Preconditioning and diazoxide attenuate P-selectin expression and PMN adhesion in post-ischemic heart

EFFECT OF INHIBITION OF NEUTRAL ENDOPEPTIDASE 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

known

endopeptldasL:

to play

cnz~mc

an Important

role

(NEP,

EC

3 4 2-1 I I)

in the pathomechamsm

15 ot

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

tcnslon

arteries The with 30 mM (BK. I-1000

of

porcine

Isolated

epicardial

coronar\

administered to the rings 30 mm did not change the resting and

before the addmon of K( I KCI-Induced tensIOn The

endothelium-dependent known substrate

effect of BK (10 nhl). enhanced b\, TH (control

12.X*5.6%. n=O) The

of

TH 27 I*7 7% of KCI-induced results suggest the Importance

endothclium-dependent

rclaxatlons

artery On the basis of these findings mhibltlon of vascular NEP activity corona% blood flow, and thus the

of

of

.i

tone, p
epicardial

coronar\

It IS suggested. ma!. Improve: survival of the

thit th; hc;Lrr

muscle in pathologIcal settings, such as cardiac f&lure Thrs work was .supported hy the Hungarran Aurdcrn~
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 ilY‘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

coronary artery rings Mere pamally depolarrzcd potassium chloride (KCI). and then bradykinm nM) was cumulatlvelv applied TH (10 ~51)

relaxing NEP. was

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

1’0303/)1)

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 )

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 1525 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, i:. and was not affected by ischem~a alone (Fig.). 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 I’ were prevented by IPC, and the effacJ on P- , ,. 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, ’ j :*s++ +a,Q;O’c respectively Thus. the cardloproteotlon 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

We lnvestialed pressure evoked

the relation

between

the reduction

of blood

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 not the sole mechanism remodeling by calcium

that reducliin of bbod involved in the prevention

pressure is of cardiac

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.