Experimentally induced arrhythmias in rat Adrenergic hyperstimulation Hyperkalemia Block of cardiac calcium channels Sarcoglycan OmV Phase 2 (Ica^d Ik) Phase 0 iNa Phase 3 (l^ Effective refractory period (ERP) Phase 4 -85 mV Na Outside A \ also ^ ICa) Pacemake_r___ Nonpacemaker * * t ■ Na Na 4 Membrane ATP Inside Action potential currents K " Ca Na Ca Kl Sodium Na/Ca Diastolic currents pump exchanger Electrical System of the Heart Bachmann's Bundle Sinoatrial (SAJ Node Anterior Internodal Ira et Middle Internodat 1 racl Posterior Internodal Tract Left Bundle Branch Conduction Pathways Atrioventricular (AV) Node Right Bundle Branch Normal ECG curve in human... ...and in rat heart Note the missing ST segment (phase 2 = plateau of the ventricles) SA nodal rate about 300/min Vegetative nervous system and the heart Receptors: Sympathetic nervous system: (31 - positively inotropic, dromotropic and chronotropic (mainly through opening of pacemaker F-channels and Ca2+ channels in SA node, AV node and working myocardium) (32 - apical myocardium, vessels -vasodilatation a1, a2 - vasoconstriction (lower effect in coronary vessels, norepinephrine effect) Parasympathetic: M2 - negatively chronotropic (inhibits opening of Ca2+ channels, opens KAch channels) Effects of vegetative nervous system on pacemaker cells A - adrenergní stimulace (SYMPATIKUS) B - cholinergní stimulace {PARASYMPATIKUS) > M2-receptor uzávěr L-kanálů pro Ca2+ pacemakeřové kanály pro kationty (zejm. Na+) M2-receptor -> otevřeni kanálů pro K+ čas (s) Heart during catecholamine overload 1s heart rate 1s contractility - Increase systolic function at the expense of diastolic dysfunction Calcium overload of cardiomyocytes - DAD —> premature beats - t oxygene consumption —> ischemia (32-receptor phosphorylation - transition from Gs to Gj signalization —► decreased contractility in the apex - but it acts against Ca overload and necrosis ^ Vasoconstriction? ^^^^^^hkh ■ The most abundant intracellular cation (98% intracellular) ■ Most willingly passes cellular membrane ■ Concentration gradient is maintained by Na+/K+ ATPase ■ The extra/intracellular distribution is regulated by hormones (insulin, adrenaline, aldosterone) and pH ■ Its total body content depends mainly on renal functions ■ Both hyper- and hypokalemia are frequent conditions in clinical practice and both are proarrhythmogenic ^ Potassium and the membrane potentia Positively charged, intracellular ion: f concentration —► lowering of membrane polarity (analogy of a small and a large basin connected by a hose) Various functionally different K+ channels By various mechanisms, potassium increases the permeability of K+ channels - direct binding - competion with Mg2+ that closes the K+ channels - changes in expression and translocation Effect on sodium channels Mild hyperkalemia - easier excitation Severe hyperkalemia - block of a portion of Na+ channel - Slower conduction - Finally the threshold voltage „runs away" from baseline voltage and the depolarization is no longer possible Mild hypokalemia - hyperpolarization Severe hypokalemia - lack of substrate for the Na/K ATP-ase —> lower polarity, easier excitation Potassium - main effects Hyperkalemia - Peaked T wave (dif. dg. hyperacute phase of Ml) - Wide QRS (may merge into sinusoid wave with T) - Widening, flattening and event, disappearing of the P wave (but sinus rhythm remains for a long time) - Higher excitability at the beginning, then lower, diastolic arrest in the end (heart is depolarized compared to the normal state) - | risk of re-entry (f differences in conduction velocities) Hypokalemia - Flat, wide T-wave - Pathologic U wave (delayed repolarization), lengthening of QT (QU) interval - EAD, torsades de pointes - Sometimes, peaked P is present - | risk of re-entry (f differences in refraktory periods) - First lower excitability (hyperpolarization), then higher Changes of ECG in hyper- /hypokalemia ■ Ion that is necessary for muscle contraction ■ Intracellular, it is present in very low concentration (making high gradient between cytoplasm and cell) ■ In cardiomyocyte and skeletal muscle, it is also present in sarcoplasmic reticulum ■ Cardiomyocyte (and smooth muscle cell) bears specific Ca2+-channels, that are necessary for phase 2 (plateau), pacemaker function and conduction through slow cells ■ They can be blocked by specific agents to slow the heart rate and enhance vasodilatation by smooth muscle^ relaxation Calcium and the membrane potential Extracellular ion - Membrane potential gets into more negative values During the action potential, Ca2+activate potassium (and chloride) channels, which shortens the phase 2 —► repolarization leads into the closing of Ca2+ L-channels - the proces is impostant for maintaining the calcium homeostasis in the cell - in extreme hypercalcemia, phase 2 may be missing - opposite effect may be present in hypocalcemia Mechanical effects - Extreme hypercalcemia: triggered activity (DAD), systolic arrest (very rare) - Extreme hypocalcemia: triggered activity (EAD), hypocalcemic cardiomyopathy, heart failure Blocking the calcium channels Verapamil - class IV antiarrhythmic drug Tissue distribution roughly symmetrically in the heart and smooth muscle Indikace: antiarrhythmic, antihypertenzive (rather rarely), local vasodilatant Overdose - effect mainly on the slow cells - SA arrest and block - AV block ^ - Low contractility - Long QT may sometimes be present ECG in calcium levels changes ■The Ca2+ channels-blockers mainly induce the conduction (SA or AV) node blocks and slower pacemaker function Practical KCI 12.5% (celkem 2ml) sledování průběhu EKG změn opakovaná aplikace 0.5ml frakcí do celk. objemu 2ml po 5 minutách