Impairment of right coronary voltage-gated K+ current inrat with hypoxic pulmonary hypertensionJean-Marc Hyvelin, Marie Christine Lemaire, Véronique Eder,Pierre Bonnet. LABPART EA3852, Faculty of Medicine,Tours, France

Chronic hypoxia leads to the development of pulmonaryhypertension (PHT) and right ventricle (RV) remodeling.Following chronic hypoxia, altered right coronary reactivitycould potentially reduced myocardial O2-supply and conse-quently leads to RV failure. K+ channels are well known toregulate membrane potential and vascular tone. We previouslyshowed that Kv currents are differentially expressed betweenthe right and left coronary artery (RCA, LCA). We postulatedthat coronary myocytes adaptation to PHT should differ bet-ween RV and LV.

Wistar rats were exposed to chronic hypoxia for 3 weeks orkept under normoxic condition. In microelectrodes experi-ments, membrane potential was depolarized in hypoxic rightcoronary artery (H-RCA) myocytes and increased in H-LCAmyocytes when compared to normoxic RCA and LCA. In patchclamp experiments Kv currents were decreased in H-RCA cellswhereas they were increased in H-LCA cells. In contractionexperiments the effect of 4-AP on the resting tension of the H-RCA was smaller than that in normoxic RCA. Finally westernblot analysis of Kv channel subunits indicated a decrease in Kvchannels expression in H-RCA. This suggests that, in H-RCA,Kv currents were decreased following transmural pressure in-crease. The altered membrane potential and consequently vas-cular reactivity could be involved in occurrence of RV failureduring chronic obstructive pulmonary disease and more gene-rally in RV hypertrophic cardiomyopathies.

Keywords: Coronary; Hypoxia; Right cardiomyopathies

doi:10.1016/j.yjmcc.2007.03.686

Doxycycline ameliorates diabetes-induced vasculardysfunctionAslihan Koksoy, Esma Zeydanli, Evrim Tanriverdi, RichardSchulz*. Belma Turan Ankara University, Ankara, Turkey.*University of Alberta, Edmonton, AB, Canada

The long-term morbidity of diabetes mellitus is characterizedby increased oxidative stress and may involve the increasedactivity of matrix metalloproteinases (MMPs) in differenttissues. The activities of matrix metalloproteinases (MMPs)may be increased and their endogenous inhibitors (TIMPs)decreased, in response to enhanced oxidative stress. This im-balance may contribute to the functional changes in thevasculature in diabetes. We therefore investigated the effect ofthe MMP inhibitor doxycycline treatment (Doxy, 15 mg/kg/day) on the contractile function of aorta from streptozotocin-induced (50 mg/kg) diabetic rats. Doxy treatment of diabeticrats improved the aortic depressed contraction response to

phenylephrine (10−8–10−5 M) and the impaired relaxationresponse to isoproterenol (10−9–10−4 M) caused by diabetes.MMP-2 protein levels were reduced by 15% in diabetic aorta (amarker of oxidative stress activation and indicates release fromtissues) with respect to controls. Doxy treatment of diabetic ratssignificantly attenuated these changes. The protective effect ofan MMP inhibitor on the contractile and vasodilator activitiesand MMP-2 level in the aorta from the diabetic rat suggest a roleof MMPs in diabetes-induced vascular dysfunction. Our datasuggest that inhibitors of MMP activity may be potentially oftherapeutic benefit in reducing the severity of vascular injuryassociated with diabetes.

Acknowledgments

Supported by Ankara University Research Funds 20030809120, TUBITAK-SBAG-3056 and CIHR MGP 66953.

Keywords: Diabetes mellitus; Cardiovascular disease;Metalloproteinases

doi:10.1016/j.yjmcc.2007.03.687

Altered coronary vasodilator mechanisms in fetal sheepduring maternal nutrient restrictionStephen O'Rourke, Srinivas Ghatta, Radhika Tunstall, KimVonnahme, Joel Caton. Lawrence Reynolds North Dakota StateUniversity, Fargo, ND

The mechanisms underlying fetal programming are poorlyunderstood but may be associated with adaptations by the fetusin response to changes in maternal environment during preg-nancy. We hypothesized that maternal nutrient restriction duringpregnancy alters vasodilator responses in fetal coronary arteries.Pregnant ewes were fed a control (100%NRC; n=6) or nutrient-restricted (60% NRC; n=6) diet from day 50 to 130 of gestation(term=145 days). Coronary arteries with endothelium from fetallambs (130 days gestation) were cut into rings, placed in organbaths and contracted with U46619 (10 nM). Relaxations tobradykinin (B; 0.1–100 nM) were similar in control rings(pD2=8.06±0.3; Emax=86±10%) and rings from nutrient-restricted animals (pD2=8.22±0.3; Emax=84±8%) and wereunaffected by indomethacin (10 μM). In nutrient-restrictedanimals, relaxation to Bwas fully suppressed by nitro-L-arginine(NLA; 30 μM) and converted to a contractile response (30±7%increase in tone). NLA had no effect on B-induced relaxation incontrol rings. The NLA-resistant response to B in control ringswas nearly abolished by iberiotoxin (100 nM), a selective BKCa

channel blocker and by depolarization (KCl 40mM). A selectiveKATP channel blocker, glyburide (1 μM), had no effect on B-induced relaxation. In control animals, B-induced relaxation ismediated primarily via a pathway independent of NO orarachidonic acid metabolites and may be due to release of amediator that activates BKCa in coronary arteries. In fetalcoronary arteries from nutrient-restricted animals, B-induced

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relaxation is completely dependent on NO, which may be anadaptive response to ensure adequate coronary perfusion.

Keywords: Nutrition; Endothelium; Nitric oxide

doi:10.1016/j.yjmcc.2007.03.688

Beneficial effect of sodium selenate on vascular dysfunctionin diabetic ratsEsma Zeydanli, Evrim Tanriverdi, Aytac Seymen, ErkanTuncay, Hakan Gurdal, Aslihan Koksoy, Belma Turan.Department of Biophysics, Turkey

Since selenium compounds can restore some metabolicparameters and structural alterations of diabetic rat tissues, wetempted to investigate whether these beneficial effects extend tothe diabetic rat isolated thoracic aorta dysfunctions. Diabeteswas induced by streptozotocin (50 mg/kg body weight) and ratswere treated with sodium selenate (15 μmol/kg body weight/day) for 4 weeks. Sodium selenate treatment of diabetic ratsinduced a significant recovery (80% wrt diabetes) in thedepressed phenylephrine (10−8–10−5 M) stimulated isometriccontractions (50% wrt control) in aorta while we obtained 100%recovery in the depressed relaxation responses (30% wrt con-trol) with isoproterenol (10−9–10−4 M) without any significantchanges in Log50 values. Sodium selenate treatment of thediabetic rats also restored the altered activities of severalantioxidants enzymes of which are involved in the glutathionemetabolism of the heart as well as the levels of glutathione andoxidized protein sulphydryls while no significant effect on highblood glucose level. Our data indicate that an oxidant shift ofcellular thiolic pools can modulate contraction-relaxationactivities of thoracic aorta in diabetic rats. Therefore, it can besummarized that selenium employs important roles in alteredcontraction-relaxation activities of thoracic aorta via affectingthe glutathione redox cycle to combat oxidative stress indiabetes and small doses of selenium compounds may be usefulas an adjunctive therapy in human diabetes.

Acknowledgments

Supported by projects Ankara University Research FundsNo.: 20030809120 & TUBITAK-SBAG-3056.

Keywords: Antioxidants; Diabetes mellitus; Mechanics

doi:10.1016/j.yjmcc.2007.03.689

Adiponectin improves endothelial dysfunction inhyperlipidemic ratsR. Lia, H.F. Zhanga, F. Gaoa, T.L. Christopherb, B.L. Lopezb,L. Taoa,b, X.L. Maa,b. aFMMU, Xi'an, China. bThomasJefferson University, Philadelphia, USA

Hyperlipidemia-induced endothelial (EC) dysfunction is amajor contributing factor to cardiac complications in diabeticpatients. Plasma level of adiponectin (AD) has recently beenreported to be inversely related to the risk of MI. Current studyinvestigated whether AD may improved EC function inhyperlipidemic rats and determined the mechanisms involved.Adult rats were fed with a regular or a high-fat diet (1%cholesterol) for 8 weeks and aorta was isolated. Rings (2 mm inlength) were incubated with vehicle or AD (1 μg/ml) for 2 h invitro and EC function was determined by comparing vasor-elaxation to ACh, an EC-dependent and SNAP, an EC-in-dependent vasodilator. NOS activity (eNOS and iNOS) andanti-oxidant capacity were determined. Serum cholesterol wassignificantly increased and maximal vasorelaxation to ACh wasdecreased (70.3±3.3% vs. 95.2±2.5%, n=8, p<0.01) in fat-fed group. The eNOS activity was unchanged but iNOS activitywas increased (0.9±0.1 vs. 0.6±0.1 U/mg, p<0.05), and anti-oxidant capacity was diminished (p<0.05) in fat-fed rats. Mostinterestingly, incubation of rings from fat-fed rats with ADimproved vasorelaxation (80.5±4.4%, p<0.05) to ACh, re-versed antioxidant capacity (p<0.05), increased eNOS activity(1.3±0.1 vs. 1.0±0.1 U/g, p<0.05) and reduced iNOS activity.In conclusion, our study demonstrated that adiponectin is anatural molecule that protects endothelial function against hy-perlipidemic injury by multiple mechanisms including promot-ing eNOS but inhibiting iNOS activity, preserving antioxidantcapacity and attenuating oxidative/nitrative stress.

Keywords: Endothelium;Diabetes; Nitric oxide synthase activity

doi:10.1016/j.yjmcc.2007.03.690

Functional and morphological changes in vessels ofhypertriglyceridemic rabbits with normocholesterolemiaAkira Ishihata, Yumi Katano*. Division of Pathophysiology,Ohu University. *Division of Nursing Pharmacology andPathophysiology, Yamagaga University School of Medicine

To explore the effect of post-prandial hypertriglyceridemiaon the progression of atherosclerosis, we examined thevascular function and morphological changes in newlydeveloped PHT rabbits, which showed post-prandial hyper-triglyceridemia with normocholesterolemia. Thoracic aortawas isolated from PHT rabbits and Japanese white rabbits(JW) to measure the developed tension of the ring prepara-tion. Histological examination was carried out with hematox-ylin–eosin and elastica-Masson trichrome staining. Both JWand PHT rabbits had no atheromatous lesions in the aorticluminal surface. The vasorelaxing responses to acetylcholinein endothelium-intact preparations were not altered in the 3-month-old PHT rabbits, while they were significantlyattenuated in the 10-month-old PHT rabbits compared toJW. In the endothelium-denuded vessels, the response tosodium nitroprusside was not affected in PHT. In contrast,isoproterenol-induced vasorelaxation was less in the 10-

S229ABSTRACTS / Journal of Molecular and Cellular Cardiology 42 (2007) S219–S233