Ca²⁺ sensitization during sustained hypoxic pulmonary vasoconstriction is endothelium dependent

Abstract

Robertson, Tom P., Philip I. Aaronson, and Jeremy P. T. Ward. Ca 2ϩ sensitization during sustained hypoxic pulmonary vasoconstriction is endothelium dependent. Am J Physiol Lung Cell Mol Physiol 284: L1121-L1126, 2003. First published February 28, 2003 10.1152/ajplung.00422. 2002The main aim of this study was to determine the effects of endothelium removal on tension and intracellular Ca 2ϩ ([Ca 2ϩ ]i) during hypoxic pulmonary vasoconstriction (HPV) in rat isolated intrapulmonary arteries (IPA). Rat IPA and mesenteric arteries (MA) were mounted on myographs and loaded with the Ca 2ϩ -sensitive fluorophore fura PE-3. Arteries were precontracted with prostaglandin F 2␣, and the effects of hypoxia were examined. HPV in isolated IPA consisted of a transient constriction superimposed on a second sustained phase. Only the latter phase was abolished by endothelial denudation. However, removal of the endothelium had no effect on [Ca 2ϩ ]i at any point during HPV. The endothelin-1 antagonists BQ-123 and BQ-788 did not affect HPV, although constriction induced by 100 nM endothelin-1 was abolished. In MA, hypoxia induced an initial transient rise in tension and [Ca 2ϩ ]i, followed by vasodilatation and a fall in [Ca 2ϩ ]i to (but not below) prehypoxic levels. These results are consistent with sustained HPV being mediated by an endothelium-derived constrictor factor that is distinct from endothelin-1 and that elicits vasoconstriction via Ca 2ϩ sensitization. pulmonary circulation; arteries; hypoxia THE MECHANISM(S) UNDERLYING hypoxic pulmonary vasoconstriction (HPV), a unique and vital homeostatic mechanism that matches ventilation to perfusion in the event of localized alveolar hypoxia (32), remain unresolved. Because HPV can be observed in isolated pulmonary arteries (8,10,18,22,24,25), the oxygen sensor and subsequent constrictor mechanism(s) must reside in either the smooth muscle, endothelium, or both. In rat intrapulmonary arteries (IPA), the response to acute hypoxia, usually in the presence of a small degree of agonist-induced tone, is biphasic in nature (9,10,18,19,(22)(23)(24)(25)(26), consisting of an initial transient rise in tension (phase I) superimposed on a more slowly developing sustained constriction (phase II). Under similar experimental conditions, an almost identical transient phase I constriction has been observed in a variety of isolated systemic arteries (6, 22, 37), whereas the second phase of the response in systemic arteries to hypoxia is vasodilatation (22). Because the phase II constriction is peculiar to pulmonary arteries, we have argued that phase II is the more physiologically important process for sustained HPV (2, 33). In support of this contention, we have reported that the selective Rho kinase antagonist Y-27632 inhibited the hypoxic pressor response in perfused rat lungs yet only inhibited the second phase of HPV in rat isolated arteries (25).We have reported that the sustained phase II constriction of HPV is endothelium dependent (22). This is in agreement with other reports th...

Src tyrosine kinase is crucial for potassium channel function in human pulmonary arteries

“…Acute hypoxia causes vasoconstriction by several mechanisms. It depolarises PASMCs by inhibiting potassium channels, leading to calcium influx as described above [17], causes the release of calcium from the sarcoplasmic reticulum and subsequent repletion through storeoperated channels [18,19], increases calcium influx into PASMCs through L-type calcium channels, independent of the membrane potential [20] and also promotes calcium sensitisation [21], thus increasing pulmonary vascular resistance [22]. Most of the calcium responsible for the increase in cytosolic calcium induced by hypoxia comes from outside the PASMC but some is released from internal stores, such as the sarcoplasmic reticulum [1].…”

Enhancement of myofilament calcium sensitivity by acute hypoxia in rat distal pulmonary arteries

“…vascular smooth muscle; endothelium; nitric oxide; Rho kinase; temperature; endothelin-1; N -nitro-L-arginine methyl ester; Y-27632 HYPOXIC PULMONARY VASOCONSTRICTION (HPV) is thought to result from an increase in intracellular Ca 2ϩ concentration ([Ca 2ϩ ] i ) in pulmonary arterial smooth muscle cells (PASMC) (37,40,48,51,52,54,56,62,72,77,82). The increased [Ca 2ϩ ] i leads in turn to calmodulin-dependent activation of myosin light chain (MLC) kinase (MLCK), MLCK-dependent phosphorylation of the 20-kDa regulatory MLC (P-MLC 20 ), P-MLC 20 -dependent activation of the actin-myosin interaction, and PASMC contraction (38,42,74,75,83).…”

“…These results suggest that phase 2 contraction resulted from an increase in PASMC Ca 2ϩ sensitivity and that this sensitization was due to release of factors from endothelial cells, rather than direct effects of hypoxia on smooth muscle. The identities of these factors remain unknown; however, antagonists of endothelin-1 (ET-1) had no effect on phase 2 HPV in endothelium-intact IPA, suggesting that ET-1 played no role (51). Although the nitric oxide/guanylate cyclase/protein kinase G (NO/GC/PKG) transduction pathway can alter Ca 2ϩ sensitivity in pulmonary arteries (27,57), its effect on Ca 2ϩ sensitivity during acute hypoxia has not been examined.…”

Hypoxia-induced vasoconstriction in alligator (Alligator mississippiensis) intrapulmonary arteries: a role for endothelin-1?

“…Nevertheless, other studies have shown that the hypoxic contraction is endothelium dependent (Aaronson et al, 2002;López-Valverde et al, 2005). Removal of the endothelium from rat pulmonary arteries does not suppress the rise in [Ca 2+ ] i during sustained hypoxia, but abolishes the hypoxic contraction, suggesting that the endothelium releases a factor that sensitises the contractile apparatus of the SMC to calcium enabling hypoxic vasoconstriction (Robertson et al, 2003).…”

“…Numerous controversies, however, surround the role of the endothelium and the involvement of endothelin-1 (ET-1) (Aaronson et al, 2002). Thus, while several studies show that HPV is intrinsic to PASMC, other studies indicate that the endothelium, possibly through the release of ET-1, is essential for HPV (Madden et al, 1992;Shimoda et al, 2002;Robertson et al, 2003).…”