Abstract

Resistance vessels regulate blood flow by continuously adjusting activity of the wall smooth muscle cells. These cells integrate a variety of stimuli from blood, endothelium, autonomic nerves, and surrounding tissues. Each stimulus elicits an intracellular signaling cascade that eventually influences activation of the contractile machinery. The characteristic time scale of each cascade and the sharing of specific reactions between cascades provide for complex behavior when a vessel receives multiple stimuli. Here, we apply sequential stimulation with invariant concentrations of vasoconstrictor (norepinephrine/methoxamine) and vasodilator (SNAP/carbacol) to rat mesenteric vessels in the wire myograph to show that (1) time elapsed between addition of two vasoactive drugs and (2) the sequence of addition may significantly affect final force development. Furthermore, force oscillations (vasomotion) often appear upon norepinephrine administration. Using computational modeling in combination with nitric oxide (NO) inhibition/NO addition experiments, we show that (3) amplitude and number of oscillating vessels increase over time, (4) the ability of NO to induce vasomotion depends on whether it is applied before or after norepinephrine, and (5) emergence of vasomotion depends on the prior dynamical state of the system; in simulations, this phenomenon appears as “hysteresis.” These findings underscore the time-dependent nature of vascular tone generation which must be considered when evaluating the vasomotor effects of multiple, simultaneous stimuli in vitro or in vivo.