Opening Tunnels -- in Big and Small ways

As the active ingredient in dynamite, nitroglycerin is a powerful explosive that can blast tunnels through solid rock. When used in tiny amounts - in a pill or patch - it turns out that nitroglycerin is also able to re-open constricted blood vessels in the human body, making it easier for the heart to pump blood.

When nitroglycerin was invented in 1847 it was valued for its explosive properties. But it wasn't long before people noticed that working with nitroglycerin commonly caused severe headaches. This eventually led to the discovery that nitroglycerin could be used to treat angina, the chest pain caused by heart disease.

Alfred Nobel made his fortune by developing safer forms of nitroglycerin such as dynamite and gelignite. Later in life, Nobel developed heart disease and, ironically, came to rely on nitroglycerin's mysterious medicinal properties as a remedy for his ailment. Nobel died in 1896 and it would be another 100 years before scientists fully understood the therapeutic action of nitroglycerin.

Solving the mystery

The story is well known: Not wanting to be remembered only for his destructive inventions, Nobel specified that his estate be used to fund annual awards to people or institutions whose work most benefited mankind in the preceding year. In 1998, the Nobel Prize for Physiology and Medicine was awarded to three researchers who discovered the role of nitric oxide (NO) in the dilation of blood vessels. In the process, they solved the mystery of what makes nitroglycerin work.

The researchers discovered that NO is a gaseous signaling molecule that carries important information throughout the body. In a blood vessel, nitroglycerin releases NO, which causes smooth muscles to relax, allowing vessels to dilate. This new knowledge led to the development of a new series of vasodilatory drugs that combat not only angina but also impotence (Viagra® is perhaps the best-known vasodilator). One of the newest and most commonly used compounds is isosorbide-5-mononitrate (ISMN), an organic nitrate vasodilatory drug modeled after nitroglycerin.

New drugs, new dosing strategies

Organic nitrates are typically more effective than their predecessors because they are designed to have better solubility in body tissues. However, the human body can develop nitrate tolerance, which lowers the effectiveness of these compounds. As a result, vasodilators require different dosing strategies than other medicines.

For most drugs, dosage amounts and intervals are designed to maintain a drug concentration that just exceeds the level needed to make it effective. The dosing strategy is completely different for organic nitrates. To avoid the onset of nitrate tolerance, blood levels must be allowed to fall until there is almost no trace of the drug before another dose is taken. Because these minute levels are very difficult to detect, highly sensitive blood analysis is required to determine the best dosing strategy.

Simpler, more sensitive analysis

Human blood is a particularly complex mixture with many possible interferences that make it difficult to detect and analyze the presence of compounds such as ISMN. Using a new generation of analytical instrumentation, a commercial laboratory in the UK has developed a simple method for extracting and analyzing ISMN in human plasma. This detection method makes use of negative chemical ionization, a special feature of the Agilent Gas Chromatograph and Mass Selective Detector (GC-MSD).

In this form of mass spectrometry, a cloud of electrons is created inside the detector. Only molecules capable of capturing electrons are detected and their mass determined. This enables very sensitive and very selective analysis -- it can detect ISMN at concentrations below 10 parts per billion, more than 100 times lower than the maximum concentration reached in blood. The results are highly accurate and fully reproducible.

For more information

Agilent's Chemical Analysis Group develops a wide range of solutions for chemical and biochemical researchers. To learn more about the Agilent Gas Chromatograph and Mass Selective Detector, as well as other products and resources, please return to the main page of the Chemical Analysis section of our Web site.

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