcirculaţiei 2.1. Reglare pe termen scurt miogene mecanisme metabolice mesageri chimici
18 Presiune (mm Hg) artere arteriole capilare vene A.2. Reglarea locală a microcirculatiei arterioloconstricţie arteriolodilataţie normal 25 0 Efectul motricităţii arteriolare asupra presiunii sanguine(w.boron)
19 Q x normal A.2.1. Reglare pe termen scurt f(x) metabolism celular Rata metabolică (x normal)
20 Efectul CO2
21 Q x normal A.2.1. Reglare pe termen scurt f(x) cerinţa tisulară de O Saturaţie O 2 %
22 A.2.1. Reglare pe termen scurt Teoria vasodilataţiei indusă de produşi metabolici adenozină CO 2, O 2, K, ph, ADP, Teoria deficitului de oxigen - hiperemia activă flux sang.musc.-repaus -750ml(4ml/100g)/min flux sang.musc.-efort ml(80ml/100g/)min rata metabolică musc.-efort-60 x - hiperemia reactivă
23 A.2.1. Reglare pe termen scurt Mecanism miogen de autoreglare a circulatiei - canale ionice senzitive la întindere - activitatea pacemaker a CMNV
24 A.2.2. Reglare pe termen lung Rolul oxigenului- altitudine, scăderea conc. O 2 in incubator Rolul factorilor angiogeni factor de creştere derivat din endoteliu (VEGF), factor de creştere fibroblastic,.
25 A.2.2. Reglare pe termen lung angiopoietina I, II sintetizate în celulele endoteliale în condiţii de modificare a fluxului sanguin sau de lezare a endoteliului efecte: angiogeneza, limfangiogeneza Early Growth Response-1 Regulates angiopoietin-1- Induced Endothelial Cell Proliferation, Migration,and Differentiation Nelly A. Abdel-Malak et al. Arterioscler Thromb Vasc Biol February 2009 Angiopoietin-2 Exocytosis Is Stimulated by Sphingosine- 1-Phosphate in Human Blood and Lymphatic Endothelial Cells Cholsoon Jang et al. Arterioscler Thromb Vasc Biol. 2009;29:
26 A.2.2. Reglare pe termen lung Hem- oxigenaze I, II sintetizate în celulele endoteliale în condiţii de ischemie, leziuni endoteliale, stres oxidativ Probucolul şi Sucinobucolul- produşi farmacologici - stimulează sinteza HO1 Efecte: - metabolizează hem-ul cu producerea de CO, Fe şi biliverdină - stimulează producerea de progenitori cel. endot. din măduva hematogenă - repară endoteliul lezat
27 A.2.2. Reglare pe termen lung hem- oxigenaze I, II Efecte: -antiinflamator -antioxidant -inhibă proliferarea m. neted vascular EFECT ANTIATEROSCLEROTIC
28 Heme Oxygenase-1 Increases Endothelial Progenitor Cells Ben J. Wu et al. Arterioscler Thromb Vasc Biol. 2009;29: Physiological significance of heme oxygenase in hypertension. Jian Cao et al. Int J Biochem Cell Biol May ; 41(5):
29 ENDODELIU INTERFAŢĂ-ORGANISM-MEDIU
30 role for EC in providing functional support to subjacent cardiomyocytes by communicating via soluble paracrine mediators. In this study, HG was a common stimulus for HepL secretion from the EC, in addition to promoting its uptake into the cardiomyocyte. The presence of heparanase in the cardiomyocyte dramatically changed the expression of apoptosisrelated genes, providing an acute cardiorotective effect. Wang F et al.high glucose facilitated endothelial heparanase transfer to the cardiomyocyte modifies its cell death signature.cardiovascular Research (2016)
31 A sheet of cobblestone-like endothelial cells is transformed to resemble the inner surface of a blood vessel, comprising highly ordered and highly elongated cells. Some aspects of the mechanisms controlling this are known. Vascular endothelial cells exposed to an EF in culture increase secretion of the angiogenesis producing VEGF). Secretion increases severalfold within 5 min, peaks around 30 min before dropping off, and undergoes a second peak in VEGF release between 4 and 24 h. McCAIG C.D. et al. Controlling Cell Behavior Electrically: Current Views and Future Potential. Physiol Rev 85: , 2005.
32 Reglarea sistemică - Reglare de scurtă durată - Reglare de lungă durată - Reglare nervoasă - Reglare umorală - Reglare lineară - Reglare modulară integrată
33 Reglare modulară integrată p.umplere t.umplere cpl. ventr. întoarcere venoasă presar. postsar. contract. VTD VTS RIn REx SNV F.U VS DC FC PAM CVS CVL RVP
34 REGLAREA NERVOASĂ - reflexă cu răspuns rapid - corelaţii cu reglarea umorală - factori de reglare - tipuri de receptori
35 Reflexe
36
37 Reglarea nervoasă NTS + NDV NA ACI n.hering n.vag - AVM n.vag MSR Fb. pgg. simpatice venule arteriole
38 Nr impulsuri/sec. din nn. sinusului carotidian Mecanisme de stimulare mmhg Efectul PA asupra răspunsului baroreceptorilor carotidieni
39
40 Funcţia reflexului sinocarotidian Mecanisme de stimulare - baroreceptori r. de întindere - Frecvenţa cardiacă - R-R Efecte P A Particularităţi funcţionale - responsivitate nelineară - resetarea baroreceptorilor
41 Presiune arterială (mm Hg) Declampare carotide Clampare carotide min. Efectul refl. sinocarotidian asupra PA
42 Presiune arterială (mm Hg) Rolul SNVS Anestezie spinală NA min. Efectul S.N.S asupra PA
43 P r e s i u n e a r t e r i a l ă mm Hg 200 Rolul SNV 100 Normal Denervat senzitiv 0
44 - Stimularea simpatică -efecte cardiace (NA, β 1 ) -n.cardiac dr.: tahicardie, creşterea contractilităţii -n.cardiac stg.: tahicardie, creşterea contractilităţii - Efecte vasculare - Vasoconstricţie (NA α 1, α 2 ) rinichi, cutanat, digestiv - Vasodilataţie (A, β 2 ), (Ach) muşchi
45 - Stimularea parasimpatică - Efecte cardiace (Ach, M 2 ) -n.vag dr.: bradicardie, scăderea contractilităţii -n.vag stg.: scăderea conductibilităţii şi contractilităţii - Efecte vasculare -Vasodilataţie -M 2 - CMNV, -M 3 - celula endotelială-no, VIP
46 Reflexe secundare - determinate de stimularea chemoreceptorilor din corpusculii carotidieni (cel.glomice) şi corpusculii aortici de scăderea O 2,pH, PA şi creşterea CO 2 Efecte: bradicardie vasoconstricţie P A
47 Reflexe secundare- reflexe atriale P R T Q S Fb.A Fb.B efecte: Tahicardie (Reflex Bainbridge) irigaţie renală AVP PAN
48 Reflexe secundare Raspunsul SNC la ischemie cerebrală ultima linie deapărare Reacţia Cushing
49 REGLAREA UMORALĂ
50 DILATATOARE CONSTRICTOARE Substanţa Sursă Rol fiziologic - mecanism Noradrenalina s.n.s reflex presor ( receptor a) Endotelina endoteliu mediator paracrin Serotonina neuroni, trombocite agregare plachet. nervos, local Substanţa P neuroni, tr. digestiv durere, permeabilt. capilară Vasopresina neuroni creşte PA posthemoragică Angiotensina II plasmă sanguină creşte PA Prostaciclina endoteliu hemostaza primară Oxid nitric endoteliu paracrin Peptidul atrial miocard atrial, neuroni reduce PA VIP neuroni nervos, hormonal Histamina mastocite flux sanguin ; local, sistemic Adrenalina msr flux sanguin,hormonal β 2 Acetilcolina s.n.p neural - muscarinic Bradikinina ţesuturi flux sanguin, local(no)
51 REGLAREA UMORALĂ Adrenalina α 1 - vasoconstricţie β 1 - tahicardie şi creşterea contracţiei β 2 - vasodilataţie: muşchi scheletic, miocard, ficat catecolaminele plasmatice au efect mai redus decât stimularea simpatică
52 REGLAREA UMORALĂ Serotonina- produsă de neuroni, trombocite şi mastocite determină vasocostricţie locală în hemostază Histamina- produsă de neuroni şi mastocite- determină vasodilataţie locală,relaxare m.neted digestiv şi contracţie m.neted respirator
53 REGLAREA UMORALĂ Angiotensina II Efecte cu impact cardiovascular: -prin recept. AT 1A -vasoconstricţie renală şi splanhnică -inotrop pozitiv, reduce fluxul sanguin renal, stimulează secreţia de aldosteron, ADH şi sete -facilitează eliberarea de NA, factor hipertrofiant cardiac
54 Ischemie renala Angiotensinogen Renină Agiotensină I Enzimă de conversie Agiotensină II Aminopeptidază Agiotensină III
55 KININE F.XII Plasmina prekalikreina F.XII a kininogen kalikreina bradikinină lizil-bradikinină(kalidină) metionil-kalidină kinine (vasodilatatoare) Kininaze (K I,KII) EC cataboliţi kininici inactivi
56 Endeotelina I Sinteză : CE, neuron, cel gliale Efecte: Vasoconstricţie prin actiune directă Stimularea neuronilor din organul subfornical determină: - secreţia de ADH - stimularea activităţii simpatice prin aria vasomotorie Neurotransmiţător peptidergic Role of paraventricular nucleus vasopressin v1a receptors in the response to endothelin 1 activation of the subfornical organ in the rat N. F. Rossi and m. Maliszewskascislo. J Physiol Pharmacol Dec;59 Suppl 8:
57 SUBSTANTA SURSA EFECT VASOCONSTRICTOR nor-adrenalina sns α 1 Gα q/11 PLC [IP 3 ] i IP 3 receptor in SR Ca 2+ release [Ca 2+ ] i angiotensina II sra ANG II AT 1 receptor Gα q/11 PLC [IP 3 ] i IP 3 receptor in SR Ca 2+ release [Ca 2+ ] i endotelina endoteliu ET A Gα q/11 PLC [IP 3 ] i IP 3 receptor in SR Ca 2+ release [Ca 2+ ] i AVP (argininvasopresina) Ht-Nhz AVP V 1a receptor Gα q PLC [IP 3 ] i IP 3 receptor in SR Ca 2+ release [Ca 2+ ] i acetilcolina snp ach M 2 rcpt Gα i/o AC [camp] i PKA phos-on of MLCK MLCK phos-on MLC ATP cel [ATP] o P 2X rcpt (receptor-operated Ca 2+ channel = ROC) Ca 2+ entry [Ca 2+ ] i Tromboxan A2 Serotonina endoteliu trombocit trombocit, mastocite, s.n. TXA 2 TP rcpt (tromboxan/pgh 2 ): Ca 2+ channels open Ca 2+ entry [Ca 2+ ] I O 2 - NO 5-HT 5-HT 2A or 5-HT 2B receptor Gα q/11 PLC [IP 3 ] i IP 3 receptor in SR Ca 2+ release [Ca 2+ ] i
58 SUBSTANTA SURSA EFECT VASODILATATOR nor-adrenalina sns., msr adrenoreceptor β 2 Gα s AC [camp] i PKA phosphorylation of MLCK MLCK phosphorylation of MLC adenozina cel.metab A 1, A 2A, and A 2B rcpt. on VSMC Gα s AC [camp] i PKA K ATP Cn. D hyperpolariz voltage-gated Ca 2+ Cn. Î [Ca 2+ ] I [Adenosine] o A 1 on endothelial cell NO NO endoteliu NO sgc [cgmp] i PKG phos. of MLCK MLCK activity phos.of MLC SERCA2 in SR [Ca 2+ ] i histamina Peptidul atrial natriuretic Angiotensina II mastocite, s.n. cel.musc. atriala H 2 receptor Gα s AC [camp] i PKA phosphorylation of MLCK MLCK phosphorylation of MLC ANP NPR1 receptor GC [cgmp] I PKG phosphorylation of MLCK MLCK phosphorylation of MLC SERCA2 in SR [Ca 2+ ] I ANG II AT 2 receptor Gα q/11 PLC [Ca 2+ ] i NOS NO release Bradykinin NOS III NO release
59 Eritropoietina Secreţie ischemie renală Efecte -eritropoietic -neuroprotecţie -cardioprotecţie -terapeutic - rh
60 Intregul = o reţea de relaţii You may say I m a dreamer, But I m not the only one. I hope some day you ll join us And the world will live as one Jhon Lennon
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