Harris J. Granger

Role of resistance and exchange vessels in local microvascular control of skeletal muscle oxygenation in the dog.

The effects of reduction in perfusion pressure, arterial hypoxia, muscle contraction, and adrenergic stimulation on the hindlimb muscle circulation were studied. Under normal conditions (venous Po2 ≤ 40 mm Hg), oxygen delivery to the muscle was maintained mainly by large increases in the capillary exchange capacity and the oxygen extraction ratio in accord with tissue demand following the application of the above stresses. The participation of the resistance vessels under these conditions was minimal. The prevailing venous oxygen tension then was reduced by several means and the response of vascular resistance and capillary exchange capacity to the same stresses was reexamined. At the lower prevailing venous Po2, the sensitivity of the resistance vessels to metabolic and hemodynamic disturbances was greatly increased. Consequently, blood flow autoregulation, functional hyperemia, and hypoxic hyper-emia were more intense when venous oxygen tension was low. In contrast, the contribution of exchange capacity was diminished, probably owing to the fact that most of the capillaries already are open at low venous Po2. These data suggest that the locus of local microvascular control of muscle oxygenation shifts from the normally more sensitive precapillary sphincters to the proximal flow-controlling arterioles as the prevailing venous oxygen tension falls. Yet, although the relative contribution of the resistance and exchange vessels to intrinsic regulation of tissue oxygenation is related to the prevailing venous oxygen tension, the two compensatory mechanisms operating in concert maintain tissue Po2 above the critical level over a wide range of stresses.

Whole-Body Circulatory Autoregulation and Hypertension

A possible cause of elevated arterial pressure involves the interrelationship between autoregulation of blood flow and control of arterial blood pressure. An autoregulatory response could theoretically result in an elevated arterial pressure and an elevated peripheral resistance with normal or nearly normal cardiac output. Several experimental studies support this theory. Autoregulation of blood flow has been observed in a number of the bodys tissues, and the summated effect, whole-body autoregulation, has been demonstrated in areflex dogs. An increase in cardiac output precedes an increase in total peripheral resistance, and a decrease in cardiac output precedes a decrease in total peripheral resistance. The gain of the system was calculated to be slightly greater than three. This same hemodynamic pattern, that is, an increase in cardiac output preceding an increase in resistance, has been observed at the onset of hypertension. We have observed increases in cardiac output at the beginning of salt-induced hypertension in dogs and at the beginning of hypertension secondary to fluid volume expansion in anephric patients, while other investigators have observed this hemodynamic pattern in a number of instances, including labile hypertension, perinephritis hypertension, and Goldblatt hypertension. The increased cardiac output can be caused by several factors, although in many instances the cause appears to be fluid retention. A hemodynamic response suggesting the involvement of whole-body autoregulation, that is, a decrease in cardiac output precedes a decrease in peripheral resistance, has been observed in the reversal of hypertension. Dehydrating overhydrated (and hypertensive) anephric patients and unclipping the renal artery in Goldblatt hypertension elicits this pattern, as well as administration of diuretics or several other antihypertensive drugs to hypertensives. Theoretically, the role of the kidney in hypertension is either to initiate the autoregulatory response by causing fluid retention or to allow the autoregulatory response to occur by preventing the loss of fluid in the face of an elevated arterial pressure.

Intrinsic Metabolic Regulation of Blood Flow, O2 Extraction and Tissue O2 Delivery in Dog Skeletal Muscle

In a recent systems analysis of intrinsic microvascular control of tissue oxygen deliveryl, we proposed that O2 delivery to skeletal muscle cells was autoregulated in accordance with their metabolic requirements through local metabolic control of blood flow and O2 extraction. We also suggested that blood flow is regulated through feedback regulation of arteriolar tone, and O2 extraction is modulated through precapillary sphincter control of capillary surface area and capillary-to-cell diffusion distance. Our analysis, which includes as a major feature the assumption that precapillary sphincter sensitivity to metabolic control is greater than that of the arterioles, suggests that: 1) When the venous oxygen reserve is large, increased extraction is the major mechanism by which tissue oxygen delivery is maintained in accordance with cellular requirements, whenever the O2 availability-to-demand ratio is reduced. Under these conditions, the contribution of local flow regulation is minimal. 2) As the prevailing venous oxygen reserve decreases, the contribution of the arteriolar flow control system increases and the importance of the precapillary sphincter control of O2 extraction diminishes. Indeed, at a venous oxygen saturation of 25 per cent, blood flow responses account for over 90 per cent of the total compensation. 3) Thus, as metabolic stresses become greater, the major locus of intrinsic microvascular control of tissue oxygen delivery moves from the normally more sensitive sphincters to the upstream arterioles. In this manner, adequate tissue oxygenation is maintained over a wide range of metabolic stresses, the relative contribution of blood flow and O2 extraction to the regulation of tissue oxygen delivery being determined by the prevailing venous oxygen level. The data presented in this paper represent the experimental basis of our analysis.

Mechanisms of Increased Tissue Oxygen Delivery Following Release of Arterial Occlusion in Canine Skeletal Muscle and Skin

Tissue oxygen delivery is dependent on the local blood flow and the extent of oxygen extraction. Concerning the intrinsic microvascular control of tissue O2 delivery, a recent system analysis (1) and experimental data (2) suggest that adequate tissue oxygenation is maintained over a wide range of metabolic stresses, the relative contribution of blood flow and O2 extraction to the regulation of tissue O2 delivery being determined by the prevailing venous oxygen level. The previous study (2) has shown that in skeletal muscle perfused with constant pressure, both reactive hyperemia and elevated arteriovenous (A-V) O2 difference contribute to the O2 debt repayment following arterial occlusion when the initial A-V O2 difference is in the normal range. However, at low prevailing A-V O2 difference, increased O2 extraction is the major mechanism by which the tissue repays its O2 debt and the contribution of blood flow is minimal. As the prevailing venous O2 reserve is lowered, the contribution of O2 extraction diminishes and reactive hyperemia becomes more important for the compensation. Thus, the immediate post-occlusion O2 extraction is only slightly elevated or even transiently depressed.