Stimulation history affects vasomotor responses in rat mesenteric arterioles
- 81 Downloads
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.
KeywordsContractile state Vasomotion Mesenteric artery Non-linear dynamics
Smooth muscle cell
Cycles per minute
Physiological saline solution
BOH is supported by the Danish Council for Independent Research (DFF – 1333-00172) and Weimann-fonden.
Compliance with ethical standards
All experimental protocols conformed to the European Convention for the Protection of Vertebrate Animals used for Experimental and other Scientific Purposes and were approved by the Danish National Animal Experiments Inspectorate.
Conflict of interest
The authors declare that they have no conflict of interest.
- 3.Atkins P, de Paula J (2009) Atkins’ physical chemistry, 9th edn. Oxford University Press, OxfordGoogle Scholar
- 5.Broegger T, Jacobsen JCB, Secher Dam V, Boedtkjer D M B, Kold-Petersen H, Pedersen F S, Aalkjaer C, Matchkov V (2011) Bestrophin is important for the rhythmic but not the tonic contraction in rat mesenteric small arteries. Cardiovasc Res 91:685–693. https://doi.org/10.1093/cvr/cvr111 CrossRefGoogle Scholar
- 10.Gustafsson H, Mulvany M J, Nilsson H (1993) Rhythmic contractions of isolated small arteries from rat: influence of the endothelium. Acta Physiol Scand 148:153–163. https://doi.org/10.1111/j.1748-1716.1993.tb09545.x CrossRefGoogle Scholar
- 11.Hill M A, Davis M J, Meininger G A, Potocnik S J, Murphy T V (2006) Arteriolar myogenic signalling mechanisms: Implications for local vascular function. Clin Hemorheol Microcirc 34(1-2):67–79Google Scholar
- 12.Jacobsen JCB, Aalkjaer C, Matchkov V, Nilsson H, Freiberg JJ, Holstein-Rathlou NH (2008) Heterogeneity and weak coupling may explain the synchronization characteristics of cells in the arterial wall. Philos Transact A Math Phys Eng Sci 366(1880):3483–3502. https://doi.org/10.1098/rsta.2008.0105 CrossRefGoogle Scholar
- 13.Jacobsen JCB, Aalkjaer C, Nilsson H, Matchkov V, Freiberg J, Holstein-Rathlou NH (2007) Activation of a cgmp-sensitive calcium-dependent chloride channel may cause transition from calcium waves to whole cell oscillations in smooth muscle cells. Am J Physiol Heart Circ Physiol 293(1):H215–H228. https://doi.org/10.1152/ajpheart.00726.2006 CrossRefGoogle Scholar
- 17.Nausch LWM, Bonev AD, Heppner TJ, Tallini Y, Kotlikoff MI, Nelson MT (2012) Sympathetic nerve stimulation induces local endothelial ca2+ signals to oppose vasoconstriction of mouse mesenteric arteries. Am J Physiol Heart Circ Physiol 302(3):H594–H602. https://doi.org/10.1152/ajpheart.00773.2011 CrossRefGoogle Scholar
- 23.Rådegran G, Saltin B (1999) Nitric oxide in the regulation of vasomotor tone in human skeletal muscle. Am J Phys 276:H1951–H1960Google Scholar
- 29.Somlyo AP, Wu X, Walker LA, Somlyo AV (1999) Pharmacomechanical coupling: the role of calcium, g-proteins, kinases and phosphatases. Rev Physiol Biochem Pharmacol 134:201–234Google Scholar