Endothelial Modulation of Vascular Tone: Relevance to Coronary Angioplasty and Restenosis DAVID G. HARRISON,
MD
A~lonra, Ceorgio
emu in patIm uodrrgoing mmm-y anpjcpasty alter many facetsof enddhelial fu~~~tionand may prediipw to adverse clinical scqwlae of sngiopt&ty, iocludii inuwdiite thmmbmis, rerttnoriraod rarularsp~~rn. Severalfeatumoftbe eodotheliumderived retexing factor, ho- it b altered by path+ loate pmwszus sod how dwx ce&de&~ r&Se to the hum* diate and late pm(sngioplastyperiods are dtwnwt. 0 Am Co;r Cut&l 1991:17:7156lt)
The vascuhwendathelium importantly modulatesmvly biwbm. ical and physiologicpropertiesof Ihe vaseul~rwall, including the releaw of p+eot vawactiw factors, maintenattceof ao antlcoug. ulsnt state sod modulation of vaxular growth by the t~leaw of both prdiferative and aotiproliferstive substances.Rominont among these rodothelist rote is the prmhwdan of a potent vasodilntor or family of va9oditatorJtermed the eodothrtium. derived relaxing B&r, one of which has been identified to be nitric oxide ur a closely related coiupound. Severaldiwasesthat
cmmonly
Historically, the vascular endothelium was thought to serve its primor; purpose as a barrier to the diffusion of macromolecules. It was not until the 1980sthat i( became apparent that this cell layer is metabolically very active and plays a major role in modulating vast-lar smaolh muscle tone. In 1980, Furchkwtt and Zawadski (I) made the impmtant ohserwion that the endothelium had to be present for acetytcholine to produce vascular relaxation. 11is now known that the endothelium releases a variety of potent wsoaclive substances. These include prosracyclin (2.3). the endotheliurn-derived relaxing factor (responsible for the effect of acetylcholine and a variety of alher neurohumoral substances) ll,4,5). angiotensin II (6). several vasoconstrictor prostaglandins (7.8). the superoxide anion (which may serve as a vasoconstrictor) (9) and endothelin (IW.
by oxidatmn of the ~uanidino-nitrogenof arginine has been ldcntificd 16.17). This cyrosolic enzyme IS activated by an intenct~oo of calcium and calmodulin and requires uicolinamide &nine dinucleotide phosphate, reduced form INADPHI as a cofactor. Recenr work has shown that nitrogen oxides produced by other mammalian cells, including macrophages 18 monrha. “esels were st”died in vitro in P prerrunzed state.
Responses to either bradykinin. acrtykboline. A*3187 0; nitropnxside were examined after precanstriction with the lhromboxanc anaIogU46619. Chronic hypercholesterolem~ markediy impaxed endothelium-dependem
~.~wlar
relar-
ation but did not alter relaxation in response to endothedum-independent agonists. Reprinred from Sellkeet al. (39)with permissionof Amelican HeaR Arswiation. Inc.
the
dependent vasodilation. Thrombin, ADP and serotonin. however, directly constrict vessels with abnormal or denuded endothelium. The patient with atherosclerosis is thus predisposed to abnormal vasoconstriction ar the site of angioplasty. even ifthe endothelium remains intact or is only partially denuded. Obviously. if angioplasty results in complete endothelial denudation, the predisposirion to vascular constriction caused by these agenlr would be great.
Effect of Coronary Atherosclerosis on Coronary Microvascular EndotheliumDependent Relaxation Impaired ondothelial rell function in the coronary microcirculation. Early studies examining the effect of cholesterol feeding and atherosclerosis on endothelium-depcndcnt WIcular relaxation invol,)ed large conduit vessels such as rabbit aorta. iliac arteries or epicardial coronary arterie\. It WI% reasonable to suspect that this defect in endothebal cell function might not occur in the mlcrocirculation. where overt atherasclerosir doa not develop. Recently. howew. we identified three condiltons that occur in the setting of coronary atherosclerosis and clearly impair endothelial cell function in the coronary micracirculatlon. Theze included chronic bypercholcsterolemia (Fig. 2) (39). ischemia followed by reperfusion (Fig. 31 (40) and chronic perfuwon through mature coronary collateral vessels 141I. Thu,. \evend conditions that occu: a, a rewh of or coexist rcith coronary atherosclerosis can impair enduthelial function of the coronary microci~culation. II i) now clsar that coronary ntberosclerocir IS not simply a discase of large ve~elb. but
alw Sect> the microvasculatorc and thus potentially WV alter neuronumoml regulation of tissu: perfosion. Microvascukdure constriction after angioplasty. Alterations of the micmvascular endothelium produced by one of these three mechanisms may alter perfusion in segments of myocardium downstream from the site of angioplasty. This may be particularly true in the retring of intimsl dissection. where thrombus formation and platelet deposition invariably occur. \‘asoactive products released from plctelrt and thrombin may thus not only produce spasm at the site of the angioplasty. but predispose to inappropriate microvascular constriction. Such phenomena may unduly the not infrequent occurrence of unexplained chat pain in the hours vRer angioplasty. even when the site of the angioplasty is uidely raten,.
Mechanisms Underlying Abnormal Endothelium-Dependent Vascular Relaxation in Atherosclerosis Defeel in recxptw signaling. The precise defect respowible for abnarmaiendotheliumdependent relaxation in athcroxlemsis and other disease states remains unrdenutied. It her been suggested (361 that it is related to alterations of membrane-*ignaling mechanisms caused by chronic hypercholestemlemia. The hypothesis is based on the finding in 5omc experiments 1361that vessels from cholesterol-fed animals or arherosclerotic human vessels respond normally to the calcium ionophore A23187 hut demonstrate impaired relaution 10 an agoonistthat requires mleraction with membrane receptws. This is not a uniform finding. At least two
Figure 3. Responseol large coronary arteriesCteR)and coronary microvessels(ri%t)lotbeendotbelium-dcpcndeP~”d~”, vasudilaroradenosine dipbarphate (ADPI. Responserwere obtained in normal vesselsand in vesselsafter either ischemiaalone II hl or iscbemia tt bl and reperfusion(I b). Neilher iscbemianor iscbemiawith repeliusion altered relaxation in respanre to ADP in the larger wselr. In contrast.endotbelium.dependentvascularrelaxation in responseto ADP was dramaticallysltered by ischemiawith reperlusion in camnary micravessels.*P < 0.05.ischcmis + reperfurion versuscontml: tp c 0.05,iscbemiaV-XEUS iscbcmia+ reperfusion. Reprintedfrom Quillen et al. 140)whh Pamission of the American Heart Association.Inc.
studies (37.42) have shown endothelium-dewndent relaxation in response to the calcium ionophore tobe abnormal in atherosclerosis (Fig. I) and bioassay studier (43) have demonstrated impaired release of endolhelium-derived relaxing factor in response to the calcium ionophore in aiherosclerotic vesse!s. Defect in nitric oxide synlhetase enzyme or d&dewy in arginine. A second mechanism potentially responsible. for abnormal cndothelium-dependent relaxation is related to a defect in the nilric oxide synthetase enzyme. a deficiency of one of the required cofactors or a deficiency of arginine. In concert with this hypothesis, recent studies (44) have suggested that high concentrations of argininc can restore vasodilation to normal after acetylcholine in the hindlimb of atherosclerotic rabbits. Aeeelerated degradation of endothelium-derived relaxing factor. Another explanation for abnormal endotheliumdependent relaxation in alherosclemtic vessels relales to accelerated degradation of endothelicm.derived relaxingfactar Several cell types within atherosclerotic blood vessels are capable of releasing oxygen-derived free radicals. The superoxide radical, io F9rhh.r. degrades endotheliumderived relaxing factor. presumably by reacting with nitric
oxide to form nitrite (or reacting with a nitmsyl compound to heterolytically release nitrous oxide, which then is degraded to nitrite). This possibility is strengthened by the recent observation (45) that nitric oxide production by atherosclerotic vessels is actually increased rather than decreased. This finding strongly suggests that increased degradation rather than decreased synthesis of endothelium-derived relaxing factor occurs in atherosclerotic vessels. Iiwthemwre, preliminary studies from our laboratory have shown that short-term (I week) treatment with polyethylene glycolated superoxide dismutase partially restores endothelium-decadent relaxation lo normal in cholesterol-fed rabbits. &nilar treatment had no effect on endothelium-dependent relaxation in vessels removed from normal animals. These studies stmngly suggest that excess generation of the superoxide anion within the atherosclerotic vessel may at least partly account for impaired endothelium-dependent vascular relations.
Prevention or Correction of Altered Endothelium-Dependent Relaxation in Atherosclerotic Vessels Several investigators have attempted to prevent or COTrat abnormal endothelium-dependent responses in enperimental animals. Successful approaches include the concomitant administration of a calcium channel antwonist (461. treatment with dietary cod liver oil (47). the administration of PEG-SOD (oreliminarv studies from our laboratoM and reversion froma high ch&sterol diet to a normal diei for a prolonged period (Fig. 4) (48). Recently, Vckshtein et al. (49) presented preliminary data suggesting that 6 months of treatment with the omega-3 fatty acids can reverse the abnormal coronary vasoconstriction in response to acetylcholine il patients with early atherosclerosis.
Figme 4. EUecr of atherosclerosis ,c@essiOnon endorhelium-dependent wscuki, relaxarion in rraponrr to drombin. Reprerentadve aampler of w”sio” recordbus fmm iliac atteries fmm normal monkeys. monkeys fed a high chol~steml die1 for 18 months fathe,orclc,ow and monkeys fed a high cholesterol diet for 18 months followed by P “~,,,,a, met for 18 months (regrcsrion, ~,e rhown. Atherorclcrosis markedly impaired Ihe endotheliumdependem wc”la, relaxation in response to thmmbm. After regnssion of athsroscleroris. ,&xadon I” rerfnnre to thmmbm was restored 10 “Olm8.L FGF,a = Qma,aglandin Fxo. Re. printed fmm Harrison et al. (48) with pemdsrio” afrhe Am&an Hean Association, Inc.
Conclusions It is now clear thab endothelium plays an importam role in modulating vascular tone both in large vessels and in the microcirculation. Furthermore. endothelial cell dysfunclion or removal can dramatically alter responses to a variety of vasoactive circulating compounds. This has obvious implications in the setting of the immediate postangioplasty period and may influence the long-term sequelae of angioplasty. The endalbelium also has important antilhrombotic properties. These include the elaboration of prostacyclin and endothelium.derived relaxing factor. tiwe plasmininogen activator and other anrithrombotic substances. Loss or dysfunction d the endothelium may result in the deposition of platelets, the release of pnfent growth factors and eventually predispose to intimal proliferaion and restenosi%. Finally, endothelial dysfunction may predispose to altered neurohumoral regulation of coronary vascular tone both immediately after and during the first several months after angioplasty.
768
HARRmm ENMTHELIAL
IACC Vol. 17. No. 6 May IWI fm-68
MODULATlON OF VASCULARTONE
23. Alheid U. Frolich JC, Forslermwn U. Endolhclium.derived relaxing factor from cuhured human cndolhclisl cells inhlbitr aggregation of human platelets Thromb Res 19117:47:561-171. 24. Alheid U. Rcichwehr 1. FSrswmann L;. Human endothelird cells inhibit plalelel agprcgalion by rcpmlcly slimulatmg plalclct cyclic AMP and cyclic GMP’. Euro J Pharmacol 1989:164~103-IO. 25. Bull H. Fret HR. Van den Borrche RM. Herman AG. klatelet inhibihon by endothelium-derived relaxing faclor from Ihe rabbit wrfurad aorta. Br J Pharmac 19BU:9~1308-14. 26. Mendrlrohn ME, O’Neilli S, George D. Las&o 1. Inhibition of 6bnn. ogen bindingro human plalrlel by S-nilrosDN.aCe~ylcystlnc. J Biol Chum 1990:265:1928-34. 17. FagI OE. EDRF-a proteclivc factor. Nalure 1988:311:4%1. 28. Parker-Botctha L. Cantor EH. Ho WH. Lumma WC. Buhnyi GM. Nitric oxide inacrivater supcmxidc radicals produced by human kukocytrs. Circ Rer lruppl III 1989:tl-5-6. 29. Habib JB. Boss&r C. Welts S. Wllliarns C. Morriwt JD. Henry PD. Reservation of cndothcliumdependem varcular rclaxslion in cholerter&fed rabbi1 by trealmcnt wb the calcium blocker PN 2001lO. Circ Res 1986:58:305-10. 30. Vcrbcurea TJ. Jordacns FH. Zonnekcyn LL. Van Hove CE. Coat MC. Herr&i AG. Effect olhypcrcholestcrolemia on varcular rcactivily in the rabbit. Circ Res IPB618:U2-M. 31. Jayakody L. Senamtne M. Thomson A. Kappagoda T. Endathcliumdependent r&nation in exprimental atherosclerosis in the rabbit. Circ Rrr 1987;60:25,-M. 12. Frriman PC, Mitchell GC. Heirlad DD. Amxtmng ML, Hamson DG. Athcrorclemsis impairs cndothclium-depcnden vascular relaxation to acotylcholinr and thrambmin primatcr.Circ Res 19%58:783-S 33. Wei EP: Kantas HA. Christman CW. DoWia DS. Povlishock Jl’. Supemxlde generation and reversal of acetylchulineinduced cerebral artcriolar dilation after acute hypertension, Circ Res 194%1:57:%1-7. 34. Mayhan WG. Impairment of endo!hclium-drpndenl dilation of rerebnl arterioles during dinbets meltitus. Am J Physiol 1%9:25[1:H621-S, 35. Ku D. Coronuy Y~KUIQT nacrivily tier aculc myowdial ixhcmia. Sciena 1982:218:576-8. 36. Borralltr C, Habib GB, Yamamolo H. Williams C, Wells S. Henry PD. Impaired murcarinic rndolhelium.dependmr relaxation and cyclic guanosinc 5’.nxwpiwsphate formation in athcmsclmlic humn cowwy artery and rabbit aorta. J Clin Invert 1987:79:170-4. 37. Fhrstrrmann U, Mllggt A. Alhcid U, Hawich A, Frblich JC. Selective
attenuation of rndolhelium-mcdwcd vasodilalian in mherosclrwic man camnary arteries. Circ Rer 198B:62:IBM.
hu-
38. Ludmrr PL. Selwyn AP. Shook TL, Alexander RW. Ganz P. Paradoxical vwwonsuictio~ inducrd by scnylcholinc in .uhrro~lerotx coronary awrier. N En&l I Mcd 1986;315:11,46-51. 39. Sellkc FW. Armstrong ML. Harrison DG. Endothckum.dcpenderU “as. culw relation is abnormal m the cornwry micmsircutation of atherw sckrolic Primarer. Clrc Rcs 1990:Sl: 1586-93. 40. QuiltcnJE. Scllkc FW. Brwks LA, Harrison DG. Ixhcmiweperfwion impairs CndMhLbwo-dCpCnded rclaxalion alcoronary microvewls bul does not affect Israe ancries. Circ Res 1990:82:%5-94. 41. SctlkcFW. Quillen JE. BmoksLb. Haniron IX. Endotheliplmcdulatia of the Mronaty varculalurc in wrsclr pafused via mslurc sollata&. Qrc Res 1990:81:19X3-“7. 42. Hruriron DG, Frriman PC. Milchcll CC. Atmrtmng ML, Mvcur ML, Heirlad DD. Altemtionr of vascular rcaslivily in athcrorclemrir. Circ Rea 198?;61(r”pPl lI):ll-74-U-SO. 43. Guern It Jr. Brothwon AFA. G&win PI, Clwk CR. Annslmn8 ML, Harrison DG. MechnnJvns abnormal codotheliundopcndcnl vmsul~r relaxation in athrmsckrorir: implicsions fora!wcd sulccrins and para crinc funclans of EDRF. Blood Vewls I!%P.~XI-14.
cf
44 Girerd XI. Hirsch AT, Cooke JP. Creaper MA. Mrginine &ugment~ cndothchum.depmdcnr va%dilmion in cholewrobftd rabbits. Circ Ber I9w$aMruppl ll):lI-1115. 45. Minor RL. Myers PR. Guera R Jr. Bates IN. HanisonDO. Diet induced Mhemrelrrm13 increases the r&art ofnitmpena#idcs from rabbi1 aorta. J Clin Invert l9?%86:2IC?-16. 46 Habib JB. Bar&r SW, Wiilisml C, hior& JD! Henry PD. Rcwrva. lian of cndalkliumdspendecnl vascular rolaxatmn tn choJc#rol&d rabbit by warnen, with the c&urn blocker PN Mollo. Cii Rrr 198618:3&9.
49. Vckrktein VL. Yew
AC. Vita IA. et al. Fish oil imsmw
cndothelilm:.
MD
A~lonra, Ceorgio
emu in patIm uodrrgoing mmm-y anpjcpasty alter many facetsof enddhelial fu~~~tionand may prediipw to adverse clinical scqwlae of sngiopt&ty, iocludii inuwdiite thmmbmis, rerttnoriraod rarularsp~~rn. Severalfeatumoftbe eodotheliumderived retexing factor, ho- it b altered by path+ loate pmwszus sod how dwx ce&de&~ r&Se to the hum* diate and late pm(sngioplastyperiods are dtwnwt. 0 Am Co;r Cut&l 1991:17:7156lt)
The vascuhwendathelium importantly modulatesmvly biwbm. ical and physiologicpropertiesof Ihe vaseul~rwall, including the releaw of p+eot vawactiw factors, maintenattceof ao antlcoug. ulsnt state sod modulation of vaxular growth by the t~leaw of both prdiferative and aotiproliferstive substances.Rominont among these rodothelist rote is the prmhwdan of a potent vasodilntor or family of va9oditatorJtermed the eodothrtium. derived relaxing B&r, one of which has been identified to be nitric oxide ur a closely related coiupound. Severaldiwasesthat
cmmonly
Historically, the vascular endothelium was thought to serve its primor; purpose as a barrier to the diffusion of macromolecules. It was not until the 1980sthat i( became apparent that this cell layer is metabolically very active and plays a major role in modulating vast-lar smaolh muscle tone. In 1980, Furchkwtt and Zawadski (I) made the impmtant ohserwion that the endothelium had to be present for acetytcholine to produce vascular relaxation. 11is now known that the endothelium releases a variety of potent wsoaclive substances. These include prosracyclin (2.3). the endotheliurn-derived relaxing factor (responsible for the effect of acetylcholine and a variety of alher neurohumoral substances) ll,4,5). angiotensin II (6). several vasoconstrictor prostaglandins (7.8). the superoxide anion (which may serve as a vasoconstrictor) (9) and endothelin (IW.
by oxidatmn of the ~uanidino-nitrogenof arginine has been ldcntificd 16.17). This cyrosolic enzyme IS activated by an intenct~oo of calcium and calmodulin and requires uicolinamide &nine dinucleotide phosphate, reduced form INADPHI as a cofactor. Recenr work has shown that nitrogen oxides produced by other mammalian cells, including macrophages 18 monrha. “esels were st”died in vitro in P prerrunzed state.
Responses to either bradykinin. acrtykboline. A*3187 0; nitropnxside were examined after precanstriction with the lhromboxanc anaIogU46619. Chronic hypercholesterolem~ markediy impaxed endothelium-dependem
~.~wlar
relar-
ation but did not alter relaxation in response to endothedum-independent agonists. Reprinred from Sellkeet al. (39)with permissionof Amelican HeaR Arswiation. Inc.
the
dependent vasodilation. Thrombin, ADP and serotonin. however, directly constrict vessels with abnormal or denuded endothelium. The patient with atherosclerosis is thus predisposed to abnormal vasoconstriction ar the site of angioplasty. even ifthe endothelium remains intact or is only partially denuded. Obviously. if angioplasty results in complete endothelial denudation, the predisposirion to vascular constriction caused by these agenlr would be great.
Effect of Coronary Atherosclerosis on Coronary Microvascular EndotheliumDependent Relaxation Impaired ondothelial rell function in the coronary microcirculation. Early studies examining the effect of cholesterol feeding and atherosclerosis on endothelium-depcndcnt WIcular relaxation invol,)ed large conduit vessels such as rabbit aorta. iliac arteries or epicardial coronary arterie\. It WI% reasonable to suspect that this defect in endothebal cell function might not occur in the mlcrocirculation. where overt atherasclerosir doa not develop. Recently. howew. we identified three condiltons that occur in the setting of coronary atherosclerosis and clearly impair endothelial cell function in the coronary micracirculatlon. Theze included chronic bypercholcsterolemia (Fig. 2) (39). ischemia followed by reperfusion (Fig. 31 (40) and chronic perfuwon through mature coronary collateral vessels 141I. Thu,. \evend conditions that occu: a, a rewh of or coexist rcith coronary atherosclerosis can impair enduthelial function of the coronary microci~culation. II i) now clsar that coronary ntberosclerocir IS not simply a discase of large ve~elb. but
alw Sect> the microvasculatorc and thus potentially WV alter neuronumoml regulation of tissu: perfosion. Microvascukdure constriction after angioplasty. Alterations of the micmvascular endothelium produced by one of these three mechanisms may alter perfusion in segments of myocardium downstream from the site of angioplasty. This may be particularly true in the retring of intimsl dissection. where thrombus formation and platelet deposition invariably occur. \‘asoactive products released from plctelrt and thrombin may thus not only produce spasm at the site of the angioplasty. but predispose to inappropriate microvascular constriction. Such phenomena may unduly the not infrequent occurrence of unexplained chat pain in the hours vRer angioplasty. even when the site of the angioplasty is uidely raten,.
Mechanisms Underlying Abnormal Endothelium-Dependent Vascular Relaxation in Atherosclerosis Defeel in recxptw signaling. The precise defect respowible for abnarmaiendotheliumdependent relaxation in athcroxlemsis and other disease states remains unrdenutied. It her been suggested (361 that it is related to alterations of membrane-*ignaling mechanisms caused by chronic hypercholestemlemia. The hypothesis is based on the finding in 5omc experiments 1361that vessels from cholesterol-fed animals or arherosclerotic human vessels respond normally to the calcium ionophore A23187 hut demonstrate impaired relaution 10 an agoonistthat requires mleraction with membrane receptws. This is not a uniform finding. At least two
Figure 3. Responseol large coronary arteriesCteR)and coronary microvessels(ri%t)lotbeendotbelium-dcpcndeP~”d~”, vasudilaroradenosine dipbarphate (ADPI. Responserwere obtained in normal vesselsand in vesselsafter either ischemiaalone II hl or iscbemia tt bl and reperfusion(I b). Neilher iscbemianor iscbemiawith repeliusion altered relaxation in respanre to ADP in the larger wselr. In contrast.endotbelium.dependentvascularrelaxation in responseto ADP was dramaticallysltered by ischemiawith reperlusion in camnary micravessels.*P < 0.05.ischcmis + reperfurion versuscontml: tp c 0.05,iscbemiaV-XEUS iscbcmia+ reperfusion. Reprintedfrom Quillen et al. 140)whh Pamission of the American Heart Association.Inc.
studies (37.42) have shown endothelium-dewndent relaxation in response to the calcium ionophore tobe abnormal in atherosclerosis (Fig. I) and bioassay studier (43) have demonstrated impaired release of endolhelium-derived relaxing factor in response to the calcium ionophore in aiherosclerotic vesse!s. Defect in nitric oxide synlhetase enzyme or d&dewy in arginine. A second mechanism potentially responsible. for abnormal cndothelium-dependent relaxation is related to a defect in the nilric oxide synthetase enzyme. a deficiency of one of the required cofactors or a deficiency of arginine. In concert with this hypothesis, recent studies (44) have suggested that high concentrations of argininc can restore vasodilation to normal after acetylcholine in the hindlimb of atherosclerotic rabbits. Aeeelerated degradation of endothelium-derived relaxing factor. Another explanation for abnormal endotheliumdependent relaxation in alherosclemtic vessels relales to accelerated degradation of endothelicm.derived relaxingfactar Several cell types within atherosclerotic blood vessels are capable of releasing oxygen-derived free radicals. The superoxide radical, io F9rhh.r. degrades endotheliumderived relaxing factor. presumably by reacting with nitric
oxide to form nitrite (or reacting with a nitmsyl compound to heterolytically release nitrous oxide, which then is degraded to nitrite). This possibility is strengthened by the recent observation (45) that nitric oxide production by atherosclerotic vessels is actually increased rather than decreased. This finding strongly suggests that increased degradation rather than decreased synthesis of endothelium-derived relaxing factor occurs in atherosclerotic vessels. Iiwthemwre, preliminary studies from our laboratory have shown that short-term (I week) treatment with polyethylene glycolated superoxide dismutase partially restores endothelium-decadent relaxation lo normal in cholesterol-fed rabbits. &nilar treatment had no effect on endothelium-dependent relaxation in vessels removed from normal animals. These studies stmngly suggest that excess generation of the superoxide anion within the atherosclerotic vessel may at least partly account for impaired endothelium-dependent vascular relations.
Prevention or Correction of Altered Endothelium-Dependent Relaxation in Atherosclerotic Vessels Several investigators have attempted to prevent or COTrat abnormal endothelium-dependent responses in enperimental animals. Successful approaches include the concomitant administration of a calcium channel antwonist (461. treatment with dietary cod liver oil (47). the administration of PEG-SOD (oreliminarv studies from our laboratoM and reversion froma high ch&sterol diet to a normal diei for a prolonged period (Fig. 4) (48). Recently, Vckshtein et al. (49) presented preliminary data suggesting that 6 months of treatment with the omega-3 fatty acids can reverse the abnormal coronary vasoconstriction in response to acetylcholine il patients with early atherosclerosis.
Figme 4. EUecr of atherosclerosis ,c@essiOnon endorhelium-dependent wscuki, relaxarion in rraponrr to drombin. Reprerentadve aampler of w”sio” recordbus fmm iliac atteries fmm normal monkeys. monkeys fed a high chol~steml die1 for 18 months fathe,orclc,ow and monkeys fed a high cholesterol diet for 18 months followed by P “~,,,,a, met for 18 months (regrcsrion, ~,e rhown. Atherorclcrosis markedly impaired Ihe endotheliumdependem wc”la, relaxation in response to thmmbm. After regnssion of athsroscleroris. ,&xadon I” rerfnnre to thmmbm was restored 10 “Olm8.L FGF,a = Qma,aglandin Fxo. Re. printed fmm Harrison et al. (48) with pemdsrio” afrhe Am&an Hean Association, Inc.
Conclusions It is now clear thab endothelium plays an importam role in modulating vascular tone both in large vessels and in the microcirculation. Furthermore. endothelial cell dysfunclion or removal can dramatically alter responses to a variety of vasoactive circulating compounds. This has obvious implications in the setting of the immediate postangioplasty period and may influence the long-term sequelae of angioplasty. The endalbelium also has important antilhrombotic properties. These include the elaboration of prostacyclin and endothelium.derived relaxing factor. tiwe plasmininogen activator and other anrithrombotic substances. Loss or dysfunction d the endothelium may result in the deposition of platelets, the release of pnfent growth factors and eventually predispose to intimal proliferaion and restenosi%. Finally, endothelial dysfunction may predispose to altered neurohumoral regulation of coronary vascular tone both immediately after and during the first several months after angioplasty.
768
HARRmm ENMTHELIAL
IACC Vol. 17. No. 6 May IWI fm-68
MODULATlON OF VASCULARTONE
23. Alheid U. Frolich JC, Forslermwn U. Endolhclium.derived relaxing factor from cuhured human cndolhclisl cells inhlbitr aggregation of human platelets Thromb Res 19117:47:561-171. 24. Alheid U. Rcichwehr 1. FSrswmann L;. Human endothelird cells inhibit plalelel agprcgalion by rcpmlcly slimulatmg plalclct cyclic AMP and cyclic GMP’. Euro J Pharmacol 1989:164~103-IO. 25. Bull H. Fret HR. Van den Borrche RM. Herman AG. klatelet inhibihon by endothelium-derived relaxing faclor from Ihe rabbit wrfurad aorta. Br J Pharmac 19BU:9~1308-14. 26. Mendrlrohn ME, O’Neilli S, George D. Las&o 1. Inhibition of 6bnn. ogen bindingro human plalrlel by S-nilrosDN.aCe~ylcystlnc. J Biol Chum 1990:265:1928-34. 17. FagI OE. EDRF-a proteclivc factor. Nalure 1988:311:4%1. 28. Parker-Botctha L. Cantor EH. Ho WH. Lumma WC. Buhnyi GM. Nitric oxide inacrivater supcmxidc radicals produced by human kukocytrs. Circ Rer lruppl III 1989:tl-5-6. 29. Habib JB. Boss&r C. Welts S. Wllliarns C. Morriwt JD. Henry PD. Reservation of cndothcliumdependem varcular rclaxslion in cholerter&fed rabbi1 by trealmcnt wb the calcium blocker PN 2001lO. Circ Res 1986:58:305-10. 30. Vcrbcurea TJ. Jordacns FH. Zonnekcyn LL. Van Hove CE. Coat MC. Herr&i AG. Effect olhypcrcholestcrolemia on varcular rcactivily in the rabbit. Circ Res IPB618:U2-M. 31. Jayakody L. Senamtne M. Thomson A. Kappagoda T. Endathcliumdependent r&nation in exprimental atherosclerosis in the rabbit. Circ Rrr 1987;60:25,-M. 12. Frriman PC, Mitchell GC. Heirlad DD. Amxtmng ML, Hamson DG. Athcrorclemsis impairs cndothclium-depcnden vascular relaxation to acotylcholinr and thrambmin primatcr.Circ Res 19%58:783-S 33. Wei EP: Kantas HA. Christman CW. DoWia DS. Povlishock Jl’. Supemxlde generation and reversal of acetylchulineinduced cerebral artcriolar dilation after acute hypertension, Circ Res 194%1:57:%1-7. 34. Mayhan WG. Impairment of endo!hclium-drpndenl dilation of rerebnl arterioles during dinbets meltitus. Am J Physiol 1%9:25[1:H621-S, 35. Ku D. Coronuy Y~KUIQT nacrivily tier aculc myowdial ixhcmia. Sciena 1982:218:576-8. 36. Borralltr C, Habib GB, Yamamolo H. Williams C, Wells S. Henry PD. Impaired murcarinic rndolhelium.dependmr relaxation and cyclic guanosinc 5’.nxwpiwsphate formation in athcmsclmlic humn cowwy artery and rabbit aorta. J Clin Invert 1987:79:170-4. 37. Fhrstrrmann U, Mllggt A. Alhcid U, Hawich A, Frblich JC. Selective
attenuation of rndolhelium-mcdwcd vasodilalian in mherosclrwic man camnary arteries. Circ Rer 198B:62:IBM.
hu-
38. Ludmrr PL. Selwyn AP. Shook TL, Alexander RW. Ganz P. Paradoxical vwwonsuictio~ inducrd by scnylcholinc in .uhrro~lerotx coronary awrier. N En&l I Mcd 1986;315:11,46-51. 39. Sellkc FW. Armstrong ML. Harrison DG. Endothckum.dcpenderU “as. culw relation is abnormal m the cornwry micmsircutation of atherw sckrolic Primarer. Clrc Rcs 1990:Sl: 1586-93. 40. QuiltcnJE. Scllkc FW. Brwks LA, Harrison DG. Ixhcmiweperfwion impairs CndMhLbwo-dCpCnded rclaxalion alcoronary microvewls bul does not affect Israe ancries. Circ Res 1990:82:%5-94. 41. SctlkcFW. Quillen JE. BmoksLb. Haniron IX. Endotheliplmcdulatia of the Mronaty varculalurc in wrsclr pafused via mslurc sollata&. Qrc Res 1990:81:19X3-“7. 42. Hruriron DG, Frriman PC. Milchcll CC. Atmrtmng ML, Mvcur ML, Heirlad DD. Altemtionr of vascular rcaslivily in athcrorclemrir. Circ Rea 198?;61(r”pPl lI):ll-74-U-SO. 43. Guern It Jr. Brothwon AFA. G&win PI, Clwk CR. Annslmn8 ML, Harrison DG. MechnnJvns abnormal codotheliundopcndcnl vmsul~r relaxation in athrmsckrorir: implicsions fora!wcd sulccrins and para crinc funclans of EDRF. Blood Vewls I!%P.~XI-14.
cf
44 Girerd XI. Hirsch AT, Cooke JP. Creaper MA. Mrginine &ugment~ cndothchum.depmdcnr va%dilmion in cholewrobftd rabbits. Circ Ber I9w$aMruppl ll):lI-1115. 45. Minor RL. Myers PR. Guera R Jr. Bates IN. HanisonDO. Diet induced Mhemrelrrm13 increases the r&art ofnitmpena#idcs from rabbi1 aorta. J Clin Invert l9?%86:2IC?-16. 46 Habib JB. Bar&r SW, Wiilisml C, hior& JD! Henry PD. Rcwrva. lian of cndalkliumdspendecnl vascular rolaxatmn tn choJc#rol&d rabbit by warnen, with the c&urn blocker PN Mollo. Cii Rrr 198618:3&9.
49. Vckrktein VL. Yew
AC. Vita IA. et al. Fish oil imsmw
cndothelilm:.
