Feedback signal?

Fig. 11.9 Metabolic local control. Over the autoregulatory range of perfusion pressure (Pa − Pv, arterial pressure minus venous pressure), arterial resistance and the number of perfused capillaries are modulated by a feedback signal linked to oxygen delivery (JO2) and parenchymal metabolism (VO2)

gain (Fig. 11.8) [13, 16]. Such a regulatory feedback loop would permit the vessel radius adjustments necessary to maintain ßow when pressure changes (e.g., if arterial pressure increases, the arterial contraction must decrease the radius below control to maintain blood ßow constant). Johnson also noted that in terms of homeostasis, the myogenic mechanism is better suited to regulating tissue capillary hydrostatic pressure than blood ßow (e.g., if arterial or venous pressure rises, arterial myogenic vasoconstriction in both cases would tend to preserve capillary hydrostatic pressure).

11.3.2 Metabolic Local Control

The basic premise of metabolic local control is that tissues regulate their blood ßow to insure the delivery of nutrients and removal of waste in accordance with their metabolic requirements (Fig. 11.9) [17]. The metabolic hypothesis assumes communication between parenchymal cells and the smooth muscle cells controlling the tissue vascular resistance (arterioles) and capillary ßow distribution (precapillary sphincters and pericytes) [18, 19]. Because most tissues utilize aerobic metabolism, the convective delivery of oxygen by blood ßow to the tissue is often considered the regulated variable. If oxygen delivery decreases (e.g., due to a fall in arterial pressure)

Fig. 11.10 Coronary reactive hyperemia. Blood ßow overshoot in canine circumßex artery after release of 15 s (top) and 30 s (bottom) arterial occlusions before (left) and 120 min after (right) administration of the nonselective adenosine antagonist, theophylline. Magnitude of postocclusion blood ßow overshoot increases with occlusion duration and is blunted by adenosine blockade [20]

or oxygen demand increases (e.g., increased neuronal activity), the parenchymal cells produce a vasodilatory signal that increases tissue blood ßow and capillary perfusion such that oxygen delivery is again matched to oxygen demand. Conversely, if oxygen delivery exceeds demand, the parenchymal cells decrease production of the vasodilatory signal until delivery and demand are again matched. There are numerous vasodilator candidates linked to metabolism that can act as the feedback signal (e.g., adenosine, CO2, H+, lactate, etc.), and it is likely that all participate to a variable extent depending on the tissue. Because it is a vasoconstrictor, oxygen can also modulate local resistance in accordance with metabolic demand.

Several lines of evidence support the metabolic local control hypothesis: reactive hyperemia (Fig. 11.10), functional hyperemia (Fig. 11.11), modulation of pressure-ßow autoregulation by metabolic stimulation (Fig. 11.12), and hypoxic hyperemia (Fig. 11.13).

11.3.3 Flow-Mediated Vasodilation

In vitro and in vivo studies of large and small arteries show that ßow elicits endotheliumdependent vasodilation (Fig. 11.14) [24Ð28].

Fig. 11.11 Intestinal functional hyperemia. Blood ßow (Qb) in an isolated loop of feline ileum before and after Þlling the lumen with a glucose solution. Oxygen consumption (VO2) increased during glucose absorption, which was achieved by increased Qb rather than increased arteriovenous oxygen extraction (A-VO2). The increased Qb was due to a decrease in vascular resistance (Rt) since arterial (Pa) and venous (Pv) pressures were unaltered [21]

Tyrodes + Glucose

J VM = 0.70 ml/min/100g

Time (min)

Fig. 11.12 Gastric mucosal autoregulation and metabolic activity. Effect of changing perfusion pressure on total oxygen consumption and mucosal blood ßow in a pres- sure-perfused canine stomach preparation before and

during pentagastrin-stimulated acid secretion. Increased oxygen consumption was associated with an upward shift in the mucosal pressure-ßow relationship [22]

Fig. 11.13 Hypoxic vasodilation. Systemic hypoxia elicits increased hind limb skeletal muscle blood ßow (FA) in a denervated dog preparation [23]

a

The response appears to be mediated by shear stress exerted on the endothelial cells by the velocity and viscosity of blood moving within the vessel lumen (Fig. 11.15). The response is inhibited by indomethacin (Fig. 11.15) and nitric oxide synthase inhibitors, indicating that endothelial release of vasoactive prostaglandins and nitric oxide play a role in the response [29, 30]. The role of ßow-mediated vasodilation in local control of tissue blood ßow is complex since it has the potential to be inherently unstable (i.e., an increase in ßow elicits a vasodilation that causes a further increase in ßow). However, the robustness of the response varies with location in the arterial tree and is likely modulated by metabolic and myogenic local control mechanisms.

11.3.4Flow Control by Intercellular Conduction

One potential integrating mechanism for the various local control mechanisms is intercellular communication along the arterial tree [31]. The evidence for this mechanism is the rapid propagation of a focal vasodilation elicited by iontophoretic application of acetylcholine (Fig. 11.16) [32]. The vasodilation spreads from one region of

b

1.060 cmH2O Intraluminal pressure (n = 14)

0.6Endothelium denuded

0.5

Pressure gradient (cmH2O)

Fig. 11.14 Flow-mediated vasodilation. (a) Isolated pig coronary arterioles dilate in response to ßow increase caused by increased perfusion pressure ( P) while holding

the midpoint intraluminal pressure constant. (b) Flowinduced vasodilation is abolished after removal of endothelium [28]

Diameter (μm)

140

120

Diameter (μm)

140

120

100

80

Shear stress (dyn/cm2)

Fig. 11.15 Flow-mediated vasodilation and shear stress. Isolated rat cremaster arterioles dilate in response to shear stress increased by raising ßow (top) or viscosity (bottom).

Shear stress-induced dilatation is eliminated by endothelial removal (left) or indomethacin (right) [29]

Fig. 11.16 Propagated vasodilation. In hamster b cheek pouch arterioles (a), a

point application of acetylcholine (ACh) causes vasodilation (b) that propagates upstream past a double occlusion (c) indicative of cell-to-cell communication along the arterial tree [32]

Diameter (µm)