© 1997 by European Society of Cardiology
Copyright © 1997, European Society of Cardiology
Effects of glycosylated hemoglobin on vascular responses in vitro
Department of Internal Medicine and the Cardiovascular Center, University of Iowa, Iowa City, IA and the Department of Veterans Affairs, Iowa City, IA, USA
* Corresponding author: 200 ML, Department of Internal Medicine, University of Iowa, 200 Hawkins Drive, Iowa City, IA 52242, USA. Tel. +1 319 335-7633; Fax +1 319 353-6343; E-mail: coltman@blue.weeg.uiowa.edu
Received 10 October 1996; accepted 23 December 1996
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Abstract |
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 Top Abstract 1 Introduction2 Methods3 Results4 DiscussionReferences |
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Vascular responses to endothelium-dependent vasodilators are greatly impaired in vivo, while isolated blood vessels from animals with diabetes mellitus demonstrate less consistent degrees of impairment. Glycation of proteins, such as hemoglobin, has been implicated in the vascular abnormalities associated with diabetes. Objective: The purpose of this study was to test the hypothesis that glycosylated hemoglobin is capable of reducing endothelium-dependent vasodilator responses, possibly explaining impaired dilation observed in vivo. Methods: To test this hypothesis, the effect of glycosylated hemoglobin (GH) on vascular responses was studied in several vascular beds, including ventricular microvessels and coronary, mesenteric, femoral, and renal arteries. Coronary arterioles were isolated and mounted between two glass pipettes in a pressurized (30 cmH2O) organ chamber. Isolated artery segments were studied using a standard isometric ring technique. Results: In ventricular microvessels, 10 nM nGH (non-GH) and GH both attenuated the relaxation to Ach. A lower concentration, 1 nM nGH or GH, did not alter dilation to Ach. In coronary, femoral, mesenteric and renal artery segments, endothelium-dependent responses were not altered by the presence of 10 or 100 nM nGH or GH. Conclusion: In coronary microvessels, and coronary, femoral, mesenteric and renal arteries, GH is not responsible for the impaired endothelial function associated with diabetes mellitus.
KEYWORDS Glycosylated hemoglobin; Diabetes; Coronary vasculature; Microcirculation; Acetylcholine; Dog, arteries
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1 Introduction |
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TopAbstract1 Introduction2 Methods3 Results4 DiscussionReferences |
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Diabetes mellitus is associated with increased cardiovascular morbidity and mortality [1–3]. Reasons for the increased morbidity and mortality are uncertain, but impairment of endothelial function and platelet–endothelium interactions are likely contributing factors [4–7]. In animals and patients with diabetes, endothelial modulation of vascular responses is impaired to endogenous vasodilators such as acetylcholine (Ach) and adenosine [8, 9]. Several investigators have observed an impaired response to Ach in vitro which occurred due to endothelial production of vasoconstrictor prostanoids such as TX A2 and PGH2 [4, 5, 7]. Others have suggested that oxygen-derived free radicals may play an important role in the reduced dilation [8, 10–12]. Despite these in vitro abnormalities, in vivo vascular responses in diabetes are more often and more severely attenuated than those observed in vitro. The reason for this discrepancy is uncertain.
Since long-term hyperglycemia appears to be the central initiating factor responsible for the development of many of the complications of diabetes [4, 9, 13], glucose or glucose-derived metabolites may irreversibly modify long-lived extracellular or intracellular macromolecules which can inactivate nitric oxide [14]. Thus, a circulating factor or factors may play a role in endothelial dysfunction associated with diabetes. A recent study by Rodriguez-Manas [15]and colleagues suggests that high levels of glycosylated hemoglobin impair endothelium-mediated vasoactive responses in rat aorta. This study is consistent with the hypothesis that glycosylated hemoglobin, a factor present in vivo, is responsible for impaired coronary microvascular responses during hyperglycemia. To test this hypothesis, the effect of glycosylated hemoglobin on endothelium-dependent vasodilatation was studied in several vascular beds, including ventricular microvessels and coronary, mesenteric, femoral, and renal conduit arteries.
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2 Methods |
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TopAbstract1 Introduction2 Methods3 Results4 DiscussionReferences |
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All protocols were approved by the University of Iowa Animal Care and Use Committee and conform with the Guide for the Care and Use of Laboratory Animals published by the US National Institutes of Health (NIH Publication No. 85-23, revised 1985).
2.1 Animals and tissue
Twenty adult mongrel dogs of either sex (20–25 kg) were euthanized with an overdose of sodium pentothal (50 mg/kg). Tissues, including the heart, femoral, mesenteric and renal arteries, were quickly harvested. Hearts and arteries were immediately placed in cold (4°C), oxygenated (20% O2, 5% CO2 and 75% N2) Krebs' bicarbonate buffer solution (see solutions) for dissection. Ventricular arterioles and arteries were dissected and trimmed of fat and connective tissue. In some studies of rings, the endothelium was removed by gentle rubbing of the luminal surface with silk suture.
2.2 Isolated microvessels
A standard isolated pressurized arteriole preparation was used to study coronary microvessels [16]. Each end of the arteriole was cannulated with a glass micropipette and attached to independent hydrostatic pressure reservoirs (20 mmHg) under conditions of no flow. The organ chamber was placed on the stage of an inverted microscope. Attached to the microscope were a video camera, a video monitor, and a calibrated video calliper. The organ chamber was connected to a rotary pump which continuously circulated oxygenated Krebs buffer warmed to 37°C. Internal diameters were measured by manually adjusting the video micrometer.
Arterioles were allowed to equilibrate for 30 min at a distending pressure of 20 mmHg. KCl (50 mM) was added to the bath to test constrictor capacity. After washing with fresh buffer, vessels were incubated for 30 min in Krebs buffer alone (control), or Krebs with 1 or 10 nM non-glycosylated human hemoglobin (nGH) or 14% glycosylated human hemoglobin (GH). Endothelin-1 (0.40–8.0 nM) was used to constrict the arterioles to 30–60% of their resting diameter. Cumulative concentration–response relationships were evaluated for acetylcholine (Ach; 10–10 to 10–4 M) and sodium nitroprusside (SNP; 10–10 to 10–4 M) by adding the drug directly to the organ bath. The order of the drugs was randomized. The following criteria were required for an acceptable experiment: (1) arterioles could not demonstrate obvious leaks; (2) arterioles had to constrict >50% to 50 mM KCl, and >30% to endothelin; and (3) dilate by >80% to 10–4 M SNP.
2.3 Isolated vascular rings
Coronary, femoral, mesenteric and renal arteries were studied using a standard isometric ring technique [10, 17]. Vascular rings were mounted on two stirrups made by passing stainless steel wires through the vessel lumen. One stirrup was attached to a force transducer, and the other to a micrometer microdrive to allow the vessel to be stretched by known increments. Each vessel apparatus was placed in a 25-ml jacketed organ bath containing Krebs buffer equilibrated at 37°C and aerated with 20% O2, 5% CO2 and 75% N2. Isometric contractions and relaxations were measured on a computer. Rings were individually stretched to the maximum of the length–developed tension relationship by repeated test exposures to 75 mM KCl at increasing vessel diameters.
The vessels were allowed to stabilize 30 min prior to concentration–response curves in either control solution (normal Krebs), or 10 or 100 nM concentrations of nGH or GH solutions. PGF2
was used to constrict the vessels to 30–50% of their resting tension. After steady–state tension was achieved, a concentration–response curve to Ach (10–10 to 10–4 M) was performed to evaluate endothelium-dependent relaxation. Vessels were then washed with fresh Krebs, incubated in control or one of 4 hemoglobin solutions, and constricted with PGF2. A concentration–response curve to SNP (10–10 to 10–4 M) was then performed to evaluate smooth muscle vasodilatation. The order of Ach and SNP was randomized. Acceptable experiments met the following criteria: (1) development of >1 g of tension to PGF2; (2) dilate by 75–150% to SNP; (3) denuded vessels must dilate <30% to Ach (10–6 M).
2.4 Solutions and drugs
Krebs solution contained (in mM): NaCl 131.5; KCl 5; CaCl2 2.5; MgCl 1.2; NaHCO3 23.5; KH2PO4 1.2; and glucose 11. Solutions were aerated with 20% O2, 5% CO2, and 75% N2 and maintained at 37°C with pH maintained at 7.4. Human hemoglobin solutions were purchased from Sigma Chemical (St. Louis, MO) and prepared by diluting in distilled H2O. Glycosylated hemoglobin content was quantified in the clinical pathology laboratory at the University of Iowa. Endothelin-1 was purchased from Calbiochem (San Diego, CA). All solutions and vasoactive agents were prepared fresh on the day of the experiment. Acetylcholine and sodium nitroprusside were purchased from Sigma Chemical.
2.5 Statistical analysis
All concentration–response curves were evaluated for changes in maximal responses and differences at each dose using ANOVA with repeated measures and the Bonferroni correction for multiple comparisons. EC50 is defined as the vasodilator concentration that produced 50% of maximal relaxation of the endothelin or PGF2 preconstriction. Significance of differences among mean values of resting conditions, maximal effect, and EC50 values was assessed with a one-way ANOVA. Data are expressed as mean±s.e.m. Differences with P<0.05 were considered significant.
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3 Results |
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3.1 Coronary microvascular responses
Baseline diameter was 123±12, 105±13, and 117±9 µm for arterioles in control, nGH, and GH groups respectively (P=n.s.). Arterioles in all groups were preconstricted with similar amounts with endothelin (0.40–8.0 nM). Arterioles were preconstricted to 49±3, 51±4, and 55±2% resting diameter in control, nGH, and GH groups, respectively (P=n.s.). Ach produced concentration-related relaxation in canine coronary arterioles. These responses were not affected by incubating the microvessels in 1 nM nGH or GH (Fig. 1, left panel). EC50 values for ACh were –6.3±0.1, –7.0±0.3, and –6.4±0.1 for control, 1 nM nGH and 1 nM GH, respectively. The response to Ach in vessels which were incubated in 10 nM GH was reduced compared to control (Fig. 1, right panel). A similar reduction in dilation to Ach was seen in arterioles incubated with 10 nM nGH (Fig. 1, right panel). EC50 values for ACh were –8.2±0.3, –6.8±.03, and –6.8±0.1 for control, 10 nM nGH and 10 nM GH, respectively (P<0.05)
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SNP produced a concentration-related increase in diameter in coronary arterioles. These responses were not altered by the presence of 1 or 10 nM hemoglobin solutions (data not shown).
The decrease in sensitivity of the arterioles to Ach in the presence of 10 nM nGH or GH suggests a non-specific effect of hemoglobin on Ach responses.
3.2 Coronary artery responses
Coronary artery segments were taken from the left circumflex and left anterior coronary arteries. Resting tension was 6.5±0.2, 5.7±0.3, 5.5±0.2, and 5.2±0.2 g in control, nGH, GH and denuded groups respectively (P=n.s.). Developed tension to PGF2 was similar among groups and 3.6±0.3, 3.9±0.4, 4.5±0.5, and 3.5±0.9 g in control, nGH, GH and denuded groups, respectively; P=n.s. In canine coronary arteries preconstricted with PGF2, Ach (Fig. 2) and SNP produced concentration-related relaxation. Vessels incubated in 10 or 100 mM GH or nGH did not show an altered response to Ach or SNP. EC50 values for ACh and SNP were not altered by the presence of 10 or 100 nM GH or nGH (data not shown). Following endothelial removal, the response to Ach was significantly reduced. Endothelium removal did not alter the response to SNP.
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3.3 Femoral artery responses
Resting tension was 5.8±0.4, 6.0±0.2, 6.1±0.2, and 5.7±0.5 g in control, nGH, GH and denuded groups, respectively (P=n.s.). All femoral segments constricted similarly to PGF2
(3.7±0.4, 5.7±0.4, and 3.7±1.0 g in nGH, GH and denuded groups, respectively; P=n.s. vs control 5.2±0.7). In canine femoral arteries preconstricted with PGF2, Ach and SNP (Table 1) produced concentration-related relaxation. In arteries denuded of endothelium, the response to Ach was significantly impaired. Femoral artery response to ACH in the presence of 100 nM nGH and GH is shown in Fig. 3. Vessels incubated in 10 or 100 mM GH or nGH did not show altered responses to Ach or SNP. Endothelium removal did not alter the response of the vessels to SNP. EC50 values are presented in Table 1.
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3.4 Mesenteric artery responses
Resting tension was 6.1±0.2, 5.8±0.3, 6.1±0.2, and 6.4±0.2 g in control, nGH, GH and denuded groups, respectively. Developed tension to PGF2
was 5.2±0.5, 5.7±0.8, 7.3±0.8, and 4.7±0.9 g in control, nGH, GH and denuded groups, respectively (P=n.s.). Ach (Fig. 3) and SNP (Table 2) produced concentration-related relaxations which were not altered by the presence of 10 or 100 nM GH and nGH. Dilation to Ach was significantly impaired, but the response to SNP was not affected by endothelium removal. EC50's are presented in Table 2.
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3.5 Renal artery responses
In canine renal artery segments, developed tension to PGF2
was 7.1±0.6, 6.3±0.8, and 8.4±1.0 g in control, nGH, and GH groups, respectively (P=n.s.). Preconstricted renal artery segments produced concentration-related relaxation to Ach and SNP. The presence of 100 nM GH and nGH did not alter the response to Ach or SNP (Table 3).
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4 Discussion |
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There are three major findings of the present study. First, glycosylated hemoglobin at concentrations expected in diabetic patients and at concentrations considered supraphysiological for diabetes fails to attenuate conduit artery dilation to Ach in the coronary, mesenteric, femoral or renal vascular beds. Second, the effect of hemoglobin on vascular reactivity varies according to vessel size in the coronary bed. Third, the impaired coronary microvascular responses to Ach in the presence of nGH and GH appears not to be related to glycosylation of hemoglobin. It appears to be an effect that is related to hemoglobin per se, as previously discussed. These results suggest that circulating factors other than glycosylated hemoglobin are responsible for the impaired endothelium-dependent vasodilatation observed in diabetic subjects, in vivo. Our results and conclusions are dependent upon several methodological considerations.
We used standard in vitro preparations to study isolated ventricular coronary microvessels [16]and conduit arteries from the coronary, mesenteric, femoral and renal vascular beds [10, 15, 17]. These methods have been used by several laboratories, including our own [17]. The concentration of GH we used was high (14%). However, it reflects the degree of glycosylated hemoglobin seen in diabetic subjects [18–20]. In our study, there were no differences in dilation to Ach among vessels treated with nGH or GH (see Figs. 1–3
). Furthermore, in coronary, femoral, mesenteric and renal artery segments, endothelium-dependent responses were not altered by the presence of 10 or even 100 nM GH or nGH. In normal subjects, free plasma hemoglobin in the nanomolar concentrations has been reported [21]. Thus, the use of concentrations greater than 100 nM GH would not provide useful physiological information.
Hemoglobin has been used to inhibit endothelium-dependent nitric oxide relaxations in several vascular beds, including coronary arteries [22]and rabbit aorta [23]. Myers et al. [16]have shown concentrations of 10 mM hemoglobin to inhibit Ach relaxation in canine coronary microvessels. Lower concentrations of hemoglobin were not investigated in that study [16]. In our study, both 10 nM nGH and GH attenuated the relaxation to Ach in ventricular microvessels. The effect appears specific for endothelium-dependent responses, since smooth muscle responses were not altered by the presence of nGH or GH.
The results of Rodriguez-Manas et al. [15]contrast with the findings of the current study. Segments of rat aorta which were incubated in 10 nM GH solution for 10 min showed decreased responses to Ach. Our study suggests that even with 10-fold higher concentrations of GH (100 nM), endothelium-dependent responses in canine arteries were not altered. Several potential explanations exist for these results which contrast with those of Rodriguez-Manas. First, in our study a different species of animal was studied. Second, in their isolated aortic ring studies, the organ chambers were aerated with 95% O2 and 5% CO2, while we used a gaseous mixture containing 20% O2, 5% CO2 and 75% N2. It is well established that oxygen-derived free radicals are produced by auto-oxidation of glucose [4, 10, 11]. These reactive oxygen species may combine with the NO, producing a relatively weak vasodilator, peroxynitrite [24]. Third, agents used to preconstrict the vessels were different (PGF2 vs norepinephrine) [17, 25]. Finally, we investigated the reactivity of conduit vessels from the coronary, mesenteric, femoral and renal vascular beds in addition to coronary microvessels, whereas Rodriguez-Manas et al. studied aortic segments. It is possible that responses are different in regional organ blood vessels.
This study was intended to shed light on the discrepancies observed between in vivo and in vitro preparations which evaluate vascular responses in diabetes. Our study fails to provide an explanation for this discrepancy. It is possible that glycation of other circulating proteins within the serum of diabetic individuals may be responsible for the abnormalities in endothelium-dependent vasodilatation observed in vivo in diabetic subjects. Further studies are necessary to clarify this possibility.
In summary, in dog coronary arterioles, and coronary, mesenteric, femoral and renal arteries, GH is not responsible for the impaired endothelium-dependent vasodilatation in response to Ach associated with diabetes mellitus.
Time for primary review 29 days.
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Acknowledgements |
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We thank Gilbert Falcon for technical assistance during portions of this study. Supported by: NIH RO1 HL51308 (KCD) and VA Merit Review (DDG). Dr. Oltman was supported by a National Research Service Award (F32HL09198 and T32HL07121). Ms. Bocker was supported by a pre-doctoral American Heart Association Fellowship. Drs. Gutterman and Dellsperger are Established Investigators of the American Heart Association.
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References |
|---|
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TopAbstract1 Introduction2 Methods3 Results4 DiscussionReferences |
|---|
- Bierman EL. Atherogenesis in diabetes. Arterioscler Thromb 1992;12:647–656.
- Uusitupa MIJ, Niskanen LK, Siitonen O, et al. 5-Year incidence of arterosclerotic vascular disease in relation to general risk factors, insulin level, and abnormalities in lipoprotein composition in non-insulin-dependent diabetic and nondiabetic subjects. Diabetes Spectrum 1991;4:323–330.
- Koskinen P, Manttari M, Manninen V, Huttunen JK, Heironen OP, Frick MH. Coronary heart disease incidence in NIDDM patients with the Helsinki heart study. Diabetes Care 1992;15:820–825.
- Tesfamariam B, Brown ML, Deykin D, Cohen RA. Elevated glucose promotes generation of endothelium-derived vasoconstrictor prostanoids in rabbit aorta. J Clin Invest 1990;85:929–932.
- Kolri MZ, Hadhazy P, Koszeghy A, et al. Prostaglandins and altered diabetic vasoregulation (Abstract). Biomed Biochim Acta 1988;9:849–854.
- Mayhan WG. Impairment of endothelium-dependent dilation of the basilar artery during diabetes mellitus. Brain Res 1992;580:297–302.
- Tesfamariam B, Jakubowski JA, Cohen RA. Contraction of diabetic rabbit aorta caused by endothelium-derived PGH2-TxA2. Am J Physiol 1989;257:H1327–H333.
- Tesfamariam B, Cohen RA. Free radicals mediate endothelial cell dysfunction caused by elevated glucose. Am J Physiol 1992;263:H321–H326.
- Tesfamariam B, Brown ML, Cohen RA. Elevated glucose impairs endothelium-dependent relaxation by activating protein kinase C. J Clin Invest 1991;87:1643–1648.
- Langenstroer P, Pieper GM. Regulation of spontaneous EDRF release in diabetic rat aorta by oxygen free radicals. Am J Physiol 1992;263:H257–H265.
- Hattori Y, Kawasaki H, Abe K, Kanno M. Superoxide dismutase recovers altered endothelium-dependent relaxation in diabetic rat aorta. Am J Physiol 1991;261:H1086–H1094.
- Mugge A, Elwell JH, Peterson TE, Harrison DG. Release of intact endothelium-derived relaxing factor depends on endothelial superoxide dismutase activity. Am J Physiol 1991;260:C219–C225.
- Kersten JR, Brooks, LA, Dellsperger KC. Impaired microvascular response to graded coronary occlusion in diabetic and hyperglycemic dogs. Am J Physiol 1995;268:H1667–H1674.
- Bucala R, Tracey KJ, Cerami A. Advanced glycosylation products quench nitric oxide and mediate defective endothelium-dependent vasodilation in experimental diabetes. J Clin Invest 1991;87:432–438.
- Rodriguez-Manas L, Arribas L, Giron C, Villamor J, Sanchez-Ferrer CF, Marin J. Interference of glycosylated human hemoglobin with endothelium-dependent responses. Circulation 1993;88(part 1):2111–2116.
- Myers PR, Banitt PF, Guerra R, Harrison DG. Characteristics of canine coronary resistance arteries: importance of endothelium. Am J Physiol 1990;257:H603–H610.
- Oltman CL, Parker JL, Laughlin MH. Endothelium-dependent vasodilation of proximal coronary arteries from exercise-trained pigs. J Appl Physiol 1995;79:33–40.
- Arfken CL, Schmidt LE, McGill JB, White NH, Santiago JV. Major decrements in glycated hemoglobin levels between 1978 and 1989 in patients with insulin-dependent diabetes mellitus. J Diabetes Complications 1996;10:12–17.
- Brinchmann-Hanser O, Dahl-Jorgensen K, Hanssen KF, Sandvik L. Oscillatory potentials, retinopathy, and long-term glucose control in insulin-dependent diabetes. Acta Ophthalmol 1992;70:705–712.
- Migdalis IN, Kalogeropoulou K, Zachariadis D, Koutoulidis K, Samartzis M. Serum levels of type III procollagen peptide and peripheral vascular disease in diabetic patients. Diabetes Res Clin Pract 1994;23:179–182.
- Hanks GE, Cassell M, Ray RN, Chaplin H. Further modification of the benzidine method for measurement of hemoglobin in plasma: definition of a new range of normal values. J Lab Clin Med 1960;56:486–498.
- Beny JL, Brunet PC, van der Bent V. Hemoglobin causes both endothelium-dependent and endothelium-independent contraction of the pig coronary arteries, independently of an inhibition of EDRF effects. Experientia 1989;45:132–134.
- Martin W, Villani GM, Jothianandan D, Furchgott RF. Selective blockade of endothelium-dependent and glyceril trinitrate-induced relaxation by hemoglobin and by methylene blue in the rabbit aorta. J Pharmacol Exp Ther 1985;232:708–716.
- Liu S, Beckman JS, Ku DD. Peroxynitrite, a product of superoxide and nitric oxide, produces coronary vasorelaxation in dogs. J Pharmacol Exp Ther 1994;268(3):1114–1121.
- Rapoport RM, Campell AK, Bazan E. Effects of PKC downregulation on norepinephrine- and prostaglandin F1 alpha-induced contration in rat aorta. Am J Physiol 1995;269(2 Pt 2):H590–H598.
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