Effect of myogenic tone on agonist-mediated vasoconstriction in isolated arteries: A computational study

Background and objective: Vasoconstriction of the resistance artery is mainly determined by an integrated action of multiple local stimuli acting on the vascular smooth muscle cells, which include neuronal delivery of alpha-adrenoceptor agonists and intraluminal pressure. The contractile activity of the arterial wall has been extensively studied ex vivo using isolated arterial preparations and myography techniques. However, agonist-mediated vasoconstriction response is often confounded by local effects of other stimuli (e.g., pressure) and, it remained unclear whether the pressure-induced myogenic response has any implication on the efficacy of agonist-mediated vasoconstriction during blood flow regulation in tissues. A quantitative understanding of the influence of each stimulus is necessary to understand the interaction between multiple regulatory mechanisms, which is required to ensure timely oxygen delivery to meet tissue needs. Methods: We developed a simple empirical model of isolated vessel vasoreactivity that includes passive vessel wall mechanics and a lumped representation of active smooth muscle activation as a function of agonist concentration and pressure. Pressure myograph data in dog renal arterioles and rat femoral arterioles, isovolumic myograph data in rat femoral arteries, and vasoactive data in rat skeletal muscle arterioles were analyzed using the model. The effect of physiological pressure changes on the sensitivities of vascular segments to adrenergic agonists phenylephrine and norepinephrine was evaluated. Results: Model-based analysis of isolated vasoreactivity data, obtained due to changes in pressure and vasoconstricting agonists revealed that the strength of myogenic response of a resistance vessel has a strong influence on the sensitivity and dynamics of agonist response. An increase in intraluminal pressure was found to reduce the magnitude of agonist-mediated tone by lowering the sensitivity of the vessel segment to agonist. The passive mechanical properties of arterial wall considearably influence the agonist-mediated contraction in isolated arteries. These results demonstrate how passive vessel wall mechanics may dominate the vasoactive responses of the common myogenic and adrenergic pathways of smooth muscle contraction in blood flow regulation, supporting a long standing notion that there exists segment-specific vasoregulation in microvascular networks of various tissues. Conclusion: The present model provides a simple and powerful tool for quantifying ex vivo vasoreactivity of asolated arteries to qualitatively study the interaction between myogenic and alpha-adrenergic control of vascular tone in isolated vessels. Analysis of pressure myography data and isovolumic myography data in different sizes of vessels and tissues, in response to norepinephrine and phenylephrine revealed the importance of passive vessel mechanics in arteriolar vasomotion and setting up of basal vasomotor tone at single vessel-level. The present study will be useful to quantify the extent to which myogenic tone may influence agonist-mediated vasoconstriction and agonist effect on pressure-mediated myogenic response in microvascular networks during blood flow regulation in tissues.