The veins are also somewhat relaxed, but this has not been shown to have any therapeutic importance.

The Heart

On the isolated heart ordinary doses have no effect, whether the ends of the vagus and accelerator nerves are paralyzed or not. But larger doses depress the vagus, and therefore tend to increase the tone and contractility of the heart.

With the fall in arterial pressure from an ordinary dose the heart's rate is accelerated, and after amyl nitrite may increase 20 or 30 beats a minute. The increase is due to vagus depression, for if the vagus endings are first paralyzed by atropine, the nitrite does not cause any additional increase in the rate of the heart. The question arises, "Is the vagus depression due to the direct action of the drug upon the center, or is it the regular reflex depression which accompanies lowered arterial pressure?" Sollmann brings forward some evidence that it is due to direct depression of the vagus center by the drug. He finds that if the drug is allowed to act upon the general circulation, but prevented from reaching the brain, there is no increase in rate, though the general arterial pressure is lowered; and if the drug is confined to the cerebral circulation, the increased rate occurs without a lowering in the general arterial pressure; other pharmacologists, however, consider it secondary to the fall in pressure.

The effects of nitrites upon the circulation are, therefore - (1) Depression of the arterial muscles, resulting in dilatation of 16 the arteries; (2) increased rate of the heart's beat; (3) perhaps increased tone and strength of the heart.

With all the stronger members of the series, the arterial pressure shows a marked fall, and then gradually returns almost or entirely to where it was before. But the drugs differ in their rapidity of action.

Amyl nitrite is given by inhalation. The arterial pressure in normal animals falls to the maximum degree almost instantly, rises again to the original pressure in two to five minutes, and shows complete restoration in from fifteen to twenty minutes. In human cases with systolic pressure above 200 mm. Hg the author has found that after 5 minims of amyl nitrite the change in pressure varies considerably. It might drop as much as 70 mm., to rise again almost to the original height in about five minutes. But so marked a fall in pressure is unusual, the change being mostly between 20 and 40 mm. In some of these high-pressure cases the response is very little, and in a few cases there is actually a rise in pressure of 10 to 20 mm. The action of amyl nitrite is too fleeting for use except in emergencies.

Nitroglycerin is given by mouth or hypodermatically, and in either case is almost instantly absorbed. The fall in pressure begins in one-half to three minutes, reaches its maximum in five to fifteen minutes, and disappears in one-half to one hour. In conditions of general arteriosclerosis the effect sometimes lasts several hours, and sometimes there is no change in pressure at all.

Sodium nitrite is given by mouth, and is less rapidly absorbed. It has been reported by G. A. Gibson and others as less effective than nitroglycerin, but recently several investigators (Matthews, and Wallace and Ringer, and Lawrence) have found it just as active as the other preparations, though slower in its action. Its effects come on in five to thirty minutes, reach their maximum in twenty to eighty minutes, and are completely over in one to two hours. In solution the nitrite changes to nitrate on exposure to air, and this may account for the adverse clinical reports.

Erythrol tetranitrate is administered by mouth, and is likely to be more slowly absorbed and more slowly decomposed by the blood. As a consequence, its effects are more gradual in their development. The drop in pressure begins in five to thirty minutes, reaches its maximum one-half hour to two hours later, and disappears in two to five hours.

Mannitol hexanitrate has an effect about the same as that of erythrol.

Wallace and Ringer found that with any member of the series the greater the dose, the greater was the fall in pressure. In one of their cases 1/80 grain of nitroglycerin reduced the pressure from 210 to 60 mm. Hg in ten minutes, the pressure rebounding to 168 mm. in four minutes, and reaching its original figure in fifty minutes. In another patient sodium nitrite caused the pressure to fall from 210 to 100 mm. In cases with high arterial pressure the author has never secured such striking results, even from the administration of 1/50 grain of nitroglycerin hypodermatically every two minutes for five doses.

Blood

After enormous doses the hemoglobin is reduced and its power of liberating oxygen lessened by the formation of methemoglobin and nitric oxide hemoglobin. But in the therapeutic use of the drug this reduction is never enough to produce ill effects, and even after very large therapeutic amounts no methemoglobin has been present in the blood.

Respiratory System

The nitrites stimulate the respiratory center, so that breathing is deeper and more rapid. This may be because of increased supply of carbon dioxide from improved medullary circulation. From very large doses there is later a depression of the center and asphyxia. In bronchial asthma nitrites may be effective in overcoming the spasm of the bronchial muscles. This is a direct muscular effect, and is not antagonistic to the action of epinephrine in the same condition. (When amyl nitrite is inhaled, it may cause a momentary reflex stoppage of respiration from irritation of the respiratory passages, but this is of no significance, for the respiration goes on again immediately.)

Cerebrum

There is no direct action on the brain structures. The cerebral arteries are dilated along with all others, and either because of this or of the general fall in pressure, there may be, after amyl nitrite or nitroglycerin, dizziness, blurring of the sight, and a momentary faintness. Frequently after nitroglycerin and erythrol tetranitrate there is such severe occipital headache that the administration requires to be stopped. In animal experiments convulsions of cerebral origin have been noted after large doses.