Mechanisms of hypoxic vasoconstriction in the canine isolated pulmonary artery: role of endothelium and sodium pump

Abstract

Contraction of canine pulmonary artery to hypoxia in vitro is both endothelium dependent and independent. The mechanisms which underlie this phenomenon were studied. Rings of canine pulmonary artery were suspended for isometric force recording in tissue baths containing modified Krebs-Ringer bicarbonate solution. Tissues were first contracted with norepinephrine [effective dose at 35% (ED35) concentration]. Subsequent exposure to hypoxia induced a triphasic response: an initial phasic transient contraction (phase 1), a transient reduction in force (phase 2), followed by a sustained tonic contraction (phase 3). In the absence of endothelium, all phases of the hypoxic response were reduced, and phase 2 was reversed from a contraction to a relaxation (with endothelium: 0.68 +/- 0.2 g; without endothelium: -0.34 +/- 0.1 g). Similar data were obtained in the presence of nitro-L-arginine (3 x 10(-5) M). In the absence of endothelium, indomethacin (10(-5) M) abolished the phase 2 relaxation and converted phase 3 from a contraction to a relaxation (control: 0.99 +/- 0.2 g; indomethacin: -0.44 +/- 0.1 g); and ONO-3708 (thromboxane A2/prostaglandin H2 receptor antagonist) diminished phase 3 (control: 0.99 +/- 0.2 g; ONO-3708: 0.3 +/- 0.04 g). In the absence of endothelium, but in the presence of indomethacin (10(-5) M), K(+)-free solution diminished phase 1 (contraction) and converted phase 2 (relaxation) to a contraction (control: -0.74 +/- 0.1 g; K(+)-free solution: 0.1 +/- 0.06 g). Similar results were obtained with ouabain (4 x 10(-7) M), and cooling of the bathing medium (20 degrees C).(ABSTRACT TRUNCATED AT 250 WORDS)

Ca2+ sensitization during sustained hypoxic pulmonary vasoconstriction is endothelium dependent

“…This is in agreement with other reports that the full expression of sustained HPV requires an intact endothelium (10,13,18), although this is not a universal finding (4,16). We have also reported that the generation of tension during phase II appears to involve Ca 2ϩ sensitization of the contractile apparatus, which is protein kinase C independent (24) and which appears to involve activation of Rho kinase (25).…”

“…In agreement with our earlier observations (22), we found that, whereas phase I was endothelium independent, phase II was completely dependent on the presence of an intact endothelium. Analogous biphasic responses to hypoxia have been described in a number of pulmonary vascular preparations, and a similar endothelium dependency of the full generation of sustained HPV has also been observed (10,13,18), although it is noted that this finding is not universal (4,16).…”

Endothelium-derived NO, but not cyclic GMP, is required for hypoxic augmentation in isolated porcine coronary arteries

“…This possibility is made unlikely by the lack of effect of TRAM34, UCL1684, iberiotoxin (17), ouabain (inhibitor of Na ϩ /K ϩ -ATPase; Ref. 27) and BaCl 2 (17). Alternatively, the activation of SERCA by NO is also cyclic GMP independent (1).…”

The role of the endothelium in hypoxic pulmonary vasoconstriction

“…1). Whereas the phase 1 constriction is relatively unaffected by removal of the endothelium, in most reports phase 2 is abolished (Hoshino, Morrison & Vanhoutte, 1994;Leach et al 1994;Zhang & Morice, 1994). It is notable that a biphasic response of similar time course has also been observed in some salt-perfused lung preparations (Robertson, Clapham & Ward, 1994).…”