Neurons release nitric oxide (NO) in response to activation of receptors for the excitatory amino acid N-methyl-D-aspartate (NMDA). We examined the hypothesis that activation of receptors for NMDA produces dilatation of the cerebral microcirculation that is mediated by NO. Diameters of cerebral arterioles were measured using a closed cranial window in anesthetized rabbits. Under control conditions, topical NMDA produced concentration-related dilatation of pial arterioles. Dilatation in response to NMDA was inhibited selectively by MK-801 (an NMDA receptor antagonist) and tetrodotoxin, suggesting that responses to NMDA were receptor mediated and dependent on neuronal activation. Increases in arteriolar diameter in response to NMDA were not affected by L-arginine but were inhibited by NG-nitro-L-arginine, suggesting that the vasodilatation was mediated by NO. Dilatation of cerebral arterioles in response to NMDA was not inhibited by indomethacin, suggesting that cyclooxygenase products do not mediate the response. Using isolated cerebral arteries, we also examined whether NMDA elicited direct cerebral vascular effects. In intact arteries studied in vitro, NMDA had no effect on vascular tone, suggesting that cerebral arteries lack receptors for NMDA. These findings suggest that NO generated in response to activation of receptors for NMDA in vivo is neuronally derived and not due to a direct vascular effect. Thus, NO may mediate increases in local blood flow during increases in neuronal activity in response to excitatory amino acids.

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Objective Determine the efficacy and safety of high dose vitamin D supplementation for ARI prevention in older long-term care residents. Design, Setting, and Participants Randomized controlled trial investigating high dose vs standard dose vitamin D conducted from 2010–2014. Participants were older residents (≥60 years) of Colorado long-term care facilities. Interventions 1) The high dose group received monthly supplement of 100,000 IU vitamin D3; 2) The standard dose group received either a monthly placebo (for participants taking 400–1,000 IU/day as part of usual care) or a monthly supplement of 12,000 IU of vitamin D3 (for participants taking <400 IU/day as part of usual care). Main Outcomes Incidence of ARI during the 12-month intervention. Secondary outcomes included falls/fractures, 25-hydroxyvitamin D levels, hypercalcemia, and kidney stones. Results We randomized 107 participants (55 high dose, 52 standard dose) and included all in the final analysis. The high dose group had 0.67 ARIs per person-year compared to 1.11 in the standard dose group (incidence rate ratio [IRR] 0.60; 95%CI 0.38–0.94; p= 0.02). Falls were more common in the high dose group (1.47 per person-year) compared to 0.63 in the standard dose group (IRR 2.33; 95%CI 1.49–3.63; p<0.001). Fractures were uncommon and similar in both groups (high dose 0.10 vs standard dose 0.19 per person-year; p=0.31). The mean 25-hydroxyvitamin D level during the trial was 32.6 ng/mL in the high dose group and 25.1 ng/mL in the standard dose group. There was no hypercalcemia or kidney stones in either group. Conclusion Monthly high dose vitamin D3 supplementation reduced the incidence of ARI in older long-term care residents but was associated with a higher rate of falls without an increase in fractures.

Thus, activation of glibenclamide-sensitive potassium channels may contribute to dilatation of cerebral arterioles during hypercapnia. Cerebral vasodilatation during hypercapnia is dependent in large part on production of nitric oxide.

Nitric oxide (NO) or related nitroso compounds are an endothelium-derived relaxing factor (EDRF), originating from metabolism of L-arginine, L-Arginine analogues with chemically altered guanidino moity are potent and specific inhibitors of EDRF(NO) release. We evaluated effects of two L-arginine analogues, NG-monomethyl-L-arginine (L-NMMA, 100 microM) and N omega-nitro-L-arginine (L-NARG, 30 microM), on acetylcholine-, substance P-, and nitroglycerin-induced relaxation in the blood-perfused rabbit hindlimb in vivo and femoral arteries in vitro. L-NMMA and L-NARG selectively inhibited the vasodilator response to acetylcholine in rabbit femoral arteries in vitro, whereas endothelium-independent response to nitroprusside increased. L-NMMA (1.6 mg/min ia) in the blood-perfused rabbit hindlimb in vivo increased vascular resistance in the hindlimb by 23 +/- 3% (means +/- SE; n = 10) but did not inhibit the vasodilator responses to acetylcholine or substance P. L-NARG (10 mg/kg iv) increased systemic blood pressure by 26 +/- 3% (n = 7) and vascular hindlimb resistance by 22 +/- 9% (n = 8), and blood flow to hindlimb musculature, measured with microspheres, decreased by 46 +/- 5% (n = 6). Pretreatment with L-NARG, however, did not impair vasodilator responses to acetylcholine and substance P. These findings are consistent with the view that basal tone in resistance vessels in the rabbit hindlimb may be mediated by nitroso compounds, whereas agonist-stimulated vasodilation may be mediated by other mechanisms that do not involve the NO-synthesizing enzyme.