High Oxidative Stress Inhibits Production of Potent Blood Vessel Dilator in Men

Lower levels of a cofactor nitric oxide which is required to make potent blood vessel dilator are linked to higher levels of oxidative stress in men, reports a new study. The findings of the study are published in the journal Bioscience Reports. An antioxidant appears to help level the playing field between males and females of the cofactor BH deep inside the kidneys where the fine-tuning of our blood pressure happens and restore similar production levels of protective nitric oxide.

Higher nitric oxide levels help reduce blood pressure both by enabling dilation of blood vessels and increasing the kidneys' excretion of sodium, which decreases the volume in those blood vessels.

"BH has to be there," says Dr. Jennifer C. Sullivan, pharmacologist, and physiologist in the Department of Physiology at the Medical College of Georgia at Augusta University, who is exploring gender differences in hypertension. "We found that oxidative stress makes a big difference in BH? levels."

The study is the first to look at sex differences of BH in a rodent model of hypertension.

Male humans generally have higher blood pressures and oxidative stress levels than females, at least until menopause. The findings provide more evidence that the cofactor might be a novel treatment target for both sexes, says Sullivan, the study's corresponding author. BH, or tetrahydrobiopterin, is required for the precursor nitric oxide synthase to make nitric oxide. Oxidative stress, which results from high levels of natural byproducts of oxygen use, is known to reduce BH levels are implicated in high blood pressure and, at least before menopause; females tend to be less sensitive to it, possibly because of the protective effects of estrogen.

In an attempt to figure out why females, even in the face of hypertension, have more nitric oxide, the scientists measured BH levels in the innermost part of the kidney in male and female spontaneously hypertensive rats.

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"We found BH levels were higher in the hypertensive females than the hypertensive males," Sullivan says. Females also had more nitric oxide and lower but still high blood pressures, and the males had more oxidative stress.

They had previously shown that young spontaneously hypertensive female rats have significantly more nitric oxide and nitric oxide synthase activity in the inner portion of their kidney than their male hypertensive counterparts, and that difference holds as the rats mature. The new work helps explain why.

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"If we don't understand why females have more nitric oxide, we can't do things to potentiate our ability to make it," Sullivan says.

The scientists theorized and found that the elevated levels of oxidative stress in the males meant less BH, and ultimately less nitric oxide compared to females.

They found that reducing oxidative stress improved BH, levels and nitric oxide production and "normalized the playing fields between the two sexes," Sullivan says.

Pouring more BH on the situation, on the other hand, didn't work without reducing oxidative stress.

"If you have a ton of oxidative stress, you can give as much BH as you want, and all you are going to get is more BH," Sullivan says of BH's destructive counterpart and the unhealthy, vicious cycle it helps create.

Without BH, nitric oxide synthase becomes "uncoupled" and instead produces superoxide, which decreases nitric oxide production but also interacts with the nitric oxide that is available to form the oxidant peroxynitrite. Destructive peroxynitrite, in turn, targets the BH that is present, so it becomes BH?, which further interferes with BH's normal job of helping nitric oxide synthase make nitric oxide.

"You don't make the product you want nitric oxide synthase to make, which is nitric oxide," Sullivan says.

While it's not clear that females are any better of making BH, it is clear that the cofactor is easily altered by oxidative stress to become its unhealthy counterpart BH?, Sullivan says.

Giving both males and females the synthetic antioxidant treatment Tempol for two weeks is what leveled the gender field.

Bottom line: the antioxidant treatment essentially eliminated the sex differences in BH and nitric oxide synthase activity in that key region of the kidneys.

Males had higher blood pressure at baseline, and the antioxidant treatment did not affect the blood pressure of either sex. More work is needed to explore BH's treatment potential in both sexes, Sullivan says.

BH is widely available without a prescription, and its impact has been evaluated in many clinical trials including a current study at the University of Nebraska, Omaha, looking at its effect on blood flow and exercise capacity in patients with peripheral artery disease.

Source-Eurekalert