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


CONCLUSIONS
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.
The Öresund Cardiovascular Research Collaboration, The Clinic for Heart Failure and Valvular Disease, Skåne University Hospital, Lund, Sweden.
J
J
Lundgren
D
D
Kylhammar
P
P
Hedelin
G
G
Rådegran
D000818:Animals; D001794:Blood Pressure / Q000187:drug effects / Q000502:physiology; D004195:Disease Models, Animal; D004305:Dose-Response Relationship, Drug; D004359:Drug Therapy, Combination; D065128:Endothelin Receptor Antagonists; D020536:Enzyme Activators / Q000494:pharmacology / Q000627:therapeutic use; D005260:Female; D006162:Guanylate Cyclase / Q000187:drug effects* / Q000502:physiology*; D006976:Hypertension, Pulmonary / Q000188:drug therapy / Q000209:etiology* / Q000503:physiopathology; D000860:Hypoxia / Q000150:complications*; D008168:Lung / Q000098:blood supply; D009025:Morpholines / Q000494:pharmacology* / Q000627:therapeutic use; D011725:Pyridines / Q000494:pharmacology* / Q000627:therapeutic use; D011743:Pyrimidines / Q000494:pharmacology* / Q000627:therapeutic use; D017466:Receptors, Endothelin / Q000187:drug effects / Q000502:physiology; D013552:Swine; D013777:Tetrazoles / Q000494:pharmacology* / Q000627:therapeutic use; D014655:Vascular Resistance / Q000187:drug effects* / Q000502:physiology; D014661:Vasoconstriction / Q000187:drug effects / Q000502:physiology; D014665:Vasodilator Agents / Q000494:pharmacology / Q000627:therapeutic use
C450679:BAY 41-8543; D065128:Endothelin Receptor Antagonists; D020536:Enzyme Activators; D009025:Morpholines; D011725:Pyridines; D011743:Pyrimidines; D017466:Receptors, Endothelin; D013777:Tetrazoles; D014665:Vasodilator Agents; C120582:tezosentan; D006162:Guanylate Cyclase