EFFECT OF INHIBITION OF NEUTRAL ENDO- PEPTIDASE ON THE TONE OF ENDOTHELIUM INTACT PORCINE CORONARY ARTERIES lrbn Krass6i’, JBnos Patariczah & Julius Gy. Papp’.h. ‘Division of Cardiovascular Pharmacology, Hungarian Academy of Sciences, bDept of Pharmacology and Pharmacotherapy, Univ of Szeged, Szeged, Hungary.

The neutral endopeptldasL: cnz~mc (NEP, EC 3 4 2-1 I I) 15

known to play an Important role in the pathomechamsm ot

heart failure. In the present study the sclectlre NEP-mhlbltor thlorphan (TH), was studied on the endothehum-dependent

isometric tcnslon of porcine Isolated epicardial coronar\

arteries The coronary artery rings Mere pamally depolarrzcd with 30 mM potassium chloride (KCI). and then bradykinm (BK. I-1000 nM) was cumulatlvelv applied TH (10 ~51)

administered to the rings 30 mm before the addmon of K( I did not change the resting and KCI-Induced tensIOn The

endothelium-dependent relaxing effect of BK (10 nhl). .i known substrate of NEP. was enhanced b\, TH (control

12.X*5.6%. TH 27 I*7 7% of KCI-induced tone, p<O (15 n=O) The results suggest the Importance of NEP III the

endothclium-dependent rclaxatlons of epicardial coronar\

artery On the basis of these findings It IS suggested. thit mhibltlon of vascular NEP activity ma!. Improve: th; corona% blood flow, and thus the survival of the hc;Lrr

muscle in pathologIcal settings, such as cardiac f&lure Thrs work was .supported hy the Hungarran Aurdcrn~ <I! Scrences clnd the Hungarrun Natlonul Research Foundor~co~

(OTKA 1’0303/)1)

PRECGNDITIONING AND DWOXIDE ATTENUATE P.SELECTIN EXPRESStONAMD~ADMES0NlNPO6l~8Cl+EMlCHEART Michal Ku&ewski’. Eltieta Czamowskab d Andrzaj brgsew(czs %Ied~cal Center of Postgraduate Education, and vhe Children’s Memonal Health Institute, Warsaw Poland

isdemc precondltlonmg (IPC) prevents neutrophll (PMN)-medIated myccardial !schemialreperfusm (IR) Injury We tested a hypothests Vlat IPC prevents myocardti PMN accumulabon by preventing P-seleotin expresson In IR heart in a mechanism lnvolvlng aotivabon of mitochondrial I~v channels (mitoK*rp) Isolated guinea-pig hearts were subjected to 30 mln lschemia alone. ltiemia followed by either 15 (IR-15’) or 35 mln of reperfusm (IR-35’) or were preconditioned mth ischemla or 0.5 FM dlazoxlde (DX) prior to IR The IR-35’ groups were Infused with PMNs at 15- 25 mln of the rep&son Coronary flow responses to acatyichol~ne (ACh) and nboprusside (SNP) served as measures of endomelium- dependent and independent vascular function. respectively. P-seleotin expression and PMN adheston were assessed in histological pfeparabons P-sekcbn expression was simtlarty lnueas& in IR-15’ and IR-35’ groups, and was not affected by ischem~a alone (Fig.).

i:. i ,

An &fold inaease in PMN adhesion and 54% 1 reducbon In ACh response ocarrred In IR-35’ vs 1; sham group IR-Induced P-selac%n expressIon, _p.*.. PMN adhesion, and endothellal dysfunction were prevented by IPC, and the effacJ on P-

I’ , ,.

s&&in was seen already at 15 mtn of i: reperfusion All the effects of IPC were 1: mlmtied by DX, and prevented by 100 ph4 5 ; a HD, the opener and Inhibitor of mdolG.-P, respectively Thus. the cardloproteotlon

’ j :*s++ +a,Q;O’c

afforded by IPC may involve mito)(nrp-madletad prevention of P-selecbn expression and/or of endothelial dysfunction and subsequent PMN aaumulation in the IR myccardlum

PHARMACOLOGICAL CHARACTERISATIOK OF EXTRANEURONAL TRAFwmmRrnRE IN PORCINE AND HUMAN CORONARY AR’IERIES AttiIa Kun’, I& KrasG?, M&t& Opinauiub, Jti Palarica’ & Julius Gy. Papp=‘. %iv of Cardiovascular Pbmuxdogy. Hungarian Academy of Sbences. Szeged, bept of Surgery and Wept of Pharmacobgy, Univ of Szeged, Szeged, Hungary

l‘hc Inactivdtron 01 clr4aung Iransmitten depcnd5 on the uprdhc into neuronal and extr~neuronJ tissues b> uptake1 and upticlis’. rqxctivel\ The purpose of the pmnt stud\, was to mvestigatc the possible role of extraneuronal stores in the regulation of porcme i lY‘Xj and human IHVA) coronq arterial tone and IL\ modularror by -l-ammopyndmr: I-I-,-V,. iht: blocker of volrage~ependenr I<’ &nnels (K, J. I-AI’ induced dosedependenr increase of rhc bawl [one of both K‘4 and IKXA. dnd the preparations responded i\ lrh 9gnificdnt contrdclion. \ihen rhc blood vessels Herr pitzmcub+& irith I mM S- hydroxycptaminc 15-HT). In P(‘A. the uptake1 hltrker dcslprammc. consrderably daread the contracnons evoked hy 4-AP. while after incubation the blood vessels with 1 mM S-HT. desipramine only slightly inhibited the contmcnom Teuodo~oxm dd nor rrtiulatc the enhanced tone induced by 4-AP In contrast. the uptake2 blocker I?-P-oestradiol almost total& abolished the -I- ,\I’ induced conuactlons. Similarly. in IICA desipramine w;1\ Lvithout an> efrect but I7-~%-cuz.stradiol produced a complete Inhibition of the incl-ex% in basal tone evoked by A-.@ Thr PIV\C~I srudy suppom the existence of both neuronal and exuaneuronal stores tar 5.HT regulated by voltagedependent K- channel< III porcmc and human coronq arteries. M(ra)ver. the= large‘ c‘xtraneuronal uptake and/or stordgc capacities may play an unpor%int role in the sliminatiun of 5HT from circulation. 731f.5 ~.ufk :t OS .srcppond ln ihr Hungcuiun Acudem~ of Scretuw dud Ir\ drc I~Iw~I~ 1t01 .M~Nw-. q II(wMI I f.Tt 0 129 WI )

We lnvestialed the relation between the reduction of blood pressure evoked by two long-acting caMurn channel blockers and their protective effect e&nsl cardiac and renal damage In salt-loaded stroke-prone hypertensive rala (SHRSP) SHRSP were exposed lo high dielaty sall intake tram 8 to 14 weeks of age. wtlh or without amlodiptne or lacidipine at three dosage regimens producing similar effects on blood pressure (BP) The iowe& dosagas of both drugs had noneigntficanl effects on BP but inhlbited the paradoxical increases in plasma renin aclii (PRA) and In renin mRNA In kidney lhal were found in salt-loaded SHRSP. The lowest dosage of Wdipine (but not of amlodipine) reduced left ventricular hyperhophy and mRNA levels of atria1 nalriuretic factor and lranatorming growth factor-81. The intermediate do-es reduced BP and PRA in a comparable manner, but cardiac hyperlrophy was more reduced by laddlpine than by amlodipine AllMugh the highest doees exhibited a further action on BP, they had no &Monal e?lect on cardtac hyperlrophy, and they increased PRA and kidney levels of renin mRNA even more than in the absence of drug treatment. We conclude that reducliin of bbod pressure is not the sole mechanism involved in the prevention of cardiac remodeling by calcium channel blockers and that prolecticm against kidney damage and excessive renin production by low and inlermedlate dosages of these drugs should contribute to their beneficial cardlovaacular effects.