Affiliation:
1. From the Department of Pharmacy and Pharmacology, University of Bath, Claverton Down, United Kingdom.
Abstract
Arterial hyperpolarization to acetylcholine (ACh) reflects coactivation of K
Ca
3.1 (IK
Ca
) channels and K
Ca
2.3 (SK
Ca
) channels in the endothelium that transfers through myoendothelial gap junctions and diffusible factor(s) to affect smooth muscle relaxation (endothelium-derived hyperpolarizing factor [EDHF] response). However, ACh can differentially activate K
Ca
3.1 and K
Ca
2.3 channels, and we investigated the mechanisms responsible in rat mesenteric arteries. K
Ca
3.1 channel input to EDHF hyperpolarization was enhanced by reducing external [Ca
2+
]
o
but blocked either with forskolin to activate protein kinase A or by limiting smooth muscle [Ca
2+
]
i
increases stimulated by phenylephrine depolarization. Imaging [Ca
2+
]
i
within the endothelial cell projections forming myoendothelial gap junctions revealed increases in cytoplasmic [Ca
2+
]
i
during endothelial stimulation with ACh that were unaffected by simultaneous increases in muscle [Ca
2+
]
i
evoked by phenylephrine. If gap junctions were uncoupled, K
Ca
3.1 channels became the predominant input to EDHF hyperpolarization, and relaxation was inhibited with ouabain, implicating a crucial link through Na
+
/K
+
-ATPase. There was no evidence for an equivalent link through K
Ca
2.3 channels nor between these channels and the putative EDHF pathway involving natriuretic peptide receptor-C. Reconstruction of confocal z-stack images from pressurized arteries revealed K
Ca
2.3 immunostain at endothelial cell borders, including endothelial cell projections, whereas K
Ca
3.1 channels and Na
+
/K
+
-ATPase α
2
/α
3
subunits were highly concentrated in endothelial cell projections and adjacent to myoendothelial gap junctions. Thus, extracellular [Ca
2+
]
o
appears to modify K
Ca
3.1 channel activity through a protein kinase A–dependent mechanism independent of changes in endothelial [Ca
2+
]
i
. The resulting hyperpolarization links to arterial relaxation largely through Na
+
/K
+
-ATPase, possibly reflecting K
+
acting as an EDHF. In contrast, K
Ca
2.3 hyperpolarization appears mainly to affect relaxation through myoendothelial gap junctions. Overall, these data suggest that K
+
and myoendothelial coupling evoke EDHF-mediated relaxation through distinct, definable pathways.
Publisher
Ovid Technologies (Wolters Kluwer Health)
Subject
Cardiology and Cardiovascular Medicine,Physiology
Cited by
193 articles.
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