Venous Myogenic Tone and Its Regulation Through K+ Channels Depends on Chronic Intravascular Pressure
Abstract In this study, we compared the level of myogenic tone and its negative-feedback control through specific K+ channels in two types of human veins (saphenous [SV] and cephalic [CV] veins), which experience different ranges of pressure in vivo. We also investigated whether an experimental model of increased venous pressure in rats exposed to head-up tilt for 2 weeks produced changes similar to those observed in the human veins. Cylindrical vein segments were cannulated, their diameters were measured, and the intraluminal pressure was set at different levels (2 to 30 mm Hg) in vitro. Acetylcholine test showed that during the regular harvesting process 76% of the human SVs exposed for coronary bypass grafts had no functional endothelium. We found significant myogenic tone in the human SV, where the in vivo pressure is high, but it was not present in the human CV, where the in vivo pressure is low. The nonspecific K+ channel antagonist, tetraethylammonium (TEA), decreased the diameter of the human SV but not the CV. Iberiotoxin and 4-aminopyridine, blockers of the Ca2+-sensitive (KCa) and voltage-gated K+ (KV) channels, also decreased the diameter of the human SV by 10.2±4.8% and 19.5±4.7%, respectively. In the rat SV, significant myogenic tone was found, but TEA had no effect, even after 2 weeks of in vivo pressure increase in the hindlimb by head-up tilt. We conclude that (1) an increased venous myogenic tone correlates with higher chronic intraluminal pressure loads, (2) KCa and KV channels counterregulate the myogenic tone in human, but not in rat, saphenous vein, (3) the counterregulatory effect is more effective at high than at low intraluminal in vitro pressure levels, and (4) its development is probably a long-term process.
Since the study by Bayliss1 in 1902 reporting arterial myogenic tone, a few investigations involving veins have been made.2 Recent studies describe myogenic tone as a significant intrinsic capability of the veins to maintain or decrease their diameters against increasing pressure or flow.3–5 However, this myogenic tone does not exist in all regions and all species. Higher myogenic tone has been observed in human saphenous veins than in rat and dog saphenous veins, and it was hypothesized that this finding correlated with the magnitude and duration of the chronic pressure load present in the given vein.2–4 However, there are no data in the literature to prove that low pressure load (eg, in human forelimb veins) would result in the lack of venous myogenic tone.
Recently, several studies have shown a substantial K+ channel–dependent vasodilation in several arteries from different species in response to increased intraluminal pressure6–8 and myogenic tone.9,10 This vasodilation can be mediated through KCa,10–12 KV,13,14 and KATP15 channels. Thus, the K+ channels may serve as negative-feedback controllers of myogenic tone. Nevertheless, the literature accepts the view that KIR channels are not involved in this process.11 Only a single study of K+ channel function in veins has been reported by Zhang et al16 using human saphenous vein rings and patch-clamp experiments. They showed that KCa and KV channels play a significant role in the regulation of smooth muscle tone and membrane potential. In that study, however, no data were presented about intravascular pressure-induced changes in venous tone and about the role of K+ channels in the regulation of the venous myogenic tone, since intraluminal pressure cannot be controlled in the ring preparation.
Thus, the purpose of the present study was (1) to compare the presence of myogenic tone in two types of human veins exposed to different ranges of pressure in vivo, (2) to determine the activity of the specific K+ channels in the negative-feedback control of venous myogenic tone, and (3) to determine whether an experimental model of increased venous pressure in rats provides activity similar to that in human veins.
Materials and Methods
We examined the myogenic tone and the role of K+ channels in the feedback regulation of myogenic tone in veins subjected to either a high-pressure load for a long-term or an intermediate-term period or to a low-pressure load. The long-term high-pressure load was modeled by human saphenous veins (lifelong intravascular pressure, 20 to 80 mm Hg17), whereas the intermediate-term high-pressure load was modeled by saphenous veins from rats maintained in head-up tilted position for 2 weeks (intraluminal pressure, 6 mm Hg18,19). The low-pressure load was modeled by the human cephalic vein (2 mm Hg20) and saphenous vein from rats maintained in a horizontal position (3 mm Hg18,19).
The protocol was approved by the Ethical Committee of the Semmelweis University of Medicine. Informed consent was obtained from all patients. The 29 saphenous and three cephalic veins came from 41- to 74-year-old (average age, 60 years) and 53- to 72-year-old (average age, 61 years) patients of both sexes, respectively. Their average mean arterial pressure was 98±3 and 101±9 mm Hg (saphenous and cephalic vein groups, respectively). The patients in the saphenous vein group had myocardial infarction earlier (15 patients) and suffered from angina (14 patients), hypertension (8 patients), and/or diabetes (7 patients), whereas those of the cephalic vein group suffered from diabetes (3 patients), atherosclerosis (2 patients), and/or uremia (1 patient). The patients in the saphenous group received β-blocking agents (15 patients), Ca2+ antagonists (11 patients), nitroso agents (10 patients), diuretics (furosemide, 7 patients), and/or angiotensin-converting enzyme inhibitors (6 patients); in the cephalic vein group, the patients received insulin (2 patients), vasodilators (nitroso agents and vinpocetine, 2 patients), and/or diuretics (furosemide, 2 patients).
The saphenous veins were dissected for coronary bypass grafting, while the cephalic vein segments were dissected from the forelimb either during the preparation of a Brescia-Cimino fistula or for femoropopliteal bypass surgery. Only macroscopically healthy veins were used. The small number of the cephalic vein segments (n=3) was due to the extreme rarity of using cephalic vein for bypass surgery and their limited availability for isolated experiments when the Brescia-Cimino fistula was prepared. The venous segments were obtained from the Department of Cardiovascular Surgery and the 2nd Department of Surgery, Semmelweis University of Medicine.
The 1.5- to 2-cm-long vein segments (the unused portion of the grafts) were cut out carefully and placed in a 4°C KR solution bubbled with 95% O2/5% CO2 to keep Po2 and pH constant. Transport from the operating room to the Physiology Department took ≈30 minutes. During this procedure, the veins remained functionally intact, as demonstrated by the NE test at the beginning of the experiments. The veins were placed in a tissue bath containing KR solution, cannulated at both ends, and extended to approximately their in vivo length (axial force was 60 mN), and their diameters were measured with a strain-gauge cantilever transducer.3
The vessels were perfused with an infusion pump (Cole-Parmer Instrument Co), and the intraluminal pressure was set at 2, 5, 10, 15, 20, and 30 mm Hg for ≈30 minutes by changing the outflow resistance of the vessels. Inflow and outflow pressures and axial force were measured using Gould pressure heads and a Grass FT03 force transducer, respectively.3
At the beginning of the experiments, functional integrity of the vein segments was assessed by applying NE and ACh. NE (6×10−5 mol/L, Arterenol, Hoechst) was administered in superfusion, while ACh (5.5×10−6 mol/L, Acetylcholinum ophthalmicum, Dispersa) was present in the perfusion fluid during NE superfusion. During these procedures, intraluminal pressure was kept at 5 mm Hg. Only vessels showing an NE-induced constriction of at least 20% were included in the study.
In one series of experiments, the effect of TEA (1, 3, and 10 mmol/L, Sigma), a general inhibitor of the K+ channels, was tested at different intraluminal pressure levels. The intraluminal pressure of the vein segment was set at 2 mm Hg by decreasing the resistance of the outflow cannula while the venous diameter was measured. Then 1, 3, and 10 mmol/L TEA was administered in superfusion, and the diameter was measured again. These procedures were repeated at intraluminal pressures of, 5, 10, 15, 20, and 30 mm Hg.
In another series of experiments on saphenous vein segments, specific K+ channel blockers were used instead of TEA. For the four types of K+ channels present on the vascular smooth muscle membrane,11 the following inhibitors were administered in superfusion: IBTX (1.2 and 12 nmol/L, Sigma) to block the KCa channels, 4-aminopyridine (0.5 and 5 mmol/L) to block the KV channels, glibenclamide (20 and 200 nmol/L, Sigma) to block the KATP channels, and Ba2+ (2 and 50 μmol/L, Sigma) to block the KIR channels. 4-Aminopyridine, glibenclamide, and Ba2+ were administered at each pressure step; IBTX was added before changing the intraluminal pressure. The latter procedure was followed to limit the use of this expensive substance. Since TEA had no effect on human cephalic veins, this protocol was carried out only on human saphenous vein segments.
At the end of the experiments, venous myogenic tone was assessed by measuring the venous diameter in the resting condition (KR superfusion) and during superfusion with Ca2+-free KR at pressure steps of 2, 5, 10, 15, 20, and 30 mm Hg. Myogenic tone (T) was defined as where Dpassive is the venous diameter after administration of Ca2+-free KR solution, and Dcontrol is the diameter during KR superfusion at the same pressure level.
Twenty saphenous veins were obtained from Sprague-Dawley rats (body weight, 255 to 380 g) anesthetized with pentobarbital (40 mg/body wt). The veins were carefully dissected, and an ≈5- to 8-mm-long segment was removed. Two series of rats were used: a control group in which rats were kept in normal cages and a tilt group in which rats were kept in the head-up position in a tilted cage for 2 weeks. The details of this method have been described elsewhere.18 Briefly, the rats could not turn in the tubelike cage, which was elevated by 45°, and they received food and water ad libitum. Each animal was removed from the cage for a 1-hour period daily for grooming and exercise.
The vessel segment was placed in a tissue bath containing KR solution bubbled with 95% O2/5% CO2. The vein was cannulated at both ends and extended to its original length (axial force was 60 mN), and its diameter was measured via videomicroscopy. The vessel was imaged on a monitor with a video camera, and the diameter was measured automatically, as described elsewhere.18 Briefly, a single television-line technique was used to identify the two most pronounced contrast transitions (representing the outer vessel walls), and the distance between these transitions (being the outer vessel diameter) was measured.
The vessels were perfused using a Harvard pump, and the intraluminal pressure was set by changing the outflow resistance of the vessels. Inflow and outflow pressures and axial force were measured and recorded as described above.
An NE-ACh test was performed as in the human experiments. In the TEA experiments, the diameter of the rat saphenous vein segment was determined under control conditions (KR superfusion) at pressure levels of 2, 5, 10, 15, and 20 mm Hg. Diameters were not measured at a pressure of 30 mm Hg (as in the human saphenous vein experiments), because the physiological pressure range of the saphenous vein is much lower in rats than in humans. After the pressure steps were completed, the superfusate was changed to 1, 3, and 10 mmol/L TEA, and the pressure steps were repeated. Myogenic tone was determined as described above.
Composition of KR and Ca2+-free KR Solutions
The composition of the normal KR solution in both human and rat experiments was (mmol/L) NaCl 119, KCl 4.7, NaH2PO4 0.89, MgSO4 1.17, NaHCO3 24.0, CaCl2 2.5, glucose 5.0, and EDTA 0.026. The composition of the Ca2+-free KR solution was (mmol/L) NaCl 92, KCl 4.7, NaH2PO4 1.18, MgSO4 1.17, NaHCO3 24.0, MgCl2 20, glucose 5.5, EDTA 0.026, and EGTA 2.0.
Diameter values are presented as an absolute value (mm or μm) or as a percentage of the untreated diameter. Computerized data analysis was carried out. For statistical comparisons, Student’s t test (myogenic tone experiments), one-way ANOVA (NE-ACh test), and two-way repeated-measures ANOVA (K+ channel blocker experiments) were performed using Statview for Macintosh and SigmaStat 2.0 softwares. To evaluate the differences between means, the Tukey test, a multiple-comparisons test, was used. The changes were considered significant at levels of P<.05. Mean±SEM values are shown.
Twenty-nine (71%) of the 41 human saphenous vein segments investigated were included in the evaluation. The criteria were that in these cases the vessel diameter decreased at least 20% after NE administration. The average diameter decrease of the NE-responder group was 30.0±2.1% (P<.05). However, the intactness of the endothelium was not maintained in all selected human veins. Only 7 (24.2%) of the 29 vein segments used in the evaluation showed a significant vasodilator response to ACh; in these segments, the diameter increased by 42.6±4.7% of the constricted value (P<.05). However, as far as the effects of K+ channel blockers and Ca2+-free KR are concerned, no significant differences were found between the ACh-responder and ACh-nonresponder groups. Also the vasoconstrictor effect of NE was maintained in the ACh-nonresponder group (Table⇓). These findings indicate that smooth muscle function of the ACh-nonresponder veins was not destroyed; their maximal response to TEA as well as their maximal myogenic tone was not changed significantly. The effect of NE, however, was slightly but significantly decreased.
We found significant myogenic tone in the human saphenous vein segments but not in the human cephalic vein segments: the venous diameter in Ca2+-free KR solution was significantly larger than in normal KR solution in the human saphenous vein segments, whereas it was statistically not significantly different in the human cephalic vein segments (Fig 1⇓).
After TEA administration, a significant dose-dependent vasoconstriction was found in human saphenous vein segments at pressure steps of 10 mm Hg and higher (Fig 2A⇓). The changes were statistically significant at the highest dose of TEA administered (10 mmol/L). The largest change (16.3±5.4%) occurred at 20 mm Hg intraluminal pressure (P<.05) after 10 mmol/L of TEA superfusion. In human cephalic vein segments, however, there was no change in the outer diameter after TEA administration at any pressure level (Fig 2B⇓).
4-Aminopyridine, a blocker of the KV channels, as well as IBTX, a blocker of the KCa channels, decreased the diameter of the saphenous vein segments dose-dependently by 10.2±4.8% and 19.5±4.7% of the initial diameter, respectively (Fig 3A⇓ and 3B⇓). The maximum response to the two blockers occurred at different pressure steps. The responses to 4-aminopyridine increased with pressure up to 20 mm Hg and decreased thereafter, whereas the responses to IBTX were maximal at the maximum pressure applied (30 mm Hg). In contrast, blocking the KIR channels with BaCl2 or the KATP channels with glibenclamide caused no significant change in the diameter of the human saphenous vein segments at any of the pressure steps investigated (Fig 3C⇓ and 3D⇓)
NE constricted the saphenous veins of control rats by 23.9±3.4% (outer diameter decreased from 727±19 to 553±29 μm, P<.05) and of tilted rats by 20.4±3.3% (outer diameter decreased from 850±14 to 676±26 μm, P<.05). All these vessel segments had functioning endothelium, as demonstrated by the ACh response. ACh dilated the veins of control rats by 25.5±6.7% of the constricted diameter value (from 553±29 to 665±39 μm, P<.05), whereas vessels from tilted rats were dilated by 14.0±2.5% of the constricted diameter value (from 676±26 to 728±27 μm, P<.05).
Rat saphenous vein segments exerted significant myogenic tone (Fig 4⇓), which increased significantly after noninvasive pressure load by 2 weeks of tilting, especially at low intraluminal pressure (at 2 mm Hg, 24.2±6.7% versus 6.5±2.6%, and at 10 mm Hg, 14.4±2.8% versus 9.7±3.0%, tilt versus control, respectively; P<.05). After 2 weeks of tilt, outer vascular diameter increased by ≈14% (P<.05). TEA (1, 3, and 10 mmol/L) did not change the venous diameter of the rat saphenous vein segments at any pressure steps investigated in both control and tilted rats (Fig 5⇓).
The findings in the present study show for the first time that (1) the human cephalic vein subjected to low in vivo pressure does not exhibit pressure-dependent myogenic tone, (2) in the human saphenous vein exposed to chronically high in vivo pressure, the KV and KCa channels counterregulate the myogenic tone in vitro in a pressure-dependent fashion, and (3) blocking of K+ channels does not influence the pressure-diameter curve in human cephalic and rat saphenous veins, which have no or low myogenic tone, respectively.
The human cephalic vein exposed to low in vivo pressure permanently (≈2 mm Hg)20 does not exhibit significant myogenic tone, whereas the human saphenous vein, being exposed to high pressure for decades (10 to 80 mm Hg),17 exhibits significant myogenic tone. There are no data in the literature on pressure-dependent venous myogenic tone in humans except our earlier publication involving the human saphenous vein.3 Tone development due to sudden stretch was found only in a special vessel, the buccal segment of the human facial vein, but the pressure dependence or the effect of Ca2+-free or any smooth muscle relaxing solution was not investigated.21 Since changes in venous compliance, mean circulatory filling pressure, and probably myogenic tone, via an increased cardiac output, may trigger autoregulatory mechanisms leading to elevated peripheral resistance and blood pressure,22 it is essential to investigate the existence and magnitude of human myogenic tone in different regions.
Both the venous KCa and the KV channel function are strongly pressure dependent, as indicated by two facts. First, they were activated only in those veins in which the in vivo resting pressure is the highest (human saphenous veins). Second, they were activated only at intraluminal pressures at or higher than a certain pressure value (10 mm Hg, which is the resting value of human saphenous vein in the recumbent position17), and the activation was higher at higher intravascular pressure steps. Thus, K+ channel function may be part of a long-term adaptation process to a chronically elevated intraluminal pressure load. It is important to investigate this adaptation process because chronic venous diseases, such as varicosity, thrombophlebitis, and orthostatic intolerance, affect a large portion of the population.
It is generally agreed that K+ channels play a role in the counterregulation of the arterial myogenic tone,6,9,10 but it is not clear which types of K+ channels are involved. It has been proposed that KCa channels are mainly responsible for this counterregulation,9,10,23,24 and their activation is as follows. The increase in arterial pressure induces membrane depolarization opening the voltage-gated Ca2+ channels and resulting in an increase in the intracellular Ca2+ concentration, which not only causes an increase in arterial tone but also opens the KCa channels. The latter inhibits membrane depolarization and thus the vasoconstriction.10–12 Some investigators have indicated that KV channels open directly as a result of membrane depolarization and inhibit contraction, establishing a second negative-feedback loop11,13,14 independent of the KCa channels. In the present study involving human saphenous veins, we found that both KCa and KV channels are involved in the counterregulation of myogenic tone, indicating that the same mechanism exists in the veins as described in the arteries. The pressure dependence of the KCa channels is also similar in the arteries, but pressure dependence of the arterial KV channels was not observed,8,25,26 suggesting a difference between arterial and venous smooth muscle cells in this regard.
Concerning the veins, only one study16 was published indicating that KCa channels have a role in the regulation of venous smooth muscle tone. However, the relation between K+ channel function and venous myogenic tone as well as their pressure dependence have not been investigated, since these experiments were carried out on rings. We performed our experiments on cylindrical segments, because in these segments the geometry and the axial stretch of the vein are maintained physiologically, and intraluminal pressure can be controlled. This is essential for studying myogenic tone as well as pressure-dependent responses and thus for modeling in vivo conditions.
In humans, standing in an erect position results in a remarkably increased pressure load in the leg (up to 87 mm Hg)17 due to gravitational forces. We assume that this chronic long-term elevated pressure enhances the sensitivity of the KCa and KV channels (eg, via an increased number of the channels, an enhanced open-state probability, or larger membrane depolarization) and thus counterregulates the myogenic tone. This may be an important mechanism in the blood flow improvement during walking in humans and may contribute to the stabilization of venous diameter similar to the arteries.15 The K+ channel–dependent process seems to be common in different types of smooth muscle cells. It was also identified in gall bladder and taenia coli muscle cell membranes.27
In the rat saphenous vein, where the intravascular pressure is much lower (≈3 mm Hg)19 than in the human saphenous vein,17 we found a limited but significant myogenic tone that increased ≈5% (Fig 4⇑) when the intraluminal pressure was doubled after 2 weeks of head-up tilt (from 2.9±0.2 to 5.9±0.2 mm Hg).18,19 After this period, myogenic tone was found to be increased, especially at a low pressure level of 2 mm Hg, indicating that indeed an increase in pressure modifies myogenic tone. In our animal model, however, K+ channels did not oppose this myogenic tone, suggesting that saphenous veins of rats may not generate this pressure-dependent ionic compensatory mechanism. It also supports the hypothesis regarding the pressure dependence of the K+ channels. One would expect that after 2 weeks of tilting, the K+ channels are activated by the increased pressure load, just as the myogenic tone is enhanced. We assume that the lack of increased K+ channel function may be explained by the fact that head-up tilting for 2 weeks does not depolarize the smooth muscle membrane of rat saphenous vein but rather causes hyperpolarization.18 Similar findings were shown in dogs, where the more depolarized basilar arteries exhibited both myogenic tone and K+ channel–dependent vasodilation, whereas the less depolarized mesenteric arteries presented none of them.9 In addition, two other possible explanations may arise: (1) activation and/or upregulation of KCa and KV channels requires more time than the development of an elevated myogenic tone, or (2) the chronic pressure load in the rat saphenous vein after tilting is not high enough to activate the K+ channels, but it is high enough to develop an increased vascular tone. In aortas of spontaneously hypertensive rats, however, 2 weeks of antihypertensive therapy was sufficient to induce a decrease in KCa-dependent current density.8 Thus, time dependence in the development of the counterregulation may be another difference between arterial and venous smooth muscle cells.
It cannot be excluded that the difference in venous diameter regulation through K+ channels between rats and humans is not exclusively caused by the long-term pronounced elevation of intraluminal pressure in humans; species differences have to be considered as well. To address this question, one could compare the diameter changes of saphenous vein segments after the administration of K+ channel antagonist in infants (quadruped mode of locomotion, low saphenous venous pressure) and in toddlers (bipodal mode of locomotion, increased saphenous venous pressure). Harvesting veins at such an early age, however, would be extremely difficult, if at all possible.
Since our data are based on in vitro experiments, we cannot extend our findings directly to in vivo conditions, where multiple endogenous inputs (eg, hormonal factors, neurotransmitters, etc) contribute simultaneously to vascular tone and blood flow and may influence K+ channel function. However, since our specific antagonists preferentially block the different K+ channel types,27–30 our findings are related directly to the K+ channel functions. In addition, since the vascular diameter corresponds fairly strongly to the changes in the membrane potential4,13,18,23,31 altered between others by K+ channels,11,13,23 our findings about changes of the venous diameter are likely describing the K+ channel function of the veins.
We showed that endothelial cell function seems to be impaired in 76% of the human saphenous vein segments used as coronary bypass grafts, as indicated by the absence of ACh-mediated dilation. Thus, endothelium does not seem to play a role in the K+ channel–dependent control of the venous caliber similar to that found in arteries.6 It also suggests that a significant part of the segments may lose their endothelium or endothelial cell function during routine surgical dissection, as shown by others.32 It cannot be excluded, however, that endothelial function is influenced by the patient’s original cardiovascular status or by the damaging effects of the drugs administered before or during surgery. Endothelial cell damage may lead to early stenosis of the veins grafted into the heart32,33 and is detrimental to the heart muscle, since endothelial substances from coronary bypass grafts influence the myocardial contractile response to ischemia and reperfusion.34
In conclusion, we have demonstrated that (1) a higher level of venous myogenic tone correlates with higher chronic intraluminal pressure loads, (2) KCa and KV channels counterregulate the myogenic tone in human, but not in rat, saphenous vein, (3) the counterregulatory effect is pressure dependent in vitro, and (4) its development is a long-term process and is different from that found in arteries.
Selected Abbreviations and Acronyms
|KATP channel||=||ATP-sensitive K+ channel|
|KCa channel||=||Ca2+-activated K+ channel|
|KIR channel||=||inward rectifier K+ channel|
|KV channel||=||voltage-gated K+ channel|
This study was supported by Hungarian national grant OTKA No. T-017789, Fogarty grant No. RO3 TW00350, and Dutch-Hungarian Joint grant NWO No. 94/19588. The authors are thankful for the careful surgical preparation, the beneficial comments, and the technical help of Dr Gábor Biró, Dr Gyula Jámbor, Prof Alexander Juhász-Nagy, Dr Nancy J. Rusch, Meredith M. Skelton, Ildikó Oravecz, and Ágnes Maurer and of the cardiac surgeons of the Department of Cardiovascular Surgery, Semmelweis University of Medicine, Budapest.
- Received February 10, 1997.
- Accepted September 18, 1997.
- © 1997 American Heart Association, Inc.
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