Mechanistic basis of differential conduction in skeletal muscle arteries

Authors


Corresponding author D. G. Welsh: Smooth Muscle Research Group, HMRB-G86, Heritage Medical Research Building, University of Calgary, 3330 Hospital Dr. N.W., Calgary, Alberta, Canada, T2N-4N1. Email: dwelsh@ucalgary.ca

Abstract

The goal of this investigation was to probe intercellular conduction in skeletal muscle feed arteries and to address why smooth muscle-initiated responses fail to robustly spread like their endothelial counterpart. Using computational and experimental approaches, two interrelated rationales were developed to explain this apparent discrepancy in cell-to-cell communication. The first rationale stressed that smooth muscle electrical responses, if initiated, will be actively dissipated as they spread from cell-to-cell along the arterial wall. Charge dissipation is promoted within arteries by the structural and connectivity properties of vascular cells. The second rationale centred on the idea that when agents other than KCl stimulate a limited number of smooth muscle cells, they fail to generate the currents required to elicit a localized membrane potential (VM) response. This insufficiency results in part from charge loss, via gap junctions, to neighbouring unstimulated cells. Experiments confirmed the latter rationale by showing that focal phenylephrine application: (1) elicited a localized constriction insensitive to L-type Ca2+ channel blockade; and (2) failed to substantially depolarize vascular smooth muscle cells. Further investigation revealed that while focal phenylephrine-induced constriction was VM independent, it was reliant on internal Ca2+ mobilization and the activation of inositol 1,4,5-trisphosphate (IP3) receptors. The preceding findings illustrate that by using computational modelling and experimentation in a complementary manner, one can isolate key cellular properties and rationally examine their role in limiting the conduction of smooth muscle-initiated responses. Functionally, these observations enable investigators to assign the concept of ‘local and global’ blood flow control to the electrical and/or non-electrical behaviour of specific cell types.

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