Effect of hypoxia on force, intracellular pH and Ca2+ concentration in rat cerebral and mesenteric small arteries.

Aalkjær, Christian; Lombard, Julian H.

doi:10.1113/jphysiol.1995.sp020528

Cited by 35 publications

(31 citation statements)

References 37 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…The simplest explanation to account for a decrease in shortening velocity with a concomitant decrease in MLC phosphorylation levels, as occurred dur ing NE stimulation, is a hypoxia-induced decrease in cel lular Ca2+. Relaxation of NE-stimulated contractions by hypoxia is independent of the endothelium [15], cyclic nucleotide concentrations [16], pi I [17] and probably changes in [Mg2+] [18]. If hypoxia-induced relaxation of an agonist-stimulated contraction is due to a decrease in activator Ca2+ as we suggest, it does not involve receptorphospholipase C coupling mediated by a decrease in GTP concentration [16].…”

Section: Discussionmentioning

confidence: 84%

Decreased PO<sub>2</sub> and Rabbit Aortic Smooth Muscle Mechanics

Moreland

Coburn²,

Moreland³

1995

J Vasc Res

View full text Add to dashboard Cite

Rabbit thoracic aorta was used to determine the effects of decreasing PO₂ on the mechanical properties of contractions in response to norepinephrine (NE) and KC1. Aortae were aerated with 45% O₂/5% CO₂/50% N₂ and stimulated with 10 µM NE or 50 mM KCl. At 5 min of stimulation, 5% CO₂/95% N₂aeration was introduced for 15 min, defined as hypoxia. This time period was previously shown to produce similar decrease in [ATP] in either stimulation condition. Force, stiffness and isotonic shortening velocity were monitored during the initial stimulation, during hypoxia and during re-oxygenation. Hypoxia produced a substantial and rapid decrease in force and a concomitant decrease in stiffness during NE stimulation; delayed and smaller decreases in force and stiffness were observed during KC1 stimulation. The force-stiffness relationship was steeper during KC1 than NE stimulation, and hypoxia did not affect these relationships. Isotonic shortening velocity was significantly depressed by hypoxia during both stimulations although the decrease during KC1 stimulation required a longer time. These data demonstrate that relaxation of an agonist-induced contraction in response to hypoxia results from a decrease in the number of activated crossbridges and not formation of rigor bridges.

show abstract

Section: Discussionmentioning

confidence: 84%

Decreased PO<sub>2</sub> and Rabbit Aortic Smooth Muscle Mechanics

Moreland

Coburn²,

Moreland³

1995

J Vasc Res

View full text Add to dashboard Cite

show abstract

“…Relaxation occurs by Ca 2ϩ -dependent and Ca 2ϩ -independent mechanisms. Ca 2ϩ -independent mechanisms involve a change in the Ca 2ϩ sensitivity of the contractile apparatus of the cell (e.g., 1,17,40). Hypoxia also inhibits calcium entry (35) and lowers [Ca 2ϩ ] i (e.g., Fig.…”

Section: Discussionmentioning

confidence: 99%

Effects of hypoxia, anoxia, and metabolic inhibitors on K_ATP channels in rat femoral artery myocytes

Quayle¹,

Turner²,

Burrell³

et al. 2006

American Journal of Physiology-Heart and Circulatory Physiology

View full text Add to dashboard Cite

Effects of hypoxia, anoxia, and metabolic inhibitors on KATP channels in rat femoral artery myocytes. Am J Physiol Heart Circ Physiol 291: H71-H80, 2006. First published February 17, 2006 doi:10.1152/ajpheart.01107.2005.-Vascular ATP-sensitive potassium (KATP) channels have an important role in hypoxic vasodilation. Because KATP channel activity depends on intracellular nucleotide concentration, one hypothesis is that hypoxia activates channels by reducing cellular ATP production. However, this has not been rigorously tested. In this study we measured K ATP current in response to hypoxia and modulators of cellular metabolism in single smooth muscle cells from the rat femoral artery by using the whole cell patch-clamp technique. KATP current was not activated by exposure of cells to hypoxic solutions (PO2 ϳ35 mmHg). In contrast, voltagedependent calcium current and the depolarization-induced rise in intracellular calcium concentration ([Ca 2ϩ ]i) was inhibited by hypoxia. Blocking mitochondrial ATP production by using the ATP synthase inhibitor oligomycin B (3 M) did not activate current. Blocking glycolytic ATP production by using 2-deoxy-D-glucose (5 mM) also did not activate current. The protonophore carbonyl cyanide m-chlorophenylhydrazone (1 M) depolarized the mitochondrial membrane potential and activated K ATP current. This activation was reversed by oligomycin B, suggesting it occurred as a consequence of mitochondrial ATP consumption by ATP synthase working in reverse mode. Finally, anoxia induced by dithionite (0.5 mM) also depolarized the mitochondrial membrane potential and activated K ATP current. Our data show that: 1) anoxia but not hypoxia activates KATP current in femoral artery myocytes; and 2) inhibition of cellular energy production is insufficient to activate K ATP current and that energy consumption is required for current activation. These results suggest that vascular K ATP channels are not activated during hypoxia via changes in cell metabolism. Furthermore, part of the relaxant effect of hypoxia on rat femoral artery may be mediated by changes in [Ca 2ϩ ]i through modulation of calcium channel activity. smooth muscle; ion channels; potassium channels ATP-SENSITIVE POTASSIUM (K ATP ) channels are involved in the hypoxic vasodilation that couples blood flow to metabolic demand, for example, in the coronary (44), skeletal muscle (30), and cerebral circulations (42). Hypoxia is thought to activate K ATP channels either by acting directly on the smooth muscle cells or by causing release of vasodilator metabolites from surrounding tissue or endothelial cells, which in turn activates channels via receptor-coupled signal transduction pathways (e.g., 9, 23, 30, 37, 43, 44). K ATP channels are regulated by intracellular ATP and ADP, and the direct vasodilator action of hypoxia may therefore occur as a consequence of hypoxia changing intracellular nucleotide levels in arterial myocytes (9, 27, 44). Alternatively, oxygen tension regulates the activity of some channels independently of changes i...

show abstract

“…6 In some cases of vascular hypoxia or mitochondrial inhibition, the intracellular free Ca 2ϩ concentration ([Ca 2ϩ ] i ), measured as an average from multiple cells, is unchanged or even increased at high stimulus levels while force is reduced. [7][8][9][10] Thus mechanisms based on decreased global [Ca 2ϩ ] i are insufficient to explain hypoxic relaxation. It is puzzling also that in many studies myosin light chain phosphorylation does not decrease, 6,9 even though exceptions are seen.…”

mentioning

confidence: 99%

Influence of Mitochondrial Inhibition on Global and Local [Ca ²⁺ ] _i in Rat Tail Artery

Swärd

Dreja

Lindqvist

et al. 2002

Circulation Research

View full text Add to dashboard Cite

Abstract-Inhibition of oxidative metabolism is often found to decrease contractility of systemic vascular smooth muscle, but not to reduce global [Ca 2ϩ ] i . In the present study, we probe the hypothesis that it is associated with an altered pattern of intracellular Ca 2ϩ oscillations (waves) influencing force development. In the rat tail artery, mitochondrial inhibitors (rotenone, antimycin A, and cyanide) reduced ␣ 1 -adrenoceptor-stimulated force by 50% to 80%, but did not reduce global [Ca 2ϩ ] i . Less relaxation (about 30%) was observed after inhibition of myosin phosphatase activity with calyculin A, suggesting that part of the metabolic sensitivity involves the regulation of myosin 20-kDa light chain phosphorylation, although no decrease in phosphorylation was found in freeze-clamped tissue. Confocal imaging revealed that the mitochondrial inhibitors increased the frequency but reduced the amplitude of asynchronous cellular Ca 2ϩ waves elicited by ␣ 1 stimulation. The altered wave pattern, in association with increased basal [Ca 2ϩ ] i , accounted for the unchanged global [Ca 2ϩ ] i . Inhibition of glycolytic ATP production by arsenate caused similar effects on Ca 2ϩ waves and global [Ca 2ϩ ] i , developing gradually in parallel with decreased contractility. Inhibition of wave activity by the InsP 3 receptor antagonist 2-APB correlated closely with relaxation. Furthermore, abolition of waves with thapsigargin in the presence of verapamil reduced force by about 50%, despite unaltered global [Ca 2ϩ ] i , suggesting that contraction may at least partly depend on Ca 2ϩ wave activity. This study therefore indicates that mitochondrial inhibition influences Ca 2ϩ wave activity, possibly due to a close spatial relationship of mitochondria and the sarcoplasmic reticulum and that this contributes to metabolic vascular relaxation. Key Words: arterial smooth muscle Ⅲ metabolic inhibition Ⅲ myosin phosphorylation Ⅲ calcium waves Ⅲ confocal imaging T he distribution of blood flow in tissue depends on the sensitivity of arterial tone to the local oxygen tension, but the nature of the mediating signal is yet unclear. Proposed mechanisms include reduced Ca 2ϩ inflow across the cell membrane, 1-4 decreased myosin phosphorylation, 5 or inhibition of cross-bridge cycling. 6 In some cases of vascular hypoxia or mitochondrial inhibition, the intracellular free Ca 2ϩ concentration ([Ca 2ϩ ] i ), measured as an average from multiple cells, is unchanged or even increased at high stimulus levels while force is reduced. [7][8][9][10] Thus mechanisms based on decreased global [Ca 2ϩ ] i are insufficient to explain hypoxic relaxation. It is puzzling also that in many studies myosin light chain phosphorylation does not decrease, 6,9 even though exceptions are seen. 5 Finally, insufficient MgATP for cross-bridge interaction, although clearly a possibility with severe metabolic inhibition, does not seem to be a general explanation for hypoxic relaxation. 10 Within the vessel wall, individual cells may exhibit asynchron...

show abstract

Effect of hypoxia on force, intracellular pH and Ca2+ concentration in rat cerebral and mesenteric small arteries.

Cited by 35 publications

References 37 publications

Decreased PO<sub>2</sub> and Rabbit Aortic Smooth Muscle Mechanics

Decreased PO<sub>2</sub> and Rabbit Aortic Smooth Muscle Mechanics

Effects of hypoxia, anoxia, and metabolic inhibitors on K_ATP channels in rat femoral artery myocytes

Influence of Mitochondrial Inhibition on Global and Local [Ca ²⁺ ] _i in Rat Tail Artery

Contact Info

Product

Resources

About

Effect of hypoxia on force, intracellular pH and Ca2+ concentration in rat cerebral and mesenteric small arteries.

Cited by 35 publications

References 37 publications

Decreased PO<sub>2</sub> and Rabbit Aortic Smooth Muscle Mechanics

Decreased PO<sub>2</sub> and Rabbit Aortic Smooth Muscle Mechanics

Effects of hypoxia, anoxia, and metabolic inhibitors on KATP channels in rat femoral artery myocytes

Influence of Mitochondrial Inhibition on Global and Local [Ca 2+ ] i in Rat Tail Artery

Contact Info

Product

Resources

About

Effects of hypoxia, anoxia, and metabolic inhibitors on K_ATP channels in rat femoral artery myocytes

Influence of Mitochondrial Inhibition on Global and Local [Ca ²⁺ ] _i in Rat Tail Artery