CARDIOVASCULAR EFFECTS OF SULFONYLUREAS EXPERIMENTAL AND CLINICAL EXPERIENCES
PhD thesis
Eve Nieszner M.D.
Semmelweis University 2nd Department of Cardiology National Center of Health Sciences Department of Cardiology and Internal Medicine Budapest
Semmelweis University
2002.
Introduction Notwithstanding that typ.2. Diabetes Mellitus can be treated excellently nowadays the complications of diabetes are still taking place in the front lines of the mortality data. High blood sugar in consideration of high diabetic cardiovascular mortality plays an important role in the progressive atherosclerosis as being the main origin of this multiorgan disease. In spite of the effective treatment of hyperglycaemy the high number of cardiac death means a great demand for revaluation the risk factors among diabetic patients. Beside the needed normoglycaemy , the necessity of interventions for primer prevention and multifactorial treatment has to be underlined. However sulfonylurea treatment has arised as a possible new risk factor as possessing special channel blocking effects on ATP dependent potassium channels. Besides beta cells they may have an influence on all other ones in extrapancreatogen localisation. As K+ATP channels are actors of protection in the cardiovascular system and are mainly metabolically controlled . During sulfonylurea treatment their activity is inhibited, so their participation in vasodilation and cardioprotection is supposed to be impeded in the diabetic patients. As extrapancreatic localisation of these channels are widespread in the cardiovascular system SU treatment may result in the depression of preconditioning or vasodilation. There are only a small information about the activity and potency of K+ATP channels in the cardiovascular system under chronic sulfonylurea treatment. Should we need account with a paralysed cardiovascular protection in the diabetic patient treated with sulfonylurea.? Does sulfonylurea treatment mean an increased or anlarged hazard?? Aim of study The aim of the study was to investigate the influence of two distinct sulfonylureas (glibenclamide and glimepiride) on the adaptation properties of the cardiovscular system. 1./
Myocardial preconditioning and its metabolic modulation was assessed in vivo
and in vitro experimental studies to get information about, how these reactions are influenced by sulfonylurea treatement and metabolic circumstances. 2./
Clinical relevances were assessed in diabetic patiens treated or untreated with
diabetes mellitus.
3./
Different sulfonylureas (glibenclamid, glimepirid) and their effects on
vasoregulatory adaptation were assessed in coronary patients and in patients with eriferial artery disease.
Method Alloxan induced (145mM·kg-1) diabetic (n=189) New Zeland male rabbits (BW:1650±250g) were used in the experiments. They were regularly controlled and consumed when their blood sugar reached the pathological range(BS>12.5mM). In clinical studies healthy (n=26, kor:56±12y) control and diabetic patients (n=43year :63±0,8years) were employed. (HbA1C>7.0%). We possessed their inform concent for diagnostic assessement. In vivo animal models : preconditioning were provoked by 2 min of no flow ischaemia, followed by 2 min reperfusion (for two occasions). Myocardial infarction was provoked by 60 min coronary artery ligation after. 0.05- 0.2- 0.6· 10-3 mM×kg-1 of glibenclamid or glimepirid treatment both in healthy control and diabetic animals. Planymetry was carried out after tetrazolium blue (TTC) vital painting, and histological measurements were done with the help of flurescens signal followed with fluorescens stereo microscope (Eclyps 600, NIKON, VIRGINIA IBM PC,IMAN 2.0 beta KFKI) In vitro experimental studies: rabbit hearts were perfused retrogradely according to Langendorff-II. method (constant 80watercm) and exposed to 2min no flow ischaemia followed by 2min reperfusion (2 times). Infarction was provoked by 20 min ligation of coronary perfusion and 30 min reperfusion. and concentration dependent influence of glibenclamide and gliclazid treatment (5-25-250-1224ng/l) on contraction and relaxation in healthy control and diabetic hearts were observed. Experimental data were analysed by 3way variance and by regression analysis. In human studies the effects of glibenclamid and glimepiride on microcirculation in healthy controls and newly diagnosed diabetics without obliterative
artery disease (n=22) was assessed by a laser Doppler method (He-Ne monocromatics, Perimed 5000,Perisoft 5.1 IBM PC) Flow mediated vasodilatory capacitiy of the brachial artery was assessed in controls and diabetic patients with and without obliterativ artery disease (n=22) (FMVD, 11MHz, PD). Measuremets were repeated in metabolic modulation (exposition to adenosine (500mg/min iv.), L-arginin (0.1gtskg-1 iv.), trimetazidine (60mg p.o.) and NO (p.o.). Vasodilatory response (endothel dependent and independent) to these agents were compared in patients with and without sulfonylurea treatment (glibenclamid or. Glimepirid). Transthoracal
echocardiography
(TTE,
Powervision,
2D,PD,3.5MHz)
measurements , diameteres and pulsed Doppler measurements - from the apex of the heart – were done to compare the effects of vascular complications and/or different types of treatments in the diabnetic group (Observed parameteres: E/A, prejection period-PEP, circumferential shortening-CRS, PEP/LVET, periferial stress-ESMWS) Transoesophageal echocardiography (TEE, Powervision, PD, 4.5MHz,45-600 ) assessment supplied data about the vasodilation capacity and flow velocity in the coronary system of sulfonylurea treated patients (n=23). Treadmill test (Bruce protokol) served as a method for clinical type of preconditoning as being repeated within 60 mins following the first test. Developed changes (per centum) in load capacitiy, ischaemic tolerance and time of reconvalescens in the second compared to the first measurement expressed the possibility of preconditioning. The effect of metabolic (trimetazidine) and sulfonylurea (glibenclamid and glimepirid ) treatment were assessed. Different types of statistical methods were used in analysis.(t probe,oneway variance, Bonferroni analysis).
Results In vitro studies prconditioning in healthy control rabbits reduces infarcted area (F=30.247 p<0.0005, oneway ANOVA sign.p<0.0) and infarctus/risk area (F=23.948 p<0.001, oneway ANOVA sign.p<0.0). Alloxan treatment enlarged the infarcted area in
diabetics (controlprecond vs. diabprecond :0.0005 MD:-0.286 SE:0.46, MCT by Tukey, sign.p<0.05).While in controls all of the applied doses enlarged the infarcted area (: area: p1<0.003 vs. p2<0.002 vs. p3<0.001, infarktus/risk: p1<0.004 vs. p2<0.002 vs. p3<0.001, MCT by Tukey, sign.p<0.05).) in diabetic rabbits a concentration dependent effect of glibenclamide can be observed In vitro experiments non of the glibenclamid doses caused changes in contraction and relaxation , while in substantial metabolic disorder glib evoked a dose-dependenet effect (y=-35.399Ln(x)+986.15 R2=0.254, p<0.05). The direction of sulfonylurea effect depends on the severity of metabolic impairement (control:y=-3.0958Ln(x)+110.14 R2=0.7336 p<0.001 vs. D1: y= -1.9644Ln(x)+108.39 R2=0.3471 p<0.01 vs. D2: y= 2.6956Ln(x)+92.067 p<0.01). While in controls dose – dependent effect can not be assessed in spite of the strong influence of preconditioning and sulfonylurea treatment, (F=7.9907 p<0.0005 3way ANOVA, sign.p<0.05), precondítioning (F=17.6725 p<0.0000 3way ANOVA, sign.p<0.05), in diabetic rabbits presumable in the consecvences of the more activated potassium channels glibenclamide effect seems to be concentration dependenet and interaction between doses of glibenclamide and metabolic state exist (F=5.6069 p<0.0003 3way ANOVA, sign.p<0.05). ). The same observation can be won in relaxation parameteres Antioxidant effects of gliclazid as a metabolic inflence of the sulfonylurea without cardiac effect could be observed. Results in humans No evidences of different vasodilatory response in microcirculation was observed in the newly diagnosed diabetic and the healthy control patients. However in glibenclamid treated patients
both basic flow and vasodilator capacity proved
diminished (F0-diab vs. F0-glib: 15.6PU/s SE:0.38 vs. 13.7PU/s SE:0.63 p=0.001 - dFglib vs. dFkont : 220.0% SE:11.2 vs. 443% SE:18.8 p<0.0005 comp.Bonferroni, sign.p<0.05). Glimepirid treatment did not diminished flow or vasodilating capacitiy in microcirculation)
Both endothel dependent and independent vasodilation is reduced in diabetic patient with periferial obliterative disease, while in glimepirid treatment endothel independent reflection is not involved in the pathological reaction. L-arginin and trimetazidine according to the metabolic impairement may improve both type of vasodilation .(endothel dependent dilatation: contr. vs. glim. vs. glib.: 9.9%±2.5 vs. 13.48 %±3.1 vs. 2.51%±2.3 p<0.05 – independent: 16.2%±0.4 vs. 20.63%±1.4 vs. 4.63%±1.7 p<0.05.
Both the existing complications, and the effects of permanent
treatments can be involved in the transthoracal echocardiaographical measurements, especially the ESMWS the perferial stress parameter can be used in thismeasurements. Transoesophageal echocardiography is the proper method of choice for assessing pathological changes in coronary flow reserv capacity as glibenclamide substantially reduces vasodilatator capacity in patients with no coronary sclerosis (CFRglib vs. CFRins vs. CFRglim: 1.21 vs. 2.25 vs. 2.31 p<0.05). In the consequences of metabolic effects of Glimepiride coronary flow reserv capacitiy may be preserved in the diabetics treated with glimeopiride unless in the case of hyperlipidaemia. By repeated loading test in healthy controls clinicasl typőe of preconditioning can be modellized. Diabetic patients preconditioning is determinated simultonosly
by
metabolic circumstances, sulfonylurea treatment .
Summary The participation of K+ATP channels in the cardioprotectiv procedure that is in precondotioning is proved. Either being a signal or the main participant of .this procedure sulfonylurea tretament can modify the activity of K+ATP channels. In this way the efficacy of preconditioning can be modified . Modification of channel activity and so the influence of preconditioning on myocardial infarction are modified by effects and sulfonylurea treatment as well. Both effects can be assessed by clinical diagnostic equipmnets, so it is possibble today to choose the proper, personal therapy,
Articles in connection with the paper 1.
Nieszner É., Nádas I., Simon J., Baranyi É., Préda I: Macroangiopathiaban szenvedő cukorbetegek anyagcserehelyzetének értékelése. Érbetegségek, 2. 11-15. 1994.
2.
Nieszner É., Nádas I., Baranyi É.,Tóth K.,Vereczkei K., Préda I.,: Balkamrafunkció értékelése diabetes mellitus okozta microangio -pathiaban. Érbetegségek, 4. 5-11. 1996.
3.
Baranyi É., Winkler G., Nieszner É., Tóth J.: A nem inzulin dependens cukorbetegek (NIDDM) kezelésének ujabb lehetősége: egyénre szabott szabott szulfonilurea therapia. Orvosképzés, 2:122-7. 1998.
4.
Nieszner É., Posa I., Kocsis E., Pogátsa G., Préda I., Koltai MZS.: A precondicionálás jelenségének módosulása kezelt és kezeletlen diabetes mellitusban. Diabetologia Hungarica, 8(1) : 19 - 26. 2000.
5.
E.Kocsis, P.Pacher, I.Pósa, E.Nieszner, G. Pogátsa and M.Z.Koltai.: Hyperglycaemia alters the endothelium-dependent relaxation of canine coronary arteries. Acta Physiol Scand 169; 183-187, 2000. Impact f.: 1.764
6.
Nieszner É., Baranyi É., Simon J., Vereczkei K., Nádas I., Préda I.: Kis dózisú ACE gátló kezelés renoprotectív hatásának vizsgálata normo/hypotóniás diabetes mellitusban szenvedő betegekben. Medicus Universalis XXXV/1. 2002.
7.
E.Nieszner, I.Pósa, E.Kocsis, G. Pogátsa, I.Préda, M.Z.Koltai.: Influence of diabetic state and that of different sulfonylureas on the size of myocardial infarction with and without ischemic preconditioning in rabbits. Exp.Clin.Endocrinol.Diabetes. 110: 212-218. 2002. Impact f.: 1.617
8.
Nieszner É., Vereczkei K., Farkas K., Márkus R., Nádas I., Baeanyi É., Préda I.: A glimepiride kedvező hatása a mikrocirculacióban 2. típusú diabetes korai stadiumában. Érbetegségek 2:49-57. 2002 E.Nieszner*, J.Radó,F.Bányai*, M.Horváth, I.Nádas*, F.Gonda, I.Préda*: Haemodynamic benefits for diabetic heart in insulin treated patients Advances in Recent Cardiovascular Research (Proceedings of the 22nd European Section Meeting of the International Society for Heart Research) Cardiovasc.Research – folyamatban Impact f.: 4.552
9.
Abstracts in connection with the paper 1. Nieszner É., Nádas I., Simon J., Baranyi É., Préda I.: Macroangiopathiaban szenvedő cukorbetegek anyagcserehelyzetének értékelése. Magyar Diabetes Társaság XII.Kongresszusa, Győr Diabetologia Hungarica II.Suppl. 2. 35.o. 1994. 2. Nieszner É., Nádas I., Baranyi É., Préda I.: Diabeteses microangiopathias betegek echocardiographias parametereinek értékelése Magyar Diabetes Társaság XIII. Kongresszusa, Keszthely Diabetológia Hungarica IV..Suppl.2.19.o. 1996. 3. É.Nieszner, I.Nádas, É.Baranyi, K.Tóth, K.Vereczkei, I.Préda: Left ventricular function in diabetic microangiopathy. International Union of Angiology European Chapter¢s Congress, Budapest International Angiology, Vol. l5. Suppl.1. p.73. 1996. Impact f.: 0,295 4. K.Vereczkei, L.Major, K.Tóth, I.Nádas, É.Nieszner, I.Préda: Late results of periferial stenting. International Union of Angiology European Chaper¢s Congress, Budapest International Angiology, Vol. 15. Suppl. l. p.45. 1996. Impact f.: 0,295 5. Vereczkei K. , Major L., Molnár F., Regős L., Tóth K., Nádas I., Nieszner É., Préda I.: Stentbeültetésen átesett betegeink klinikai utánkövetése. Magyar Kardiológusok Társasága Tudományos Kongresszusa Cardiologia Hungarica Suppl.1 75.o. 1996. 6. Nieszner É., Farkas K., Vereczkei K., Nádas I., Préda I.: Szulfanylurea kezelés hatása a periferias microcirculatióra II.tipusú diabetes mellitusban. Magyar Kardiológusok Társasága Tudományos Kongresszusa Cardiol.Hung. Suppl.3. 57.o. 1997. 7. É.Nieszner, K.Vereczkei, K.Farkas, I.Nádas, I.Préda: Effect of Sulfonylurea treatment on periferial microcirculation in NIDDM 7thInternational Symposium on Cardiovascular Pharmacotherapy, Jerusalem Cardiovascular Drugs and Therapy 11. Suppl.2. p.332. 1997. Impact f.: 1,098 8. K.Vereczkei, É.Nieszner, K.Farkas, I.Nádas, I.Préda: Effect of serum glucose level and sulfonylurea treatment on periferial microcirculation in NIDDM. International Union of Angiology European Chapter¢s Congress, Rome, 1997. International Angiology, 19. p.111. 1997. Impact f.: 0,295
9. E.Nieszner, K. Vereczkei, K. Farkas, I.Nádas, É.Baranyi I.Préda: Hat die Sulphonylurea Therapie eine nachteilige Wirkung auf die Mikrocirkulation im Diabetes Mellitus? ² XIV. Internationales Donausymposium ² über Diabetes Mellitus Tschechische Medizinische Gesellschaft J.E.Pyrkiné, Prag, 1997. 10 Nieszner É., Vereczkei K., Farkas K., Nádas I., Baranyi É., Préda I.: A SU . therapia hatása a NO dependens vasodilatiós mechanizmusra Magyar Diabetes Társaság XIV. Kongresszusa, Eger . Diabetológia Hungarica VI.Suppl.1.53.o.1998. 11 Nieszner É., Vereczkei K., Nádas I., Baranyi É., Préda I.: Kis dózisú ACE gátló . kezelés renoprotectív hatása normotenziós diabetes mellitusban szenvedő betegekben. Magyar Kardiológusok Társasága Tudományos Kongresszusa, Balatonfüred Cardiologia Hungarica.Suppl.1. 77.o. 1998. 12 Nieszner É., Pósa I., Kocsis E., Koltai M.ZS., Pogátsa G., Préda I.: A kóros . szénhidrát anyagcsere és a glyburide hatása a szív precondícionálására nyúlban. Magyar Kardiológusok Társasága Tudományos Kongresszusa, Balatonfüred Cardiologia Hungarica, Suppl.2. 59.o. 1999. 13 Simon J., Nieszner É., Baranyi É., Vilimi B., Tari A., Ferencz A.: . A microalbuminuria összefüggése a szénhidrát- és lipidanyagcsere laboratóriumi jellemzőivel. Magyar Laboratóriumi Diagnosztikai Társaság 49. Nagygyűlése, 1999. Siófok Előadáskivonat 122.o. 14 E. Nieszner, I.Posa, MZS.Koltai, I.Préda, G.Pogatsa: Effect of sulfonylurea . treatment on preconditioning in alloxan diabetic rabbits. 8th International Symposium on Cardiovascular Pharmacotherapy, Amsterdam Cardiovascular Drugs and Therapy.13(1):12. 1999. Impact f..: 1,098 15 E.Nieszner, I.Posa, MZS.Koltai, G.Pogátsa: Do Sulfonylureas limit protective . effect of preconditioning ? International Society for Heart Research, XX.th European Section Meeting, Maastricht J. Mol.Cell.Cardiol.31:(6): A 100. 1999. Impact f.: 3,255 16 E.Nieszner, I.Posa, E.Kocsis, I.Préda, G.Pogatsa, MZS.Koltai.: Is sulfonylurea . treatment determinative on preconditioning in alloxan diabetic rabbits ? 35th Annual Meeting of the EASD, Brussel Diabetologia, 42.Suppl.1.A 282. 1999. Impact f.: 5,347
17 Nieszner É., Baranyi É., Horányi P., Préda I.:Gondolatok az idős cukorbetegek . komplex ellátásának problémáiról súlyos hypoglikaemiás esetek értékelése során. MDT XV.Kongresszusa, 2000. Tihany Diabetologoa Hungarica Suppl.I. 8: 64.o. 2000. 18 Rimanóczy É., Baranyi É., Nieszner É., Ferencz A.: Anti-GAD-meghatározás: Új . diagnosztikai lehetőség a szénhidrátanyagcsere-zavarban szenvedő betegek vizsgálatában és kezelésük elörejelzésében. MDT XV.Kongreasszusa, 2000. Tihany Diabetologoa Hungarica Suppl.I. 8: 72.o. 2000. 19 Nieszner É, Vereczkei K., Farkas K., Nádas I., Márkus R., Baranyi É.,Préda I.: . Glibenclamid és glimepirid eltérő hatása a reactív hyperaemiara 2.típusú diabetes mellitusban. MB Nagygyűlés 2000. Budapest MBA 20 Nieszner É., Nádas I., Vereczkei K., Baranyi É., Préda I.: A microalbuminuria . predictív szerepe a diastoles functió értékelésében diabeteses és egészséges anyagcsereállapotban. Magyar Atherosclrosis Társaság Kongresszusa, 2000. Sopron Előadáskivonat 21 E.Nieszner, I. Nádas, K.Vereczkei, E.Baranyi, I.Préda: Degree of . microalbuminuria is related to diastolic performance in diabetic and non-diabetic patients as well. XXII.Congress of the ESC, Amsterdam Eur. H. J. 21. Suppl. P3745, 2000 Impact: f.: 3,84 22 Pósa I., Kocsis E., Nieszner É., Koltai MZS., Pogátsa G.: Haemodinamika és . metabolismus:vércukorcsökkentő sulfonylureak hatása eltérő anyagcsereállapotban. Magyar Kardiológusok Társasága Tudományos Ülése , Balatonfüred Cardiologia Hungarica Suppl. 3. 42.o., 2001. 23 Nádas I., Nieszner É., Bányai F., Baranyi É., Simon J., Bencze J., Borsányi T., . Kerecsen G., Préda I.: A microalbuminuria predictív szerepe a balkamrai diastoles functió értékelésében diabetses és egészséges anyagcsereállapotban. Magyar Kardiológusok Társasága Tudományos Ülése , Balatonfüred Cardiologia Hungarica Suppl. 3. 76.o., 2001. 24 Nieszner É., Kocsis E., Posa I., Koltai MZS., Préda I.: Glibenclamid hatása a . kontrakcióra és relaxacióra precondícionalt nyúlszívben Magyar Kardiológusok Társasága Tudományos Ülése , Balatonfüred Cardiologia Hungarica Suppl. 3. 26.o., 2001.
25 E.Nieszner, E.Kocsis, I.Posa, MZS Koltai,I.Préda: Glibenclamide induced . changes in contraction and relaxation in preconditioned rabbit heart. International Society for Heart Research, XVII.World Congress,Winnipeg J. Mol.Cell. Cardiol. 2001. Impact f.: 3,383 26 Nieszner É., Kocsis E., Posa I., Pogátsa G., Préda I., Tóth M., Koltai M.Zs.:A . gliclazid és gléibenclamid hatása a kontractiora és relaxatiora precondícionálással elökezelt nyúlszben. Magyar Kardiológusok Társasága Tudományos Ülése , Balatonfüred Cardiologia Hungarica Sullp.1.É 69.o. 2002. 27 E.Nieszner, J.Radó, F.Bányai, M.Horváth, I.Nádas, F.Gonda, I.Préda: . Haemodinamic benefits for diabetic heart in insulin treated patients 22nd European Section Meeting of th International Society for Heart Research, Szeged J.Mol.Cell.Cardiol. 34: A46, 2002 Impact f.: 3,255 28 Nieszner É., Szabó A., Nádas I., Borbély J., Baranyi É., Préda I.: Sulfanylurea csoporton . belüli eltérő endothelhatások. Magyar Atherosclrosis Társaság Kongresszusa, 2002. Sopron Előadáskivonat 29 Nieszner É., Szabó A., Nádas I., Baranyi É., Borbély J., Préda I.: A metabolikus . moduláció hatása az artériás endothelfunkcióra. MB Nagygyűlés 2002. Budapest MBA, Előadáskionat
