Tetrahydrobiopterin Is Present in High Quantity in Human Milk and Has a Vasorelaxing Effect on Newborn Rat Mesenteric Arteries

Weinmann, Ângela Regina Maciel; Post, Martin; Pan, Jingyi; Rafi, Mahroukh; O'Connor, Deborah L; Unger, Sharon; Pencharz, Paul B.; Belik, Jaques

doi:10.1203/pdr.0b013e31820bc13a

Cited by 15 publications

(9 citation statements)

References 23 publications

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“…Breast milk, as opposed to infant formulas, has a high BH4 content (46), and IHPS rarely occurs in infants that are exclusively breastfed (24). However, in a small study involving only six infants, BH4 supplementation failed to reverse the IHPS clinical manifestations (8).…”

Section: Discussionmentioning

confidence: 96%

Infantile hypertrophic pyloric stenosis (IHPS): A study of its pathophysiology utilizing the newborn hph-1 mouse model of the disease

Welsh

Shifrin

Pan

et al. 2014

American Journal of Physiology-Gastrointestinal and Liver Physi

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Welsh C, Shifrin Y, Pan J, Belik J. Infantile hypertrophic pyloric stenosis (IHPS): A study of its pathophysiology utilizing the newborn hph-1 mouse model of the disease. Am J Physiol Gastrointest Liver Physiol 307: G1198 -G1206, 2014. First published October 30, 2014 doi:10.1152/ajpgi.00221.2014.-Infantile hypertrophic pyloric stenosis (IHPS) is a common disease of unknown etiology. The tetrahydrobiopterin (BH4)-deficient hyperphenylalaninemia-1 (hph-1) newborn mouse has a similar phenotype to the human condition. For hph-1 and wild-type control animals, pyloric tissue agonist-induced contractile properties, reactive oxygen species (ROS) generation, cGMP, neuronal nitric oxide synthase (nNOS) content, and Rhoassociated protein kinase 2 (ROCK-2) expression and activity were evaluated. Primary pyloric smooth muscle cells from wild-type newborn animals were utilized to evaluate the effect of BH4 deficiency. One-week-old hph-1 mice exhibited a fourfold increase (P Ͻ 0.01) in the pyloric sphincter muscle contraction magnitude but similar relaxation values when compared with wild-type animals. The pyloric tissue nNOS expression and cGMP content were decreased, whereas the rate of nNOS uncoupling increased (P Ͻ 0.01) in 1-wk-old hph-1 mice when compared with wild-type animals. These changes were associated with increased pyloric tissue ROS generation and elevated ROCK-2 expression/activity (P Ͻ 0.05). At 1-3 days of age and during adulthood, the gastric emptying rate of the hph-1 mice was not altered, and there were no genotype differences in pyloric tissue ROS generation, nNOS expression, or ROCK-2 activity. BH4 inhibition in pyloric smooth muscle cells resulted in increased ROS generation (P Ͻ 0.01) and ROCK-2 activity (P Ͻ 0.05). Oxidative stress upregulated ROCK-2 activity in pyloric tissue, but no changes were observed in newborn fundal tissue in vitro. We conclude that ROSinduced upregulation of ROCK-2 expression accounts for the increased pyloric sphincter tone and nNOS downregulation in the newborn hph-1 mice. The role of ROCK-2 activation in the pathogenesis of IHPS warrants further study. superoxide; Rho-associated protein kinase; smooth muscle SPHINCTER TONE IS DETERMINED by the balance between the neuronal nitric oxide (NO) synthase (nNOS)-dependent relaxant and the Rho-associated protein kinase 2 (ROCK-2)-dependent contraction effects. nNOS is the most abundant NOS isoform in gastrointestinal smooth muscle (42), and its NO generation potential depends on the coupled dimeric state of the enzyme. When uncoupled, nNOS predominantly generates reactive oxygen species (ROS) (11,37,42).Infantile hypertrophic pyloric stenosis (IHPS) is a relatively common disease affecting 2 in 1,000 live births (34) and manifesting clinically at 3-6 wk of age. The IHPS etiology and pathogenesis are unknown, but the increased sphincter tone is believed to be related to reduced pyloric tissue nNOS expression (2) and the resulting lower NO generation (13,34,45). Several experimental animal models of the condition have been studied...

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Section: Discussionmentioning

confidence: 96%

Infantile hypertrophic pyloric stenosis (IHPS): A study of its pathophysiology utilizing the newborn hph-1 mouse model of the disease

Welsh

Shifrin

Pan

et al. 2014

American Journal of Physiology-Gastrointestinal and Liver Physi

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“…Transfusion has been shown to impair this postprandial increase in blood flow velocity in the superior MA (15). Circulating catecholamines (16,17), the sympathetic system, and endothelin (6) are considered to be primary constrictors of the mesenteric circulation. Therefore, we used NE and ET-1 as the constricting agents for isolated mesenteric arterial ring studies.…”

Section: Discussionmentioning

confidence: 99%

Packed red cell transfusions alter mesenteric arterial reactivity and nitric oxide pathway in preterm lambs

et al. 2013

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BACKGROUND Cases of necrotizing enterocolitis occurring within 48 h of packed red blood cell (PRBC) transfusions are increasingly being described in observational studies. Transfusion-associated gut injury is speculated to result from an abnormal mesenteric vascular response to transfusion. However, the mechanism of disruption of the balance between mesenteric vasoconstriction and relaxation following transfusion is not known. METHODS Preterm lambs (n = 16, 134 d gestation; term: 145–147 d) were delivered and ventilated for 24 h. All the lambs received orogastric feeds with colostrum. In addition, 10 of these lambs received PRBC transfusions. Vasoreactivity was evaluated in isolated mesenteric arterial rings using norepinephrine and endothelin-1 as vasoconstrictors. Endothelium-dependent (A23187, a calcium ionophore) and endothelium-independent (SNAP) nitric oxide (NO) donors were used as vasorelaxants. Mesenteric arterial endothelial NO synthase (eNOS), soluble guanylyl cyclase (sGC), and phosphodiesterase 5 (PDE5) mRNA analyses and protein assays were performed. RESULTS Transfusion with PRBC significantly increased mesenteric vasoconstriction to norepinephrine and endothelin-1 and impaired relaxation to A23187 and SNAP. Mesenteric arterial eNOS protein decreased following PRBC transfusion. No significant changes were noted in sGC and PDE5 mRNA or protein assays. CONCLUSION PRBC transfusion in enterally fed preterm lambs promotes mesenteric vasoconstriction and impairs vasorelaxation by reducing mesenteric arterial eNOS.

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“…However, this is not the case and may be explained by observations from several studies that BH4 can cross the placenta (295), is also found in breast milk (306) and that maternal transfer of both BH4 and catecholamines can occur (273).…”

Section: Role Of Bh4 In Cardiovascular Developmentmentioning

confidence: 96%

Tetrahydrobiopterin in Cardiovascular Health and Disease

Bendall

Douglas

McNeill

et al. 2014

Antioxidants & Redox Signaling

196

187

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Tetrahydrobiopterin (BH4) functions as a cofactor for several important enzyme systems, and considerable evidence implicates BH4 as a key regulator of endothelial nitric oxide synthase (eNOS) in the setting of cardiovascular health and disease. BH4 bioavailability is determined by a balance of enzymatic de novo synthesis and recycling, versus degradation in the setting of oxidative stress. Augmenting vascular BH4 levels by pharmacological supplementation has been shown in experimental studies to enhance NO bioavailability. However, it has become more apparent that the role of BH4 in other enzymatic pathways, including other NOS isoforms and the aromatic amino acid hydroxylases, may have a bearing on important aspects of vascular homeostasis, inflammation, and cardiac function. This article reviews the role of BH4 in cardiovascular development and homeostasis, as well as in pathophysiological processes such as endothelial and vascular dysfunction, atherosclerosis, inflammation, and cardiac hypertrophy. We discuss the therapeutic potential of BH4 in cardiovascular disease states and attempt to address how this modulator of intracellular NO-redox balance may ultimately provide a powerful new treatment for many cardiovascular diseases. Antioxid. Redox Signal. 20, 3040-3077.

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Tetrahydrobiopterin Is Present in High Quantity in Human Milk and Has a Vasorelaxing Effect on Newborn Rat Mesenteric Arteries

Cited by 15 publications

References 23 publications

Infantile hypertrophic pyloric stenosis (IHPS): A study of its pathophysiology utilizing the newborn hph-1 mouse model of the disease

Infantile hypertrophic pyloric stenosis (IHPS): A study of its pathophysiology utilizing the newborn hph-1 mouse model of the disease

Packed red cell transfusions alter mesenteric arterial reactivity and nitric oxide pathway in preterm lambs

Tetrahydrobiopterin in Cardiovascular Health and Disease

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