Nitroglycerin and Nitric Oxide--A Rondo of Themes in Cardiovascular Therapeutics.

The rondo is a musical form in which a single recurrent theme alternates with different melodic motifs that are each distinct from one another. The recurrent theme is typically repeated multiple times, providing both the overall unity for the musical movement and a familiar musical destination to which the piece returns after the presentation of distinct interspersed themes. The parallels between the rondo form and the cyclic temporal pattern of experimental therapeutics are uncanny. Clinical observation is a recurring theme in drug development, in which the effects of treatment observed in patients may suggest novel therapeutic indications (or unanticipated side effects) that lead to the identification of new molecular targets and pathways. These observations in patients are typically interspersed with increasingly sophisticated analyses in novel experimental models, yielding a kind of “drug-development rondo.” The rondo being reviewed in this article takes place in the key of E — for endothelium. The drug in question is nitroglycerin, and its major active principal is nitric oxide, a gaseous molecule made in the vascular endothelium (and in other tissues) that is essential for vascular homeostasis. The opening theme of our drug-development rondo can be traced back at least to the year 1768, when William Heberden coined the term “angina pectoris” and then published an evocative description of the symptoms of angina, which concluded with this discouraging admission: “With respect to the treatment of this complaint, I have little or nothing to advance.” Just 6 years later, the English chemist and theologian Joseph Priestley discovered nitric oxide. However, these two coincidental discoveries would remain isolated, and a century would pass before nitroglycerin and related organic nitrate drugs would be applied to the effective treatment of angina. Yet another century would go by before the connections among nitric oxide, nitroglycerin, and angina pectoris were revealed — both in the laboratory and in the clinic. Discoveries with regard to the physical properties of gases moved forward apace, while the clinical characteristics of angina pectoris were being systematically explored, with no notion that these seemingly distinct spheres of inquiry would ever intersect. The next new theme has its origins in organic chemistry. In 1846, the Italian chemist Ascanio Sobrero became the first person to synthesize nitroglycerin, the explosive properties of which were immediately appreciated. Like most good chemists of this bygone era, Sobrero then tasted his newly synthesized compound and noted the profound headache that ensued, a phenomenon quickly attributed to cerebral vasodilation. This simple clinical observation — that nitroglycerin dilates the vasculature — sparked a century-long dialogue between clinical pharmacologists and basic vascular physiologists, a dialogue that enabled many of the discoveries that are essential to our current understanding of the biologic functions of nitric oxide. This basic scientific advance led quickly to a return to the theme of clinical observation, and within just two decades of Sobrero’s discovery, the vasodilatory effects of nitroglycerin and the related compound amyl nitrate were exploited for therapeutic effect. By the 1860s, the British pharmacologists and physicians T. Lauder Brunton and William Murrell were using nitrate compounds to treat patients with angina and hypertension, and use of the drugs quickly became widespread.1 Indeed, the industrialist (and later philanthropist) Alfred Nobel had debilitating symptoms of angina pectoris that were ameliorated by nitroglycerin. Nobel had made his fortune after inventing a nitroglycerin detonator that permitted control of this highly explosive compound and facilitated the use of nitroglycerin in munitions. Nobel observed that his use of nitroglycerin to treat his own symptoms of angina reflected an “irony of fate.” The huge gulf between the destructive potential of nitroglyc-