Developmental Changes in the Excitation-Contraction Mechanisms of the Ventricular Myocardium and Their Sympathetic Regulation in Small Experimental Animals

Abstract

The developmental changes in the excitation-contraction mechanisms of the ventricular myocardium of small animals (guinea pig, rat, mouse) and their sympathetic regulation will be summarized. The action potential duration monotonically decreases during pre- and postnatal development in the rat and mouse, while in the guinea pig it decreases during the fetal stage but turns into an increase just before birth. Such changes can be attributed to changes in the repolarizing potassium currents. The T-tubule and the sarcoplasmic reticulum are scarcely present in the fetal cardiomyocyte, but increase during postnatal development. This causes a developmental shift in the Ca²⁺ handling from a sarcolemma-dependent mechanism to a sarcoplasmic reticulum-dependent mechanism. The sensitivity for beta-adrenoceptor-mediated positive inotropy decreases during early postnatal development, which parallels the increase in sympathetic nerve innervation. The alpha-adrenoceptor-mediated inotropy in the mouse changes from positive in the neonate to negative in the adult. This can be explained by the change in the excitation-contraction mechanism mentioned above. The shortening of the action potential duration enhances trans-sarcolemmal Ca²⁺ extrusion by the Na⁺-Ca²⁺ exchanger. The sarcoplasmic reticulum-dependent mechanism of contraction in the adult allows Na⁺-Ca²⁺ exchanger activity to cause negative inotropy, a mechanism not observed in neonatal myocardium. Such developmental studies would provide clues towards a more comprehensive understanding of cardiac function.

Keywords: Ca2+ handling; Na+-Ca2+ exchanger; action potential; adrenoceptors; development; inotropy; myocardium; sarcoplasmic reticulum.

Figure 1

Action potentials of the guinea pig and mouse ventricle. Recordings were obtained in the guinea pig (A) and mouse (B) at fetal (a) neonatal (b) and adult (c) stages.

Figure 2

A schematic diagram of developmental and pathological changes in the excitation–contraction coupling of mouse ventricular cardiomyocytes. Fetus: The action potential triggers sarcolemmal Ca²⁺ influx through voltage-dependent Ca²⁺ channels, and a part of the Ca²⁺ diffuses towards the cell center and triggers Ca²⁺-induced Ca²⁺ release from Ca²⁺ release channels (ryanodine receptors) on the slightly present SR. Neonate: Partially developed T-tubular invaginations cause Ca²⁺-induced Ca²⁺ release from the coupled release channels on the SR. The released Ca²⁺ then triggers Ca²⁺ release from the neighboring Ca²⁺ release sites, uncoupled from the T-tubules. Adult: A well-developed T-tubular network enables simultaneous Ca²⁺ release from the SR in the entire cell on an action potential. Diseased: The T-tubule-SR coupling is partly disrupted and the SR Ca²⁺ release pattern resembles that in the immature myocardium.

Figure 3

α-Adrenoceptor-mediated inotropy in the right ventricle. (A) Adult guinea pig showing positive inotropy. (B) Neonatal (a), 2-week-old (b), and 4-week-old mice (c). The inotropy changes from positive to negative during postnatal development. (C) Neonatal mice in the presence of nifedipine (a), 4-week-old mice in the presence of SEA0400 (b). The positive and negative inotropy was inhibited by nifedipine and SEA0400, respectively. Arrows indicate α-adrenergic stimulation by phenylephrine in the presence of propranolol.