Cardiac output equals the heart rate times the stroke volume. The key factor regulating heart rate is the balance between sympathetic and parasympathetic stimulation of the heart. Increased sympathetic stimulation (due to activity or stress) increases heart rate by acting on cardiac pacemaker cells. Now let’s observe the effect of epinephrine on a frog heart. After allowing the heart to beat at baseline rate for several minutes, the heart is then given a few drops of 1:1000 solution of epinephrine. In less than 10 seconds a change in the heart rate is observed. Increased parasympathetic activity (e.g., during resting and digesting) decreases heart rate by acting on cardiac pacemaker cells. Now let’s observe the effect of acetycholine on a frog heart. Once a new baseline heart rate has been obtained, a few drops of 1:50 solution of acetylcholine are placed on the heart. Afterwards, the heart rate begins to decrease dramatically within 10 seconds. The key factor regulating stroke volume is the amount of stretching that occurs to ventricular cardiac muscle prior to ventricular contraction. The more cardiac muscle stretches, the more forcefully it contracts. These stronger contractions increase stroke volume. Increased sympathetic stimulation (due to activity or stress) increases contractility of cardiac myocytes. Sympathetic stimulation increases the amount of intracellular calcium available during each contraction. Parasympathetic activity does not directly change stroke volume because the ventricular myocytes are only sparsely innvervated by parasympathetic nerves. Cardiac muscle fibers are stretched by increased blood volume returning to the heart (increased venous return and EDV). Increased stretch results in greater force of contraction, which increases stroke volume. Venous return is affected by the skeletal muscle and respiratory pumps, which help return blood to the heart. Increased sympathetic activity also increases venous return by contracting smooth muscle in veins. This reduces their diameter and the amount of blood they contain, forcing more blood towards the heart. Heart rate and stroke volume often change in opposite directions because compensatory mechanisms attempt to maintain a constant cardiac output. Think about what would happen to heart rate and stroke volume if you suddenly lost a large amount of blood. A sudden drop in blood volume causes low venous return and therefore decreased stroke volume. This is compensated for by an increase in sympathetic activity, which increases heart rate. As a result, cardiac output is unchanged.