Role of nitrite in regulation of fetal cephalic circulation in sheep

Key points Recent evidence in adult humans demonstrates that nitrite, at physiological concentrations, can be converted into vasodilating amounts of NO, thus constituting an alternative to NO production by NO synthases. Nitrite reacts with deoxyhaemoglobin to produce NO, a reaction proposed to mediate the vasodilating effects of nitrite. We have demonstrated previously that the rate of this reaction is ∼2‐fold faster with fetal haemoglobin than adult haemoglobin. Thus, we hypothesized that nitrite would be a potent vasodilator in the cephalic vasculature served by the carotid artery in the fetal sheep. In conflict with human adult forearm studies, we find that nitrite is not a vasodilator in the fetal sheep cephalic vasculature, despite the fact that nitrite is converted to NO more efficiently by fetal haemoglobin. The results suggest that the vasodilatory effects of nitrite are age‐ and species‐specific, and that the reaction of nitrite with deoxyhaemoglobin is not rate limiting with respect to its ability to decrease vascular tone. Abstract Nitrite has been postulated to provide a reservoir for conversion to nitric oxide (NO), especially in tissues with reduced oxygen levels as in the fetus. Nitrite would thus provide local vasodilatation and restore a balance between oxygen supply and need, a putative mechanism of importance especially in the brain. The current experiments test the hypothesis that exogenous nitrite acts as a vasodilator in the cephalic vasculature of the intact, near term fetal sheep. Fetuses were first instrumented to measure arterial blood pressure and carotid artery blood flow and then studied 4–5 days later while in utero without anaesthesia. Initially l ‐nitro‐arginine (LNNA) was given to block endogenous NO production. Carotid resistance to flow increased 2‐fold from 0.54 ± 0.01 (SEM) to 1.20 ± 0.08 mmHg min ml −1 (in 13 fetuses, P < 0.001), indicating NO tonically reduces cerebral vascular tone. Sodium nitrite (or saline as control) was then infused in increasing step‐doses from ...