Published online before print March 17, 2003, doi: 10.1161/01.HYP.0000063883.83470.7B
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(Hypertension. 2003;41:912.)
© 2003 American Heart Association, Inc.
Scientific Contributions |
Coronary Myogenic Constriction Antagonizes EDHF-Mediated Dilation
Role of KCa Channels
From the Institute of Clinical Pharmacology, University of Groningen, Groningen, The Netherlands.
Correspondence to Simone Gschwend, Department of Clinical Pharmacology, University of Groningen, A. Deusinglaan 1, 9713 AV Groningen, The Netherlands. E-mail s.gschwend{at}med.rug.nl
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Abstract |
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In hypertension, pressure-induced myogenic constriction and impaired endothelium-derived hyperpolarizing factor (EDHF)-mediated dilation may contribute to increased vasomotor tone. Myogenic constriction as well as EDHF-mediated dilation may share common signaling mechanisms, and both may control KCa channel activity to set arterial tone. To investigate a potential relation between the 2 mechanisms, we studied coronary arteries of Sprague-Dawley rats for individual myogenic constriction compared with EDHF-mediated dilation of the same artery. EDHF-mediated dilation was measured as the maximal dilation to acetylcholine (100 µmol/L) after preconstriction, resistant to NO inhibition (NG-methyl-L-arginine acetate salt, L-NMMA, 100 µmol/L), and prostaglandin inhibition (indomethacin, 10 µmol/L) but abolished by charybdotoxin (100 nmol/L) plus apamin (500 nmol/L). Individual coronary myogenic constriction at an intraluminal pressure of 70 mm Hg (n=9) ranged from 6% to 44% (24±4%). EDHF-mediated dilation ranged from 18% to 84% (42±7%). Elevating pressure to 130 mm Hg (n=8) increased myogenic constriction by 2-fold (P<0.01) and decreased EDHF-mediated dilation by 2.6-fold (P<0.01). Interestingly, individual myogenic constriction inversely correlated to individual EDHF-mediated dilation (r=-0.75, P<0.001, n=17). Pretreatment with the KCa channel opener NS1619 (30 µmol/L) prevented coronary myogenic constriction and increased EDHF-mediated dilation by 2.2-fold (P<0.01), whereas the KATP channel opener cromakalim (3 µmol/L) had no effect on EDHF-mediated dilation. For comparison, in mesenteric arteries (at 70 mm Hg) low myogenic constriction (2±1%) was associated with high EDHF-mediated dilation (93±2%), and pretreatment with NS1619 had no effect. Our results demonstrate that myogenic constriction in coronary arteries antagonizes EDHF-mediated dilation. Activation of KCa channels with NS1619 reduces myogenic constriction and profoundly increases EDHF-mediated dilation, specifically in coronary arteries, suggesting a potential therapeutic impact to reduce coronary risk in hypertension.
Key Words: acetylcholine • autoregulation • endothelium-derived factors • constriction • potassium channels • vasodilation
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Introduction |
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Arterial vasomotor tone is regulated by several constrictive and dilative mechanisms. Apart from systemic hormones and regional innervation, locally produced (endothelium-derived) factors and the myogenic response also importantly contribute to set arterial tone.1 Increase in intraluminal pressure induces membrane depolarization2 and constriction of arterial smooth muscle cells, independent of systemic and endothelial factors. This vasoconstrictor response has been termed myogenic and serves to control blood flow to organs after pressure changes.3–5 The importance of the myogenic response in regulation of vasomotor tone differs among vascular beds. It plays an important regulatory role in coronary as well as cerebral and skeletal arteries, whereas in mesenteric arteries the myogenic response is less pronounced.6,7 On the intraluminal side of the blood vessel lies the endothelium, an important producer of mediators such as endothelin-1 and contractile prostaglandins, but also prostacyclin, nitric oxide (NO), and endothelium-derived hyperpolarizing factor (EDHF), all of which act on underlying smooth muscle cells causing constriction or dilation to regulate vasomotor tone.8–10
In hypertension, these vasomotor control mechanisms appear disturbed. Increased myogenic constriction in several forms of hypertension appears to be associated with more depolarized resting membrane potential and smooth muscle calcium levels also when studied at comparable/normotensive blood pressure levels.7,11–15 Impaired EDHF-mediated dilation has also been reported in several forms of hypertension, but the underlying mechanisms are not clear.16–19 Interestingly, myogenic constriction as well as EDHF-mediated dilation appear to share common signaling mechanisms, and both may control KCa channel activity to set arterial tone through alterations of membrane potential. In this respect, blockade of KCa channels in vitro has been shown to prevent EDHF-mediated dilation9,20–22 and to strongly impair the regulation of the myogenic response.23–26 Activators of potassium channels are used as vasodilative therapeutic tools in hypertension, as they oppose (myogenic) constriction.27–29 However, the effect of KCa channel activators on EDHF-mediated dilation has not yet been investigated.
Because both myogenic constriction as well as EDHF-mediated dilation may share common signaling mechanisms and both are altered in hypertension, we proposed a potential relation between the 2 processes. To address this hypothesis, we assessed the myogenic constriction in individual rat coronary arteries and related it to the extent of EDHF-mediated dilation in the same artery. Furthermore, we increased myogenic constriction by elevating intraluminal pressure and measured EDHF-mediated dilation under this condition. To account for a role of KCa channels, we investigated the effect of the KCa channel opener NS1619 on myogenic constriction and EDHF-mediated dilation and compared it with another K+ channel opener that acts on a different type of K+ channel, that is, the KATP channel opener cromakalim. Finally, to compare our results to another artery type with per se low myogenic constriction, we investigated mesenteric arteries.
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Methods |
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Preparation and Cannulation of Coronary and Mesenteric Arteries
Male Sprague-Dawley rats (275 to 300 g, Harlan, Zeist, The Netherlands) were housed at the animal facility of the University of Groningen and were studied in compliance with institutional and legislatory regulations. Rats were anesthetized with 1.5% isoflurane in N2O/O2, and intestines and hearts were removed. Third-order branches of the superior mesenteric artery were isolated from surrounding perivascular tissue. The right ventricle of the heart was incised and the middle part of the septal artery30 was prepared free in cold Krebs solution. Arteries (one coronary and one mesenteric artery per rat) were transferred to an arteriograph system for pressurized arteries31 (Living System Instrumentation). Artery segments were cannulated at both ends on glass micropipettes, secured, and the lumen of the vessel was filled with Krebs solution. The intraluminal pressure was set to 30 mm Hg and was held constant (without flow) by a pressure servo system (Living System Instrumentation). The vessel chamber was continuously recirculated with warmed (37°C) and oxygenated (5% CO2 in O2) Krebs with a pH of 7.4. The vessel chamber was transferred to the stage of an inverted light microscope with a video camera attached to a viewing tube. The video dimension analyzer (Living System Instrumentation) was used to analyze the signal obtained from the video image and to continuously register lumen diameter.
Experimental Protocol
Arteries were allowed to equilibrate for 40 minutes in regular Krebs solution at an intraluminal pressure of 30 mm Hg. Intraluminal pressure was then increased to 70 mm Hg or 130 mm Hg, respectively, and the development of active myogenic constriction was registered. Myogenic constriction was expressed in percent decrease in diameter from the maximally dilated (passive) diameter of the same vessel at the same pressure (see also Data Analysis section). After development of myogenic constriction, the level of constriction was highly variable between different arteries. In this respect, it has been described that the extent of baseline constriction may considerably influence the vasodilatory capacity.32 Therefore, after development of (different levels) of myogenic constriction, in all of the following protocols, arteries were further preconstricted with increasing doses of the thromboxane A2 analogue U46619 (30 nmol/L to 1 µmol/L) until the diameter was decreased by 
75%. The mean preconstriction for all performed dilation curves was 75±2% (n=68) for coronary arteries and 72±1% (n=39) for mesenteric arteries. By obtaining comparable levels of preconstriction throughout the whole study, we may have ruled out that different levels of baseline constriction influenced the extent of EDHF-mediated dilation. Furthermore, to rule out a specific influence of the contractile agonist, we investigated the relation between myogenic constriction and EDHF-mediated dilation in several additional arteries not pretreated with any preconstrictor drug or by using serotonin or phenylephrine instead of U46619 (data not shown). Preconstricted arteries were studied for acetylcholine (ACh)-induced EDHF-mediated dilation. To this end, cumulative doses of ACh (10 nmol/L to 100 µmol/L) were given to the recirculating bath in the continuous presence of indomethacin (10 µmol/L) and NG-methyl-L-arginine acetate salt (L-NMMA, 100 µmol/L) to inhibit production of vasoactive prostaglandins (PG) and nitric oxide (NO). The exact nature of EDHF is still under debate, and specific inhibitors are not yet available.9,21 To confirm that the indomethacin- and L-NMMA–resistant relaxation was mediated by an EDHF, we repeated the ACh concentration-response curve in additional presence of the KCa channel blockers apamin (500 nmol/L) and charybdotoxin (100 nmol/L), added to the superfusing Krebs solution as well as into the lumen of the vessel, which has been consistently shown to inhibit EDHF-mediated dilation.9,21,22,33 We always determined EDHF-mediated dilation in the presence of NO and PG inhibition to rule out any potential interference of these 2 other mediators with EDHF. In this respect, it is important to mention that NO is believed to possibly inhibit EDHF under normal conditions and that EDHF thus may only be fully active when NO is blocked.34 Furthermore, not only EDHF but also NO may be capable of mediating dilation partly through activation of KCa channels35 and may thereby partly act as an endothelium-derived hyperpolarizing factor in case that NO production is not completely blocked. In preliminary experiments, we therefore established that neither increasing the concentration of L-NMMA nor adding another inhibitor of NO production (L-NAME, 100 µmol/L) induced further inhibition of relaxation in coronary and mesenteric arteries. Furthermore, ACh dilation in rat aorta (an artery type with strong NO dependency) was nearly abolished, suggesting that NO-mediated dilation may have been effectively prevented by L-NMMA at this concentration (100 µmol/L). In the current study, we thus determined the L-NMMA– and indomethacin-resistant ACh dilation that was blocked by charybdotoxin plus apamin, and, as also proposed by others, we refer to this as EDHF-mediated dilation, though the exact nature of EDHF(s) has not yet been identified.21
In addition to ACh, we performed concentration-response curves to the endothelium-independent dilator sodium nitroprusside (SNP, 10 nmol/L to 1 mmol/L) at 70 and 130 mm Hg, respectively (n=8 for each). At the end of each experiment, the normal Krebs solution was exchanged for calcium-free Krebs solution supplemented with EGTA (2 mmol/L) to determine the maximally dilated (passive) diameter at 70 mm Hg and 130 mm Hg, respectively.
Additional experiments in coronary (n=5) and mesenteric arteries (n=5) at an intraluminal pressure of 70 mm Hg were performed in presence of the KCa channel opener NS1619 (30 µmol/L). The KCa channel opener NS161936–38 is a synthetic benzimidazole that increases the open probability of large-conductance KCa channels and shifts voltage sensitivity of the channels to more negative potentials, probably independent of ligand receptors, G-proteins, or channel phosphorylation.36 Apart from its effect on large-conductance KCa channels, NS1619 has also been described to inhibit nifedipine-sensitive L-type calcium channels,37,38 especially at higher concentrations.39 However, at the concentration used in the current study (30 µmol/L), the (dilative) effect of NS1619 has been shown to be fully prevented by TEA (1 mmol/L) or charybdotoxin (50 µmol/L), suggesting that its effect was mediated by KCa channels.39 Nevertheless, to further differentiate whether the effect of NS1619 (30 µmol/L) on EDHF-mediated dilation in the current study was due to activation of KCa channels or closure of L-type calcium channels, we additionally investigated the effect of the L-type voltage-dependent calcium channel blocker nifedipine (3 µmol/L) on coronary EDHF-mediated dilation (n=4).
Finally, to compare to another K+ channel opener that acts on a different type of K+ channel, we investigated coronary arteries (n=4) in the presence of the KATP channel opener cromakalim (3 µmol/L) given to the superfusion medium before the determination of myogenic constriction and EDHF-mediated dilation.
Solutions and Drugs
The ionic millimolar composition of Krebs solution was as follows: 120.4 NaCl, 5.9 KCl, 2.5 CaCl2, 1.2 MgSO4, 25.0 NaHCO3, 1.2 NaH2PO4, 11.5 glucose; these chemicals were obtained from Merck. Acetylcholine, apamin, charybdotoxin, ethyleneglycol-bis-(ß-aminoethylether)-N,N,N',N'-tetraacetic acid (EGTA), indomethacin, nifedipine, L-NMMA, 1,3-Dihydro-1-[2-hydroxy-5-(trifluoro methyl)- phenyl]-5-(trifluoromethyl)-2H-benzimidazol-2-one (NS1619), SNP, and 1,5,5-hydroxy-11,9-(epoxymethano)prosta-5Z,13E-dienoic acid (U46619) were obtained from Sigma-Aldrich Chemie BV. Cromakalim was obtained from Tocris, UK. Stock solution (10 mmol/L) for indomethacin, cromakalim and U46619 was prepared in 96% ethanol. All other drugs were dissolved in deionized water and diluted with Krebs solution.
Data Analysis
Data are expressed as mean±SEM. Statistical differences were determined by the Student independent t test. Significance was accepted at a level of P<0.05 (2-tailed). Myogenic constriction and preconstriction with U46619 were expressed as percent decrease in diameter from the maximally dilated (passive) diameter of the same vessel determined at the same pressure in calcium-free solution supplemented with EGTA (2 mmol/L), that is, constriction (%)=100x[(DCa-free-DCa)/DCa-free], where D is the diameter in calcium-free (DCa-free) or calcium-containing (DCa) Krebs. Concentration-dependent dilation and maximal dilation (Emax) to ACh and SNP were expressed as percent dilation of preconstriction, that is, dilation (%)=100x[(DCa-Dpre)/(DCa-free-Dpre)], where Dpre is the diameter after preconstriction with U46619. The concentrations of drugs causing half-maximal responses (EC50 values) are expressed as negative logarithm of the molar concentration (pD2 values).
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Results |
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Myogenic Constriction and EDHF-Mediated Dilation in Coronary Arteries
At maximal dilation, the mean intraluminal diameter of coronary arteries was 262±7 µm (n=22) at 70 mm Hg and 279±10 µm (n=8) at 130 mm Hg intraluminal pressure. The development of individual coronary myogenic constriction at an intraluminal pressure of 70 mm Hg (n=9) was quite variable and ranged from 6% to 44%, with a mean of 24±4% (Figure 1A). In the same arteries, EDHF-mediated dilation to ACh ranged from 18% to 84%, with a mean of 42±7% (Emax), and was abolished by the combination of charybdotoxin plus apamin (chtx/apa) (Figure 1B). Elevating intraluminal pressure to 130 mm Hg (n=8) induced myogenic constriction by a mean of 46±2% (Figure 1A), which was nearly 2 times higher as compared with myogenic constriction at an intraluminal pressure at 70 mm Hg. EDHF-mediated dilation to ACh was significantly decreased under these conditions to 16±5% (Emax) and was abolished by the combination of charybdotoxin plus apamin (chtx/apa) (Figure 1B). Interestingly, individual coronary myogenic constriction inversely correlated to EDHF-mediated dilation (r=-0.75, P<0.001 for the combined data [n=17] obtained at 70 and 130 mm Hg; see Figure 1C; r=-0.71, P=0.034 for data obtained at 70 mm Hg [n=9]). Pretreatment with the KCa channel opener NS1619 (30 µmol/L, n=5) prevented the development of myogenic constriction in coronary arteries (Figure 2A) and strongly increased EDHF-mediated dilation to a mean of 94±2% (Emax) (Figure 2B), which was abolished by charybdotoxin plus apamin (data not shown). The KATP channel opener cromakalim (3 µmol/L, n=4) also prevented the development of myogenic constriction (Figure 2A) but had no effect on EDHF-mediated dilation (Figure 2B). Similarly, the L-type calcium channel blocker nifedipine (3 µmol/L, n=4) prevented development of myogenic constriction (0.4±0.2%) but had no significant effect on EDHF-mediated dilation (Emax 34±5%, pD2 5.3±0.1, data not shown).
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Endothelium-independent dilation of coronary arteries to SNP (10 nmol/L to 1 mmol/L) did not differ between 70 and 130 mm Hg intraluminal pressure. SNP relaxed coronary arteries to 90±1% (Emax), with a pD2 of 6.1±0.1 [combined data obtained at 70 mm Hg (n=8) and 130 mm Hg (n=8), respectively]. In contrast to EDHF-mediated dilation, individual myogenic constriction was not related to endothelium-independent dilation to SNP (data not shown).
Myogenic Constriction and EDHF-Mediated Dilation in Mesenteric Arteries
At maximal dilation, the mean intraluminal diameter of mesenteric arteries was 290±9 µm (n=14) at 70 mm Hg and 311±11 µm (n=8) at 130 mm Hg intraluminal pressure. Mesenteric arteries developed low levels of myogenic constriction at an intraluminal pressure of 70 mm Hg (n=9) as well as 130 mm Hg (n=8) (2±1%, and 3±2%, respectively) (Figure 3A) and showed high levels of EDHF-mediated dilation (Emax 93±2% and 94±2%, respectively), which was abolished by charybdotoxin plus apamin (chtx/apa) (Figure 3B). Pretreatment of mesenteric arteries with the KCa channel opener NS1619 (30 µmol/L, n=5) had no effect on myogenic constriction (Figure 2C) nor on EDHF-mediated dilation (Figure 2D). Note that the difference between the 2 artery types was fully reversed by NS1619 (Figure 2).
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Discussion |
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We investigated a potential relation between individual myogenic constriction and EDHF-mediated dilation. We found that myogenic constriction inversely relates to EDHF-mediated dilation in coronary arteries of normotensive rats. Pretreatment of coronary arteries with the KCa channel opener NS1619 prevented myogenic constriction and profoundly increased EDHF-mediated dilation. In mesenteric arteries, low myogenic constriction was associated with high EDHF-mediated dilation, and pretreatment with NS1619 was without effect.
The myogenic constriction of an artery in response to an increase in intraluminal pressure may be initiated by smooth muscle depolarization,2 which then regulates calcium entry through voltage-dependent calcium channels. This basic mechanism may be modulated by several intracellular signaling mechanisms.3–5 KCa channels may play an important role in regulation of the myogenic response. In this respect, closure of KCa channels may contribute to development of myogenic constriction through membrane depolarization,25,26,40 whereas opening of KCa channels may counteract myogenic constriction through membrane hyperpolarization.23,24 KCa channels are also believed to be involved in the action mechanism of EDHF, one of the endothelium-derived dilator substances—in addition to NO and prostacyclin—underlying endothelium-dependent dilation to acetylcholine.8,9 The relative contribution of these mediators varies between different species, vascular beds, and vessel size, but EDHF appears to be of major importance, particularly in smaller vessel sizes. Its nature appears to differ depending on species and vascular bed; candidates acting as EDHF(s) include cytochrome P-450–derived epoxyeicosatrienoic acids (EETs),41,42 K+ in the subendothelial space,43 and cannabinoids,44 and electrical coupling of endothelial cells and smooth muscle cells through myoendothelial gap junctions has been proposed to underlie endothelium-dependent hyperpolarization.45 Apart from the studied species and artery type, the nature and magnitude of preconstriction used to experimentally determine EDHF-mediated dilation also might influence the nature/working mechanism of EDHF.32,46,47 For example, an increasing importance of gap junctional communications in the EDHF response has been demonstrated in mesenteric arteries stimulated with phenylephrine compared with nonstimulated arteries.46 Independent of its exact nature, however, the opening of KCa channels leading to hyperpolarization and relaxation of vascular smooth muscle cells is thought to be involved because the combination of KCa channel blockers charybdotoxin and apamin very consistently inhibit EDHF-mediated dilation.9,21,22 However, it is still under debate whether these blockers exert their effect on KCa channels located on vascular smooth muscle or endothelial cells.48 Results obtained from coronary arteries in different species suggest that in this artery type, the EDHF response may involve cytochrome P-450–mediated production of EETs in endothelial cells, causing hyperpolarization and dilation of underlying smooth muscle cells by opening of smooth muscle KCa channels.10,49
Our present results show that myogenic constriction inversely relates to EDHF-mediated dilation in coronary arteries. We showed this not only by relating variable myogenic constriction of individual rats to EDHF-mediated dilation at one intraluminal pressure step but we further supported this by increasing intraluminal pressure, resulting in increased myogenic constriction, which was associated with decreased EDHF-mediated dilation. The exact mechanism underlying this relationship may not be determined from the present study. Nevertheless, endothelium-independent relaxation to SNP was not related to myogenic constriction, suggesting that the relation was not due to general alterations in smooth muscle dilatory ability. Furthermore, EDHF-mediated dilation was always determined in arteries that were preconstricted to similar levels as to preclude that differences in baseline constriction may influence the extent of EDHF-mediated dilation. To rule out a specific influence of the contractile agonist, the relation between individual levels of myogenic constriction and EDHF-mediated dilation was confirmed in coronary arteries not pretreated with any preconstrictor drug (unpublished observations, Gschwend S, et al, 2002). The endothelial-derived vasoconstrictor endothelin-l (ET-1)—known to be upregulated/released after pressure increase50,51 —might seem to be an interesting candidate to alternatively link myogenic constriction and EDHF-mediated dilation because it modulates myogenic constriction through ETA receptors in several artery types52,53 and may also interact with endothelial dilative mediators.54 However, using the ETA receptor antagonist BQ 123 (1 µmol/L), we could not detect any involvement of ET-1 in myogenic constriction or EDHF-mediated dilation in the studied artery types (unpublished observations, Gschwend S et al, 2002). Another substance that may mediate myogenic constriction (via closure of KCa channels) and may interact with EDHF response in some artery types is 20-HETE.40 However, as it has been shown that 20-HETE is produced in smooth muscle of renal and cerebral vessels but not in coronary vessels,40 it seems unlikely that 20-HETE production underlies the relation between myogenic constriction and EDHF-mediated dilation described in the current study. It may be more conceivable that high levels of myogenic constriction may limit the competing KCa channel–mediated effect of EDHF on vascular smooth muscle cells. This may be in line with the present results, which show that under increased myogenic constriction, EDHF-mediated dilation is gradually impaired. Furthermore, additional activation/recruitment of KCa channels with NS161936 not only antagonized myogenic constriction in coronary arteries but also profoundly increased EDHF-mediated dilation. That this effect of NS1619 on EDHF-mediated dilation may be specifically due to interactions with KCa channels is further supported by our findings that the KATP channel opener cromakalim had no effect on EDHF-mediated dilation. Furthermore, nifedipine did not influence EDHF-mediated dilation, suggesting that the effect of NS1619 on EDHF-mediated dilation may not be caused by direct interactions with L-type voltage-dependent calcium channels.37,38
In several forms of hypertension, arterial myogenic constriction is increased compared with normotensive arteries also when studied at comparable/normotensive pressure levels.7,11–15 It is still unclear whether arterial changes in hypertension are a primary abnormality or a consequence of blood pressure elevation. Regardless of that, however, (acutely) increased levels of myogenic constriction per se predict decreased EDHF-mediated dilation according to our present data, and to some extent this may account for impaired EDHF-mediated response observed in several forms of hypertension.16–19 In line with this, increased myogenic constriction14 as well as impaired EDHF16 in mesenteric arteries from spontaneously hypertensive rats have been found. However, available data on myogenic constriction and EDHF-mediated dilation in hypertension derive from different studies. Therefore they are difficult to compare because they were performed under different experimental conditions (ie, wire-mounted ring preparations, pressurized arteries, and so forth) in arteries with different sizes and in rats of different ages. Furthermore, the situation may be different under conditions of chronically elevated blood pressure when several adaptation mechanisms may have occurred. In this respect, an upregulation of KCa channels (perhaps to counterregulate increased constriction) has been shown in several forms of hypertension.18 We believe that further studies in which myogenic constriction and EDHF-mediated dilation are directly compared and related to the development of hypertension may be helpful to further dissect cause-effect relations.
In the current study, activation of KCa channels with NS1619 antagonized myogenic constriction in coronary arteries. Several types of K+ channel openers are used in the clinic as vasodilative therapeutic tools in hypertension, and there are indications that they exert beneficial effects in coronary artery disease.27–29 Our current data show for the first time that acute treatment with the KCa channel opener NS1619 not only antagonized myogenic constriction but also profoundly increased EDHF-mediated dilation in coronary arteries, whereas it had no effect in mesenteric arteries. Although the exact mechanism underlying the effect of KCa channel opening on EDHF-mediated dilation may not be derived from the present study, the present findings may emphasize an important therapeutic potential, especially with respect to the high incidence of coronary artery disease in hypertension.
Differences in myogenic response and EDHF contribution to endothelium-dependent dilation between different vascular beds have already been described.6,55 Results from our laboratory show that the contribution of EDHF to total ACh dilation may be much higher in mesenteric arteries compared with coronary arteries,56 as demonstrated previously.55 Importantly, the findings of the current study emphasize that the level of EDHF-mediated dilation may not be a fixed characteristic of an artery type/species but that it strongly depends on the actual experimental condition and that acute changes in luminal pressure, myogenic constriction or KCa activity may dynamically alter the extent of EDHF-mediated dilation. This may explain some of the inconsistencies observed in different studies and in isometric ring setups compared with isobaric pressure myographs. Interestingly, the difference in EDHF-mediated dilation between the 2 artery types used in the present study, that is, coronary and mesenteric arteries, could be fully reversed by the KCa channel opener NS1619. In this respect, it has been hypothesized that differences in KCa channel density, different expression of KCa channel subtypes, or differences in KCa channel open probability and voltage-sensitivity could reflect functional differences between vascular beds.55 We believe that further research in this direction may be very useful not only to explain differences between artery types but also for the development of (vascular bed) specific therapy in hypertension.
We have shown for the first time that myogenic constriction in coronary arteries antagonizes EDHF-mediated dilation. This might imply that increased coronary myogenic constriction in hypertension may be associated with impaired EDHF-mediated dilation, thereby potentially contributing to coronary risk in hypertension. Activation of KCa channels with NS1619 prevented myogenic constriction and profoundly increased EDHF-mediated dilation specifically in coronary arteries, suggesting a potential therapeutic effect to reduce coronary risk in hypertension.
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Acknowledgments |
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S. Gschwend is a recipient of an Ubbo Emmius Fellowship of the Groningen University Institute of Drug Exploration (GUIDE).
Received August 7, 2002; accepted February 13, 2003.
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