Endothelial Nitric Oxide Suppresses Action-Potential-Like Transient Spikes and Vasospasm in Small Resistance Arteries

Abstract

Endothelial dysfunction in small arteries is a ubiquitous, early feature of cardiovascular disease, including hypertension. Dysfunction reflects reduced bioavailability of endothelium-derived nitric oxide (NO) and depressed endothelium-dependent hyperpolarization that enhances vasoreactivity. We measured smooth muscle membrane potential and tension, smooth muscle calcium, and used real-time quantitative polymerase chain reaction in small arteries and isolated tubes of endothelium to investigate how dysfunction enhances vasoreactivity. Rat nonmyogenic mesenteric resistance arteries developed vasomotion to micromolar phenylephrine (α 1 -adrenoceptor agonist); symmetrical vasoconstrictor oscillations mediated by L-type voltage-gated Ca 2+ channels (VGCCs). Inhibiting NO synthesis abolished vasomotion so nanomolar phenylephrine now stimulated rapid, transient depolarizing spikes in the smooth muscle associated with chaotic vasomotion/vasospasm. Endothelium-dependent hyperpolarization block also enabled phenylephrine-vasospasm but without spikes or chaotic vasomotion. Depolarizing spikes were Ca 2+ -based and abolished by either T-type or L-type VGCCs blockers with depressed vasoconstriction. Removing NO also enabled transient spikes/vasoconstriction to Bay K-8644 (L-type VGCC activator). However, these were abolished by the L-type VGCC blocker nifedipine but not T-type VGCC block. Phenylephrine also initiated T-type VGCC-transient spikes and enhanced vasoconstriction after NO loss in nonmyogenic arteries from spontaneously hypertensive rats. In contrast to mesenteric arteries, myogenic coronary arteries displayed transient spikes and further vasoconstriction spontaneously on loss of NO. T-type VGCC block abolished these spikes and additional vasoconstriction but not myogenic tone. Therefore, in myogenic and nonmyogenic small arteries, reduced NO bioavailability engages T-type VGCCs, triggering transient depolarizing spikes in normally quiescent vascular smooth muscle to cause vasospasm. T-type block may offer a means to suppress vasospasm without inhibiting myogenic tone mediated by L-type VGCCs.

Coronary Microvascular Dysfunction

“…106 A recent study has demonstrated the advantage of T-type calcium channel blockade in suppressing vasospasm in small coronary arteries through EDH-mediated mechanisms. 107 These results shed light on the pleiotropic effects of benidipine on coronary inflammation and vasomotion abnormalities, although benidipine is available exclusively in several Asian countries (eg, Japan, China, Korea, and the Philippines) for the treatment of hypertension and vasospastic angina. 108…”

Tracking endothelium-dependent NO release in pressurized arteries

“…Isolated arteries were mounted in a Mulvany-Halpern wire myograph chamber (model 610, Danish MyoTechnology, Denmark) as described previously ( Smith et al, 2020 ). Artery viability was determined using the α 1 -adrenergic vasoconstrictor phenylephrine (PE, 3 μM; Sigma-Aldrich, MO, United States) to assess SMC function, followed by the EC-dependent agonist acetylcholine (ACh, 10–100 nM; Merck, NJ, United States) to assess EC function.…”

Endothelium-Dependent Hyperpolarization: The Evolution of Myoendothelial Microdomains

“…103 Recruiting MEF to activate K Ca 3.1 and K Ca 2.3, and release of NO, is an essential part of the cycle that entrains vasomotion, and block of either NO synthesis or EDH input each raises vasoreactivity and abolishes sinusoidal vasomotion. 82,91,106 Vasomotion can persist in some form after EC removal, and this may be possible because of input from VSM K Ca 1.1 channels, which are voltage-and Ca 2+sensitive. 103 Vasomotion was of particular interest to Tudor Griffith, and in 1994 with David Edwards, he proposed that the ability of rhythmic changes in artery diameter to switch rapidly from sinusoidal, steady-state oscillations into nonrepetitive patterns including periodic, quasiperiodic, and intermittent activity was not random but characteristic of nonlinear systems classified as "chaotic" and amenable to fractal analysis.…”

“…When both NO and EDH are blocked, the depolarizing spikes in membrane potential become more consistent, and associated with low-amplitude, higher frequency oscillations in vasoconstriction, termed vasospasm. Modified from Smith et al, 106 the time base for membrane potential and tension represents simultaneous recordings.…”