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A Unique Role of NO in the Control of Blood Flow

Ulrich Pohl and Cor de Wit

U. Pohl and C. de Wit are in the Physiologisches Institut of Ludwig Maximilians Universität, Pettenkoferstr. 12, D-80336, München, Germany.

	Abstract

 
Nitric oxide synthase (NOS) inhibitors induce significant vasoconstriction, suggesting an indispensable role of NO as a local vasodilator. This is due mainly to its effects on large arterioles that significantly control arterial conductance while scarcely being regulated by metabolites. NO's role in adapting vascular conductance to flow is pronounced during (re)active hyperemia and autoregulation.

	Introduction

Top Introduction Continuously synthesized NO... Dilation by metabolites Is a coordinated behavior... Flow-dependent dilation Functional implications Reactive hyperemia Active hyperemia Autoregulation Summary and conclusions References

 
Nitric oxide (NO) is a signaling molecule with manifold functions in various tissues as reflected by the existence of three different isoforms of the enzyme NO synthase (NOS). Under physiological conditions, the endothelial isoform of NOS (eNOS) is the prevailing form in the vascular system. Therefore, this short overview will deal with the physiological role of endothelium-derived NO.

NO stimulates soluble guanylate cyclase in vascular smooth muscle cells, thereby increasing guanosine 3',5'-cyclic monophosphate. This second messenger reduces intracellular free calcium by several mechanisms and also reduces the calcium sensitivity of the contractile apparatus. In addition, high doses of NO can directly affect potassium channels, thereby inducing hyperpolarization and a subsequent reduction of calcium influx into the vascular smooth muscle cells. All these events, alone or in combination, lead to a relaxation of vascular smooth muscle and, eventually, maximal vasodilation by application of physiological concentrations of endothelial stimuli.

	Continuously synthesized NO controls basal tone

Top Introduction Continuously synthesized NO... Dilation by metabolites Is a coordinated behavior... Flow-dependent dilation Functional implications Reactive hyperemia Active hyperemia Autoregulation Summary and conclusions References

 
In skeletal muscle, NOS inhibition by one of the substituted analogs of L-arginine reduces resting diameters of arterioles and small arteries by ~6–15% (4) and does so more effectively in large arterioles (>50-µm diameter). Similar observations, albeit with varying degrees of vasoconstriction, were made in most other organs and explain the increase in mean arterial pressure by 30–40 mmHg after application of NOS inhibitors. This effect suggests that endothelium-derived NO is continuously released ("basal release") and thereby contributes significantly to the control of basal tone. In some organs or under certain conditions, there might be some contribution of NO from other sources, such as nitridergic nerves or skeletal muscle cells, to this control of basal tone. The dilator effect of basally released NO is not simply due to the above-mentioned direct effects on smooth muscle tone. NO also reduces the release of the neurotransmitter norepinephrine from sympathetic nerve endings. Furthermore, it augments the effects of adenosine 3',5'-cyclic monophosphate (cAMP)-elevating dilators (e.g., prostaglandins) in a synergistic manner (4). Studies with chronic application of NOS inhibitors demonstrate that the peripheral vasoconstriction is sustained throughout the application time. This is quite astonishing, because one would assume that the vasoconstriction induced by NOS inhibition should be compensated by other locally released vasodilators.

	Dilation by metabolites

Top Introduction Continuously synthesized NO... Dilation by metabolites Is a coordinated behavior... Flow-dependent dilation Functional implications Reactive hyperemia Active hyperemia Autoregulation Summary and conclusions References

 
Tissue metabolites such as CO₂, adenosine, and lactate are efficient local vasodilators. In addition, tissue acidosis, moderate hyperkalemia, as well as a low PO₂ act as relaxants that are linked to the metabolic conditions of the tissue. Most metabolites are able to relax vascular smooth muscle directly, without the action of mediators. Moreover, some of them inhibit transmitter release from sympathetic nerve endings, thus further inducing vasodilation. No one of the above-mentioned metabolites is considered the main mediator of dilation; rather, they act together in a cooperative manner, and most of them can be replaced by others. Because of this redundant control of vascular tone by metabolic factors, the absence of NO, one single dilator, should be easily compensated. This intuitive assumption is supported by the fact that virtually all effects of NO on vascular smooth muscle can be imitated by metabolites or compounds like prostaglandins, whose release is linked to PO₂-dependent processes. Because blood flow is closely linked to tissue metabolism, the ongoing vasoconstriction after NOS inhibitors could result from a decrease of tissue metabolism by these compounds. However, the contrary seems to be the case, i.e., several studies report a reduction of tissue metabolism by NO. Hence one would expect that NOS inhibitors increase metabolically linked tissue perfusion. Why then is NO so unique that it cannot be fully replaced by locally acting metabolites?

	Is a coordinated behavior of small and large arterioles required?

Top Introduction Continuously synthesized NO... Dilation by metabolites Is a coordinated behavior... Flow-dependent dilation Functional implications Reactive hyperemia Active hyperemia Autoregulation Summary and conclusions References

 
The unique role of NO in the control of blood flow might be caused by differences in the main sites of action between NO and metabolites. Although metabolites are very effective in small terminal arterioles, an accumulation of metabolites alone cannot reduce vascular resistance sufficiently. Figure 1 shows schematically that not only the small resistance arterioles (R2) but also larger arterioles and small (feeding) arteries upstream (R1) must dilate simultaneously to achieve optimal vascular conductance. It has not yet been clarified exactly how metabolites could control these upstream vessels, which have functions of feeding as well as resistance vessels (2). To dilate these vessels adequately, metabolites have to diffuse over relatively long distances, because tissue-draining veins that could transport the metabolites by convection rarely run in the vicinity of the supplying arterial vessels. Thus, to coordinate the behavior of upstream and downstream vessels, additional mechanisms are necessary to achieve an adequate conductance down to the tissue supplied by certain capillaries. Such a mechanism is the conducted dilation, which most probably is based on an electrotonic propagation of local changes in membrane potential (15). Conduction of such signals from capillaries to upstream resistance vessels and between downstream arterioles and upstream vessels has been described to have considerable mechanical length constants.

View larger version (12K): [in this window] [in a new window]   FIGURE 1. Although under resting conditions, the highest resistance resides in small arterioles below 50-µm diameter, larger arterioles and even small arteries contribute to the overall resistance, especially at higher flow. A simple model, consisting of two resistances (R1 and R2) in series, reveals that a decrease of the distal resistance alone increases flow much less than a combined decrease of both. The distal/proximal resistance ratio was assumed to be 30:50. The coordinated decrease of both resistances can be achieved by signals generated in the distal vessels or by direct effects of flow increase on the endothelium.

	Flow-dependent dilation

Top Introduction Continuously synthesized NO... Dilation by metabolites Is a coordinated behavior... Flow-dependent dilation Functional implications Reactive hyperemia Active hyperemia Autoregulation Summary and conclusions References

 
An increase of wall shear stress is an adequate stimulus for the augmentation of endothelial NO release with increasing flow (11, 13). The following dilation tends to bring back the wall shear stress to initial values. The basic mechanism of translation of a mechanical force into biochemical events is still not clear. There is evidence, however, that shear stress increases intracellular free calcium by several mechanisms. This leads to an increase of NO synthesis because eNOS is a calcium/calmodulin-dependent enzyme. Moreover, at least with chronic elevation of shear stress, a calcium-independent activation of the enzyme by a stronger binding to the membrane and/or the cytoskeleton has been described. It should be mentioned only briefly that chronic elevation of shear stress also augments the expression of eNOS, which is the most likely reason for an improved flow-dependent dilation after chronic exercise training. The endothelial shear stress also increases under conditions of an elevated perfusion pressure, because of a myogenic vasoconstriction and/or a flow increase. Therefore, the shear-induced augmentation of NO release also represents an important mechanism to oppose pressure-induced myogenic constrictions (13), which would otherwise tend to reduce tissue perfusion in a self-augmenting, positive feedback loop. Indeed, we (13) have demonstrated that a shear stress-dependent NO release can completely oppose myogenic constrictions of isolated mesenteric microvessels.

	Functional implications

Top Introduction Continuously synthesized NO... Dilation by metabolites Is a coordinated behavior... Flow-dependent dilation Functional implications Reactive hyperemia Active hyperemia Autoregulation Summary and conclusions References

 
The considerations of the vascular coordinating role of flow-dependent dilation in larger arterioles and the inhibitory effects of NO on myogenic constrictions imply an important functional role for NO, especially in larger arterioles (see Fig. 2). Direct experimental evidence for this concept of a predominant role for NO in larger arterioles comes from intravital microscopy and studies on small isolated arterioles. These studies show that the metabolic control of arteries increases from proximal to distal vessels, whereas NO effects decrease in the same order (9). In line with these results, recent experiments suggest that the control by NO of the myogenic constriction is more pronounced in large than in small arterioles (3). Because large arterioles are also more densely innervated by sympathetic nerve fibers, the inhibitor effect of NO on sympathetic constriction is also functionally more important in this particular vascular section. One might, therefore, predict that the inhibition of NO release by a NOS inhibitor should result not only in a reduction of basal flow but also in an inadequate adaptation of blood flow to altered demands. This should be particularly important after transient vascular occlusion (reactive hyperemia) or during exercise (active hyperemia). Moreover, the adaptation of blood flow during alterations of perfusion pressure (autoregulation) should also be affected by NOS inhibition.

View larger version (34K): [in this window] [in a new window]   FIGURE 2. Relative significance of metabolites (Meta), nitric oxide (NO), and myogenic constriction (Myo) in large and small arterioles according to Kuo et al. (9) and our own observations (3, 4). Although under control conditions these influences are balanced [see balance between constriction (C) and dilation (D)], a reduction of NO has functional consequences predominantly in large arterioles. NOS, NO synthase.

	Reactive hyperemia

Top Introduction Continuously synthesized NO... Dilation by metabolites Is a coordinated behavior... Flow-dependent dilation Functional implications Reactive hyperemia Active hyperemia Autoregulation Summary and conclusions References

Nevertheless, the hyperemic response is reduced after NOS inhibition. A reduction of reactive hyperemia, especially in its duration, by NOS inhibitors would result when NO augmented cellular respiration, because a reduced metabolism would attenuate the need for a hyperemic compensation of the transient oxygen lack. However, as pointed out before, experiments done on isolated mitochondria and tissue suggest an inhibitory effect of NO (or peroxynitrite) on the respiratory chain. An attenuation of reactive hyperemia would also result if NO mediated the vasodilating effects of metabolites or enhanced smooth muscle sensitivity for these compounds. To date, there is no indication of such a phenomenon. There is, however, some evidence that NO enhances the effect of vasodilators that act through an increase of cAMP (4). In accordance with this, some studies reported that a combined blockade of NOS and other dilators such as prostaglandins or adenosine had a much greater inhibitory effect on the reactive hyperemia than predicted by the effect of each inhibitor individually.

This cannot be the only mechanism by which NO augments the hyperemic response, especially if NO improves vascular conductance as set out above. It has been shown that reactive hyperemia is associated with an increased release of NO (8). Likewise, intravital microscopic studies in rat cremaster arterioles revealed an endothelium-dependent postocclusive dilation that significantly contributed to the duration of the hyperemic response, at least after short-term occlusions (7). Other intravital microscopic studies clearly demonstrate a "delayed" dilation that is observed in medium-sized and large coronary arterioles during reactive hyperemia. The endothelium-dependent dilation, especially of these larger arterioles. may be essential for a full response because, even if metabolite concentrations increase in their close vicinity, these vessels are less sensitive to metabolites (1) than smaller arterioles because of their characteristic -adrenergic activation (₁-receptors). Moreover, NO may be necessary to attenuate the myogenic constriction that occurs because of the rapid increase of perfusion pressure shortly after the end of the vascular occlusion, which would shorten the duration of the hyperemic response and might also reduce the peak flow. This view is supported by experiments showing a much stronger and faster increase in the coronary resistance of isolated rabbit hearts after rapid pressure elevations when NOS is inhibited (Fig. 3). This occurs despite enhanced lactate release, i.e., enhanced accumulation of metabolites (14). Accordingly, a recent study using intravital microscopy has shown that after NOS inhibition a significant myogenic constriction of large arterioles occurs, although these vessels do not normally constrict upon increases of pressure (3). Thus the myogenic control is shifted to vessels where it is not directly opposed by the increase of metabolites. Studies based on measurements of segmental resistances also revealed an enhanced myogenic response of larger arterioles (> 25 µm) after NOS inhibition. Therefore, the enhanced myogenic constriction after NOS inhibition could well contribute to the reduction of the hyperemic response despite high levels of metabolites.

View larger version (13K): [in this window] [in a new window]   FIGURE 3. Enhanced coronary vasoconstriction [measured as decrease of coronary flow (CF)] after a step increase of perfusion pressure (CPP) in rabbit hearts treated with the nitric oxide synthase (NOS) inhibitor NG-nitro- L-arginine (L-NNA). This suggests a higher myogenic activity that indeed led to enhanced autoregulation in these hearts and also reduced reactive hyperemic responses. Note that after NOS inhibition, the basal flow is lower (despite an increased venous lactate content). From Ref. 14 with permission. A: original recordings. B: means from experiments.

	Active hyperemia

Top Introduction Continuously synthesized NO... Dilation by metabolites Is a coordinated behavior... Flow-dependent dilation Functional implications Reactive hyperemia Active hyperemia Autoregulation Summary and conclusions References

 
Human and animal studies on the role of NO in active hyperemia have been performed mainly in myocardium and skeletal muscle. The results are contradictory. Although some studies demonstrate a decrease of the hyperemic response, up to 40% after NOS inhibition, others report no apparent change.

The reasons for the quite variable effects of NOS inhibition are not entirely clear. Especially in studies on patients, the concentrations of NOS inhibitors might sometimes have been too low to achieve a complete inhibition of eNOS. In addition, the functional status of the endothelium was not clear in all cases. Interestingly, reductions of hyperemic responses with NOS inhibitors could only be shown when the endothelium was presumably intact, thus indirectly supporting a functional role of NO. However, even animal studies, using presumably sufficient concentrations of a NOS inhibitor, yielded contradictory results. Nevertheless, a certain pattern might be deduced from all these studies: a lack of effect of NOS inhibitors was mainly (but not always) observed at low exercise levels. One might speculate that an enhanced metabolic dilation of small arterioles can compensate for an impaired response of larger vessels at relatively low blood flow requirements. In fact, the flow-attenuating effect of NOS inhibitors seems to be more pronounced in muscles with high oxidative capacity and high oxygen and blood flow requirements, respectively. It is therefore conceivable that some studies of total hyperemia in forearm or hindlimb have overlooked attenuating effects of NOS inhibitors on hyperemia in certain muscles. In these muscles with high oxidative capacity, the NO-dependent augmenting effect of upstream vessel dilation on vascular conductance (as discussed above) might be a prerequisite for an adequate oxygen supply. An important role of NO for the dilation of larger arterioles in exercising muscle has also been clearly demonstrated by intravital microscopy in hamster cremaster (6). These experiments have revealed that the smallest arterioles are not controlled by NO but by other mechanisms, most likely metabolites. Last but not least, studies on active coronary hyperemia after chronic NOS inhibition indicate that in metabolically very active organs other factors may partially compensate for the lack of NO, because cyclooxygenase inhibition reduced coronary flow in the presence but not in the absence of NOS inhibition. It should be mentioned that the dilator prostacyclin is always co-released with NO from the endothelium and that–-at least in cultured cells–-NO may to some extent suppress the release of prostacyclin. NOS inhibition may therefore increase the release of prostacyclin. Whether the absence of NO effects in some experiments has methodological reasons or indicates that other factors compensate partially for the lack of NO must be clarified in further studies.

Again, several mechanisms of action must be considered to explain the role of NO in enhancing active hyperemia. As discussed before, the direct effects of some metabolites might be enhanced. Moreover, with increasing blood flow and oxygen demand, the role of the flow-dependent dilation in coordinating the response of large and small arterioles to the higher flow load may become increasingly important. Particularly in skeletal and heart muscle, the overall contribution of NO to dilation should be further enhanced by the rhythmic squeezing of the blood vessels. It has been shown before that rhythmic distension or squeezing of vessels (cf. muscle contraction!) enhances NO synthesis and blood flow (10). Aside from these amplifying effects on vascular conductance, NO in active hyperemia apparently has functions similar to those of a metabolite. The anatomic conditions in skeletal muscle suggest that a spillover of the endothelial stimulator acetylcholine from neuromuscular junctions could induce NO-dependent dilation under muscle exercise (12). It remains to be established whether NO produced by neuronal-type NOS located in myocytes or nerve endings contributes to the hyperemic response as well. The latter may be the case in the initial phase of active hyperemia in skeletal muscle vessels that possess sympathetic cholinergic neural activity. Neurally released NO also acts as a mediator of active hyperaemia in cerebral vessels.

Altogether, there is some indication that NO modulates active hyperemia in a way similar to reactive hyperemia. At low levels of exercise, NO may be replaced by other factors or its lack may be compensated for by other mechanisms. In contrast to reactive hyperemia, NO can act as a true mediator of active hyperemia.

	Autoregulation

Top Introduction Continuously synthesized NO... Dilation by metabolites Is a coordinated behavior... Flow-dependent dilation Functional implications Reactive hyperemia Active hyperemia Autoregulation Summary and conclusions References

 
Autoregulation is thought to be based on two principal mechanisms, namely, vascular myogenic response to changes in transmural pressure and metabolic vascular control. Studies that show arteriolar constriction caused by increases of arterial pressure or elevation of venous pressure (which should have opposite effects on tissue supply) support the idea of myogenic control.

It is thought, however, that alterations in the level of tissue metabolites modify this myogenically based autoregulatory behavior to some extent. Therefore, a permanent increase of tissue activity would produce enhanced levels of metabolites and "reset" the autoregulated flow to a new, higher level. Moreover, it has been suggested that there is a true "metabolic autoregulation." According to this theory, an increase in pressure induces an initial increase in flow, which leads to an enhanced washout of metabolites that results in a vasoconstriction, thus normalizing blood flow to the previously existing level. Autoregulation is therefore principally controlled by the same basic regulatory mechanisms of blood flow as reactive hyperemia. However, the relative influences of the myogenic and metabolic components may vary between certain vascular beds or hemodynamic situations. This may explain why the vasculature of the skin, a tissue with low metabolic activity that normally shows no autoregulation, does so after NOS inhibition. These data are consistent with the idea that NO in this vascular bed is able to completely oppose the predominantly myogenic autoregulatory responses that lead to autoregulatory behavior.

In contrast, the vasculature of organs with high metabolic activity such as the heart shows a distinct autoregulation in the presence of NO. An inhibition of NOS enhanced the autoregulation in some studies. However, a significant number of studies reported no change of the autoregulatory range or capacity, which would be consistent with a predominantly metabolic autoregulation. In all cases, however, an inhibition of NOS reduced the absolute flow plateau, which emphasizes again that the conductance of the vasculature is generally reduced after NOS inhibition.

Altogether, there is evidence that NO can attenuate autoregulation at least when myogenic autoregulation prevails. This is best explained by the known opposing effect of NO on myogenic vascular constriction. There is no evidence that a metabolic effect of NO is involved in autoregulatory responses.

	Summary and conclusions

Top Introduction Continuously synthesized NO... Dilation by metabolites Is a coordinated behavior... Flow-dependent dilation Functional implications Reactive hyperemia Active hyperemia Autoregulation Summary and conclusions References

 
The available data suggest that an inhibition of NOS reduces the hyperemic response and enhances the autoregulation of blood flow at the expense of tissue oxygenation. The data are best explained by a loss of the dilator and coordinating functions of NO in large arterioles, which leads to reduced conductance and enhanced myogenic activity. These data are consistent with a strategic role of NO in large resistance vessels that cannot be replaced by other vasodilators and give NO a unique role in the local control of blood flow. Plumbers have instinctively understood these concepts for many years, as the following lines seem to prove:

There once were some plumbers constructing new pipes

Without any idea of their radial size.

Is there help when conductance is low?

The answer is simply—NO!

	Acknowledgments

 
The help of Sarah Neuhaus in the scientific editing of this manuscript is deeply appreciated.

The restriction of references to a total number of 15 did not allow giving credit to all the authors whose work was reviewed for this short overview. A detailed reference list can be obtained from the authors on E-mail request (ulrich.pohl{at}physiol.med.uni-muenchen.de).

	References

Top Introduction Continuously synthesized NO... Dilation by metabolites Is a coordinated behavior... Flow-dependent dilation Functional implications Reactive hyperemia Active hyperemia Autoregulation Summary and conclusions References

 

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3. De Wit, C., B. Jahrbeck, C. Schäfer, S. S. Bolz, and U. Pohl. Nitric oxide opposes myogenic pressure responses predominantly in large arterioles in vivo. Hypertension 31: 787–794, 1997.[Abstract/Free Full Text]
4. De Wit, C., P. von Bismarck, and U. Pohl. Synergistic action of vasodilators that increase cGMP and cAMP in the hamster cremaster microcirculation. Cardiovasc. Res. 28: 1513–1518, 1994.[Medline]
5. Griffith, T. M., D. H. Edwards, R. L. I. Davies, T. J. Harrison, and K. T. Evans. EDRF coordinates the behaviour of vascular resistance vessels. Nature 329: 442–445, 1987.[Medline]
6. Hester, R. L., A. Eraslan, and Y. Saito. Differences in EDNO contribution to arteriolar diameters at rest and during functional dilation in striated muscle. Am. J. Physiol. 265 (Heart Circ. Physiol. 34): H146–H151, 1993.[Abstract/Free Full Text]
7. Koller, A., and G. Kaley. Role of endothelium in reactive dilation of skeletal muscle arterioles. Am. J. Physiol. 259 (Heart Circ. Physiol. 28): H1313–H1316, 1990.[Abstract/Free Full Text]
8. Kostic, M. M. and J. Schrader. Role of nitric oxide in reactive hyperemia of the guinea pig heart. Circ. Res. 70: 208–212, 1992.[Abstract/Free Full Text]
9. Kuo, L., M. J. Davis, and W. M. Chilian. Longitudinal gradients for endothelium-dependent and -independent vascular responses in the coronary microcirculation. Circulation 92: 518–525, 1995.[Abstract/Free Full Text]
10. Lamontagne, D., U. Pohl, and R. Busse. Mechanical deformation of vessel wall and shear stress determine the basal EDRF release in the intact coronary vascular bed. Circ. Res. 70: 123–130, 1992.[Abstract/Free Full Text]
11. Melkumyants, A. M., S. A. Balashov, and V. M. Khayutin. Control of arterial lumen by shear stress on endothelium. News Physiol. Sci. 10: 204–210, 1995.[Abstract/Free Full Text]
12. Pierzga, J. M., and S. S. Segal. Spatial relationships between neuromuscular junctions and microvessels in hamster cremaster muscle. Microvasc. Res. 48: 50–67, 1994.[Medline]
13. Pohl, U., K. Herlan, A. Huang, and E. Bassenge. EDRF-mediated, shear-induced dilation opposes myogenic vasoconstriction in small rabbit arteries. Am. J. Physiol. 261 (Heart Circ. Physiol. 30): H2016–H2023, 1991.[Abstract/Free Full Text]
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15. Segal, S. S., D. N. Damon, and B. R. Duling. Propagation of vasomotor responses coordinates arteriolar resistances. Am. J. Physiol. 256 (Heart Circ. Physiol. 25): H832–H837, 1989.[Abstract/Free Full Text]

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