Myogenic contraction in rat skeletal muscle arterioles: smooth muscle membrane potential and Ca²⁺signaling

Abstract

The present studies examined relationships between intraluminal pressure, membrane potential (E(m)), and myogenic tone in skeletal muscle arterioles. Using pharmacological interventions targeting Ca(2+) entry/release mechanisms, these studies also determined the role of Ca(2+) pathways and E(m) in determining steady-state myogenic constriction. Studies were conducted in isolated and cannulated arterioles under zero flow. Increasing intraluminal pressure (0-150 mmHg) resulted in progressive membrane depolarization (-55.3 +/- 4.1 to -29.4 +/- 0.7 mV) that exhibited a sigmoidal relationship between extent of myogenic constriction and E(m). Thus, despite further depolarization, at pressures >70 mmHg, little additional vasoconstriction occurred. This was not due to an inability of voltage-operated Ca(2+) channels to be activated as KCl (75 mM) evoked depolarization and vasoconstriction at 120 mmHg. Nifedipine (1 microM) and cyclopiazonic acid (30 microM) significantly attenuated established myogenic tone, whereas inhibition of inositol 1,4,5-trisphosphate-mediated Ca(2+) release/entry by 2-aminoethoxydiphenylborate (50 microM) had little effect. Combinations of the Ca(2+) entry blockers with the sarcoplasmic reticulum (SR) inhibitor caused a total loss of tone, suggesting that while depolarization-mediated Ca(2+) entry makes a significant contribution to myogenic tone, an interaction between Ca(2+) entry and SR Ca(2+) release is necessary for maintenance of myogenic constriction. In contrast, none of the agents, in combination or alone, altered E(m), demonstrating the downstream role of Ca(2+) mobilization relative to changes in E(m). Large-conductance Ca(2+)-activated K(+) channels modulated E(m) to exert a small effect on myogenic tone, and consistent with this, skeletal muscle arterioles appeared to show an inherently steep relationship between E(m) and extent of myogenic tone. Collectively, skeletal muscle arterioles exhibit complex relationships between E(m), Ca(2+) availability, and myogenic constriction that impact on the tissue's physiological function.

Enhanced spontaneous Ca2+ events in endothelial cells reflect signalling through myoendothelial gap junctions in pressurized mesenteric arteries

“…The exact contribution possible by Ca 2+ and IP 3 passing through gap junctions remains to be defined. Generally, PE acts to increase IP 3 and thus release Ca 2+ from the sarcoplasmic reticulum, while KCl increases Ca 2+ via depolarization and the opening of smooth muscle voltage-gated Ca 2+ channels [53,54]. As PE and KCl each had a similar effect on spontaneous Ca 2+ events in the endothelium, Ca 2+ rather than IP 3 may be expected to be the predominant influence diffusing from the smooth muscle to the endothelial cells.…”

Low intravascular pressure activates endothelial cell TRPV4 channels, local Ca 2+ events, and IK Ca channels, reducing arteriolar tone

“…The myogenic response stabilizes local blood flow and capillary filtration pressure as blood pressure changes and provides a basal tone that can be enhanced or attenuated by nerve transmitters, autacoids, and hormones (15). Myogenic contraction relies in large part on SMC depolarization, so hyperpolarization originating from either cell type will exert a significant influence on tone (17).…”

T-type Ca2+channels and autoregulation of local blood flow

“…41,54 However, a direct pressure-dependent activation of Ca 2C influx via VGCCs cannot play a major role in the myogenic response, since myogenic depolarization is dependent on opening of non-selective cation channels, 30,33 and is not affected by application of the L-type antagonist nifedipine. 114,115 The role of Ca V 3.1 channels (and perhaps Cav3.3 channels in human MCAs) in myogenic tone at lower pressures can be explained by a corresponding low myogenic depolarization in the range from approximately ¡65 to ¡50 mV, which activates a non-inactivation window-type Ca 2C current through these channels. Figure 1.…”