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sGC stimulation totally reverses hypoxia-induced pulmonary vasoconstriction alone and combined with dual endothelin-receptor blockade in a porcine model.

Lundgren, J; Kylhammar, David LU ; Hedelin, P and Rådegran, Göran LU (2012) In Acta Physiologica 206(3). p.178-194
Abstract
AIM:

Stimulation of soluble guanylate cyclase (sGC) with BAY 41-8543 was hypothesized to attenuate acute hypoxic pulmonary vasoconstriction alone and combined with dual endothelin (ET)-receptor antagonist tezosentan.



METHODS: Measurements were taken in 18 anaesthetized pigs with a mean ± SEM weight of 31.1 ± 0.4 kg, in normoxia (FiO(2) ~0.21) and hypoxia (FiO(2) ~0.10) without (control protocol, n = 6), and with right atrial infusion of BAY 41-8543 at 1, 3, 6, 9 and 12 μg min(-1) per kg (protocol 2, n = 6) or tezosentan at 5 mg kg(-1) followed by BAY 41-8543 at 1, 3 and 6 μg min(-1) per kg (protocol 3, n = 6).



RESULTS:

Hypoxia (n = 18) increased (P < 0.001) mean pulmonary... (More)
AIM:

Stimulation of soluble guanylate cyclase (sGC) with BAY 41-8543 was hypothesized to attenuate acute hypoxic pulmonary vasoconstriction alone and combined with dual endothelin (ET)-receptor antagonist tezosentan.



METHODS: Measurements were taken in 18 anaesthetized pigs with a mean ± SEM weight of 31.1 ± 0.4 kg, in normoxia (FiO(2) ~0.21) and hypoxia (FiO(2) ~0.10) without (control protocol, n = 6), and with right atrial infusion of BAY 41-8543 at 1, 3, 6, 9 and 12 μg min(-1) per kg (protocol 2, n = 6) or tezosentan at 5 mg kg(-1) followed by BAY 41-8543 at 1, 3 and 6 μg min(-1) per kg (protocol 3, n = 6).



RESULTS:

Hypoxia (n = 18) increased (P < 0.001) mean pulmonary artery pressure (MPAP) and pulmonary vascular resistance (PVR) by 14.2 ± 0.6 mmHg and 2.8 ± 0.3 WU respectively. During sustained hypoxia without treatment, MPAP and PVR remained stable. BAY 41-8543 (n = 6) dose-dependently decreased (P < 0.001) MPAP and PVR by 15.0 ± 1.2 mmHg and 4.7 ± 0.7 WU respectively. Tezosentan (n = 6) decreased (P < 0.001) MPAP and PVR by 11.8 ± 1.2 mmHg and 2.0 ± 0.2 WU, respectively, whereafter BAY 41-8543 (n = 6) further decreased (P < 0.001) MPAP and PVR by 6.6 ± 0.9 mmHg and 1.9 ± 0.4 WU respectively. Both BAY 41-8543 and tezosentan decreased (P < 0.001) systemic arterial pressure and systemic vascular resistance. Blood-O(2) consumption remained unaltered (P = ns) during all interventions.



CONCLUSION:

BAY 41-8543 totally reverses the effects of acute hypoxia-induced pulmonary vasoconstriction, and enhances the attenuating effects of tezosentan, without affecting oxygenation. Thus, sGC stimulation, alone or combined with dual ET-receptor blockade, could offer a means to treat pulmonary hypertension related to hypoxia and potentially other causes. (Less)
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author
organization
publishing date
type
Contribution to journal
publication status
published
subject
in
Acta Physiologica
volume
206
issue
3
pages
178 - 194
publisher
Wiley-Blackwell
external identifiers
  • wos:000309392300004
  • pmid:22682645
  • scopus:84866902404
ISSN
1748-1708
DOI
10.1111/j.1748-1716.2012.02445.x
language
English
LU publication?
yes
id
86659260-e30d-4c18-b020-dcb08ce5c318 (old id 2859623)
alternative location
http://www.ncbi.nlm.nih.gov/pubmed/22682645?dopt=Abstract
date added to LUP
2012-07-04 13:21:17
date last changed
2017-04-02 04:12:41
@article{86659260-e30d-4c18-b020-dcb08ce5c318,
  abstract     = {AIM: <br/><br>
Stimulation of soluble guanylate cyclase (sGC) with BAY 41-8543 was hypothesized to attenuate acute hypoxic pulmonary vasoconstriction alone and combined with dual endothelin (ET)-receptor antagonist tezosentan. <br/><br>
<br/><br>
METHODS: Measurements were taken in 18 anaesthetized pigs with a mean ± SEM weight of 31.1 ± 0.4 kg, in normoxia (FiO(2) ~0.21) and hypoxia (FiO(2) ~0.10) without (control protocol, n = 6), and with right atrial infusion of BAY 41-8543 at 1, 3, 6, 9 and 12 μg min(-1) per kg (protocol 2, n = 6) or tezosentan at 5 mg kg(-1) followed by BAY 41-8543 at 1, 3 and 6 μg min(-1) per kg (protocol 3, n = 6). <br/><br>
<br/><br>
RESULTS: <br/><br>
Hypoxia (n = 18) increased (P &lt; 0.001) mean pulmonary artery pressure (MPAP) and pulmonary vascular resistance (PVR) by 14.2 ± 0.6 mmHg and 2.8 ± 0.3 WU respectively. During sustained hypoxia without treatment, MPAP and PVR remained stable. BAY 41-8543 (n = 6) dose-dependently decreased (P &lt; 0.001) MPAP and PVR by 15.0 ± 1.2 mmHg and 4.7 ± 0.7 WU respectively. Tezosentan (n = 6) decreased (P &lt; 0.001) MPAP and PVR by 11.8 ± 1.2 mmHg and 2.0 ± 0.2 WU, respectively, whereafter BAY 41-8543 (n = 6) further decreased (P &lt; 0.001) MPAP and PVR by 6.6 ± 0.9 mmHg and 1.9 ± 0.4 WU respectively. Both BAY 41-8543 and tezosentan decreased (P &lt; 0.001) systemic arterial pressure and systemic vascular resistance. Blood-O(2) consumption remained unaltered (P = ns) during all interventions. <br/><br>
<br/><br>
CONCLUSION: <br/><br>
BAY 41-8543 totally reverses the effects of acute hypoxia-induced pulmonary vasoconstriction, and enhances the attenuating effects of tezosentan, without affecting oxygenation. Thus, sGC stimulation, alone or combined with dual ET-receptor blockade, could offer a means to treat pulmonary hypertension related to hypoxia and potentially other causes.},
  author       = {Lundgren, J and Kylhammar, David and Hedelin, P and Rådegran, Göran},
  issn         = {1748-1708},
  language     = {eng},
  number       = {3},
  pages        = {178--194},
  publisher    = {Wiley-Blackwell},
  series       = {Acta Physiologica},
  title        = {sGC stimulation totally reverses hypoxia-induced pulmonary vasoconstriction alone and combined with dual endothelin-receptor blockade in a porcine model.},
  url          = {http://dx.doi.org/10.1111/j.1748-1716.2012.02445.x},
  volume       = {206},
  year         = {2012},
}