William F. Jackson, Ph.D., FAHA, FCVS, FAPS
Professor, Pharmacology & Toxicology
Michigan State University
“Potassium channels and the regulation of arteriolar tone in
skeletal muscle: a tale of three channels.”
Vascular smooth muscle (VSM) cells and endothelial cells (EC) that form the walls of arterioles express a diverse array of ion channels that play important roles in the function of these cells and the microcirculation in both health and disease. Potassium channels, in particular, importantly regulate arteriolar function primarily through their impact on membrane potential. Membrane potential importantly controls the open state probability of the voltage-gated Ca2+ channels (VGCC), which determines intracellular calcium and hence the contractile activity (tone) of VSM cells. Membrane potential also importantly impacts the electrochemical gradient for diffusion of calcium into cells through non-voltage gated channels such as those in the transient receptor potential family of ion channels. Finally, membrane potential, through its ability to be transmitted between cells through gap junctions, also acts as an important signal for cell-cell communication in the arteriolar wall. Arteriolar VSM cells express at least four different classes of potassium channels. For the sake of time, I will focus on three channels that we have shown to importantly regulate the tone of skeletal muscle arterioles including ATP-sensitive potassium (KATP) channels, large conductance calcium-activated potassium (BKCa) channels and inward-rectifier potassium (KIR) channels. In both in vivo and in vitro experiments, we have found that KATP channels are active at rest, mediate vasodilation induced by vasodilators that act through GS-coupled receptors such as adenosine, isoproterenol and prostacyclin. We have also shown that KATP channels are inhibited vasoconstrictors that act through GQ-coupled receptors such as norepinephrine. Skeletal muscle arteriolar tone also is determined by the activity of BKCa channels, although only when VGCCs are active and arteriolar BKCa channels do not seem to be controlled by ryanodine receptor mediated calcium sparks. This is in contrast to upstream resistance arteries where BKCa channel activity is coupled to ryanodine receptor function. Nevertheless, arteriolar BKCa channels importantly contribute to the negative-feedback regulation of both pressure-induced myogenic and vasoconstrictor-induced tone. Finally, skeletal muscle KIR channels contribute to potassium-induced arteriolar vasodilation, but are not the sole mediators of this response, in contrast to arterioles in the brain, for example. In skeletal muscle arterioles the sodium-potassium ATPase also importantly mediates potassium-induced vasodilation, with KIR channels acting to amplify and sustain dilation activated by the sodium/potassium pump. Thus, KATP, BKCa and KIR channels appear to importantly contribute to regulation of the function of skeletal muscle arterioles. Supported by PHS grant HL 32469.
Friday April 11, 2025, 11:00AM-12:00PM, LIB-110
University of North Texas Health Science Center
Fort Worth, Texas