Does arterial myogenic tone determine blood flow distribution in vivo?

BLOOD FLOW DISTRIBUTION at rest and during exercise is intricately controlled by centrally driven neuroeffector mechanisms and circulating hormones (particularly epinephrine), local autacoids, and metabolites, all superimposed on the inherent or “myogenic” reactivity of the arterial smooth muscle. During exercise, the cardiac output of a trained athlete can increase 5-fold, and these mechanisms serve to coordinate a huge ( 20-fold) increase in the amount of blood routed to the exercising muscle (3). The dramatic nature of this increase is illustrated by the fact that the proportion of the cardiac output diverted to skeletal muscle can change from 20% to 80%! Importantly, and to the benefit of the individual, despite this enormous increase in the flow of blood to muscle, brain blood flow is not compromised (3). But to what extent do the inherent characteristics of the arteries of the brain and musculature explain these distinct changes? As cerebral arteries are not particularly responsive to the sympathetic nerves surrounding them, myogenic reactivity is thought to be a fundamental determinant of the constant flow of blood to the brain and, as a consequence, has been extensively studied. The most direct studies have assessed how changes in intraluminal pressure links to smooth muscle contraction/relaxation in isolated arteries, where reflex and most local influences are absent and steady-state conditions can be achieved. It is technically extremely difficult to make intracellular recordings from the very small ( 10 m width) smooth muscle cells, particularly in isolated arteries under physiological pressure. However, a now classic study in 1984 by Harder (13) first showed that increasing pressure alone caused depolarization and as a result stimulated Ca influx and vasoconstriction. Unfortunately, technology at the time did not allow accurate simultaneous measurement of diameter. This was achieved in later studies, notably from Nelson’s group (19), as the complexity of the myogenic control mechanism became apparent. It is now known that voltage-activated calcium entry is not the only mechanism responsible for changes in myogenic tone (16) and that the relative contributions from different mechanisms vary between and within vascular beds. In this issue of the American Journal of Physiology-Heart and Circulatory Physiology, Kotecha and Hill (21) are the latest to attempt the extremely difficult task of quantifying the importance of membrane potential for myogenic reactivity, but this time in a resistance artery from a striated muscle bed (the rat cremaster muscle, pressurized arteries with a passive diameter of 140 m at 70 mmHg). This is the first study in a muscle resistance artery that has attempted to assess the effect of a stepwise increase in luminal pressure on smooth muscle membrane potential and arterial diameter. In addition, the authors have compared their data with published data from rat isolated cerebral arteries [distal posterior, passive diameter of 200 m at 70 mmHg (19)] to attempt to reveal how closely arteries from vascular beds with quite distinct roles may or may not share the mechanisms responsible for myogenic tone. Of course, a key question is “What are the physiological pressures in each bed?” While we cannot answer this absolutely, measurement of arterial pressure in anesthetized animals has shown that the pressure at small cerebral arteries [including 180m feline pial arteries (10)] is only about 50–60% of systemic (14). In contrast, even in skeletal muscle arteries and arterioles with diameters 100 m, the pressure is still 75–95% of systemic [a staggering 90–95% in 70to 100m feline tenuissimus muscle arteries! (11)] (14). However, it is not known what these relative pressures are during exercise, such delicate measurements not being feasible in moving tissue. Given these approximate values for pressure in vivo, and a mean systemic blood pressure of 100 mmHg (15), what would the corresponding arterial smooth muscle membrane potential be in the respective vascular beds? These values must be estimated, as there are no available direct measurements in rat distal posterior cerebral or cremaster arteries. However, by using data from isolated arteries (19, 21), the predicted values would be near 45 mV (at 60 mmHg) in the cerebral artery and 37 mV (at 80 mmHg) in the muscle arteries. At these (nonexercise resting) levels, active myogenic tone (defined as the percentage of passive diameter) would be near 40% in cerebral arteries and closer to 50% in the muscle arteries (taken from Ref. 21). In effect, “resting” resistance to blood flow would be somewhat greater in the muscle arteries, which is of course what we might predict. To put this into some sort of context, based on the present data, a hyperpolarization of 10 mV (e.g., during exercise) would dilate the cerebral artery by only 15%, whereas the cremaster artery would dilate by 50% [taken from Fig. 8 (21)]. So it seems difficult to deny the conclusion that the intrinsic nature of the arteries underlies the more dramatic increase in blood flow to striated muscle during exercise. Although direct electrophysiological recording from striated muscle arteries in vivo is difficult, it is possible to see that the arteries and arterioles in the cremaster muscle of anesthetized animals have active tone (which is partly dependent on tissue PO2) (12). Furthermore, arterial diameter and blood flow can be increased by contracting a subset of muscle fibers (1, 12). The exact nature of the dilator factors that are active during exercise is not clear (27). Some data do suggest a key role for arterial hyperpolarization, such as the sensitivity of muscle fiber contraction-mediated dilation to glibenclamide (4, 24), an inhibitor of ATP-sensitive K channels (and ABC transporters), and the release of ATP into the lumen of arteries during exercise (26). ATP is released in response to low PO2 [from red blood cells (8, 9)] and may have a key role in regulating tissue perfusion. Stimulation of endothelial cell purinergic receptors evokes dilation that can spread upstream through the wall of arteries/ arterioles and against the direction of blood flow (termed “spreading dilation”) (9, 22). In addition, an increase in vasAddress for reprint requests and other correspondence: K. A. Dora, Dept. of Pharmacy and Pharmacology, Univ. of Bath, Bath BA2 7AY, UK (e-mail: [email protected]). Am J Physiol Heart Circ Physiol 289: H1323–H1325, 2005; doi:10.1152/ajpheart.00513.2005.