Types of chemical explosives
Basically, chemical explosives are of two types: (1) detonating, or high, explosives and (2) deflagrating, or low, explosives. Detonating explosives, such as TNT and dynamite, are characterized by extremely rapid decomposition and development of high pressure, whereas deflagrating explosives, such as black and smokeless powders, involve merely fast burning and produce relatively low pressures. Under certain conditions, such as the use of large quantities and a high degree of confinement, some normally deflagrating explosives can be caused to detonate.
Detonating explosives are usually subdivided into two categories, primary and secondary. Primary explosives detonate by ignition from some source such as flame, spark, impact, or other means that will produce heat of sufficient magnitude. Secondary explosives require a detonator and, in some cases, a supplementary booster. A few explosives can be both primary and secondary depending on the conditions of use.
History of black powder
It may never be known with certainty who invented the first explosive, black powder, which is a mixture of saltpetre (potassium nitrate), sulfur, and charcoal (carbon). The consensus is that it originated in China in the 10th century, but that its use there was almost exclusively in fireworks and signals. It is possible that the Chinese also used black powder in bombs for military purposes, and there is written record that in the mid-13th century they put it in bamboo tubes to propel stone projectiles.
There is, however, some evidence that the Arabs invented black powder. By about 1300, certainly, they had developed the first real gun, a bamboo tube reinforced with iron, which used a charge of black powder to fire an arrow.
A strong case can also be made that black powder was discovered by the English medieval scholar Roger Bacon, who wrote explicit instructions for its preparation in 1242, in the strange form of a Latin anagram, difficult to decipher. But Bacon read Arabic, and it is possible that he got his knowledge from Arabic sources.
Some scholars attribute the invention of firearms to an early 14th-century German monk named Berthold Schwarz. In any case they are frequently mentioned in 14th-century manuscripts from many countries, and there is a record of the shipment of guns and powder from Ghent to England in 1314.
Not until the 17th century was black powder used for peaceful purposes. There is a doubtful claim that it was used in mining operations in Germany in 1613 and fairly authentic evidence that it was employed in the mines of Schemnitz, Hungary (modern Banská Štiavnica, Czechoslovakia), in 1627. For various reasons, such as high cost, lack of suitable boring implements, and fear of roof collapse, the use of black powder in mining did not spread rapidly, though it was widely accepted by 1700. The first application in civil engineering was in the Malpas Tunnel of the Canal du Midi in France in 1679.
For 300 years the unvarying composition of black powder has been approximately 75 percent saltpetre (potassium nitrate), 15 percent charcoal, and 10 percent sulfur. The saltpetre was originally extracted from compost piles and animal wastes. Deposits found in India provided a source for many years. During the 1850s tremendous quantities of sodium nitrate were discovered in Chile, and saltpetre was formed by reaction with potassium chloride, of which there was a plentiful supply.
Chilean nitrate was not at first considered satisfactory for the manufacture of black powder because it too readily absorbed moisture. Lammot du Pont, an American industrialist, solved this problem and started making sodium nitrate powder in 1858. It became popular in a short time because, although it did not produce as high a quality explosive as potassium nitrate, it was suitable for most mining and construction applications and was much less expensive. To distinguish between them, the potassium nitrate and sodium nitrate versions came to be known as A and B blasting powder respectively. The A powder continued in use for special purposes that required its higher quality, principally for firearms, military devices, and safety fuses.
Manufacture of black powder
Manufacture of black powder was accomplished originally by hand methods. Ingredients were ground together with a mortar and pestle. The next step was to use crushing devices of wood (wooden stamps), also operated by hand, in wooden or stone bowls. The stamping process was gradually mechanized and, about 1435, the first powder mill driven by water power was erected near Nuremberg, Germany.
Metallic crushing devices, introduced in the early 1800s, slowly and steadily replaced the wooden stamp mills.
In the modern process, charcoal and sulfur are placed in a hollow drum along with heavy steel balls. As the drum rotates, the steel balls pulverize the contents; this device is called a ball mill. The saltpetre is crushed separately by heavy steel rollers. Next, a mixture of several hundred pounds of saltpetre, charcoal, and sulfur is placed in a heavy iron device shaped like a cooking pan. There it is continuously turned over by devices called plows, then ground and mixed by two rotating iron wheels, which weigh from 10 to 12 tons each. The process takes several hours; water is added periodically to keep the mixture moist.
The product of the mills is next put through wooden rolls to break up the larger lumps and is then formed into cakes under high pressure—namely, from about 210 to 280 kilograms per square centimetre (3,000 to 4,000 pounds per square inch) of pressure. Coarse-toothed rolls crack the cakes into manageable pieces and the corning mill, which contains rolls of several different dimensions, reduces them to the sizes desired.
Glazing (the next operation) consists of tumbling the grains for several hours in large wooden cylinders, during which friction rounds off the corners, and, aided by forced air circulation, brings the powder to a specified moisture content. The term glazing derives from the fact that graphite is added during this process, forming a thin film over the individual powder grains. Glazed powder flows more readily than unglazed powder and is more moisture resistant.
After glazing, the powder is graded by sieves into different sizes and packaged, usually in kegs.
Because the burning of black powder is a surface phenomenon, a fine granulation burns faster than a coarse one. Grain sizes are designated as F, 2F, etc., up to 7F, which is the finest, and from C up as the grains become larger. For the A powder the letter indicating the fineness becomes 3FA, etc., and if the powder is glazed, this is followed by the letter g—e.g., 3FAg. For many years the B blasting material was offered in pellet as well as granular form. Four pellets, each 5 centimetres (2 inches) in length and from 2.75 to 6.25 centimetres (1.1 to 2.5 inches) in diameter, were packed in waxed paper cartridges. Each pellet had a hole through its centre to accommodate a safety fuse or an electric device used to ignite the powder. Pelleted powder was used almost entirely in underground coal mines, but now regulations generally prohibit both it and the granular type.
Ignition of black powder
Black powder is relatively insensitive to shock and friction and must be ignited by flame or heat. In the early days such devices as torches, glowing tinder, and heated iron rods were used to ignite the powder and, in most cases, a train of the powder was led to the main charge in order to give the firer time to get to a safe place.
In cannons a small touchhole was drilled into the breech and filled with fine powder. Ignition of the charge was usually by means of a slow-burning punk. The same principle was employed in flintlockmuskets and rifles except that ignition resulted from sparks produced by contact between flint and steel.
Percussion methods of firing guns have long been in universal use. In the most common procedure, pulling the trigger releases a hammer, which strikes an impact-sensitive explosive mixture. This explosion then ignites the black powder or other powder charge.
Some black powder is still used as the propellant in guns in spite of the superiority of smokeless powder. Besides antique gun experts, who employ it mostly with hand-loaded shells and cartridges, hunters in South and Central America still use guns that require black powder.
In mining, a succession of crude means for ignition (fuses) included straws filled with pulverized black powder, reeds in which the pith was scooped out and replaced with a paste of powder and water (later bound with string and dried), or powder paste spread on wool threads. All of these fuses were ignited either by a piece of wool yarn impregnated with sulfur, called a sulfur mannikin, or some equivalent slow-burning device. A later, and extremely popular, type of fuse was formed of goose quills. The quills were cut so that they could be inserted one into the other and then filled with powder. Quill fuses could be ignited directly, that is, without any delaying element such as the sulfur mannikin. Unfortunately, their reliability was not high, and they often burned erratically.
A major contributor to progress in the use of explosives was William Bickford, a leather merchant who lived in the tin-mining district of Cornwall, England. Familiar with the frequency of accidents in the mines and the fact that many of them were caused by deficiencies inherent in the quill fuse, Bickford sought to devise an improvement. In 1831 he conceived the safety fuse: a core of black powder tightly wrapped in textiles, one of the most important of which was jute yarn. The present-day version is not very different from the original model. The cord is coated with a waterproofing agent, such as asphalt, and is covered with either textile or plastic.
The safety fuse provided a dependable means for conveying flame to the charge. Its timing (the time required for a given length to burn) was amazingly accurate and consistent, compared to that of its predecessors, and it was much better from the standpoints of resistance to water and abuse.
Underground coal mining was formerly by far the largest consumer of black powder. From a performance standpoint, it is probably the best explosive for that purpose. Its relatively gentle, heaving action gives a high yield of lump and leaves the coal in good position for rapid loading. Before the advent of oil, gas, and electric heating and cooking, coal was produced in tremendous quantities for household use and lump demanded a premium price. But black powder has a dangerous tendency to ignite coal gas (mostly methane) and coal dust, and many mine explosions occurred. About 1880 several European governments, seeking to develop safer substitutes for black powder, set up testing stations. Similar action was taken in the United States a few years later. The result was a series of special dynamites approved for use in gassy and dusty coal mines when used in the specified manner. Their blasting action was not as good as that of black powder, but they were much safer. These dynamites are discussed below.
The use of black powder in underground coal mines is no longer allowed in most countries. As a result, black powder production has decreased tremendously. Further, black powder is now more expensive than dynamite and is used only for special purposes. There is, for example, no substitute for black powder in certain military applications, and nothing equal to it has yet been found for the manufacture of the safety fuse. The fact that black powder is relatively nonshattering is of value in blasting certain types of stone.
Nitroglycerin, another chemical explosive, was discovered by an Italian chemist, Ascanio Sobrero, in 1846. Although he first called it pyroglycerin, it soon came to be known generally as nitroglycerin, or blasting oil. Because of the risks inherent in its manufacture and the lack of dependable means for its detonation, nitroglycerin was largely a laboratory curiosity until Immanuel Nobel and his son Alfred made extensive studies of its commercial potential in the years 1859–61. In 1862 they built a crude plant at Heleneborg, Sweden; Alfred, a chemist, was basically responsible for the design of this factory that was efficient and relatively safe considering the state of knowledge of the times. Nevertheless, it exploded in 1864 and killed, among others, Alfred’s youngest brother Emil Oskar. Although deeply affected by the accident, Alfred continued work, at first on a barge that he moored in the middle of a lake. In 1865 he erected a plant at Krümmel, Germany, and another in Sweden at Vinterviken near Stockholm. A third plant was built a year later in Norway. Nobel was granted a patent for the manufacture and use of nitroglycerin in the United States, in 1866, and since importation on a large scale was impractical, he visited the United States in an effort to interest local capital. The victim of a number of unscrupulous businessmen, he finally sold his American holdings in 1885 for only $20,000.
Even today most experts regard Nobel’s invention of the blasting cap, a device for detonating explosives, in 1865, as the greatest advance in the science of explosives since the discovery of black powder. Combined with Bickford’s safety fuse, the blasting cap provided a dependable means for detonating nitroglycerin and the many other high explosives that followed it. After a number of attempts that were only partially successful, Nobel settled on a charge of mercury fulminate, which had been known for many years, in a copper capsule. With one or two minor changes, this blasting cap remained in general use until the 1920s.
The second most important of Nobel’s inventions was dynamite, in 1867. He coined the name from the Greek dynamis, “power.” The basis for the invention was his discovery that kieselguhr, a porous siliceous earth, would absorb large quantities of nitroglycerin, giving a product that was much safer to handle and easier to use than nitroglycerin alone.
Dynamite No. 1, as Nobel called it, was 75 percent nitroglycerin and 25 percent guhr. Shortly after its invention, Nobel realized that guhr, an inert substance, not only contributed nothing to the power of the explosive but actually detracted from it because it absorbed heat that otherwise would have improved the blasting action. He turned, therefore, to active ingredients such as wood pulp for an absorbent and sodium nitrate for an oxidizing agent. By varying the ratio of nitroglycerin to these “dopes,” as they came to be called, Nobel not only improved the efficiency of dynamite but also was able to prepare it in varying strengths, termed straight dynamites. Thus 40 percent straight dynamite contained 40 percent nitroglycerin and 60 percent dope.
Nobel patented the use of active ingredients in dynamite in 1869. Several others obtained similar patents at about the same time, however, and the result was that no one could establish a clear-cut claim to the invention.
Nobel’s next outstanding contribution was his invention of gelatinous dynamites in 1875. There is a legend that he hurt a finger and used collodion, a solution of relatively low nitrogen content nitrocellulose in a mixture of ether and alcohol, to cover the wound. Later, unable to sleep because of the pain, Nobel went to the laboratory to find out what effect collodion would have on nitroglycerin. To his great satisfaction, he found that after evaporation of the solvents, there remained a tough, plastic material. He discovered that he could duplicate this by the direct addition of 7 to 8 percent of collodion-type nitrocotton to nitroglycerin and that lesser quantities of nitrocotton decreased the viscosity and enabled him to add other active ingredients. He called the original material blasting gelatin and the dope mixtures gelatin dynamites. The principal advantages of these products were their high water resistance and greater blasting action power than the comparable dynamites. This added power resulted from a combination of higher density and a degree of plasticity that allowed complete filling of the borehole (the hole that was bored in the coal seam or elsewhere for implantation of the explosive).
The first large-scale manufacture of nitroglycerin in the United States is attributed to George Mowbray, a chemist of considerable ability who had followed the work of Sobrero and others in Europe with great interest. Mowbray published an advertisement offering to supply nitroglycerin. This led to an invitation to manufacture it for completion of the Hoosac Tunnel at North Adams, Massachusetts. Mowbray’s plant was built near North Adams in the latter part of 1867. Most of its product went to the tunnel, but a substantial amount was shipped, frozen, throughout the eastern United States and Canada. Pure nitroglycerin, relatively insensitive in frozen form, freezes at about 11° C (52° F) and is, therefore, easy to keep frozen by packing it in ice. Before closing his plant down because of patent difficulties, Mowbray made about 450,000 kilograms (1,000,000 pounds) of nitroglycerin without accidents in either manufacture or shipment.
One of the earliest major uses of nitroglycerin in the United States was in blasting oil wells to increase the flow of oil. E.A.L. Roberts in that country obtained a patent covering this procedure and later acquired the right to manufacture and use nitroglycerin under the Nobel patents. Theoretically, this gave him a monopoly on shooting oil wells, and his company dominated the field, but many of his competitors ignored his patent rights.
After 1883 the use of nitroglycerin was, with a few unimportant exceptions, restricted to oil-well shooting. In recent years more efficient means have been developed for increasing oil flow. Nitroglycerin is still used occasionally because it is more economical in small wells.
Three tunnels stand out as benchmarks in the history of the use of explosives: first is Mont Cenis, a 13-kilometre (8-mile) railway tunnel driven through the Alps between France and Italy in 1857–71, much the largest construction job with black powder up to that time; second was the 6.4-kilometre (4-mile) Hoosac, also a railway project, during the construction of which (1855–66) nitroglycerin first replaced black powder in large-scale construction; third was the Sutro mine development tunnel in Nevada (1864–74) where the switch from nitroglycerin to dynamite for this type of work started.
After the straight dynamites and gelatins, the next important advance in dynamite was the substitution of ammonium nitrate for part of the nitroglycerin to give a safer and less expensive product. The use of ammonium nitrate in explosives had been patented by others in Sweden in 1867, but it was Nobel who made the new “extra dynamites” successful by devising gelatins that contained from 20 to 60 percent ammonium nitrate.
During the period 1867–84, many people worked to develop nongelatinous ammonium nitrate mixtures, but nothing of value resulted, largely because ammonium nitrate is too hygroscopic; that is, it picks up moisture too readily. In 1885 R.S. Penniman, an American, found a solution to the problem by coating the ammonium nitrate with a small percentage of paraffin, or some similar substance, prior to use. With this development a series of ammonia dynamites soon became popular. Coating was discontinued when other, safer means were developed to handle the moisture problem.
All major underground-coal-mining countries have similar explosives and regulations. In the United States explosives that have been approved by the U.S. Bureau of Mines for use in underground coal mines are called permissibles. Besides passing the Bureau’s safety tests, these explosives must be used in a manner specified by the Bureau. In England the explosives are known as permitted; in France, explosifs antigrisouteux; in Belgium, explosifs S. G. P. (sécurité, grisou, poussière); and in Germany, schlagwettersichere Sprengstoffe. Almost without exception the major ingredient in these explosives is ammonium nitrate, chosen because of its low explosion temperature, and nearly all of them contain a cooling agent such as sodium chloride (common salt) or ammonium chloride to prevent the heat of their explosion in a mine from igniting underground gases such as methane, or a combination of them and coal dust, and causing a fire or disastrous secondary explosion. The sensitizer is usually a small amount of nitroglycerin, but in some cases it is TNT, trinitrotoluene (discussed later); for example, it is said that a typical Russian permissible would be 68 percent ammonium nitrate, 10 TNT, 20 sodium chloride, and 2 powdered bark.
As synthetic ammonia became less expensive because of improvements in manufacture and a raw material change from coal to natural gas, the explosives industry concentrated its efforts on substituting ammonium nitrate for nitroglycerin. Two important products were (1) low-density ammonia dynamites and (2) semigelatins. Prior to their development, the density of most dynamites was about the same and was quite high. Strength was changed in the different grades by varying the amount of explosives used. The new concept was to employ the strongest formula possible, with a minimum of nitroglycerin and a maximum of ammonium nitrate, and to dilute it systematically with suitable low-density ingredients such as bagasse (the pulp remaining after extraction of sugar from the cane) so that one stick of the new product would give the same blasting action as one of the old. This provided a substantial saving to the user because the cost per stick of the new product was much lower.
The only difference between the low-density ammonia dynamites and the semigelatins is that the latter are partially gelatinized through the use of nitrocellulose and a higher nitroglycerin content. This gelatinization provides good water resistance and a degree of plasticity that is desirable in loading holes prior to blasting.
Means are available to obtain a moderate amount of water resistance in the ammonia dynamites without resorting to gelatinization of the nitroglycerin. The most common involve the use of water repellents, such as calcium stearate, and ingredients that form a water gel on the surface of the dynamite that slows down the further penetration of water. Examples of the latter are pregelatinized starch products and rye flour.
Attempts to reduce the freezing point of nitroglycerin began shortly after the Nobels introduced it commercially. Frozen dynamite is very insensitive, sometimes so much so that it will not give dependable performance, and it is difficult to use, since it cannot be punched for the insertion of a blasting cap or slit and tamped into a borehole. Consequently, almost all of it had to be thawed for use, and careless thawing methods caused many accidents. Not until 1907 was a reasonably successful procedure for producing low-freezing dynamite developed. This involved adding 20 to 25 percent of the liquid isomers (molecules with identical formulas but different structure) of TNT to the nitroglycerin. This was replaced for a short time by a nitrated solution of sugar in glycerin. In 1911 a practical way to manufacture diglycerin (a glycerin polymer) was discovered. Its nitration product, tetranitrodiglycerin, when mixed with nitroglycerin, reduced its freezing point materially.
The ultimate solution to the freezing problem was found in 1925, when synthetic ethylene glycol became available. The explosive properties of ethylene glycol dinitrate are practically identical with those of nitroglycerin, and its low-freezing qualities are extremely good. Dynamite containing a mixture of it and nitroglycerin was stored in the open at Point Barrow, Alaska, for four years without freezing.
Nitroglycerin, which was originally synthesized by Ascanio Sobrero, was used by Alfred Nobel to manufacture dynamite. It was in Nobel's dynamite factories in the late 1860s that the antianginal effect of nitroglycerin was discovered. Two interesting observations were made. First, factory workers on Monday mornings often complained of headaches that disappeared over the weekends. Second, factory workers suffering from angina pectoris or heart failure often experienced relief from chest pain during the work week, but which recurred on weekends. Both effects were attributed to the vasodilator action of nitroglycerin, which quickly became apparent to the physicians and physiologists in local communities. But what was the mechanism of this vasodilator action of the most powerful explosive chemical discovered in the nineteenth century? The answer to this question was not to come for another century. In the late 1970s and early 1980s, the vasodilator effect of nitroglycerin was discovered to be caused by nitric oxide (NO), which was apparently generated from nitroglycerin in vascular smooth muscle (1–4). These early observations on NO culminated less than 10 years later, in 1986, with the discovery that mammalian cells synthesize NO (5). In 1998, about 130 years after Alfred Nobel's invention of dynamite and the first observed clinical benefit of nitroglycerin, the Nobel Prize in Physiology or Medicine was awarded for “Nitric Oxide as a Signaling Molecule in the Cardiovascular System”. Despite these achievements, the precise molecular mechanism by which NO is generated from nitroglycerin remained elusive until the work of Chen et al. (6), reported in this issue of PNAS.
Previous studies showed that the bioactivation of nitroglycerin somehow involved thiols or sulfhydryl-containing compounds, and that NO or NO-containing compounds constituted the biologically active species (1–5, 7). The earliest studies suggested that an interaction between nitroglycerin and sulfhydryl (-SH)-containing cellular receptors was necessary for vascular smooth muscle relaxation to occur and that repeated administration of nitroglycerin caused sulfhydryl depletion (via oxidation) and consequent tolerance to further vasodilation (7–9). Subsequent studies addressing the activation of cytosolic guanylate cyclase by organic nitrate esters (nitroglycerin), organic nitrite esters (isoamyl nitrite), and nitroso compounds revealed that a chemical reaction occurred between the nitro compound and a thiol to generate an intermediate S-nitrosothiol, which then decomposed with the liberation of NO (3). Tolerance to nitroglycerin was explained simply by thiol utilization and depletion in the presence of excess nitroglycerin, thereby resulting in deficient production of S-nitrosothiol and NO. This working hypothesis was supported by animal and clinical studies showing that the administration of relatively large doses of cysteine or N-acetylcysteine could prevent or reverse the tolerance to the vasodilator action of repeated administration of nitroglycerin (see ref. 5). There were many unanswered questions associated with these earlier studies, however. The molecular mechanism of the interaction between nitroglycerin and thiol to generate S-nitrosothiol and NO remained an enigma. Moreover, the basis of the earlier hypotheses was activation of cytosolic guanylate cyclase in enzyme reaction mixtures and not vascular smooth muscle relaxation (3). Isolated enzyme reaction mixtures or broken cell preparations are very different from intact cells or tissues. The early work with cellular extracts did not address the likely possibility that the reaction between nitroglycerin and thiol might be enzymatic in nature. In fact, the evidence was in favor of a nonenzymatic chemical reaction (3). Subsequent studies suggested that one or more enzymatic mechanisms might be responsible for the bioactivation of nitroglycerin (10–16). However, none of these enzyme systems could catalyze the selective formation of 1,2-glyceryl dinitrate from nitroglycerin and no correlation could be found between tolerance to nitroglycerin action and tolerance to enzyme activities. The article by Chen et al. (6) uncovers the role of mitochondrial aldehyde dehydrogenase, which specifically generates 1,2-glyceryl dinitrate from nitroglycerin, in the bioactivation of nitroglycerin to elicit vasorelaxation and in the development of tolerance to nitroglycerin.
Chen et al. (6) used several ingenious approaches to elucidate the enzymatic mechanism of bioactivation of nitroglycerin: a source of large numbers of cells so that the lack of starting material would not be a limiting factor. By using mouse macrophages grown in cell culture, physiologically relevant, relatively low concentrations of nitroglycerin (0.1 μM) were shown to generate 1,2-glyceryl dinitrate through the catalytic action of an enzyme that was virtually identical to mouse mitochondrial aldehyde dehydrogenase. Mitochondrial aldehyde dehydrogenase purified from bovine liver showed identical catalytic properties to the mouse enzyme. Inhibitors of aldehyde dehydrogenase, such as cyanamide and chloral hydrate, blocked the formation of 1,2-glyceryl dinitrate from nitroglycerin. Aldehyde dehydrogenase possesses esterase activity (17) in addition to the classical NAD+-dependent dehydrogenation activity, and the catalytic action on nitroglycerin was analogous to its esterase activity, with the important exception that nitrite (NO2−) rather than nitrate (NO3−) was a product of the enzymatic reaction. Thus, these observations were in agreement with the earliest biological findings that nitroglycerin is metabolized by tissues to inorganic nitrite or NO2− (3–5, 7–9). The classical sulfhydryl requirement for vascular smooth muscle relaxation by nitroglycerin (7) was explained as a chemical reaction between nitroglycerin and thiol sulfhydryl group to generate an intermediate S-nitrosothiol species, which then decomposed with the liberation of NO (3). Other explanations and hypotheses were offered, but none of them could be replicated or confirmed across different tissues (18–19). Therefore, the selective conversion of 1,2,3-glyceryl trinitrate (nitroglycerin) to 1,2-glyceryl dinitrate plus nitrite, together with the dependence on a reducing thiol cofactor, made mitochondrial aldehyde dehydrogenase a compelling choice for the elusive enzyme pathway responsible for nitroglycerin bioactivation in vascular smooth muscle.
Repeated and prolonged administration of nitroglycerin and other organic nitrate esters causes the development of tolerance or desensitization of vascular smooth muscle to further vasorelaxation by nitroglycerin. This phenomenon has become a serious limitation to the chronic use of organic nitrate esters to treat angina pectoris. Understanding the molecular mechanisms associated with the development of “nitroglycerin tolerance” would undoubtedly lead to the discovery either of ways to avoid tolerance or of new NO-generating drugs that do not cause tolerance. The studies of Chen et al. (6) demonstrate that in vascular tissue made tolerant to the vasorelaxant effect of nitroglycerin, a comparable decrease occurs in both mitochondrial dehydrogenase activity and tissue cGMP accumulation. Consistent with this observation is the report that aldehyde dehydrogenase activity is markedly inhibited in patients undergoing chronic administration of nitroglycerin and other organic nitrate esters (20). These findings also are consistent with previous reports that nitroglycerin tolerance in patients can sometimes be overcome by administration of N-acetylcysteine (5, 21).
The authors reveal that mitochondrial aldehyde dehydrogenase functions also as a nitroglycerin reductase, where nitroglycerin acts as a substrate for the enzyme's reductase activity. As illustrated in Scheme 1 of the article (6), the authors suggest that nitroglycerin binds to one of the two cysteine sulfhydryl groups adjacent to the active-site thiol to form a thionitrite-enzyme complex intermediate plus the product 1,2-glyceryl dinitrate. Then, presumably, the NO2− is released from the thionitrite intermediate and is reduced to NO. These observations are analogous to the earlier views of a “thiol receptor model,” where nitroglycerin bioactivation required the presence of thiols, NO2− was generated as an intermediate (in the production of NO), and tolerance was explained as thiol depletion (3–5, 7–9). Since nitroglycerin was discovered to elicit vascular smooth muscle relaxation via mechanisms involving conversion to NO and stimulation of cGMP production, experiments were conducted to ascertain exactly how nitroglycerin and NO activate cytosolic guanylate cyclase (22). Using unpurified sources of enzyme, NO activated guanylate cyclase in the absence of further additions, whereas nitroglycerin required the addition of cysteine to cause the enzyme activation. Additional experiments revealed that nitroglycerin can undergo chemical reactions with cysteine to form NO2− and S-nitrosocysteine (3). Several S-nitrosothiols, including S-nitrosocysteine, were synthesized and found to activate guanylate cyclase in the absence of further additions. No other thiol (including DTT or glutathione) or reducing agent could substitute for cysteine in enabling nitroglycerin to activate guanylate cyclase. Interestingly, the reaction between nitroglycerin and cysteine to form NO2− occurred best at pH 9.6, which is near the pH optimum of mitochondrial aldehyde dehydrogenase. However, the pH-dependent chemical reaction between nitroglycerin and cysteine occurred in the absence of any aldehyde dehydrogenase or in the absence of any tissue extract, for that matter. Therefore, this reaction was a nonenzymatic reaction that was responsible for the activation of guanylate cyclase by nitroglycerin. These earlier observations taken together with the recent findings of Chen et al. (6) indicate that both enzymatic and nonenzymatic mechanisms may play roles in the bioactivation of nitroglycerin.
Several key questions arise from these findings. First, what is the role and precise effects of NAD+ in catalyzing the apparent organic nitrate ester reductase activity of mitochondrial aldehyde dehydrogenase? Second, what is the influence of NAD+ on the kinetic parameters associated with the organic nitrate reductase activity? Third, because glutathione does not “reactivate” the enzyme in vitro, what thiol is responsible for reactivation in vivo? Fourth, because nitroglycerin is well known to be a more potent and effective venodilator than arteriodilator, what are the differences in distribution and activities of mitochondrial aldehyde dehydrogenase in venous vs. arterial smooth muscle? Answers to these important questions will enable an even deeper understanding of the mechanism of nitroglycerin bioactivation.
The study of Chen et al. (6) teaches us that mitochondrial aldehyde dehydrogenase is at least partially responsible for the bioactivation of nitroglycerin and is likely to be the target of nitroglycerin tolerance. Moreover, by understanding the molecular mechanism of nitroglycerin bioactivation and tolerance, it may now be possible to design and develop novel nitrovasodilator drugs that do not cause tolerance. One approach might be to develop drugs that do not engage mitochondrial aldehyde dehydrogenase for the generation of NO. Ideally, the most appropriate kind of NO-donor drug might be one that is targeted to an enzyme that is selectively distributed to the vascular smooth muscle and acts as a substrate with only limited capacity to inhibit catalytic activity. Such a drug would be an effective vasodilator that could be used in combination with other drugs for the symptomatic treatment of hypertension. To be useful for the symptomatic treatment of angina pectoris, however, the drug would need to be targeted more to venous than arterial smooth muscle. Despite the desire to avoid tolerance, it may be a difficult task, indeed, to come up with an overall better antianginal drug than the 130-year-old nitroglycerin.
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