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HIGHLIGHTED TOPICS
Skeletal and Cardiac Muscle Blood Flow
,11Department of Pathophysiology, Semmelweis University, H-1445 Budapest, Hungary; and 2Department of Physiology, New York Medical College, Valhalla, New York 10595
Submitted 2 February 2004 ; accepted in final form 8 June 2004
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ABSTRACT |
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150 µm). Lower concentrations of H2O2 (10–6–3 x 10–5 M) elicited constrictions, whereas higher concentrations of H2O2 (6 x 10–5–3 x 10–4 M), after initial constrictions, caused dilations of arterioles (at 10–4 M H2O2, –19 ± 1% constriction and 66 ± 4% dilation). Endothelium removal reduced both constrictions (to –10 ± 1%) and dilations (to 33 ± 3%) due to H2O2. Constrictions due to H2O2 were completely abolished by indomethacin and the prostaglandin H2/thromboxane A2 (PGH2/TxA2) receptor antagonist SQ-29548. Dilations due to H2O2 were significantly reduced by inhibition of nitric oxide synthase (to 38 ± 7%) but were unaffected by clotrimazole or sulfaphenazole (inhibitors of cytochrome P-450 enzymes), indomethacin, or SQ-29548. In endothelium-denuded arterioles, clotrimazole had no effect, whereas H2O2-induced dilations were significantly reduced by charybdotoxin plus apamin, inhibitors of Ca2+-activated K+ channels (to 24 ± 3%), the selective blocker of ATP-sensitive K+ channels glybenclamide (to 14 ± 2%), and the nonselective K+-channel inhibitor tetrabutylammonium (to –1 ± 1%). Thus exogenous administration of H2O2 elicits 1) release of PGH2/TxA2 from both endothelium and smooth muscle, 2) release of nitric oxide from the endothelium, and 3) activation of K+ channels, such as Ca2+-activated and ATP-sensitive K+ channels in the smooth muscle resulting in biphasic changes of arteriolar diameter. Because H2O2 at low micromolar concentrations activates several intrinsic mechanisms, we suggest that H2O2 contributes to the local regulation of skeletal muscle blood flow in various physiological and pathophysiological conditions. arteriole; thromboxane A2; nitric oxide; endothelial hyperpolarizing factor; potassium channels
10–9 s) by superoxide dismutases to the still reactive but much more stable and highly diffusible hydrogen peroxide (H2O2) (48). Indeed, it has been documented that H2O2 is produced and released from several cell types, such as vascular endothelial and smooth muscle cells acting in a paracrine and/or an autocrine manner (11, 42, 55). Also, in various diseases of the cardiovascular system, such as hypertension (26, 34, 40), diabetes mellitus (21), and hyperhomocysteinemia (38), there is an increased vascular formation of H2O2, which activates vascular signaling mechanisms, resulting in functional and morphological changes of vessels. Furthermore, in pathological conditions, such as tissue injury and/or inflammation, local concentrations of extracellular H2O2 could increase to high levels (up to 0.3 mM) due to oxidative burst of activated leukocytes (28, 33, 35, 55). However, there are no data available to show the direct effect of H2O2 on the myogenic tone of skeletal muscle arterioles. Previous studies showed that H2O2 causes either contraction (20, 32, 34, 52) or relaxation (4, 5, 13, 18) of large vessels, depending on the species, types of vessels, and experimental protocols used. In vessels of several tissues, it has been shown that administration of millimolar concentrations of H2O2 increased the tension of isolated arterial rings (32) and constricted isolated cannulated mouse tail arterioles (31). In contrast, in vivo studies showed that H2O2 induced dilations of cat and piglet pial arterioles (27, 47) and rat cremaster muscle arterioles (49).
These discrepant findings could be because, in these experiments, different types of vessels and different conditions and concentrations of H2O2 were used (5, 34). Other confounding factors could have also been present in most of these previous studies; that is, vascular tone was induced by vasoactive agents with different mechanisms of action, such as epinephrine, thromboxane analogs, and potassium chloride (5, 13, 19, 54), all of which are known to interfere with the cellular mechanisms activated by H2O2. Thus the direct effect of H2O2 on the diameter of skeletal muscle arterioles could have been masked, and the underlying mechanisms remain uncertain.
On the basis of previous findings and our preliminary results (8), we hypothesized that H2O2 has a role in the regulation of skeletal muscle blood flow, and, if this is so, it should elicit significant changes in the spontaneous, pressure-induced myogenic tone of arterioles at relatively low micromolar concentrations. Thus we aimed to characterize the effects of increasing concentrations of H2O2 (10–6–10–4 M) on the myogenic tone of isolated skeletal muscle arterioles and to elucidate the cellular mechanisms responsible for eliciting its vasomotor action.
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METHODS |
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Isolation of Arterioles
Experiments were conducted on isolated arterioles (inside active diameter of 156 ± 6 µm and passive diameter of 248 ± 5 µm, at 80 mmHg) of rat gracilis muscle as described previously (2, 39). Briefly, at 12 wk of age, rats were anesthetized with intraperitoneal injection of pentobarbital sodium (50 mg/kg). The gracilis muscle was dissected out and placed in a silicone-lined petri dish containing cold (0–4°C) physiological salt solution (PSS) composed of (in mmol/l) 110 NaCl, 5.0 KCl, 2.5 CaCl2, 1.0 MgSO4, 1.0 KH2PO4, 10.0 dextrose, and 24.0 NaHCO3. The PSS was equilibrated with a gas mixture of 10% O2 and 5% CO2 balanced with nitrogen, at pH 7.4. Using microsurgery instruments and an operating microscope, we then isolated a segment, 1.5 mm in length, of an arteriole running intramuscularly and transferred it into an organ chamber containing two glass micropipettes filled with PSS. From a reservoir, the vessel chamber (15 ml) was continuously supplied with PSS at a rate of 30 ml/min. After the vessel was mounted on the proximal (inflow) pipette and secured with sutures, the perfusion pressure was raised to 20 mmHg to clear the lumen. The other end of the vessel was then mounted on the distal (outflow) pipette. Both micropipettes were connected with silicone tubing to an adjustable PSS reservoir. Inflow and outflow pressures were measured by an electromanometer (Living Systems Instruments, Burlington, VT). The temperature was set at 37°C by a temperature controller (Grant Instruments), and the vessel was allowed to develop spontaneous tone in response to an intraluminal pressure of 80 mmHg under no flow conditions (equilibration period of 1 h). The inner diameter of arterioles was measured by videomicroscopy equipped with a microangiometer and recorded on a chart recorder (Cole-Parmer).
Experimental Protocols
After the equilibration period, an active arteriolar myogenic tone developed; we then tested function of the endothelium with 10–7 M acetylcholine (ACh). H2O2 was obtained in 30% solution from Reanal Finechemical and kept in a plastic bottle in a cool place. H2O2 solutions were made before the experiments and were kept at a cold temperature. Increasing concentrations of H2O2 (10–6–2 x 10–4 M) were abluminally administered to the organ chamber in the PSS. After each dose of H2O2, the chamber was washed out with PSS and the next concentrations of H2O2 were added after the steady-state control diameter had returned. In the next group of experiments, arterioles were incubated with the cyclooxygenase enzyme inhibitor indomethacin (2.5 x 10–5 M for 30 min) or the prostaglandin H2/thromboxane A2 (PGH2/TxA2) receptor inhibitor SQ-29548 (10–6 M) for 20 min, and H2O2-induced-responses were again obtained. In another group of experiments, arterioles were incubated with the nitric oxide (NO) synthase inhibitor N
-nitro-L-arginine methyl ester (L-NAME; 10–4 M for 20 min) or the cytochrome P-450 (CYP450) enzyme inhibitors clotrimazole (2 x 10–6 M) or sulfaphenazole (10–5 M) for 20 min (12, 17), and H2O2-induced responses were reassessed.
The effects of H2O2 on arteriolar diameter were also obtained in the absence of the endothelium. The endothelium of the arteriole was removed by perfusion of the vessel with air for 1 min at a low perfusion pressure, as described earlier (23). The arteriole was then perfused with PSS to clear the debris. The intraluminal pressure was then raised to 80 mmHg for 15 min to reestablish a stable myogenic arteriolar tone. The efficacy of endothelial denudation was ascertained by arteriolar responses to ACh (10–7 M) and sodium nitroprusside (SNP; 10–7 M) before and after the administration of the air bolus. Infusion of air resulted in loss of function of the endothelium, as indicated by the absence of dilation to ACh, whereas dilation to SNP remained intact (Table 1), as in previous studies in our laboratory (22, 23).
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Data Analyses
Peak constrictions of arterioles in response to H2O2 are expressed as a percentage of the baseline diameter at an intraluminal pressure of 80 mmHg. Peak dilations of arterioles are expressed as changes in arteriolar diameter as a percentage of the maximal dilation of the vessel, defined as the passive diameter at 80 mmHg intraluminal pressure in a Ca2+-free PSS containing 10–3 M EGTA and 10–4 M SNP. Statistical analyses were performed by two-way ANOVA for repeated measures followed by the Tukey's post hoc test or Student's t-test, as appropriate. P < 0.05 was considered statistically significant. All data are expressed as means ± SE.
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RESULTS |
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Biphasic Changes of Arteriolar Diameter to H2O2
Increasing concentrations of H2O2 elicited biphasic changes in the diameter of gracilis muscle arterioles. Lower concentrations of H2O2 (10–6–3 x 10–5 M) elicited only constrictions, whereas higher concentrations of H2O2 (6 x 10–5–2 x 10–4 M), after initial constrictions, resulted in substantial dilations of arterioles, as shown by original records and summary data (Fig. 1). Washout of H2O2 restored arterioles to their initial diameter.
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Endothelium removal significantly reduced arteriolar constrictions in response to H2O2 (Fig. 2), whereas incubation of endothelium-intact arterioles with indomethacin or SQ-29548 completely abolished the constrictions induced by H2O2 (Fig. 2).
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In the presence of indomethacin or SQ-29548, higher concentrations of H2O2 elicited only dilations (Fig. 3), the magnitude of which was not significantly different from control responses (Fig. 3). In endothelium-intact arterioles, clotrimazole and sulfaphenazole did not affect H2O2-induced dilations, whereas L-NAME significantly decreased arteriolar dilations to H2O2 (Fig. 3). Endothelium removal significantly decreased the H2O2-induced arteriolar dilations and had a more pronounced effect at lower concentrations of H2O2 (6 x 10–5 and 10–4 M) (Fig. 4).
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To facilitate comparisons of various studies, we have included the absolute data obtained in these experiments (Tables 2 and 3).
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DISCUSSION |
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Previous studies implied that H2O2 can be released from vascular and other cell types and may affect vascular tone in several vascular beds. However, there are few, if any, studies available to show the direct effects of H2O2 on skeletal muscle microvessels. Thus we aimed to characterize the effects of extravascular H2O2 on the myogenic tone of isolated skeletal muscle arterioles and to elucidate the cellular mechanisms responsible for eliciting its vasomotor action.
Arteriolar Constrictions to H2O2
We have used isolated and pressurized gracilis skeletal muscle arterioles in the absence of intraluminal flow and other neurohumoral agents to exclude their possible confounding effects, especially because previous studies in various vessel types and sizes showed both constriction and dilation in response to H2O2 administration. We have found that low concentrations of H2O2 (10–6–3 x 10–5 M) elicited substantial constriction of arterioles. The constrictions were partly reduced by endothelium removal (Fig. 2) and abolished by inhibition of prostaglandin synthesis or the presence of a PGH2/TxA2 receptor antagonist. Because the effect of PGH2/TxA2 inhibition was greater than endothelium denudation, we suggest that H2O2 induces increases in myogenic tone of skeletal muscle arterioles primarily by the release of endothelium- and smooth muscle-derived constrictor prostaglandins, most likely PGH2/TxA2. Although in large pulmonary arteries activation of phospholipase C (36) or cyclooxygenase pathways (51) in response to high concentrations of H2O2 (10–4-10–3 M) has been reported, the new findings of our present study that even low concentrations of H2O2 result in release of PGH2/TxA2 from arterioles indicate a potentially important physiological role for H2O2 in the local regulation of skeletal muscle blood flow. These results are in line with the findings of Flavahan's group (31) showing that in mouse tail arteries H2O2 contributes to the development of myogenic constriction. Also, it has been shown that a sudden increase in intraluminal pressure (16, 43) or chronic presence of high blood pressure in hypertension (15, 45) increases superoxide production, which by conversion to H2O2 could elicit an enhanced PGH2/TxA2 production, leading to an upregulation of myogenic tone (15, 45).
The exact mechanism by which H2O2 stimulates the synthesis of constrictor prostaglandins in the endothelium is not completely understood. It has been shown that H2O2 rapidly activates cyclooxygenase to produce various prostaglandins, including PGG2 and PGH2, and also likely by inhibition of PGI2 synthase can enhance the formation of TxA2 (10, 14). Although previous studies have shown that, in normal conditions in skeletal muscle arterioles, cyclooxygenase primarily produces dilator prostaglandins PGE2 and PGI2 (9, 37), our present finding provides evidence for the production of constrictor prostaglandins elicited by low micromolar concentrations of H2O2, thus suggesting a potential physiological and pathophysiological (2, 3, 9) role for H2O2 in regulation of arteriolar myogenic tone.
Arteriolar Dilations to H2O2
Interestingly, we have also found that higher concentrations of H2O2 (6 x 10–5–2 x 10–4 M) elicited a biphasic effect on arteriolar diameter (Fig. 1). After the initial phase of constrictions, H2O2 induced dose-dependent dilations of skeletal muscle arterioles that approached the maximal diameter of these vessels (95%).
NO release to H2O2. We aimed to elucidate the mechanisms responsible for H2O2-induced arteriolar dilations. We have found that, in skeletal muscle arterioles, endothelium removal significantly reduced H2O2-induced dilations (Fig. 4) and that inhibition of NO synthesis by L-NAME reduced H2O2-induced dilations in a similar manner (Fig. 3). These findings support previous observations in aortic and basilar arterial rings showing that relaxation to H2O2 was mediated in part by NO (53, 54). Collectively, these findings indicate that H2O2 activates, via an as yet unknown mechanism, endothelial NO synthase, resulting in NO-mediated dilations of skeletal muscle arterioles.
H2O2 activates K+ channels. At higher concentrations of H2O2 (10–4 and 2 x 10–4 M), endothelium removal did not completely abolish H2O2-induced dilations, suggesting a direct action of H2O2 on arteriolar smooth muscle cells. Previously, it has been suggested that H2O2 hyperpolarizes smooth muscle cells in large arteries (6, 25) and likely mediates the non-NO- and nonprostanoid-dependent, endothelial hyperpolarizing factor (EDHF)-dependent relaxation of these vessels. In addition, Yang et al. (53) suggested that the relaxing effects of H2O2 in rat aorta are mediated by activation of CYP450. In contrast, in the presence of endothelium, we found that clotrimazole and sulfaphenazole, inhibitors of CYP450, did not significantly affect H2O2-induced dilations (Fig. 3). Also, in the absence of endothelium, clotrimazole was without effect (Fig. 4). The lack of any effect of clotrimazole and sulfaphenazole on H2O2-induced dilations is unlikely due to insufficient inhibition of CYP450 because in a previous study from our laboratory (17) we used similar concentrations of these inhibitors. Collectively, these findings make it unlikely that H2O2 elicits hyperpolarization of smooth muscle of skeletal muscle arterioles via activation of CYP450. Rather, H2O2 may directly elicit membrane hyperpolarization by activation of various K+ channels in vascular smooth muscle cells (6, 25, 29). Indeed, it has been suggested that in conduit arteries the large conductance Ca2+-activated K+ channels might be directly stimulated by H2O2 (5, 13).
On the basis of the above, we hypothesized that dilations to higher concentrations of H2O2 are mediated primarily by activation of smooth muscle K+ channels. Thus, in endothelium-denuded arterioles, H2O2-induced dilations were tested after inhibition of K+ channels by the KCa-channel blocker charybdotoxin and apamin or by the KATP-channel inhibitor glybenclamide. We found that incubation and the presence of charybdotoxin plus apamin significantly but only partially reduced H2O2-induced dilations, leaving large portions of dilation still intact (Fig. 4) . Also, glybenclamide substantially inhibited the dilations but did not abolish them completely. Thus we used the nonselective K+-channel blocker TBA. We have found that TBA significantly reduced basal tone of arterioles and essentially eliminated the dilations to 10–4 M H2O2 but not to 2 x 10–4 M H2O2 (Fig. 4). These findings suggest that, in addition to KCa and KATP channels, other types of K+ channels or mechanisms are also activated by H2O2. Future studies are needed to characterize the role of these additional mechanisms in mediation of H2O2-induced arteriolar dilation.
Physiological Implications
Previous studies showed that exogenous administration of H2O2 resulted in diverse vasomotor responses. H2O2 elicited constriction of rat mesenteric (32) and mouse tail arterioles (31), whereas it resulted in dilations of human atrial (29), cat, and piglet pial arterioles (27, 47). A recent study suggested that H2O2 mediates pressure-induced myogenic constriction of isolated arterioles (31). In contrast, it has also been shown that catalase inhibits flow-mediated (29) dilations of human atrial coronary microvessels, implying a role for H2O2 in this response. Also, H2O2 induced only dilation in coronary vessels (41). The new finding of the present study is that both constriction and dilation are elicited by H2O2, which suggests a concentration-dependent mediator role for H2O2 and that it may contribute both to pressure- and flow-induced vascular responses.
It is still difficult to assess the exact concentration of H2O2 released by vascular or other cells in various physiological or pathological conditions. Also, it is difficult to assess the exact concentration reaching the arteriolar cells, when H2O2 is applied exogenously, due to the presence of catalase in the vascular wall. Earlier studies that utilized electron paramagnetic resonance (55) showed that cultured endothelial cells are able to produce H2O2. Furthermore, recently, Liu and Zweier (28) calculated that stimulation of 2 x 106/ml polymorphonuclear leucocytes with phorbol 12-myristate 13-acetate can produce as high as 0.3 mM H2O2 in in vitro conditions (28). It is noteworthy, however, that in in vivo conditions, due to the vigorous activity of intracellular peroxidases, compartmentalized concentrations of H2O2 could be close to micromolar or low millimolar ranges. Thus, depending on the conditions, it is likely that vessels may be exposed to a variety of concentrations of H2O2, which in turn can increase or decrease arteriolar myogenic tone, hence changing blood flow. For example, it is likely that H2O2 is released in a sufficient concentration to increase arteriolar diameter, when oxidative metabolism of tissues increases, thereby increasing local skeletal muscle blood flow during increased demand for oxygen. On the other hand, in certain pathological conditions that are associated with oxidative stress and low levels of inflammation, such as hypertension (16), hyperhomocysteinemia (2, 3), and diabetes mellitus (1), lower concentrations of H2O2 could contribute to the enhancement of myogenic tone that is frequently observed in these conditions (15, 46).
It remains, however, an intriguing question as to how H2O2 elicits activation of several signaling pathways (Fig. 5). One possibility is that in vascular cells several subcellular pathways are sensitive to H2O2. Alternatively, it is also likely that H2O2 via an as yet unknown common mechanism elicits activation of several signaling pathways, which then mediate vasomotor responses. The non-NO and nonprostanoid dilator factors are frequently considered to be EDHFs; thus one might conclude that H2O2 is another possible candidate for EDHF (6, 25, 29). In line with this idea, Yada et al. (50) suggested that H2O2 is a primary EDHF in the canine coronary circulation, playing an important role in coronary autoregulation. Also, Lacza et al. (27) found that H2O2 acts as an EDHF and mediates non-NO- and nonprostanoid-dependent relaxations to bradykinin in the piglet cerebral circulation. In skeletal muscle microvessels, H2O2 likely affects membrane potential via direct activation of K+ channels in the smooth muscle, eliciting hyperpolarization. Thus H2O2 could be viewed as an EDHF in skeletal muscle arterioles, only if it were released from endothelial cells. Another possibility is that H2O2 derives from activated leukocytes or macrophages.
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The costs of publication of this article were defrayed in part by the payment of page charges. The article must therefore be hereby marked "advertisement" in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.
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REFERENCES |
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C, Bagi Z, and Koller A. Modulation of arteriolar myogenic tone by reactive oxygen species (Abstract). J Vasc Res 39: 38, 2002.
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Significantly different from previous column, P < 0.05.