Internationale Zeitschrift für Herz-Kreislauf-Forschung

The Role of Estrogen and Nitric Oxide in the Prevention of Cardiac Arrhythmias in the Embryonic Zebrafish (Danio Rerio)

Jonathan Winalski and James Turner

Nitric oxide (NO) is a gaseous messenger molecule found to be critical in the regulation of cardiomyocyte contraction and blood vessel vasodilation in the cardiovascular system (CVS) of a diverse variety of organisms. NO is released by catalyzing the enzymatic transformation of L-arginine to L-citrulline by NO synthase (NOS), which is found in four distinct isoforms in the human body. The most prominent isoform in the sarcoplasmic reticulum (SR) of the CVS; however, is neuronal NO (nNOS or NOS1). Research shows that NOS1 is critical to the contraction and relaxation of cardiomyocytes. More specifically, NOS1 is believed to protect the regulation of cardiomyocyte calcium (Ca2+) release. This phenomenon occurs through specific ryanodine influenced Ca2+ channels and receptors, which allows for excitation coupling to occur. It has been hypothesized by prior research that diastolic Ca2+ leaks due to abnormally open SR ryanodine channels increases the presence of ventricular arrhythmias. The main hypothesis offered up by this research focuses on the mechanism of action in which deprivation of nNOS and its upstream regulation by estrogen leads to ventricular arrhythmias in the embryonic zebrafish via a dysregulated S-nitrosylation pathway. It was also determined that this S-nitrosylation pathway is independent of soluble guanylyl cyclase (sGC)-GMP mediated pathway, which is normally responsible for exerting NO effects throughout the body. Additionally, the goal of this research was to identify a highly successful rescue treatment that would restore normal CVS activity to the embryos. The most successful treatment option was Dantrolene, a hydantoin derivative whose mechanism of action revolves around closing ryanodine channels. When populations of nNOS deprived fish became 100% arrhythmic, Dantrolene was entirely successful as a treatment paradigm. This data allows for a better understanding of not only the entire CVS as a whole, but potentially elucidates a better understanding of ventricular arrhythmias.