兴奋缩耦联和心力衰竭的治疗

1、田野田野 教授教授哈医大二院心内科兴奋收缩耦联和心力衰竭的治疗兴奋收缩耦联和心力衰竭的治疗topicsp excitation-contraction (ec) coupling excitation calcium cycling contractionp alterations of e-c coupling in hfp inotropic agents for hfexcitation-contraction coupling the power of locomotion is that which contracts and relaxes the muscles whereby

2、the members and joints are moved, extended or flexed. this power reaches the limbs by way of the nerves and there are as many forms of power as there are of movement. each muscle has its own peculiar purpose and it obeys the decree of the composite sense. avicenna(11671248)william harvey (1578 1657)

3、 he was an english medical doctor /physician, who is credited with being the first to correctly describe, in exact detail, the systemic circulation and properties of blood being pumped around the body by the heart. we shall designate the entire seque-nce of reactions: excitation, inward acting link,

4、 and activation of contra-ction by the term excitation-contraction coupling.alexander sandow,1952(new york university)sandow a.yale j biol med . 1952.25 (3): 176201 cardiac excitationcontraction coupling is the process from electrical excitation of the myocyte to contraction of the heart (which prop

5、els blood out). the ubiquitous second messenger ca2+ is essential in cardiac electrical activity and is the direct activator of the myofilaments, which cause contraction.bers dm. nature, 2002, 415(6868): 198-205.excitation the cardiac action potential a notable difference between skeletal and cardia

6、c myocytes is how each elevates the myoplasmic ca2+ to induce contraction. in cardiac myocytes, the release of ca2+ from the sarcoplasmic reticulum is induced by ca2+ influx into the cell through voltage-gated calcium channels. calcium cycling pictorial of calcium cycling ca+ca+ca+ca+plbca+ca+ca+ca+

7、ca+ca+ca+ca+ca+ca+ca+ca+ca+ca+ca+ca+ca+ca+ca+ca+ca+ca+ca+ca+ca+ca+ca+ca+ca+ca+ca+ca+ca+ca+ca+ca+ca+ca+ca+ca+ca+ca+ca+ca+ca+ca+ca+ca+ca+na+na+na+ca+sercasrryrl-type ca+channelna+/ca+ exchangerca+sarcolemmaca+cardiac tissue and cells conduct electrical waves contract in response to an electrical stimu

8、lus(guinea-pig ventricular cell)cardiac tissuefunctionbsarcoplasmic reticulum(sr)pln and sercathe sites of interaction between pln and sercasodium-calcium exchanger(ncx) two-way transporter “forward”mode “reverse”mode na:ca=3:1ca release coincides with activation of the contractile machinery contrac

9、tion sliding filament theorya.f. huxley1954em evidence for sliding filament theorythe micrograph shows myosin bound to actinthe molecular basis for myocardial contractionthin filament (actin ,tropom-yosin, troponin) thick filament (myosin)other proteinschien, k.r., 1999zztitin28,000 amino acids (3md

10、a) the largest protein known in mammals.titin myosinmyosin mw 480 kdaforms thick filamentshydrolyses atpinteracts with f-actin 300-400 myosin molecules per 1 filaments1s1150 nmthick filament proteinsrlcelcatp binding siteactin binding siteatp （myosin） adp + pi + energymyosin head (s1) molecular moto

11、r of muscle contractiong-actin f-acting to f actin mw 42 kdathe blue and grey molecules are actin monomers (mw 42.000)ken c. holmes: max-planck-institute takeda, s. et al. nature 424, 35 41, 2003 hctnchctnihctnttropomyosintropomyosinbinding regionhypervariable regioncrystal structure of human cardia

12、c troponingordon et al. 2001regulation of thin filament in contraction muscle contractionalterations in e-c coupling in hfryr2 channel leakheart failurepde4d levelsloss of fkbp12.6ryr2 channel leakarrhythmia and progression of heart failure.jeffery d molkentin. nature medicine 11, 1284 - 1285 (2005)

13、 plnserca2a interactions in physiological and diseased cardiac functionsteven r. houser. j mol cell cardiol 32, 15951607 (2000)inotropic agents for hfinotropic agents and -blocker digitalis phosphodiesterase inhibitor - adrenoceptor blockerdigitalis (200 years)digilis purpureapurple foxglovewilliam

14、withering (1741 1799)mechanism of actiondigitalisother study some evidence suggests that the benefits of digitalis may be related in part to enzyme inhibition in noncardiac tissues. inhibition of na-k atpase in vagal afferent fibers acts to sensitize cardiac baroreceptors, which in turn reduces symp

15、athetic outflow from the central nervous system. in addition, by inhibiting na-k atpase in the kidney, digitalis reduces the renal tubular reabsorption of sodium; the resulting increase in the delivery of sodium to the distal tubules leads to the suppression of renin secretion from the kidneys.thame

16、s md. circ res. 1979;44:8 15.ferguson dw et al. circulation. 1989;80:6577.torretti j et al. am j physiol. 1972;222:1398405.50403020100placebon=3403digoxinn=3397480122436mortality %n engl j med 1997;336:525monthsp = 0.8n=6800nyha ii-iiidig trail (1997)acc/aha hf guideline 2009 long-term use of an inf

17、usion of a positive inotropic drug may be harmful and is not recommended for patients with current or prior symptoms of hf and reduced lvef, except as palliation for patients with end-stage disease who cannot be stabilized with standard medical treatment (stage d). (class iii, level of evidence: c)

18、continuous intravenous infusion of a positive inotropic agent may be considered for palliation of symptoms in patients with refractory end-stage hf(stage d). (class iib, level of evidence: c) phosphodiesterase inhibitor the different forms or subtypes of phosphodiesterase were initially isolated fro

19、m rat brains by uzunov and weiss in 1972 and were soon afterwards shown to be selectively inhibited in the brain and in other tissues by a variety of drugs the potential for selective phosphodisterase inhibitors as therapeutic agents was predicted as early as 1977 by weiss and hait. this prediction

20、meanwhile has proved to be true in a variety of fields.uzunov, p. and weiss, b biochim. biophys. acta 284:220-226, 1972 weiss, b. and hait, w.n.: ann. rev. pharmacol. toxicol. 17:441-477, 1977. phosphodiesterase-3 inhibitorpdei campamppde3yuan james rao,(2009)mechanism of action as a result of its h

21、igh expression in both the vasculature and the airways, pde3 was identified as a potential therapeutic target in cardiovascular disease and asthma. augment myocardial contractility relax vascular and airway smooth muscle inhibit platelet aggregation induce lipolysisbarnes p.j.et al. pharmacol. rev.

22、1988;40:4984. manganiello v.c.,et al. cell signal. 1995;7:445455.“i wish i had my beta-blockers handy his landmark invention of propranolol in 1964 and the h2-receptor antagonist, cimetidine, in 1972 earned him the nobel prize in medicine in 1988.james w. black - adrenoceptor receptor blockersmechan

23、ism of action density of 1 receptors inhibit cardiotoxicity of catecholamines neurohormonal activation hr antiischemic antihypertensive antiarrhythmic antioxidant, antiproliferativen = 2289iii-iv nyhaacc/aha hf guideline 2009 use of 1 of the 3 beta blockers proven to reduce mortality (i.e., bisoprol

24、ol, carvedilol, and sustained release metoprolol succinate) is recommended for all stable patients with current or prior symptoms of hf and reduced lvef, unless contraindicated . (class i, level of evidence: a)when to start ? patient stableno physical evidence of fluid retentionno need for i.v. inot

25、ropic drugs start ace-i / diuretic first start low, increase slowly increase the dose every 2 - 4 weeksrisks of treatment fluid retention and worsening hf(intensification of conventional therapy) fatigure bradycardia and heart block hypotension (block alpha-1receptors)review treatment (+/-diuretics,

26、 other drugs)reduce doseconsider cardiac pacingdiscontinue beta blocker only in severe cases how should clinical deterioration be managed in patients who have been taking a beta blocker for long periods of time (more than 3 months)? if patients develop fluid retention, with or without mild symptoms, it is reasonable to continue the beta blocker while the dose of diuretic is increased. if the deterioration in clinical status is char