A sharp paroxysmal pang of recurrent chest pain thatspreads down the left arm is the hallmark of anginapectoris. Those Latin words mean, literally, chest pain.

To cardiologists and their patients they signify the heartmuscle protesting a shortage of oxygen, brought on bytightening of the blood vessels that deliver O2.

For over a century, the quick fix for angina pectoris hasbeen a dose of nitroglycerin. In two or three minutes, atablet under the tongue dilates the body's blood vessels_ arteries, veins, capillaries. The expanded bloodpipeline relaxes the up-tight pumping pressure, easing thepain till the next time.

Since soon after an Italian chemist discoverednitroglycerin in 1846, military men, mining engineers(and lately, rocket scientists) have known it as a primeingredient of modern explosives. The perilously unstablecompound, C3H3(CNO2)3, liberates nitric oxide (NO) _either explosively or medically.

Yet "it's only within the last decade or so," observescardiologist and molecular biologist Paul Huang, "thatwe've learned how it works. I think the understandingevolved over the last 10 years," he told BioWorld Today,"that NO is a gas, and not very stable. Therefore," Huangexplained, "there has to be a way to store it in tissues. Itdoes this by binding to proteins or sulfur compounds,called thiols, and these nitrosothiols then release NO inthe blood vessels."

Huang, who runs an NO-focused lab at MassachusettsGeneral Hospital in Boston, continued: "We also knowthat the amount of NO that blood vessels make goesdown in certain human conditions _ diabetes,atherosclerosis, high blood pressure, even normal aging."

Researchers in this field, he observed, "havehypothesized that this decrease in NO production isresponsible for some of these blood-vesselabnormalities."

Mice Minus NO Have High Blood Pressure

To confirm one aspect of this supposition, Huang and hisco-workers created a strain of knockout mice unable togenerate nitric oxide in their blood vessels. The report oftheir project appears in the current Nature, dated Sept. 21,1995, under the title: "Hypertension in mice lacking thegene for endothelial nitric oxide synthase."

Neuroscientist Solomon Snyder of Johns HopkinsUniversity School of Medicine in Baltimore wrote aneditorial accompanying the Nature paper, of which Huangis first author.

"Knockout mice have been very powerful tools," Snydertold BioWorld Today, "in getting definite answers to thefundamental question: How important is NO in regulatingblood-vessel function?" He pointed out: "If NO is reallyimportant, then drugs that act on NO will be important."

Snyder chairs the scientific advisory board of GuilfordPharmaceuticals Inc., which he co-founded in 1993 as aspin-off of Scios Nova Inc., in Mt. View, Calif.

He recalled that "Most of the research in this field to thepresent time has used inhibitors of NO synthase (NOS),the enzyme that produces nitric oxide. These inhibitorsraise blood pressure," Snyder continued, "so people say,`Obviously, therefore, NO must normally relax vessels,which it does, and lower blood pressure.'"

But it's not that simple, he explained, "NOS enzymescome in three cell-identified forms, endothelial (blood-vessel walls), neuronal and macrophage. These threeisoforms differ in sequence by about 50 percent of theiramino acids.

"It's conceivable," Snyder observed, "that some of theeffects on all the inhibitors weren't by the endothelialenzyme. If so, that would have implications for drugdevelopment, because the big goal is to getpharmaceuticals that will affect the three different formsselectively to know for sure the relative contributions ofthe endothelial and neuronal forms."

Until now, Snyder said, "there haven't been drugs thatinhibit them selectively. But now we have knockout micefor each of the three forms, which works out nicely."

Huang, the Nature paper's first author, and its seniorauthor, Mark Fishman, are both cardiologists. Beforeconstructing the knockout mouse for the endothelialisoform of the NOS enzyme, they and Snyder togethercreated an NO-minus knockout for the neuronal form."So of course," observed the Hopkins neuroscientist,"one obvious question is to have mice in which you'veknocked out both of the enzymes."

Next Research Job For Murine Models: Atherosclerosis

Huang said that "our endothelial knockouts, whichnaturally have no NO production in their blood vessels,and so are hypertensive, will hopefully be useful to studydiabetes, atherosclerosis and high blood pressure. Ouraim now," he added, "is to use them in elucidating theatherosclerotic process."

His work is supported in part by a sponsored researchagreement between Bristol-Myers Squibb of New Yorkand Fishman, who is director of Massachusetts General'sCardiovascular Research Center.

It seems that NO _also known as nitrogen monoxide _is not the only hypertension-abating gaseous hormone atwork in the body. Snyder is scrutinizing carbonmonoxide _ CO _ for similar effects.

"The paper on which I'm working right now," he toldBioWorld Today, provides strong evidence. The enzymethat makes CO, heme oxygenase, is also in theendothelium, and the drugs that block its formation alsoreverse blood-vessel relaxation."

Snyder will present his CO findings to the 25th annualmeeting of the Society for Neuroscience, this Novemberin San Diego.

He explained that "Carbon monoxide kills you because itbinds to the iron in heme of hemoglobin, so it can't bindoxygen." By a comparable but metabolically controlledenzymatic process, he added, "CO relaxes blood vesselsin exactly the same way"

There are indications, Snyder said, "that nitric oxide andcarbon monoxide may act in concert throughout the body.Mice with knockouts of genes for the respectivebiosynthetic enzymes," he proposed, "should clarify thepossibly synergistic functions of these two mediatormolecules." n

-- David N. Leff Science Editor

(c) 1997 American Health Consultants. All rights reserved.

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