The excitement and rewards of research with our discovery of some of the biological effects of nitric oxide.

Abstract

The rewards of biomedical research can be very exciting and remarkable. The feeling of having done an experiment for the first time and only you know the results that will have an important effect on your research and perhaps broader applications is exhilarating. I suspect that it is not common for scientists to see their fundamental research develop during their research career into such broad clinical application for numerous diseases. While much of our work and experiments were well planned, many of our important observations came from luck or serendipitous events—undoubtedly, a common phenomenon in biomedical research. I will recount some of these experiments here. A more detailed review can be found elsewhere.1,2 I spent my early years as a trainee working with cAMP and adenylyl cyclase. As a result of this experience, after the discovery of cGMP in rat urine in the mid-1960s, I and others thought that cGMP might also be a second messenger to mediate the effects of some hormones and drugs. We transferred much of our work from cAMP to cGMP. Our earliest experiments with guanylyl cyclase in the early 1970s suggested that there were at least two isoforms of the enzyme, soluble and particulate forms, with different kinetic properties.3,4 This was of interest since adenylyl cyclase was exclusively particulate.5 The possibility of soluble and particulate isoforms of guanylyl cyclase suggested that different classes of hormones might regulate these different enzymes to produce separate pools of cGMP that may have different physiological effects. This was indeed the case from our later work with different activators of each isoform as discussed below. We ultimately demonstrated there were different isoforms with purification, cloning, and expression some years later. However, we initially took a shortcut and added various inhibitors of nucleotidases, phosphatases, and phosphodiesterases to soluble …