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Transcytosis inhibitor N-ethylmaleimide increases microvascular permeability in rat muscle
O Carlsson1, B I Rosengren, B Rippe
1Department of Nephrology, Lund University, S-221 85 Lund, Sweden. Ola.Carlsson@gambro.com
Abstract:
N-ethylmaleimide (NEM) has been claimed to markedly inhibit the transvascular passage of small proteins and albumin by interacting with the docking and fusion of plasmalemmal vesicles with their target membranes. To investigate the role of transcytosis in the transcapillary passage of albumin, we assessed the effects of NEM on (125)I-labeled radioiodinated serum albumin clearance (RISA-Cl) from blood to muscle in isolated and maximally vasodilated perfused rat hindquarters, in which vascular pressures, pre- and postcapillary resistances, and the capillary filtration coefficient (CFC) were continuously monitored. NEM (0.3-0.5 mM) caused a marked increase mainly in precapillary vascular resistance. Thus the arterial-to-venous resistance ratio in NEM-treated animals was 3.12 +/- 0.56 versus 1.66 +/- 0.17 during the control period (P < 0.05). Despite that, there was a doubling of both CFC from 0.0363 +/- 0.0028 to 0.0778 +/- 0.0101 ml x min(-1) x mmHg(-1) x 100 g(-1) (P < 0.01) and RISA-Cl, compared with the control situation, signaling markedly increased microvascular permeability. Our results strongly suggest that NEM, besides producing marked vasoconstriction, also causes damage to the capillary endothelium. Thus, instead of inhibiting transvascular transport, NEM may induce increases in the bulk transport of albumin from blood to tissue.
Insights
N-ethylmaleimide (NEM) was thought to inhibit albumin transport across blood vessels. However, this study found NEM actually increases microvascular permeability and albumin passage by damaging capillary endothelium.
Area of Science:
- Physiology
- Biochemistry
- Pharmacology
Background:
- N-ethylmaleimide (NEM) is proposed to inhibit transvascular protein transport by interfering with vesicle fusion.
- The precise role of transcytosis in albumin's passage across capillaries requires further investigation.
Purpose of the Study:
- To investigate the effect of N-ethylmaleimide (NEM) on albumin transport across the microvasculature.
- To determine if NEM inhibits or enhances the transcapillary passage of albumin.
Main Methods:
- Isolated perfused rat hindquarters were used to measure (125)I-labeled radioiodinated serum albumin clearance (RISA-Cl).
- Vascular pressures, resistances, and capillary filtration coefficient (CFC) were continuously monitored.
- The effects of NEM (0.3-0.5 mM) on these parameters were assessed.
Main Results:
- NEM significantly increased precapillary vascular resistance and the arterial-to-venous resistance ratio.
- NEM doubled both the capillary filtration coefficient (CFC) and RISA-Cl, indicating increased microvascular permeability.
- These findings contradict the hypothesis that NEM inhibits transvascular transport.
Conclusions:
- N-ethylmaleimide (NEM) causes vasoconstriction and damages the capillary endothelium.
- Contrary to previous claims, NEM enhances, rather than inhibits, the bulk transport of albumin from blood to tissue.
- NEM increases microvascular permeability, facilitating albumin passage.