Inhibition of voltage-gated, L-type Ca2+ (CaL) channels by clinical calcium channel blockers provides symptomatic improvement to some pediatric patients with pulmonary arterial hypertension (PAH). The present study investigated whether abnormalities of vascular CaL channels contribute to the pathogenesis of neonatal PAH using a newborn piglet model of hypoxia-induced PAH. Neonatal piglets exposed to chronic hypoxia (CH) developed PAH by 21 days, which was evident as a 2.1-fold increase in pulmonary vascular resistance in vivo compared with piglets raised in normoxia (N). Transpulmonary pressures (ΔPtp) in the corresponding isolated perfused lungs were 20.5 ± 2.1 mmHg (CH) and 11.6 ± 0.8 mmHg (N). Nifedipine reduced the elevated ΔPtp in isolated lungs of CH piglets by 6.4 ± 1.3 mmHg but only reduced ΔPtp in lungs of N piglets by 1.9 ± 0.2 mmHg. Small pulmonary arteries from CH piglets also demonstrated accentuated Ca2+-dependent contraction, and Ca2+ channel current was 3.94-fold higher in the resident vascular muscle cells. Finally, although the level of mRNA encoding the pore-forming α1C-subunit of the CaL channel was similar between small pulmonary arteries from N and CH piglets, a profound and persistent upregulation of the vascular α1C protein was detected by 10 days in CH piglets at a time when pulmonary vascular resistance was only mildly elevated. Thus chronic hypoxia in the neonate is associated with the anomalous upregulation of CaL channels in small pulmonary arteries in vivo and the resulting abnormal Ca2+-dependent resistance may contribute to the pathogenesis of PAH.
The development of chronic hypoxia (CH)‐induced neonatal pulmonary hypertension (PH) is associated with increased production of thromboxane (TxA2) and an upregulation of L‐type calcium (CaL) channels. Thus, we hypothesized that TxA2 synthase inhibition may blunt the development of PH by mitigating the upregulation of CaL channels. Newborn piglets were exposed to 21 days of normoxia (N), CH or CH plus the TxA2 synthase inhibitor, furegrelate (oral 3 mg/kg, 3x daily). In vivo pulmonary vascular resistance index (PVRI) was 3.15 ‐fold higher in CH (104±1 WU) compared to N (33±1 WU) piglets. Furegrelate partially blunted the elevated PVRI in CH piglets (64±0.5 WU). Furegrelate also reversed the elevated transpulmonary pressure in isolated lungs of CH piglets by 66%, and blunted the overexpression of CaL channels and anomalous Ca2+‐dependent tone. Pulmonary arterial distensibility was decreased in lungs of CH compared to N piglets, indicative of vascular remodeling. Furegrelate partially restored distensibility to normal levels. Our findings suggest that pharmacological inhibition of TxA2 synthase blunts the development of hypoxia‐induced neonatal PH by preserving vascular function and structural integrity. Funded by NIH R01 HL83013
Although the amounts of money and time associated with using shoe covers or other means to prevent floor contamination in animal research facilities can be substantial, the most effective policies and practices remain unknown. In this study, the authors subjected six occupied rodent holding rooms in their animal research facility to three conditions: use of disinfectant mats; use of shoe covers; and no disinfectant mats or shoe covers. The authors took bacterial culture samples from the rooms under each condition. There was no significant difference in the mean number of colony forming units (CFUs) cultured when the disinfectant mats or shoe covers were used. However, the mean number of CFUs obtained was significantly lower when either disinfectant mats or shoe covers were used than when neither was used. These results suggest that using disinfectant mats or disposable shoe covers may reduce the bacterial load on rodent holding room floors.
The authors evaluated the effectiveness of adhesive mats, contamination control flooring, and shoe covers in decreasing the presence of microbial agents on animal holding room floors and footwear. Swab samples taken from animal holding room floors after the use of each product were compared with samples taken from rooms after no products were used. Swab samples were also taken from the heels and soles of the footwear of animal care staff before and after use of each product. The use of contamination control flooring or shoe covers significantly reduced the amount of organic material (as indicated by ATP levels measured by a luminometer) present on floors. Bacterial and ATP contamination of footwear was significantly lower after the use of shoe covers than after the use of adhesive mats or contamination control flooring, and the use of shoe covers led to a greater decrease in contamination before and after use than did use of either of the other two products. Although shoe covers were superior to both adhesive mats and contamination control flooring for decreasing contamination of animal room floors and footwear, facilities must take into account the contamination control standards required, the cost of the product, and the labor and time associated with product use when deciding which contamination control practices to implement.
Pulmonary hypertension (PH) in neonatal piglets caused by chronic hypoxia (CH, 10% O2) is associated with increased thromboxane (TxA2) production, an upregulation of L‐type Ca2+ (CaL) channels, and elevated Ca2+‐dependent tone. Thus, we hypothesized that TxA2 synthase inhibitors may attenuate the development of CH‐induced PH by limiting the upregulation of vascular CaL channels. Two day old piglets were exposed to 3 wks of normoxia (N), CH, or CH treated by the TxA2 synthase inhibitor, furegrelate (CH‐F; 3 mg/kg tid). Subsequently, in‐vivo and isolated lung hemodynamics and CaL channel expression was evaluated. In‐vivo pulmonary vascular resistance index (PVRI) averaged 0.035±0.002 (N), 0.108±0.01 (CH) and 0.061±0.007 (CH‐F). Thus, furegrelate partially normalized PVRI in CH piglets. Furegrelate also normalized pulmonary arterial pressure (PAP) in isolated lungs of CH piglets (N, 11.8±1.1; CH, 24.5±3.1; CH‐F, 14.3±0.8 mm Hg). Nifedipine‐sensitive tone accounted for 55% of the 12.7 mm Hg increase in PAP of CH piglets, and furegrelate abolished this anomalous vascular tone. This finding correlated with a 44% reduction in the expression of the pore‐forming α1C subunit of the CaL channel in small pulmonary arteries. Our findings suggest that TxA2 ‐synthase inhibitors ameliorate the development of hypoxia‐induced neonatal PH, possibly by blunting the upregulation of CaL channels. Supported by NIH HL83013‐03
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