NAD(P)H:quinone oxidoreductase 1 (NQO1) plays a dominant role in the reduction of the quinone compound 2,3,5,6-tetramethyl-1,4-benzoquinone (duroquinone, DQ) to durohydroquinone (DQH2) on passage through the rat lung. Exposure of adult rats to 85% O2 for > or =7 days stimulates adaptation to the otherwise lethal effects of >95% O2. The objective of this study was to examine whether exposure of adult rats to hyperoxia affected lung NQO1 activity as measured by the rate of DQ reduction on passage through the lung. We measured DQH2 appearance in the venous effluent during DQ infusion at different concentrations into the pulmonary artery of isolated perfused lungs from rats exposed to room air or to 85% O2. We also evaluated the effect of hyperoxia on vascular transit time distribution and measured NQO1 activity and protein in lung homogenate. The results demonstrate that exposure to 85% O2 for 21 days increases lung capacity to reduce DQ to DQH2 and that NQO1 is the dominant DQ reductase in normoxic and hyperoxic lungs. Kinetic analysis revealed that 21-day hyperoxia exposure increased the maximum rate of pulmonary DQ reduction, Vmax, and the apparent Michaelis-Menten constant for DQ reduction, Kma. The increase in Vmax suggests a hyperoxia-induced increase in NQO1 activity of lung cells accessible to DQ from the vascular region, consistent qualitatively but not quantitatively with an increase in lung homogenate NQO1 activity in 21-day hyperoxic lungs. The increase in Kma could be accounted for by approximately 40% increase in vascular transit time heterogeneity in 21-day hyperoxic lungs.
Chronic kidney disease is a growing medical concern, with an estimated 25.6 million people in the United States exhibiting some degree of kidney injury and/or decline in kidney function. Animal models provide great insight into the study of the genetics of complex diseases. In particular, heterogeneous stock (HS) rats represent a unique genetic resource enabling rapid fine-mapping of complex traits. However, they have not been explored as a model to study renal phenotypes. To evaluate the usefulness of HS rats in the genetics of renal traits, a time course evaluation (weeks 8-40) was performed for several renal phenotypes. As expected, a large degree of variation was seen for most renal traits. By week 24, three (of 40) rats exhibited marked proteinuria that increased gradually until week 40 and ranged from 33.7 to 80.2 mg/24 h. Detailed histological analysis confirmed renal damage in these rats. In addition, several rats consistently exhibited significant hematuria (5/41). Interestingly, these rats were not the same rats that exhibited proteinuria, indicating that susceptibility to different types of kidney injury is likely segregating within the HS population. One HS rat exhibited unilateral renal agenesis (URA), which was accompanied by a significant degree of proteinuria and glomerular and tubulointerstitial injury. The parents of this HS rat were identified and bred further. Additional offspring of this pair were observed to exhibit URA at frequency between 40% and 60%. In summary, these novel data demonstrate that HS rats exhibit variation in proteinuria and other kidney-related traits, confirming that the model harbors susceptibility alleles for kidney injury and providing the basis for further genetic studies.
The purpose of the study was to determine if heat attenuates sympathetic vasoconstriction in females as it does in male rats (Kluess et al., 2005). Since females have higher α1‐adrenergic tone than males, the hypothesis was that the magnitude of heat attenuation would be less in females. The femoral arteries from 15 female (279±11g) and 16 male (290±10g) Sprague‐Dawley rats were prepared for wire myography. Field stimulation (2–60Hz for 144 impulses) and dose response curves for the P2X agonist, αβ‐methylene ATP (mATP: 10−7 to 10−3M) and the α1‐agonist, phenylephrine (PE: 10−7 to 10−4M) were performed at bath temperatures of 37°C and 41°C. Heat attenuated tension produced during field stimulation in both genders, but there was greater attenuation in males (−65±13% on average) compared to females (−48±10% on average; p<0.05). Heat reduced the tension produced by mATP in female and male femoral arteries, but the slope was higher in males at 41°C (1.39±0.17g/log M mATP), than females at 41°C (0.83±0.09 g/log M mATP; p=0.01). The responsiveness to phenylephrine was unaffected by heat. Skeletal muscle arteries in female rats experience modest heat attenuation, but the magnitude of change is less than for age and weight matched males. The primary mechanism for heat‐induced attenuation of vasoconstriction in the femoral artery in males and females is P2X purinergic receptors.
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