Diastolic depolarization

Cardiostimulation. By stimulating Pi-receptors, hence activation of ade-nylatcyclase (Ad-cyclase) and cAMP production, catecholamines augment all heart functions, including systolic force (positive inotropism), velocity of shortening (p. clinotropism), sinoatrial rate (p. chronotropism), conduction velocity (p. dromotropism), and excitability (p. bathmotropism). In pacemaker fibers, diastolic depolarization is hastened, so that the firing threshold for the action potential is reached sooner (positive chronotropic effect, B). The cardiostim-ulant effect of p-sympathomimetics such as epinephrine is exploited in the treatment of cardiac arrest Use of p-sympathomimetics in heart failure carries the risk of cardiac arrhythmias. 

Mechanism of action - Disopyramide is a class lA antiarrhythmic agent that decreases the rate of diastolic depolarization (phase 4), decreases the upstroke velocity (phase 0), increases the action potential duration of normal cardiac cells, and prolongs the refractory period (phases 2 and 3). It also decreases the disparity in refractoriness between infarcted and adjacent normally perfused myocardium and does not affect alpha- or beta-adrenergic receptors. 

Pharmacology Therapeutic concentrations of lidocaine attenuate phase 4 diastolic depolarization, decrease automaticity and cause a decrease or no change in excitability and membrane responsiveness. Action potential duration and effective refractory period (ERP) of Purkinje fibers and ventricular muscle are decreased, while the ratio of ERP to action potential duration is increased. Lidocaine raises ventricular fibrillation threshold. AV nodal conduction time is unchanged or shortened. Lidocaine increases the electrical stimulation threshold of the ventricle during diastole. 

The action potential has been divided into five phases, rapid depolarization (phase 0), early repolarization (phase 1), plateau (phase 2), rapid repolarization (phase 3) and finally the resting phase in myocytes or slow diastolic depolarization (phase 4). The last is a property in cells with the potential for automaticity (defined later). A brief outline of each of these phases in the normal myocyte is given next. 

Transmembrane action potential of a sinoatrial node cell. In contrast to other cardiac cells, there is no phase 2 or plateau. The threshold potential (TP) is -40 mV. The maximum diastolic potential (MDP) is achieved as a result of a gradual decline in the potassium conductance (gK+). Spontaneous phase 4 or diastolic depolarization permits the cell to achieve the TR thereby initiating an action potential (g = transmembrane ion conductance). Stimulation of pacemaker cells within the sinoatrial node decreases the time required to achieve the TR whereas vagal stimulation and the release of acetylcholine decrease the slope of diastolic depolarization. Thus, the positive and negative chronotropic actions of sympathetic and parasympathetic nerve stimulation can be attributed to the effects of the respective neurotransmitters on ion conductance in pacemaker cells of the sinuatrial node. gNa+ = Na+ conductance. 

Effects of norepinephrine and acetylcholine on spontaneous diastolic depolarization automaticity) in a pacemaker cell for the sinoatrial node. The pacemaker cell discharges spontaneously when the threshold potential (TP) is attained. The rate of spontaneous discharge is determined by the initial slope of the membrane potential and the time required to reach the threshold potential. 

A. Control recording showing the spontaneous diastolic depolarization. B. The effect of norepinephrine is to increase the slope of diastolic depolarization. The frequency of spontaneous discharge is increased. This effect is mediated through the activation of p-adrenoceptors in sinoatrial nodal cells. C. Acetylcholine stimulates muscarinic receptors in sinoatrial nodal cells. 

There is a decrease in the slope of diastolic depolarization as well as hyperpolarization of the cell. The time to reach the threshold potential is prolonged, with the net effect being a decrease in the rate of spontaneous depolarization. 

II Propranolol Metoprolol Nadolol Acebutolol Atenolol Pindolol Timolol Sotalol EsmoloF 3-Adrenoceptor antagonist, cardiac membrane stabilization, indirect effect on sinoatrial node to decrease rate of spontaneous diastolic depolarization. Indirect effect on A-V node to decrease conduction velocity and prolong ERR... 

The indirect effect of qutnidine on the sinoatrial node is a result of the drug s potential to exert an anticholinergic action resulting in a slight increase in heart rate. Higher concentrations of quinidine have a direct effect of depressing the rate of spontaneous diastolic depolarization. 

Pacemaker activity in the sinoatrial node is decreased because of 3-adrenoceptor blockade and a removal of sympathoadrenal influences on spontaneous diastolic depolarization. Sotalol increases the refractory period of atrial muscle. 

Spontaneous phase 4 depolarization, a characteristic of normal sinoatrial nodal cells, relies on progressive inhibition of an outward potassium current and an increase in a slow inward current that is carried by Na" and Ca " ions. Verapamil decreases the rate of rise and slope of the slow diastolic depolarization, the maximal diastolic potential, and the membrane potential at the peak of depolarization in the sinoatrial node. 

It is an amide local anaesthetic and has rapid onset of action. It depresses diastolic depolarization and automaticity in ectopic foci in ventricular tissue. Phase 4 depolarization in partially depressed Purkinje fibres and after depolarizations are antagonised. It does not depress AV conduction and decreases action potential duration, effective refractory period. It has no effect on BP. 

De Mello WC Increased spread of electrotonic potentials during diastolic depolarization in cardiac... 

The direct cardiac actions of muscarinic stimulants include the following (1) an increase in a potassium current (Ik(acii)) in atrial muscle cells and in the cells of the sinoatrial and atrioventricular nodes as well (2) a decrease in the slow inward calcium current (Ica) in heart cells and (3) a reduction in the hyperpolarization-activated current (If) that underlies diastolic depolarization. All of these actions are mediated by M2 receptors and contribute to slowing the pacemaker rate. Effects (1) and (2) cause hyperpolarization and decrease the contractility of atrial cells. 

Effect of epinephrine on the transmembrane potential of a pacemaker cell in the frog heart. The arrowed trace was recorded after the addition of epinephrine. Note the increased slope of diastolic depolarization and decreased interval between action potentials. This pacemaker acceleration is typical of i-stimulant drugs. (Modified and reproduced, with permission, from Brown H, Giles W, Noble S Membrane currents underlying rhythmic activity in frog sinus venosus. In The Sinus Node Structure, Function, and Clinical Relevance. BonkeFIM [editor], MartinusNijhoff, 1978.)... 

By stimulating p-receptors, and hence cAMP production, catecholamines augment all heart functions including systolic force, velocity of myocyte shortening, sinoatrial rate, conduction velocity, and excitability. In pacemaker fibers, cAMP-gated channels ( pacemaker channels ) are activated, whereby diastolic depolarization is hastened and the firing threshold for the action potential is reached sooner (B). cAMP activates protein kinase A, which phosphorylates different Ca2+ transport proteins. In this way, contraction of heart muscle cells is accelerated, as more Ca2 enters the cell from the extracellular space via L-type Ca2 channels and release of Ca2 from the sarcoplasmic reticulum (via ryanodine receptors, RyR) is augmented. Faster relaxation of heart muscle cells is effected by phosphorylation of troponin and phospholamban. 

The major electrophysiologic manifestation of impulse generation is found in the properties of automaticity (slope of phase 4 or diastolic depolarization) and of impulse conduction in conduction velocity. Drugs that alter pacemaker automaticity have a direct effect on the heart rate. 

Rapid diastolic depolarization leads to a rapid rate of firing, whereas a lowered slope of phase 4 diastolic depolarization elicits fewer action potentials in the same time interval. Similarly, drugs that increase conduction velocity in the heart can help alleviate heart block, whereas those that decrease conduction velocity may slow a rapid heart rate. 

Disopyramide is an antiarrhythmic agent that deaeases the rate of diastolic depolarization decreases upstroke velocity inaeases action potential duration and prolongs refractory period. It is indicated in suppression and documented prevention of ventricular arrhythmias considered to be life threatening. 

Quinidine and procainamide decrease automaticity by reducing the rate of phase 4 diastolic depolarization, which is probably mediated by a diminished membrane permeability to sodium, and they decrease conduction velocity throughout the conducting system (Figure 84). They produce an indirect (vagolytic) effect that sometimes counteracts... 

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