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only minor lack of the enzyme: homozygous mutant animals have stomachs with 1.5 3ð the stomachs of littermates and pyloric stenosis. They grow normally and breed at normal levels. Their brains appear normal. Except for the NOS, they appear to have the usual enzymes and the mutant mice seem to have the expected functions. Vasodilation of vascular penile beds does not depend upon the bNOS and the animals mate normally.
Prior to knockout mice, a number of neural functions were ascribed to NO function. The fact that these have not appeared does not mean that the functions do not exist but that more than one function can apply. Thus, in penile tissue of rates NOS nerves are prominent144 and electrical stimulation produced penile erection145,146. Normal mating of knockout mice suggests that this function can take place without NO participation, but this leaves the NO function to be assigned to an auxiliary role, perhaps to play a more important role when the alternative neuroexciter is deficient. Similarly, Huntington and Alzheimer diseases might occur when two different neurotransmitters are deficient.
The second mice to undergo a deficiency of iNOS were produced by MacMicking’s group147. These animals were again, like the bNOS, grossly normal. When tested against certain toxic elements (Listeria, lymphoma cells), the iNOS were more susceptible, showing that the NO produced had an effect but was not the difference that some of the experimenters had anticipated. Testing against septic shock, the drop in arterial pressure was only 15% in 2 hours with LPS and the animals survived whereas wild-type mice lost 64%, of the arterial pressure and all died. However, the death due to killed Propionobacterium acne, a granuloma-forming bacterium, was the same for mutant and wild-type mice. In this case it is clear that the NO does not deal with all of the functions of live bacteria and that iNOS can affect only those properties protected against by NO.
The third eNOS has very recently been knocked out in mice in work that has yet to be published by P. L. Huang. Although he cannot give the data of the paper, he indicates that the animals are fertile and that they have higher blood pressure than their littermates. Since this form of NOS is primarily concerned with blood pressure, this is the feature that is emphasized in the preliminary paper.
Within the past two years, NOS has been shown in a variety of invertebrates, from slime molds148 through molluscs149. The exact function of NO in invertebrates is still unknown and is part of the puzzle of the purpose of this material in biology. According to Nathan and Xie150, it is quite within the scope of biology for some modifications to be met on purification of the invertebrate enzymes. The nomenclature of the mammalian enzymes studied in the present situations is suggested by these authors to be mathematical in place of alphabetical. Thus bNOS, or ncNOS, would be referred to as I, iNOS would be called II and eNOS, or ecNOS, would be called III.
IX. CONCLUSIONS
From 1987 until now only a few years have passed, but in that time a new physiological mediator has been found, NO. In this short time the three enzymes that individually mediate this reaction in mammals have been characterized and the occurrence of similar enzymes in invertebrates have been determined. It is not only new, but surprising, that this physiological agent is a gas that is formed in one cell and spreads its function to nearby cells, but that its function is limited by oxidation. In the case of brain, Verma and coworkers151 have recently suggested that carbon monoxide may be a similar activator of cGMP. The period of surprises is not yet over.
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