313 PHL Lab # 6 Effect & site of action of different drugs on isolated rabbit's heart. (Langendorff preparation)

- The heart is innervated by both sympathetic and parasympathetic nerve. - This innervations alter the basic rhythm of the heart which is initiated by the pacemaker tissue of the sinoatrial node (SA node) atria AV node Bundle of His Purkinjee fibers ventricles. - When the heart is removed from the intact animal and maintained in an isolated organ system the heart will beat spontaneously by virtue of the myogenic rhythm controlled by SA node.

Heart muscle Properties: The Heart consist of special muscle called syncitium, The properties of this muscle are :  Contractility.  Rhythmicity (at certain heart rate).  Conductivity (conduction from one area to other area).  Automaticity (response to intrinsic stimuli).  Excitability (response to external stimuli).

Receptors present in the isolated rabbit heart: Neural nicotinic receptors (Nn receptors): present in parasympathetic ganglia (embedded in the heart). Muscarinic receptors (M2 receptors ) : present at postganglionic parasympathetic nerve terminal. Adrenergic receptors (β1 receptors ) : present at postganglionic sympathetic nerve terminal. Histaminergic receptors (H2 receptors ).

Autonomic nervous system supply of the heart: Autonomic nervous system Sympathetic nervous system Para sympathetic nervous system Effect- Stimulation of myocardium. - Positive inotropic (increase force of contraction). - positive chronotropic (increase heart rate). - Inhibition of myocardium. -negative inotropic (decrease force of contraction). -negative chronotropic (decrease heart rate). Receptors β1β1 M2 TransmitterAdrenalineAch

Autonomic nervous system supply of the heart: Autonomic nervous system Sympathetic nervous system Para sympathetic nervous system Synthetic agonistIsoprenalineMethacholine MOA+ Gs protein→ + adenyl cyclase→↑ cAMP→↑ calcium →contraction + Gi protein→ - adenyl cyclase→↓cAMP→↑K & ↓calcium →hyperpolarization Blocker- Propranolol “non-selective” - Atenolol, metaprolol “selective” - Labetalol → α, β blocker - phentolamine → α blocker Atropine

Autonomic nervous system supply of the heart: Isoprenaline is 10 times more potent than adrenaline on the isolated heart. Its effect are often more prolonged because it is not naturally occurring inside the body so it can not be reuptake. Atropine can cause bradycardia followed by tachycardia. If large enough dose of Ach are given to the heart this will cause cardiac arrest.

Other agents that influence the heart function: Histamine: Receptor: H2 MOA:+ Gs protein → ↑ cAMP →↑calcium → contraction Antagonist : Ranitidine.

Other agents that influence the heart function: xanthines : Examples: theophylline, caffeine & theobromine. MOA: Phosphodiesterase enz. Inhibitors (PDEI) → ↑ cAMP → ↑Ca +2 → Contraction. Effect: - Positive inotropic & chronotropic. - They produce mild stimulation of heart muscle but this effect is species dependant, Guinea-pig and rats heart show this action but is rarely seen in isolated rabbit heart.

Direct acting drug: Direct acting stimulant: e.g. calcium chloride (Cacl2). Direct acting depressant: e.g. potassium chloride (Kcl).

Arrhythmia and anti-arrhythmic drugs: e.g. alkaloid aconitine. Action: ectopic focus and generation of cardiac dysrhythmia → ventricular tachycardia and fibrillation → it can be reversed by antidysrhythmic drug such as lignocaine.

Determination of heart rate Example: Speed= 1square/sec, Number of beat/sq=6 beats/square Calculate the HR (beat per minute)? 6 beats 1 sec. x 60 sec x = 60*6 = 360 BPM

Experiment N Propranolol I soprenaline N Ach Atropine Ach N Cacl 2 N Kcl I soprenaline