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CARDIOVASCULAR

Augmented Endothelium-Derived Hyperpolarizing Factor-Mediated Relaxations Attenuate Endothelial Dysfunction in Femoral and Mesenteric, but Not in Carotid Arteries from Type I Diabetic Rats

Department of Pharmacology, Faculty of Medicine, University of Hong Kong, Hong Kong, China (Y.S., R.Y.K.M., P.M.V.); and Department of Pharmacology and Toxicology, University of Alabama at Birmingham, Birmingham, Alabama (D.D.K.)

Received December 12, 2005; accepted March 23, 2006.

	Abstract

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Individual vascular beds exhibit differences in vascular reactivity. The present study investigates the effects of streptozotocin-induced type I diabetes on endothelium-dependent responses of rat carotid, femoral, and mesenteric arteries. Rings with and without endothelium, suspended in organ chambers for isometric tension recording, were contracted with phenylephrine and exposed to increasing concentrations of acetylcholine. In carotid and femoral arteries, acetylcholine produced concentration- and endothelium-dependent relaxations that were abolished by N-nitro-L-arginine methyl ester (L-NAME; specific nitric-oxide synthase inhibitor) and were impaired slightly in preparations from streptozotocin-treated rats (STZ-rats). This impairment could be prevented by L-arginine. In femoral arteries incubated with L-NAME, acetylcholine caused endothelium-dependent contractions that were abolished by 3-[(6-amino-(4-chlorobenzensulfonyl)-2-methyl-5,6,7,8-tetrahydronapht]-1-yl) propionic acid (S18886) (antagonist of thromboxane A₂/prostaglandins H₂-receptors) and reversed to relaxation by indomethacin (inhibitor of cyclooxygenase). The latter relaxation was inhibited by charybdotoxin plus apamin, suggesting a role of endothelium-dependent hyperpolarizing factor (EDHF). This EDHF-mediated component was augmented slightly in arteries from STZ-rats. In mesenteric arteries, relaxations to acetylcholine were only partially inhibited by L-NAME, and the L-NAME-resistant component was abolished by charybdotoxin plus apamin. In the mesenteric arteries from STZ-rats, L-NAME-sensitive relaxations to acetylcholine were reduced and the EDHF-component was augmented. These findings demonstrate a marked heterogeneity in endothelium-dependent responses in rat arteries and their differential adaptation in the course of type I diabetes. In particular, the EDHF-mediated component not only compensates for the reduced bioavailability of nitric oxide in the femoral and mesenteric artery but also counteracts the augmented endothelium-dependent contractions in the former.

Diabetes mellitus is characterized by hyperglycemia resulting from a defective secretion and/or action of insulin. Data on the impairment of endothelial function caused by type I diabetes are controversial. Thus, in blood vessels from type I diabetic rats, the relaxation to acetylcholine is reported to be normal [aorta (Head et al., 1987; Harris and MacLeod, 1988; Mulhern and Docherty, 1989), mesenteric artery (Harris and MacLeod, 1988)], blunted [aorta (Vallejo et al., 2000), mesenteric artery (Heygate et al., 1995; Vallejo et al., 2000)], or augmented [aorta (Altan et al., 1989)]. Likewise, in type I diabetic patients, endothelium-dependent dilatations have been reported to be normal (Huvers et al., 1999), impaired (Makimattila et al., 1996), or enhanced (Makimattila et al., 1997).

The present experiments were designed to study endothelial function in different arteries of rats in which a type I diabetes had been induced by the injection of streptozotocin. Particular attention was paid to the varying contributions of the individual endothelium-derived vasoactive factors in these arteries.

	Materials and Methods

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Experimental Animals. Type I diabetes was induced in 16-week-old male Sprague-Dawley rats (450-600 g) by a single administration of streptozotocin (55 mg/kg intravenously) dissolved in citric 2 mM acid-trisodium citrate buffer, pH 4.0. After 72 h, tail blood samples were obtained, and the glucose concentration was measured using a one-touch glucometer (LifeScan Inc., Milpitas, CA). Induction of diabetes was considered successful when the glucose level was higher than 16.6 mM (300 mg/dl). Nondiabetic control rats were injected with vehicle solution alone and kept under identical conditions. The animals were housed in the laboratory animal unit of the University of Hong Kong, fed with regular chow, and given free access to water. Twelve weeks later, they were anesthetized with intraperitoneal pentobarbitone sodium (70 mg/kg) and heparin (0.5 U/kg), and exsanguinated. Nonfasting glucose level was measured on the day of sacrifice. Control rats with glucose higher than 11.1 mM (200 mg/dl) were excluded from the study. All procedures and protocols were approved by the institutional animal care committee.

Preparation of Arteries. The carotid, femoral, and main mesenteric arteries were dissected free, excised, and placed into ice-cold modified Krebs-Ringer solution of the following composition: 118 mM NaCl, 4.7 mM KCl, 2.5 mM CaCl₂, 1.2 mM MgSO₄, 25.0 mM NaHCO₃, 1.18 mM KH₂PO₄, 0.026 mM calcium disodium EDTA, and 11.1 mM glucose (control solution). The blood vessels were cut into rings (1.5-2 mm in length). When arterial rings without functional endothelium were needed, the arteries were perfused with 1 ml of saponin solution (1 mg/ml, diluted with Krebs-Ringer solution) before the rings were cut. The rings were suspended in organ chambers containing control solution (37°C) aerated with 95% O₂ and 5% CO₂. They were connected to a force transducer (Powerlab model ML785 and ML119; ADInstruments, Inc., Colorado Spring, CO). Changes in isometric tension were recorded. The rings were stretched progressively to their optimal resting tension (2 g in carotid and mesenteric arteries and 1.2-1.5 g in femoral arteries; determined in preliminary experiments; data not shown) and were allowed to equilibrate for 90 min.

The incubation time with drugs was 30 min before experiments. Concentration-response curves were obtained in a cumulative manner. Changes in tension were expressed as a percentage of the reference contraction to 60 mM KCl, obtained at the beginning of the experiment. To study endothelium-dependent relaxations to acetylcholine, the preparations were exposed to 10 nM to 1 µM phenylephrine (to obtain 50-70% of response to 60 mM KCl) or to high extracellular potassium (30-40 mM). Sodium nitroprusside (10 µM) was added at the end of the experiments, and the relaxations were expressed as a percentage of the maximal relaxation induced by the nitrovasodilator.

Drugs. Acetylcholine hydrochloride, phenylephrine, indomethacin, N-nitro-L-arginine methyl ester (L-NAME), sodium nitroprusside, apamin, charybdotoxin, sulfaphenazole, tiron (4,5-dihydroxy-1,3-benzenedisulfonic acid), L-arginine, esculetin, superoxide dismutase, and saponin were purchased from Sigma Chemical Co. (St. Louis, MO). Heparin was purchased from LEO Pharm (Ballerup, Denmark). Bosentan was a kind gift from Dr. Martine Clozel (Actelion, Basel, Switzerland). S18886 was a kind gift from Dr. Emmanuel Canet (Institut de Recherches Servier, Suresnes, France). Concentrations are given as final molar concentration in the bath solution.

Oxyhemoglobin was prepared from a 1 mM solution of commercial hemoglobin (MP Biomedicals Inc., Eschwege, Germany) by the addition of 10 mM Na₂S₂O₄ (Sigma Chemical Co.). The reducing agent converted methemoglobin to oxyhemoglobin and was removed by dialysis in calcium-free physiological salt solution (118 mM NaCl, 4.7 mM KCl, 1.2 mM MgSO₄, 25.0 mM NaHCO₃, 1.18 mM KH₂PO₄, 0.026 mM calcium disodium EDTA, and 5.5 mM glucose) and bubbling with nitrogen at 4°C. The purity and concentration of oxyhemoglobin was determined electrophotometrically by measuring the difference in absorbance at 577 nM with methemoglobin as the reference (Simonsen et al., 1999)

Data Analysis. Data are presented as mean ± S.E.M.; n refers to the number of rats. Statistical analysis was done by one- or two-way analysis of variance, with post hoc multiple comparisons using the Bonferroni test (Prism, version 3a; GraphPad Software Inc., San Diego, CA). Differences were considered to be statistically significant when P value was less than 0.05.

	Results

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At the beginning of the study, the two groups of rats had a comparable body weight. Three months later, the control group had gained weight, whereas streptozotocin-treated rats exhibited a significant weight loss. The glucose level of the streptozotocin-treated animals was significantly higher than in the control group (Table 1).

Carotid Arteries. The concentration-relaxation curve to acetylcholine was shifted moderately but significantly to the right in preparations from streptozotocin-treated rats (Fig. 1, A and D). L-NAME (0.3 mM) abolished the relaxation in arteries from both groups (Fig. 1, A and D). L-Arginine (1 mM) restored the relaxation of the arteries from streptozotocin-treated rats to normal (Table 2).

View larger version (22K): [in this window] [in a new window]   Fig. 1. Effects of 0.3 mM L-NAME and endothelium-removal on acetylcholine-induced relaxations in carotid (left), femoral (middle), and mesenteric (right) arteries from both control (A-C) and streptozotocin-treated (D-F) rats. Data shown as means ± S.E.M. and expressed as changes in tension as percentage of the reference relaxation to 10 µM sodium nitroprusside (n = 10-18). The asterisks indicate that the difference with control rats is statistically significant (P < 0.05).

Femoral Arteries. The relaxations to acetylcholine were slightly but significantly reduced in femoral arteries from streptozotocin-treated rats (Fig. 1, B and E). L-Arginine restored the responses to normal (Table 2). Indomethacin (10 µM) and 0.1 µM S18886 did not significantly potentiate the relaxations to the muscarinic agonist in arteries from control and streptozotocin-treated rats (data not shown). In the presence of L-NAME, acetylcholine induced a concentration-dependent contraction from 0.1 to 3 µM. Such contractions were not observed in rings without endothelium or in preparation treated with S18886. Indomethacin not only prevented the contraction to acetylcholine (in the presence of L-NAME) but also reversed it to a relaxation (Fig. 2, A and C). The latter was significantly greater in arteries from streptozotocin-treated rats than in those from control animals. The relaxations in the presence of L-NAME and indomethacin were abolished by 0.1 µM apamin plus 0.1 µM charybdotoxin (Fig. 3, A and C) as well as by 10 µM sulfaphenazole (data not shown) in arteries from both groups. In the presence of L-NAME, indomethacin, and apamin plus charybdotoxin, the response was comparable with that of rings without endothelium.

View larger version (26K): [in this window] [in a new window]   Fig. 2. Effects of indomethacin (indo) and S18886 on the response to acetylcholine in femoral (left) and mesenteric (right) arteries from control (A and B) and STZ-treated (C and D) rats in the presence of L-NAME. Data shown as means ± S.E.M. and expressed as changes in tension in the presence of the reference relaxation to 10 µM sodium nitroprusside (n = 10-18). The asterisk indicates that the difference with control rat is statistically significant (P < 0.05).

View larger version (21K): [in this window] [in a new window]   Fig. 3. Effects of 0.1 µM apamin plus 0.1 µM charybdotoxin on acetylcholine-induced relaxation in femoral (left) and mesenteric (right) arteries from control (A and B) and streptozotocin-treated (C and D) rats in the presence of 0.3 mM L-NAME and 10 µM indomethacin. Data shown as means ± S.E.M. and expressed as changes in tension in the presence of the reference relaxation to 10 µM sodium nitroprusside (n = 10-18). The asterisks indicate the difference with control rat is statistically significant (P < 0.05).

Mesenteric Arteries. The relaxations to acetylcholine were comparable in mesenteric arteries of control and diabetic rats. L-NAME caused a significant inhibition of the response to acetylcholine in arteries from both groups. The effect of L-NAME was significantly less in arteries from streptozotocin-treated rats (Fig. 1, C and F). L-Arginine did not affect the relaxation to acetylcholine in either group (Table 2). In the presence of L-NAME, 10 µM oxyhemoglobin caused no further inhibition of the response to acetylcholine (data not shown). Indomethacin did not significantly affect the relaxations to acetylcholine (10 nM-3 µM) in arteries from both control and streptozotocin-treated rats (Fig. 2, B and D). In preparations contracted with high extracellular potassium, acetylcholine induced concentration-dependent relaxations. In arteries from both control and streptozotocin-treated rats, L-NAME abolished the relaxations. Indomethacin did not further affect the acetylcholine induced relaxation when combined with L-NAME (Fig. 4).

View larger version (17K): [in this window] [in a new window]   Fig. 4. Response to acetylcholine in mesenteric arteries from control (A) and streptozotocin-treated (B) rat during contractions to high extracellular potassium (30-40 mM). Data shown as means ± S.E.M. and expressed as percentage of change in tension (n = 6).

In arteries from control, but not streptozotocin-treated rats, incubated with both L-NAME and indomethacin, higher concentrations of acetylcholine (3-100 µM) induced a further, concentration-dependent contraction. This further contraction was not affected significantly by 10 µM bosentan, 150 U/ml superoxide dismutase plus 1 mM tiron, 0.1 µM S18886, and 1200 U/ml catalase or sulfaphenazole, but it was reduced significantly after incubation with 0.1 mM esculetin (Fig. 5). The combination of L-NAME, indomethacin, apamin, and charybdotoxin, abolished the relaxation to acetylcholine in arteries from both groups (Fig. 3, B and D).

View larger version (29K): [in this window] [in a new window]   Fig. 5. A, effect of indomethacin on the response to higher concentrations of acetylcholine (3 µM-0.1 mM) in mesenteric arteries from control rats in the presence of 0.3 mM L-NAME. Data shown as means ± S.E.M. and expressed as percentage of changes in tension (n = 6-12). The asterisks indicate that the difference from control (in the presence of L-NAME) is statistically significant (P < 0.05). B, effects of 10 µM bosentan, 0.1 µM S18886, 150 U/ml superoxide dismutase plus 1 mM tiron, 10 µM sulfaphenazole, and 0.1 mM esculetin on contractions to higher concentrations acetylcholine (3 µM-0.1 mM) in mesenteric arteries from control rats in the presence of 0.3 mM L-NAME. Data expressed as area under the curve and shown as means ± S.E.M. (n = 6-12). The asterisks indicate that the difference from control condition (in the presence of L-NAME) is statistically significant (P < 0.05).

	Discussion

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In the present experiment, L-NAME abolished the relaxations to acetylcholine in carotid and femoral arteries, but only partially reduced it in the mesenteric artery. This confirms the predominance of NO as an endothelium-derived relaxing factor in conduit arteries, whereas EDHF become more important in the arteries such as mesenteric artery, which contribute more to the control of the local circulation (Nagao and Vanhoutte, 1992; Shimokawa et al., 1996). The L-NAME-sensitive relaxations were slightly but significantly reduced in the three arteries from the diabetic rats. The moderate reduction in acetylcholine-induced relaxation observed in mesenteric arteries is comparable with the studies that described either a reduced or minimally affected endothelium-dependent responsiveness in the same preparation. In the carotid artery, L-arginine restored the blunted relaxations to normal, confirming that diabetes reduces the bioavailability of nitric oxide (De Vriese et al., 2000).

In the femoral artery, in the presence of L-NAME, acetylcholine induced a dose-dependent contraction that was not observed in rings without endothelium, suggesting the release of EDCF (Vanhoutte et al., 2005). S18886 (Simonet et al., 1997), a selective antagonist for TP-receptors, abolished the contraction, whereas indomethacin, an inhibitor of cyclooxygenases, not only prevented but also reversed it to a relaxation. This then strongly suggests that the endothelium-derived contracting factor involved is produced by cyclooxygenase and activates TP-receptors. The existence of EDCF produced by cyclooxygenase and resulting in activation of TP-receptors has been well documented in the aorta of the spontaneously hypertensive rat (Lüscher and Vanhoutte, 1986; Yang et al., 2003). The occurrence of such EDCF-mediated response is augmented by spontaneous hypertension (Lüscher and Vanhoutte, 1986; Yang et al., 2003), type II diabetes (Okon et al., 2003), and vasospasm (Dhein et al., 1989). That the endothelium-dependent contraction is not observed when NO synthase is operative illustrates the inhibitory effect of NO on the release of the action of EDCF (Auch-Schwelk et al., 1992; Nakaike et al., 1995; Yang et al., 2004; Tang et al., 2005). The reversal from contraction to relaxation obtained with indomethacin revealed that when both NO synthase and cyclooxygenase are inhibited, another endothelium-derived relaxing agent takes over. It presumably is EDHF, since the relaxation was blocked by the combination of apamin plus charybdotoxin (Feletou and Vanhoutte, 2006). The TP-receptor blocker S18886 did not unmask an EDHF-mediated response, suggesting that products from cyclooxygenase may inhibit the release or the action of EDHF, as is the case for NO (Olmos et al., 1995; Bauersachs et al., 1996). Since sulfaphenazole, an inhibitor of P450 monooxygenase (Veronese et al., 1990), blocked this presumably EDHF-mediated relaxation in the presence of L-NAME plus indomethacin, the endothelium-derived hyperpolarizing factor in this artery must be derived from P450 monooxygenase, favored by arachidonic acid when cyclooxygenase is blocked (Feletou and Vanhoutte, 2006).

Judged from the effects of L-NAME and apamin plus charybdotoxin, in the mesenteric artery, both NO and EDHF contributed to endothelium-dependent relaxations under normal conditions in this blood vessel. This conclusion is strengthened by the experiments with preparations contracted with high potassium, where the relaxation became totally dependent on NO, judged from the abolition achieved with L-NAME (Feletou and Vanhoutte, 2006). Apparently, diabetes did not affect the amplitude of the acetylcholine-induced relaxation in this preparation when the NO-dependent component was reduced, because this was counteracted by a greater contribution of EDHF. The present findings differ from those reported by others in the same preparation where relaxations attributed to EDHF were depressed in arteries from streptozotocin-treated rats despite a comparable NO production (Makino et al., 2000; Wigg et al., 2001). We have no explanation for these divergent observations. In the present study, the greater contribution of EDHF observed in the mesenteric artery of streptozotocin-treated rats may be explained by the lesser production of NO (Olmos et al., 1995; Bauersachs et al., 1996; Ding et al., 2000). The exact nature of the EDHF involved in rat mesenteric arteries is not clear since sulfaphenazole and catalase did not block it, suggesting that neither a product of P450 monooxygenase nor H₂O₂ is responsible for the L-NAME-resistant relaxation in this preparation (Feletou and Vanhoutte, 2006).

Unexpectedly, in the mesenteric arteries from control, but not from diabetic rats, higher concentrations of acetylcholine induced an endothelium-dependent contraction in the presence of L-NAME and indomethacin. The unmasking effect of the inhibitor of cyclooxygenase could be explained by the interruption of the production of vasodilator prostaglandins such as prostaglandin E₂ or prostacyclin. Bosentan (Veniant et al., 1994), a blocker of endothelin receptors did not prevent the further contraction, suggesting that it cannot be attributed to the release of enothelin-1. The observation that the TP-receptor blocker S18886 and superoxide dismutase plus tiron (Devlin et al., 1981) did not prevent it either, ruled out free radical-derived isoprostanes. Likewise, sulfaphenazole, an inhibitor of P450 monooxygenase (Veronese et al., 1990), did not inhibit the response, suggesting that it was not caused by P450 metabolites of arachidonic acid. Esculetin, an inhibitor of lipoxygenases (Sekiya et al., 1982), reduced the contraction. In norepinephrine-contracted mesenteric arteries, two pathways contribute to the metabolism of arachidonic acid, cyclooxygenase and lipoxygenases (Peredo and Adler-Graschinsky, 2000; Carvalho Leone and Coelho, 2004). The present findings are explained best by the shunting of the fatty acid to the lipoxygenase pathway, resulting in the production of vasoconstrictor lipoxygenase products (Rimele and Vanhoutte, 1983). This contraction was not observed in arteries from streptozotocin-treated rats, suggesting a lesser activity of lipoxygenases as a consequence of diabetes.

In summary, the present experiments illustrate the marked heterogeneity of endothelium-depended responses in peripheral arteries of control rats and their differential adaptation in the course of the type I diabetes. NO is the major endothelium-derived dilator in larger blood vessels, whereas both NO and EDHF play a role in arteries of smaller diameter. Under physiological conditions, the production of EDHF is curtailed by the production of NO. The present findings suggest that in streptozotocin-induced diabetes, when the synthesis of NO is impaired, alleviation of this intrinsic inhibition may, at least in part, maintain endothelial vasodilator function. Furthermore the up-regulation of EDHF-mediated responses not only compensates for the reduced bioavailability of NO in the mesenteric and femoral arteries but also probably counteracts the production or action of an endothelium-derived contracting factor in the latter.

	Footnotes

 
This study was supported in part by Research Grants Council Grant HKU 7524.

Article, publication date, and citation information can be found at http://jpet.aspetjournals.org.

doi:10.1124/jpet.105.099739.

ABBREVIATIONS: STZ, streptozotocin; EDCF, endothelium-derived contracting factor; EDHF, endothelium-dependent hyperpolarizing factor; L-NAME, N-nitro-L-arginine methyl ester; S18886, 3-[(6-amino-(4-chlorobenzensulfonyl)-2-methyl-5,6,7,8-tetrahydronapht]-1-yl) propionic acid; P450, cytochrome P450; TP, thromboxane A₂/prostaglandins H₂.

Address correspondence to: Dr. Paul M. Vanhoutte, Department of Pharmacology, 2/F, Laboratory Block, Faculty of Medicine Bldg. 21, Sassoon Rd., Pokfulam, University of Hong Kong, Hong Kong, China. E-mail: vanhoutte.hku{at}hku.hk

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