The resistance network that controls blood flow to skeletal muscle comprises terminal arterioles, as well as larger arterioles and the small (feeder) arteries from which they derive. In small (terminal) arterioles the products of energy metabolism are effective dilators, but the accumulation of metabolites alone has relatively little effect on vascular resistance. The reason for this is that in order to achieve optimal vascular conductance, both small arterioles and the larger arterioles feeding them must dilate in concert. More than 70 years ago the German physician A. Schretzenmayer provided the first experimental evidence for flow-induced dilation. In the hind legs of anesthetized cats he showed that whenever blood flow to the leg was increased, there was a concomitant increase in the diameter of the feeding femoral artery. It was concluded that this flow-dependent dilator response, which improves conductivity of feeding vessels, was due to a tissue-derived signal transmitted along the vascular tree. Since distal transection did not impede the dilation of conduit arteries in response to flow, it became evident that this dilator response was a locally generated phenomenon of the vascular wall. Further studies led to the concept of an "ascending or conducted dilation" in conduit arteries under conditions of high tissue oxygen demand. This coordinated longitudinal transmission of vasomotor responses is essential for the optimization of vascular conductivity and organ perfusion.
Experimentally, ascending dilatation can be studied in vivo and in vitro by assessing the response to a vasoactive substance at the point of application (local response) as well as at a remote site. This conducted vasodilatation can travel bidirectionally and the amplitude of the conducted vasodilatation is generally smaller than that of the local response. Although there is a gradual decline in the conducted vasodilatation along some arterioles, there is no obvious decay of the conducted response along feed arteries.
Conducted responses have been intensively investigated, but the exact mechanism remains to be clarified. Most researchers agree that NO does not play a major role in this response. Indeed, conducted vasodilatation in response to a number of stimuli is not affected by NOS inhibitors and the response is apparently intact in eNOS-deficient mice. Changes in membrane potential appear to be central to the phenomenon of ascending dilatation, and responses are generally attributed to the propagation of a hyperpolarization along the vascular wall that is linked either to the actions of an EDHF or to the direct transmission of an electrical signal between vascular cells. Over the past few years evidence has accumulated to suggest that homocellular as well as hetero-cellular gap junctional communication are involved in the phenomenon of conducted dilatation.
At this point, it is necessary to note that not all vessels within one vascular bed respond in the same way in response to an accumulation of vascular metabolites or to mechanical stimuli (transmural pressure and shear stress). Metabolic control exerts a dominant influence on the smallest arterioles (< 20 mm), but is a generally less important stimulus in more upstream vessels. The pressure-induced myogenic response dominates in middle-sized arterioles, whereas its influence wanes upstream in relatively large arterioles (100-200 mm) in which fluid shear stress predominantly governs tone.
Ascending dilation: In a contracting skeletal muscle, low PO2 and vasoactive metabolites elicit a local response and initiate a conducted vasodilatation that "ascends" the vascular tree to induce the simultaneous vasodilatation of the feed arteries as well as branch arteries and thus increase blood flow. This coordinated longitudinal transmission of vasomotor responses is essential to achieve optimal organ perfusion.
Autacoid: From the Greek autos [self] and akos [remedy]. Endothelium-derived autacoids such as NO, PGI2, and O2- are generally short-lived and locally acting.
Endothelium-derived hyperpolarizing factor: Describes endothelium-dependent relaxation that is not mediated by either nitric oxide or prostacyclin but is temporally correlated with endothelial cell hyperpolarization and followed shortly thereafter by smooth muscle cell hyperpolarization and relaxation.
Myogenic tone: An intrinsic mode of control of activity in which the stretch of the vascular smooth muscle cell membrane results in the activation of stretch-sensitive channels. The result is depolarization and contraction.
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Busse, R., Edwards, G., Feletou, M., Fleming, I., Vanhoutte, P. M., and Weston, A. H. (2002). EDHF: Bringing the concepts together. Trends Pharmacol. Sci. 23, 374-380. This article is the first serious attempt by three different groups to take all of the current concepts relating to EDHF-mediated relaxation and combine them in one (more or less) unifying concept. This paper is an excellent overview and a great help to those confused by the apparent inconsistencies in the literature.
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Circ. Res. 89, 650-660. Fleming, I., and Busse, R. (2000). Activation of NOS by Ca2+-dependent and Ca2+-independent mechanisms. In Nitric Oxide (L. J. Ignarro, ed.), San Diego: Academic Press, pp. 621-632. Fleming, I., and Busse, R. (2003). Molecular mechanisms involved in the regulation of the endothelial nitric oxide synthase. Am. J. Physiol. Regul. Integr. Comp. Physiol. 284, R1-R12. Govers, R., and Rabelink, T. J. (2001). Cellular regulation of endothelial nitric oxide synthase. Am. J. Physiol. Renal. Physiol. 280, F193-F206. Ingber, D. E. (2003). Tensegrity I. Cell structure and hierarchical systems biology. J. Cell Sci. 116, 1157-1173. Ingber, D. E. (2003). Tensegrity II. How structural networks influence cellular information processing networks. J. Cell Sci. 116, 1397-1408. A pair of state-of the-art articles that describe in detail how the architecture of endothelial cells can influence signaling in response to physical stimuli.
Segal, S. S. (2000). Integration of blood flow control to skeletal muscle: key role of feed arteries. Acta Physiol. Scand. 168, 511-518.
An excellent overview of the significance of ascending dilation and the integrated control of vascular networks.
Ingrid Fleming (although from Northern Ireland) is a Professor of Physiology at the Johann Wolfgang Goethe University in Frankfurt. Her research interests center on signal transduction in vascular cells, in particular on the regulation of nitric oxide synthase activity and the phenomenon of nitric oxide/prostacyclin or endothelium-derived hyperpolarizing factor (EDHF)-mediated vascular relaxation.
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