BACKGROUND AND PURPOSE: Acute NOS inhibition in humans and animals is associated with hypersensitivity to NO donors. The mechanisms underlying this phenomenon have not been fully elucidated. The purpose of the present study was to assess whether hypersensitivity to NOS-blockade is linked to endothelin-1 (ET-1) signalling. EXPERIMENTAL APPROACH: Sprague Dawley rats were instrumented with indwelling arterial and venous catheters for continuous assessments of haemodynamic parameters and drug delivery, respectively. Mesenteric arteries were isolated and tested for reactivity by wire myography. KEY RESULTS: NOS blockade with L-N(G)-nitroarginine methyl ester (L-NAME) caused a pronounced increase in arterial blood pressure (BP) (∼40 mmHg). In L-NAME-treated animals, the dose of sodium nitroprusside (SNP) required to cause a significant reduction in arterial BP was lower than in vehicle-treated rats (P < 0.001), and the magnitude of the reduction in BP was greater. Similar results were obtained with other NO mimetics, but not isoprenaline; moreover, decreasing the BP back to baseline levels with prazosin after L-NAME treatment did not attenuate the hyper-responsiveness to NO donors. The increased responsiveness to NO donors was abolished by pretreatment with the ET(A/B) receptor antagonist, PD145065, or the ET(A) receptor-specific antagonist ABT627. Ex vivo, L-NAME treatment potentiated the constriction induced by big endothelin-1 (bET-1), the precursor to active ET-1, but had no effect on the ET-1-mediated constriction. CONCLUSIONS AND IMPLICATIONS: These data suggest that the increased sensitivity to NO donors is mediated, at least in part, by ET-1 in vivo, and the mechanism may involve the conversion of bET-1 to ET-1.
BACKGROUND AND PURPOSE: Acute NOS inhibition in humans and animals is associated with hypersensitivity to NO donors. The mechanisms underlying this phenomenon have not been fully elucidated. The purpose of the present study was to assess whether hypersensitivity to NOS-blockade is linked to endothelin-1 (ET-1) signalling. EXPERIMENTAL APPROACH: Sprague Dawley rats were instrumented with indwelling arterial and venous catheters for continuous assessments of haemodynamic parameters and drug delivery, respectively. Mesenteric arteries were isolated and tested for reactivity by wire myography. KEY RESULTS: NOS blockade with L-N(G)-nitroarginine methyl ester (L-NAME) caused a pronounced increase in arterial blood pressure (BP) (∼40 mmHg). In L-NAME-treated animals, the dose of sodium nitroprusside (SNP) required to cause a significant reduction in arterial BP was lower than in vehicle-treated rats (P < 0.001), and the magnitude of the reduction in BP was greater. Similar results were obtained with other NO mimetics, but not isoprenaline; moreover, decreasing the BP back to baseline levels with prazosin after L-NAME treatment did not attenuate the hyper-responsiveness to NO donors. The increased responsiveness to NO donors was abolished by pretreatment with the ET(A/B) receptor antagonist, PD145065, or the ET(A) receptor-specific antagonist ABT627. Ex vivo, L-NAME treatment potentiated the constriction induced by big endothelin-1 (bET-1), the precursor to active ET-1, but had no effect on the ET-1-mediated constriction. CONCLUSIONS AND IMPLICATIONS: These data suggest that the increased sensitivity to NO donors is mediated, at least in part, by ET-1 in vivo, and the mechanism may involve the conversion of bET-1 to ET-1.
Authors: Nicolaas J H Raat; D Marcela Tabima; Patricia A C Specht; Jesús Tejero; Hunter C Champion; Daniel B Kim-Shapiro; Jeff Baust; Egbert G Mik; Mariana Hildesheim; Johannes-Peter Stasch; Eva-Maria Becker; Hubert Truebel; Mark T Gladwin Journal: Antioxid Redox Signal Date: 2013-07-09 Impact factor: 8.401
Authors: Scott K Ferguson; Katherine Redinius; Ayla Yalamanoglu; Julie W Harral; Jin Hyen Baek; David Pak; Zoe Loomis; Daniel Hassell; Paul Eigenberger; Eva Nozik-Grayck; Rachelle Nuss; Kathryn Hassell; Kurt R Stenmark; Paul W Buehler; David C Irwin Journal: J Physiol Date: 2018-08-25 Impact factor: 5.182
Authors: Tiziana Cotechini; Maria Komisarenko; Arissa Sperou; Shannyn Macdonald-Goodfellow; Michael A Adams; Charles H Graham Journal: J Exp Med Date: 2014-01-06 Impact factor: 14.307