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simvastatin counterbalance reduced bioconversion of nitrates in hypercholesterolemia
ATORVASTATIN I SIIWASTATIN CO UNTERBAIANCE REDUCED BIOCONVER!GON OF NlTRATES IN HYPERCHOLESTEROLX.Mu
LJPOPROTEUWNDUCED OXIDANT STRESS IN DYSLJPID EMIC PATIENTSIS DJD’ENDWT ON COMPOSITION AND CONCENTRATION OF LIPOPROTEINS
BmnoFink,EberbardBassenge Ins&ate of Applied Physiology, Albert-Ludwigs University Hypercholesterolemiainducesvasculardysfunctionand is associated with enhancedformationof reactiveoxy8enspecies(ROS). We analyzed
Bruno
the effects of atorvastatin
Introduction: Recent data from our gmup indbtes that elMnation of atlwmgenic lipopmteins and fibrinogen significantly
(A) /simvastatin
(S) during experimental
hypzrch&stemlemia(cholesteroldiet,OS%,8 weeksin guineapigs)cm ROS pmduction, formation of atheroscleroticplaques, and nitrate bioconversion. Tl~e cholesterol diet WBS given without or with atorvastatiuor simvastatin(10 m%kglday).RO8productionwnsanalyzed both in the per&& of Langend& heartsand in blood samples.We =w=J concenhtions of reducedand oxidized SH-groupsin plasma and bioconversionof nitrates using ESR teclmiqoe. ROS production in blood samples and pcrtksates of guinea pig hearts treated with cholesterol immwed tiwn 0.237+0.03 pM/min to 0.364M.O24pM/mio and t?om 1.73M.06 to 2.73M.09 @&nin, mpectively. This was sigdicantly reduced by A both in ex viva blood samples (0.31iO.92 @Nmin) and in per&&es (1.36+0.02@Mnia) (S caused a similar but lesser reduction). Fortbcmme, concentrations of reduced SH-gmps were significantly increased 6m1 205i9.1 to 254ilSpM after 8 weeks cholesterol diet, and were signiticaotl~ augmented tien s (264+M) was added. suIprisblgly, the hypcrcholesterokmia induced im@ment in bioconversion of nitroglycezin ws completely cixrumvenkl when A or S were administaed. Bothc4nlwmatioaofredocedSH-gro~inplasmaaspsrameterof adaptation to excessive oxidative stms and excessive prodwtion of ROS during experimental hypercholestemkmia are effectively reduced by appropriate doses of atorvastatin and less by simvastatin administration. Furtbermofc, administration of statins pmmted the &airment in bioconversion of nitrates and an impaired dilation effect.
Fink, Jibgen E&es*, Karl Wi&9, Wi&ed h4&-z*, EberhardBassenge Instituteof Applied Physiology, Albert-Ludwigs University *Department of Clinical Chemistry,Albert-Ludwigs University
lowers oxidative stress and improves the enzymaticbiownversion ofGTNinvitm.Becausebothpammetersarenomulizedafter beparin-mediated extritcorporeal LDL (fibrinogen) precipitation (HELP apberesis),we testedreversibility of these effectsto identify the cause for the impressive improvement W therapy. Patients and methods: Four patients with HC and CAD were investigated hefore and after HELP therapy. At t-0 we took EDTA-plasma and isdated VLDL, IDL, LDL, and HDL particles thmllgb ultracentr@#on. Fractions were buffered with sepbadex PD-10 columnsaud~onl?esblytakenbzpaMz&bloodfrom the samepatient. After bu&ring with PD-10 colmnns, the samples were immediately (4h) added to bepatin plasma fmm CAD patients and from healthy volunreer~. Results: LDL atxi VLDL fractions iudueed enhanced ROS formation in blood samplestaken firorn CAD pat&n@ and normocbolestemlemic vohmteets.The mte was higher in LDL and VLDL particles, whereas HDL particles induced only minima& augmetd ROS formation. The HDL fraction finm a patient with 3-fold elevated Lp(a) levels increased ROS much mom thau HDL witbout auy (similar density > HDL2b) Lp(a) (n=3). Conchions: LDL am triggers of oxidative stress. The efkt of HDL fractions on ROS formation appanMy depend upon contentof Lp(a).
EXCESSIVE FORMATION OR RBACl’NE OXYGEN SPECIES NORMALUBD BY PYRUVATB OR BY EXERCISE TRAINING Brano Fink, RolfBitoger’Eb&mi Baasenge Institute of Applied Physiology, Uniwsity of Freiburg, Germany ‘Dept. of Physiology, Univ. Health Sciences, Bethesda, MD, USA.
CHARACTERIZATION OF CORONARY ADENOSINE RECEPTORS IN MOUSE Amanda Flood & John Headrick. Research Centre, Griffith Unlverslty,
Physical exercise initiates formation of reactive oxygen species (ROS).Thisintumleadstooxidativestmssaudc4lulardamageif Tbeobjectiveoftbisstudywasto not applqniately cocorrelate in vivo formation of ROS with hemodynan& parameters atrest,aswellasdurlngitm&ng levelsof&admillexercise beforeandaReratrainingperiodofSqreeks,orafterchangeof intmxw NAD/NADH ratio under 4mmMmtion of pymvate. Dogs were exercised at 5, 10 aad 15 km/h (5 % grade). In vivo generatedROS were scavengedusing IV infbsion of spin trap I-hydroxy-3carboxy-pymlidine and qua&&d by electron spin Il?wtlsnce tedmiqm. Plasma lactate CoKzntmtions were measmedspectropbotometricaUy. Arterial systolic pmssme (SAP)! heart mte (HR), and ROS formation increased significautly wttb incnz&g levels of exercise before and afler baining (* p < 0.05 vs. resting values; paired t-test,
Adenosine receptors mediating coronary dilation in the mouse heart were characterized, and the roles of nitric oxide (NO) and KATp channels in these responses were assessed. Adenosine receptor agonists induced coronary dilation in mouse heart with pEC5os of 9.4iO.l for CGS21660 (Aa selective agonist), 930.1 for NECA (At/As agonist), 6.4iO.l for 2-chloroadenosine (At/A2 agonist), 7.7iO.l for R-PIA (At/Ass selective), and 6.6i0.2 for adenosine. The agonist potency order (CGS21660=NECA>2-chloroadenosine> RPIA>adenosine) supports AsA adenosine receptor-mediated dilation in mouse coronary vessels. 0.2-2 PM of the A2sselective antagonist alloxazine failed to alter responses to CGS21660 or 2 chloroadenosine, verifying AeA-mediated dilation. NO-synthase antagonism with 50 PM No-nitro Larginine (L-NOARG) increased resistance by -25%, and inhibited responses to CGS21660 (pECso=9.0*0.1), 2chloroadenosine (pECso=7.6*0.2) and ADP (an endothelialdependent dilator) but not nitroprusside. KAv inhibition with 5 PM glyburide inhibited responses to CGS21660 to an even greater extent than L-NOARG (pEC5o=6.&O.l). The inhibitory effects of L-NOARG were unaltered by glyburide, and inhibition with glyburide was unaltered by L-NOARG. These data document the existence of functional AW adenosine receptors mediating coronary dilation in mouse. Adenosine-mediated coronary dilation involves a sensitive NO-dependent response and a major KATp-dependent response. The two response components appear unrelated.
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An increw in the level of exercise corm&es with formation of ROSandwitbanincmase in systolic aaerial pressmz or HR. This enhanced formation of ROS &ring &ma&g levels of exercise canbedepressedupto2.5timesafter8weekstrainingandlessby the change of extracellular NALYNADH ndio daring administration of pymvate, correlating with a decreasein lactateformation.
VASCULAR HEART. Heart Foundatlon Australia.
A35
LJPOPROTEUWNDUCED OXIDANT STRESS IN DYSLJPID EMIC PATIENTSIS DJD’ENDWT ON COMPOSITION AND CONCENTRATION OF LIPOPROTEINS
BmnoFink,EberbardBassenge Ins&ate of Applied Physiology, Albert-Ludwigs University Hypercholesterolemiainducesvasculardysfunctionand is associated with enhancedformationof reactiveoxy8enspecies(ROS). We analyzed
Bruno
the effects of atorvastatin
Introduction: Recent data from our gmup indbtes that elMnation of atlwmgenic lipopmteins and fibrinogen significantly
(A) /simvastatin
(S) during experimental
hypzrch&stemlemia(cholesteroldiet,OS%,8 weeksin guineapigs)cm ROS pmduction, formation of atheroscleroticplaques, and nitrate bioconversion. Tl~e cholesterol diet WBS given without or with atorvastatiuor simvastatin(10 m%kglday).RO8productionwnsanalyzed both in the per&& of Langend& heartsand in blood samples.We =w=J concenhtions of reducedand oxidized SH-groupsin plasma and bioconversionof nitrates using ESR teclmiqoe. ROS production in blood samples and pcrtksates of guinea pig hearts treated with cholesterol immwed tiwn 0.237+0.03 pM/min to 0.364M.O24pM/mio and t?om 1.73M.06 to 2.73M.09 @&nin, mpectively. This was sigdicantly reduced by A both in ex viva blood samples (0.31iO.92 @Nmin) and in per&&es (1.36+0.02@Mnia) (S caused a similar but lesser reduction). Fortbcmme, concentrations of reduced SH-gmps were significantly increased 6m1 205i9.1 to 254ilSpM after 8 weeks cholesterol diet, and were signiticaotl~ augmented tien s (264+M) was added. suIprisblgly, the hypcrcholesterokmia induced im@ment in bioconversion of nitroglycezin ws completely cixrumvenkl when A or S were administaed. Bothc4nlwmatioaofredocedSH-gro~inplasmaaspsrameterof adaptation to excessive oxidative stms and excessive prodwtion of ROS during experimental hypercholestemkmia are effectively reduced by appropriate doses of atorvastatin and less by simvastatin administration. Furtbermofc, administration of statins pmmted the &airment in bioconversion of nitrates and an impaired dilation effect.
Fink, Jibgen E&es*, Karl Wi&9, Wi&ed h4&-z*, EberhardBassenge Instituteof Applied Physiology, Albert-Ludwigs University *Department of Clinical Chemistry,Albert-Ludwigs University
lowers oxidative stress and improves the enzymaticbiownversion ofGTNinvitm.Becausebothpammetersarenomulizedafter beparin-mediated extritcorporeal LDL (fibrinogen) precipitation (HELP apberesis),we testedreversibility of these effectsto identify the cause for the impressive improvement W therapy. Patients and methods: Four patients with HC and CAD were investigated hefore and after HELP therapy. At t-0 we took EDTA-plasma and isdated VLDL, IDL, LDL, and HDL particles thmllgb ultracentr@#on. Fractions were buffered with sepbadex PD-10 columnsaud~onl?esblytakenbzpaMz&bloodfrom the samepatient. After bu&ring with PD-10 colmnns, the samples were immediately (4h) added to bepatin plasma fmm CAD patients and from healthy volunreer~. Results: LDL atxi VLDL fractions iudueed enhanced ROS formation in blood samplestaken firorn CAD pat&n@ and normocbolestemlemic vohmteets.The mte was higher in LDL and VLDL particles, whereas HDL particles induced only minima& augmetd ROS formation. The HDL fraction finm a patient with 3-fold elevated Lp(a) levels increased ROS much mom thau HDL witbout auy (similar density > HDL2b) Lp(a) (n=3). Conchions: LDL am triggers of oxidative stress. The efkt of HDL fractions on ROS formation appanMy depend upon contentof Lp(a).
EXCESSIVE FORMATION OR RBACl’NE OXYGEN SPECIES NORMALUBD BY PYRUVATB OR BY EXERCISE TRAINING Brano Fink, RolfBitoger’Eb&mi Baasenge Institute of Applied Physiology, Uniwsity of Freiburg, Germany ‘Dept. of Physiology, Univ. Health Sciences, Bethesda, MD, USA.
CHARACTERIZATION OF CORONARY ADENOSINE RECEPTORS IN MOUSE Amanda Flood & John Headrick. Research Centre, Griffith Unlverslty,
Physical exercise initiates formation of reactive oxygen species (ROS).Thisintumleadstooxidativestmssaudc4lulardamageif Tbeobjectiveoftbisstudywasto not applqniately cocorrelate in vivo formation of ROS with hemodynan& parameters atrest,aswellasdurlngitm&ng levelsof&admillexercise beforeandaReratrainingperiodofSqreeks,orafterchangeof intmxw NAD/NADH ratio under 4mmMmtion of pymvate. Dogs were exercised at 5, 10 aad 15 km/h (5 % grade). In vivo generatedROS were scavengedusing IV infbsion of spin trap I-hydroxy-3carboxy-pymlidine and qua&&d by electron spin Il?wtlsnce tedmiqm. Plasma lactate CoKzntmtions were measmedspectropbotometricaUy. Arterial systolic pmssme (SAP)! heart mte (HR), and ROS formation increased significautly wttb incnz&g levels of exercise before and afler baining (* p < 0.05 vs. resting values; paired t-test,
Adenosine receptors mediating coronary dilation in the mouse heart were characterized, and the roles of nitric oxide (NO) and KATp channels in these responses were assessed. Adenosine receptor agonists induced coronary dilation in mouse heart with pEC5os of 9.4iO.l for CGS21660 (Aa selective agonist), 930.1 for NECA (At/As agonist), 6.4iO.l for 2-chloroadenosine (At/A2 agonist), 7.7iO.l for R-PIA (At/Ass selective), and 6.6i0.2 for adenosine. The agonist potency order (CGS21660=NECA>2-chloroadenosine> RPIA>adenosine) supports AsA adenosine receptor-mediated dilation in mouse coronary vessels. 0.2-2 PM of the A2sselective antagonist alloxazine failed to alter responses to CGS21660 or 2 chloroadenosine, verifying AeA-mediated dilation. NO-synthase antagonism with 50 PM No-nitro Larginine (L-NOARG) increased resistance by -25%, and inhibited responses to CGS21660 (pECso=9.0*0.1), 2chloroadenosine (pECso=7.6*0.2) and ADP (an endothelialdependent dilator) but not nitroprusside. KAv inhibition with 5 PM glyburide inhibited responses to CGS21660 to an even greater extent than L-NOARG (pEC5o=6.&O.l). The inhibitory effects of L-NOARG were unaltered by glyburide, and inhibition with glyburide was unaltered by L-NOARG. These data document the existence of functional AW adenosine receptors mediating coronary dilation in mouse. Adenosine-mediated coronary dilation involves a sensitive NO-dependent response and a major KATp-dependent response. The two response components appear unrelated.
I.
I
I
I
I
I
An increw in the level of exercise corm&es with formation of ROSandwitbanincmase in systolic aaerial pressmz or HR. This enhanced formation of ROS &ring &ma&g levels of exercise canbedepressedupto2.5timesafter8weekstrainingandlessby the change of extracellular NALYNADH ndio daring administration of pymvate, correlating with a decreasein lactateformation.
VASCULAR HEART. Heart Foundatlon Australia.
A35