Drugs Acting on Cardiac Muscle | Veterinary Pharmacology

After reading this article you will learn about the drugs acting on cardiac muscle.

Resting Membrane Potential:

The voltage difference across the membrane of a normal cell at rest is called as “resting membrane potential” of that cell. This is also known as “resting membrane voltage”, and commonly abbreviated as V_m.

V_m of various cells are as follows:

The resting membrane potential -90 mV indicates that the electrical potential inside the fibre is 90 mV more negative than the potential outside the fibre in the interstitial fluid. The “Na⁺ – K⁺ pump”, also called as” Na⁺ – K⁺ ATPase”, which exchanges 3 Na⁺ of inside for 2K⁺ ions of outside the cell, helps in maintaining the resting trans-membrane concentration gradients of ions by an active transport process.

In normal resting state, the concentrations of ions inside, [ ]_i and outside, [ ]₀ the myocardial cells are: [K]₀ = 4, [K]_i = 150, [Na]₀ = 140, and [Na]_i = 6 to 12 milli-moles/litre of water. If there are no voltage gradient across the membrane the ions like K⁺ would diffuse out of the cell through all time permeable K⁺ channels on the membrane (not so for Na⁺ channels) until the concentrations inside and outside are equal.

How­ever, the Na⁺– K⁺ pump counteracts the diffusional forces. In addition, fixed negative charges inside cell attracts the K⁺ ions and counteract the concentration gradient that promotes diffusion, when these forces are equal to net flux of ions.

Action Potential (AP):

The electrical potential developed in a muscle or nerve cell during activity is known as action potential. It is a rapid change in the membrane potential from the normal resting negative state to a positive potential and then again back to the nega­tive potential.

The time taken for producing an action potential is termed as “action potential duration” (APD). The APD is comparatively more in cardiac muscle, which has an extra plateau phase, than that of skeletal muscle.

The two main reasons for the above fact are:

(i) At the first phase of AP of skeletal muscle the large numbers of ‘fast Na⁺ channels’ open suddenly, through which tremendous numbers of Na⁺ ions enter into the skeletal muscle fibre. Whereas, in cardiac muscle, the AP is caused by the opening of two types of channels – the ‘fast Na⁺ channels’ (similar to those in skeletal muscle), and the “Slow Ca²⁺ channels” or Ca²⁺ – Na⁺ channels’.

This second group of channels open slowly and remain open for comparatively longer period. During this time, large amounts of both Ca²⁺ and Na⁺ ions enter into the cardiac muscle fibre and thereby maintain a state of depolarization for a prolonged period to produce the plateau phase of the AP.

(ii) During the plateau phase of cardiac muscle AP, the permeability of the membrane to K⁺ is greatly decreased, which prevents K⁺ efflux and there by early recovery. When the slow Ca²⁺ channels close at the end of plateau phase (0.2 to 0.3 sec), the membrane permeability to K⁺ increases very rapidly and the efflux of K⁺ ions returns the membrane potential to its resting level, thus ending the AP.

Types of Myocardial Fibres:

Electro physiologically the following two types of myocardial fibres can be distin­guished.

(i) Non-automatic Fibres:

These are ordinary working myocardial fibres which cannot generate an impulse of their own. They show “fast channel APs” and Phase 4 of AP is stable.

(ii) Automatic Fibres:

These fibres are found in the S.A. node, A.V. node, and His-Purkinje system, i.e, in specialized conducting tissues. They are also present in the A.V. ring, interatrial septum and around opening of great veins. The speciality of these fibres is that after repolarization to the maxi­mum value the membrane potential decreases spontaneously to cause phase 4 or slow diastolic depolarization.

When it reaches to the critical threshold value sudden depolarization occurs automatically to initiate a new action potential. Thus, they are capable of generating their own impulse.

The rate of impulse generation by a fibre depends on three factors:

(a) Maximal diastolic potential,

(b) The slope of phase 4 depolarization and

(c) The thresh­old potential.

The automatic fibres produce ‘slow channel action potential.’ Purkinje fibre can produce both “fast and slow channel AP” normally, the S.A. node has the steepest phase 4 depolarization, undergoes self excitation and propagates the impulse to the rest of the heart-(acts as pacemaker).

AP of Non-Automatic Cells:

In response to either an external stimulus or propagation of impulse, the cardiac cells are excited and a sequence of voltage changes occurs due to changes in ionic conductance across the membrane. Here, AP is divided into 5 phases.

Phase 0:

At this phase, fast Na⁺ channels open suddenly and allow very intense inward Na⁺ current to flow for a brief period of time and then closed (inactivated) to end the phase.

Phase 1:

A transient outward K⁺ current flows through K⁺ channels, just after the inactivation of Na⁺ chan­nels, to cause rapid repolarization to the plateau level of AP.

Phase 2:

This plateau phase of AP occurs due to inward Ca²⁺ current through Ca²⁺ channels (specially L type). This Ca²⁺ flow causes contraction of the cell.

Phase 3:

It is the phase of rapid repolarization and occurs due to outward K⁺ current through K⁺ channels.

Phase 4:

This is the diastolic voltage time course when the membrane potential remains stable at resting state until activated by a propagating impulse or an external stimulus. Purkinje fibres show spontaneous depolarization at this phase.

The AP recorded in ventricular muscle is 105 mV, which means that the mem­brane potential rises from its normally very negative value of -85 mV to a slightly positive value of +20 mV. The positive portion is called as the “overshoot potential”.

AP of Automatic Fibres (S.A. Node):

The resting membrane potential (potential between two successive discharges) of S.A. nodal fibre is -55 to -60 mV only in comparison with – 85 to -95 mV for ventricular fibre, because, the former fibres are natu­rally leaky to Na⁺ ions.

Once the membrane potential remains less negative than -60 mV as in S.A. node for more than a few milliseconds, the fast Na⁺ channels become inactivated (closed). There­fore, only the slow Ca²⁺ channels (or slow Ca²⁺ – Na⁺ channels) can open and initiate the AP.

Sodium ions naturally tend to leak inside the S.A. nodal fibre through multiple membrane channels. Thus, the resting potential between each two heart beats (Phase 4 depolarization or spontaneous phase 4 depolarization) rises gradually. When it reaches a threshold voltage of about -40 mV, the Ca²⁺– Na⁺ channels become acti­vated and open to allow a very rapid entry of Ca²⁺ and Na⁺ ions to initiate the AP.

In S.A. nodal fibre, there are three phases of AP.

Phase 0:

Phase of depolarization caused by rapid inward Ca²⁺ and Na⁺ ions through Ca²⁺ – Na⁺ Channels.

Combined phase 1, 2 and 3:

The three independent phases are not clearly distinguished. The rapid repolarization occurs due to K⁺ efflux.

Phase 4:

It is due to spontaneous leakiness of the S.A. nodal fibre to Na⁺ ions through Na⁺ channels.

Types of APs:

Two categories of cardiac action potentials can be distinguished: fast and slow responses:

(i) Fast response is generated by an intense inward Na⁺ current, has a large fast rising phase 0, propagates very rapidly, and has a large safety factor for conduction. Normal atrial, ventricular and purkinje fibre AP_S are exam­ples of the fast response.

(ii) The slow response has a slowly rising phase 0, propagates very slowly, and has a low safety factor for conduction. Examples are AP_S of S.A. and A.V. nodal fibres. The main depolarizing current for slow response is carried by Ca²⁺ that flows through L type of Ca²⁺ channels. The purkinje fibres are capable of producing both fast and slow responses.

Differences between the Fast and Slow Channel AP_S:

Fast Channel AP:

(i) Found in atria, ventricles and Purkinje fibres.

(ii) Activation and inactivation processes of ion channels are fast.

(iii) Fast conduction velocity (0.5 to 5 me­tre/sec)

(iv) Threshold potential is about -65 mV.

(v) Inward ion in phase 0 is mainly Na⁺.

(vi) Action potential duration (APD) is more than the effective refractory period (ERP).

(vii) Tetrodotoxin, local anaesthetic are se­lective Na⁺ channel blockers and block fast channel AP or fast response.

Slow Channel AP:

(i) Found in S.A. and A.V. nodes, around A.V. ring and coronary sinus opening.

(ii) Activation and inactivation processes of ion channels are slow.

(iii) Slow conduction velocity (0.1 metre/sec).

(iv) Threshold voltage is about – 445 mV.

(v) Inward ion in phase 0 is mainly Ca²⁺.

(vi) Action potential duration is less than the effective refractory period.

(vii)Verapamil, diltizem, Mn²⁺ are selective Ca²⁺ channel blockers and block slow channel AP or slow response.