PT  - JOURNAL ARTICLE
AU  - L. A. CRANDALL, JR.
AU  - C. D. LEAKE
AU  - A. S. LOEVENHART
AU  - C. W. MUEHLBERGER
TI  - ACQUIRED TOLERANCE TO AND CROSS TOLERANCE BETWEEN THE NITROUS AND NITRIC ACID ESTERS AND SODIUM NITRITE IN MAN
DP  - 1931 Jan 01
TA  - Journal of Pharmacology and Experimental Therapeutics
PG  - 103--119
VI  - 41
IP  - 1
4099  - http://jpet.aspetjournals.org/content/41/1/103.short
4100  - http://jpet.aspetjournals.org/content/41/1/103.full
SO  - J Pharmacol Exp Ther1931 Jan 01; 41
AB  - 1. By the repeated administration to normal humans of erythrol tetranitrate, glyceryl trinitrate, ethylene glycol dinitrate, methyl nitrate, and amyl nitrite, we have developed tolerance to the headache producing action of these drugs, and to the changes which they produce in blood pressure and pulse rate. 2. Tolerance to headache producing action is more easily established than is tolerance to effects on blood pressure and pulse rate. 3. Cross tolerance has been shown to exist between most of the above substances, and it is believed that there is a complete cross tolerance between all members of this group. 4. It has been impossible to develop tolerance to sodium nitrite by repeated administration of large doses over four days in man, or over five days in the dog. When tolerance has been produced by a nitric acid ester the blood pressure and pulse rate response to a moderate dose of sodium nitrite is greatly decreased. 5. There is no cross tolerance between these drugs and histamin, a substance producing similar effects but which is chemically unrelated to the nitrites. 6. Tolerance is most readily developed by amyl nitrite, then with increasing difficulty by methyl nitrate, ethylene glycol dinitrate, glyceryl trinitrate, and erythrol tetranitrate. A partial relationship between ease of tolerance development and ease of hydrolysis by alkali is pointed out. 7. A tolerance to the headache effect of a dose which will produce a moderate headache decreases gradually and usually disappears completely in ten to twelve days. 8. It was found that the tolerance could be maintained at a constant level by the daily administration of the dose to which the individual was tolerant. 9. As the degree of tolerance was increased there was no change in the ease or difficulty of its production. 10. The tolerance is not due to decreased absorption, but is present to equal degree no matter what the route of administration of the nitrite.