DURHAM, N.C.-Few disorders these days are avoiding a go with NO.
Long snubbed as an ozone-destroying pollutant, nitric oxide has emerged as an endogenous gas crucial in tiny puffs for vasodilation, neurotransmission, and immunity. Drugmakers predict a blockbuster in NO and its three isoenzymes-nNOS (neuronal), eNOS (endothelial), and iNOS (inducible).
They’re pursuing studies that suggest NO-based therapies may help neonatal persistent pulmonary hypertension, stroke-induced ischemia, adult respiratory-distress syndrome, septic shock, post-angioplasty restenosis, and impotence, to name but a few.
The gas is found in cells in blood vessels, the CNS, peripheral nerves, adrenals, cardiac myocytes, kidney epithelium, liver, and lung. NO has “turned upside down our concepts of perfusion regulation, and changed our idea of cell-to-cell interaction and some basic concepts of nonspecific immunity,” says Dr. Salvador Moncada of University College London.
This year Duke’s Dr. Jonathan Stamler reported that hemoglobin not only mops up and inactivates NO, but hemoglobin also has other NO receptors that relax vessels for oxygen delivery. NO combines with cysteine to foster allosteric changes that promote oxygen uptake.
It was just over a decade ago that a few researchers got wind of endogenous NO synthesized from L-arginine. Dr. John Hibbs of the University of Utah saw nitrite and nitrate, end products of NO metabolism, in macrophages, a clue the gas might be bactericidal or tumoricidal.
In 1986, UCLA’s Dr. Louis Ignarro and SUNY Brooklyn’s Dr. Robert Furchgott independently proposed that endothelium-
derived relaxing factor was NO or another agent spewing it. Most found this hot air. Not Dr. Moncada. Independently, he and Dr. Ignarro proved EDRF’s identity and launched a now crowded race to create NO-based therapies.
There have been glitches, primarily with targeting NO. A 1992 UCSF study of a penile NO injection to trigger erections also led to plunging blood pressure and syncope.
There have also been successes. Because the labile gas wafts through the lung without systemic effects, inhaled NO has been used to control pulmonary hypertension among term newborns. Some 50% to 60% of neonates show an immediate response to NO. And in four multicenter randomized trials it cut the need for extracorporeal membrane oxygenation by a third.
In one trial, 80 ppm of inhaled NO boosted oxygenation in 14 of 25 term newborns, vs. two of 25 for conventional ventilation. No babies getting NO suffered systemic hypotension, says Yale’s Dr. Ian Gross.
In a Harvard study, inhaled NO gave speedy benefit to 26 newborns, increasing oxygenation within 15 minutes and boosting blood-oxygen levels within 12 hours. Slower improvements were seen among 23 controls. Only four NO babies had seizures or hemorrhage vs. eight controls.
So far no long-term toxicity has been detected. But the University of Colorado’s Dr. John Kinsella advises doses no higher than 20 ppm fearing toxic effects above 40 ppm.
In a controlled trial of more than 200 newborns, iNOS was “very effective” in improving outcomes, says Dr. Kinsella.
Among other cardiovascular uses, Dr. Stamler has been eyeing a revved-up tPA, using nitrosylated tPA to vasodilate as it lyses thrombi.
At the University of Pittsburgh, Dr. Timothy Billiar is looking at an iNOS gene transferred into the vessel wall by a viral vector to halt restenosis after angioplasty or CABG. Initial studies suggest the gene prevents proliferation of smooth muscle cells, prompts local dilation, and inhibits platelet and leukocyte adherence.
Columbia’s Dr. Mehmet Oz says NO prevents coronary spasm in newly reperfused heart grafts. And a rat study found NO for donor lungs hiked cGMP by 38%, suggesting better blood flow and lung viability, says Dr. Yoshifumi Naka, a colleague. He feels NO for recipients can be useless or toxic during reperfusion because of a superoxide cocktail.
Harvard’s Dr. Jeffrey Drazen supposes NO may be a marker for asthma because patients exhale increased levels that drop with treatment.
As a neurotransmitter, NO breezes in between synapses. Flaws may prompt memory or other neurological disorders. The surge of glutamate after strokes sparks an influx of calcium that activates NO synthase. The NO burst damages DNA and kills cells.
Guilford Pharmaceuticals, founded by Johns Hopkins’ Dr. Solomon Snyder, is developing drugs to block brain NO. That’s based on findings that knockout mice lacking brain NO synthase had much less ischemic damage after strokes than controls.
For impotence, UCLA urologist Jacob Rajfer says the key is to create a pill-rather than the current injection-that distinguishes penile vessels from other peripheral vessels.
But he has big competition from the NO-based erection-inducing pill sildenafil (Viagra, Pfizer), aimed originally at angina. In a placebo-controlled study of 351 patients, 88% of impotent men getting 50 mg of sildenafil reported improvement in erections.
Apex Bioscience is testing an NO scavenger to prevent septic shock. Pyridoxylated hemoglobin polyoxyethelene conjugate, or PHP, first developed as a blood substitute, is aimed at normalizing mean arterial pressure and systemic vascular resistance. Another septic-shock inhibitor is being studied in a 300-patient trial sponsored by Glaxo Wellcome.
-Randi Hutter Epstein
DURHAM, N.C.-Few disorders these days are avoiding a go with NO.
Long snubbed as an ozone-destroying pollutant, nitric oxide has emerged as an endogenous gas crucial in tiny puffs for vasodilation, neurotransmission, and immunity. Drugmakers predict a blockbuster in NO and its three isoenzymes-nNOS (neuronal), eNOS (endothelial), and iNOS (inducible).
