Factors Affecting Cardiac Contraction

Factors affecting cardiac contraction • • • Amount of intracellular calcium before contraction; more calcium left in the cell → more powerful contraction Internal relevant factors: o SNS and PNS o Number/state of calcium channels o Mechanism for calcium removal from cells after contraction External relevant factors: o Force opposing ejection of blood (“afterload”) depending on systemic vascular resistance (afterload + "load" that the heart must eject blood against. In simple terms, the afterload is closely related to the aortic pressure. o Amount of venous blood returning to heart (= the magnitude of the maximal (end-diastolic) ventricular volume or the end-diastolic pressure stretching the ventricles (“preload”) → Frank-Starling Law of the heart (increase in ventricular filling promotes an increase in pressure) SNS and PNS • Circulatory substances can also affect the heart rate. Catecholamines, like adrenaline, are released during stress (adrenal medulla) and will cause an increase in heart rate. o Basis for therapy ANS control •  sympathetic nerve → NA → act on adrenoceptors (β1-ARs) →  intracellular cAMP → enhance inward Ca2+ current o Positive chronotropic (influencing the heart rate) effect o Positive inotropic (influencing the force of muscle contraction) effect o Increased automaticity( intrinsic ability to contract spontaneously and rhythmically) • parasympathetic nerve → ACh → act on M2 receptor→intracellular cAMP → inhibit Ca2+ current & increase K+ permeability o Negative chronotropic effect o Decreased automaticity (intrinsic ability to contract spontaneously and rhythmically) Drug targets in the heart • Cardiac muscle cell: Inhibiting the P pump will cause an increase in intracellular Na concentration. This will make it harder for the E pump to work (due to the lower Na concentration gradient) resulting in a decreased Ca excretion by the exchanger → more contraction due to increased Ca2+. Drugs affecting the autonomic control of the heart • Sympathetic nervous system o β1 agonists → increase heart rate and contractility and thus cardiac work o β1 antagonists → reduce heart rate and contractility and thus cardiac work • Parasympathetic nervous system o Muscarinic agonists ▪ Reduce heart rate and inhibit cardiac conduction ▪ No selective M2 agonists have been developed o Muscarinic antagonists → increase HR Beta agonists Beta-adrenoceptors are coupled to Gs-proteins, which activate adenylyl cyclase to form cAMP from ATP. Increased cAMP activates a cAMP-dependent protein kinase (PK-A) that phosphorylates L-type calcium channels, which causes increased calcium entry into the cells. Increased calcium entry during action potentials leads to enhanced release of calcium by the sarcoplasmic reticulum in the heart; these actions increase inotropy (contractility). Gs-protein activation also increases heart rate by opening ion channels responsible for pacemaker currents in the sinoatrial node. PK-A phosphorylates sites on the sarcoplasmic reticulum, which enhances the release of calcium through the ryanodine receptors (ryanodine-sensitive, calcium-release channels) associated with the sarcoplasmic reticulum. This provides more calcium for binding troponin-C, which enhances inotropy (contractility). Finally, PK-A can phosphorylate myosin light chains, which may also contribute to the positive inotropic effect of beta- adrenoceptor stimulation. In summary, the cardiac effects of a β-agonist are increased heart rate and contractility. Adrenergic receptors as drug targets • Beta-adrenoceptors are coupled to Gs-proteins which activate adenyl cyclase to form cAMP from ATP. o cAMP activates protein kinase A (PK-A) which phosphorylates L-type calcium channels ▪ Causes increased calcium entry during action potentials → enhanced release by sarcoplasmic reticulum → increased inotropy o PK-A phosphorylates sites on sarcoplasmic recticulum which enhances the release of calcium through ryanodine receptors → more calcium release o PK-A also phosphorylates myosin light chains Beta-adrenergic receptor agonists • Work to increase heart rate and contractility • E.g. β1 selective – dobutamine β1 non-selective: noradrenaline, adrenaline, isoprenaline Partial agonists: alprenolol, oxprenolol – increase HR at rest but opposes exercise-induced tachycardi Used in: o Cardiogenic shock: inadequate circulation of blood due to primary failure of the ventricles o Cardiac Arrest: heart develops an arrhythmia which causes it to stop beating o Acute heart failure o Hypotension Adrenaline is used as the first drug in all cardiac arrests. This is because it concentrates blood around the brain and the heart by peripheral vasoconstriction (alpha adrenergic activity of high dose adrenaline) in addition to strengthening cardiac contraction. o o o • • Muscarinic (ACh) recptor drugs • Vagus (parasympathetic) nerves that innervate the heart release acetylcholine (ACh) as their primary neurotransmitter • ACh binds to muscarinic receptors (M2) on cells comprising the SA and AV nodes • Increases in vagal activity to the SA (and AV) node decreases the firing rate of the pacemaker cells. • Atropine is a muscarinic receptor antagonist used to inhibit the effects of excessive vagal activation on the heart, which is manifested as sinus bradycardia and AV nodal block. Therefore, atropine can temporarily revert sinus bradycardia to normal sinus rhythm and reverse AV nodal blocks.