Regulation of Vascular Tone
toimproveendothelialfunctioninchroniccigarettesmokers,asdemonstratedbyanincreased forearmbloodlowresponsetoacetylcholine,whereastherewasnoeffectontheresponseto
sodiumnitroprusside [97]
.Bradykinin-mediatedNOreleaseinducedbylisinoprilhasbeen suggestedasthepossiblemechanismresponsible
[96] .Incontrasttosmoking,nicotinee.g.
whenadministeredasapatchdoesnotreducethesurfaceareaofcoronarysegmentsandalso doesnotadditivelyenhancethevasoconstrictoreffectofsympatheticstimulationproduced
bythecoldpressortest [98]
.Differencesbetweencigarettesmokeandnicotinewerealsoseen inchangesofthelow-mediateddilatationFMDwhichdeclinedin16healthysmokers:this
variabledeclinedtoagreaterextentaftersmokingonecigarette1mgnicotinethanafter administrationofnasalspray1mgnicotinemeans:−3.6vs.−5.1;smokevs.nicotine.
Nitroglycerine-induceddilatationremainedsimilarunderbothexperimentalconditions [99]
. Irrespectiveofdifferencesinnicotinekineticsafterthetwomethodsofadministration,the
mechanismofactionofnicotineontheendotheliumremainsunclear. IntermsofnitricoxideNOrelease,endothelialNOsynthaseNOSgenepolymor-
phismabpolymorphismplaysadecisiveroleintheoccurrenceofacutemyocardial infarction.Thisriskisincreasedparticularlyinyoungersmokersaged51yearswith
aapolymorphism,irrespectiveoftheadditionalpresenceofdiabetesmellitusorhyper- tension
[100] .
Thevasoconstrictoreffectoncoronaryvesselsmaybecausedbyreducedprostacyclin PGI
2
levelsinthecoronaryendothelialcells.Incomparisonwithnon-smokers,smokers havereducedbloodlevelsofPGI
2
andincreasedbloodlevelsof11-dehydro-TXB
2
[101,
102] .Nevertheless,thereactionsproducedbycigarettesmokingintermsofadrenaline,
noradrenalineanddopaminereleasearedifferentfromthoseproducedbynicotineadmin- istration,asshownbythedatapresentedinTable
6.1 .Catecholaminereleaseduetonico-
tineadministrationisquantitativelysmallerthanthatduetocigarettesmoke [95,103]
. Duringcigarettesmoking,nicotineisabsorbedveryrapidly,leadingtovaryingdegrees
ofadrenaline-andnoradrenaline-inducedvasoconstrictionviaa
1
-adreno-ceptorstimula- tion.OccasionalsmokerscompensateforthisvasoconstrictoreffectbyreleasingNOand
prostacyclinfromendothelium,whereasinheavysmokersthismechanismnolongeroper- ates.Inthiscontextitshouldbepointedoutthatvasculartoneisregulatedbytwovasoac-
tivesubstanceswithopposingeffects:NO
·
andO
2 –·
.NOhasapivotalrolehere,particularly
Noradrenaline [pgml]
Adrenaline[pgml] Controlpatients
22723 444
Smokers 32439
11327 Plasmanicotine
AUC [ngml.h]
Noradrenaline [µgg
creatinine] Adrenaline[µgg
creatinine] Dopamine
[µgg creatinine]
Cigarettesmoking 451±62
176±23 28±3
1,099±86 Nicotinepatch
356±30 166±25
21±3 1,051±87
Placebopatch –
172±20 22±2
950±65 p-value
n.s 0.06
0.05 0.05
Table 6.1
Catecholamine release associated with cigarette smoking [38]
mean, mean standard error and urinary catecholamine excretion in smokers and following nicotine administration
patch [171]
sincepost-occlusivevasodilatationintheforearm,forexampleisassociatedwithNO productionandreleasefromendothelium.NOisformedfrom
l
-argininebyNOS,which is dependent on NADPH, lavin adenine nucleotides and tetrahydrobiopterin THB.
AtherogenicactivityhasbeenattributedtothetoxicsubstanceONOO
–
,inconjunction withactivationoftherenin-angiotensinsystem
[104] .NOisabletoformfreeradicals,and
toactivateguanylatecyclaseinendothelialcellsandplateletsFig. 6.4
. Acutecigarettesmokingleadstotemporaryendothelialdysfunction,whichisanearly
eventinatherogenesis.Suficientdataconcerningtheeffectofcigaretteswithlowtarand nicotineyieldarelacking.Therefore,Papamichaeletal.studiedseventeenhealthyindi-
vidualsninewomen,eightmen,aged27.8±3.6yearswhoweresubjectedtoevaluation ofendothelialfunctionbymeansofendothelium-dependent,FMDofthebrachialartery,
before,immediatelyafterand30,60and90minaftersmokingaregularcigarettenicotine 0.9mg,tar12mgorthecorresponding“light”cigarettenicotine0.6mg,tar8mg
[105] .
Thefollowingday,measurementswererepeatedaftersmokingtheoppositekindofciga- rette. Baseline FMD was 6.1 ± 1.6 and 7.2 ± 2.0 in the light and regular cigarette
groups,respectivelyp=NS.TheoveralleffectoftheregularcigaretteovertimeonFMD comparedwiththelightcigarettewassigniicantlydifferentF=3.039,p=0.023.FMD
wassigniicantlydepressedaftersmokingbothtypeslight:F=8.192,p0.001;regular: F=16.698,p0.001.Immediatelyaftersmoking,FMDdeclinedinbothgroupslight:3.0
±2.4andregular:1.6±3.2,p0.001andp0.001,respectively,anditremained signiicantlydepressedintheregularcigarettegroupat30min0.75±1.5,p0.001and
60min3.5±3.1,p=0.024,whileinthelightcigarettegroupFMDdifferenceswere
Smoking
lipid radical induced lipid peroxidation
lipid peroxides THB
synthesis THB
synthesis I-arginine
I-arginine
endothelium-dependent relaxation is impaired
Fe
2+
endothelium smooth muscle
Increased blood flow
Ca
2
NOS NOS
NO NO
+ +
+
smooth muscle
relaxation guanylate
cyclase
Fig. 6.4
Harmfuleffectsofsmokingonvascularrelaxation.AriseinCa
2+
causesanincreaseinNO synthesis from
l
-arginine by NOS. Tetrahydrobiopterin THB is an important co-factor. NO penetratesthevascularcellandstimulatesguanylatecyclase;thisinturnformscGMPwhichhas
avasodilatoraction.SmokinglimitsthesynthesisofcGMP.Inaddition,theradicalsformedinthe bloodpromoteoxo-LDLformation.AfallinTHBalsoreducesNOsynthesis
[209]
abolishedat30,60and90minaftersmoking.Theauthorsconcludedthatacutesmokingof bothregularandlightcigarettesleadstotemporaryvasomotordysfunction;itsdurationis
shorteraftersmokinga“light”cigarette [105]
. VasodilatationandinhibitionofplateletaggregationisachievedasaresultofcGMP
release.NOisthereforeofmajorpathogeneticimportanceinthatitpreventsplateletaggre- gation,monocyteadhesionandvascularsmoothmusclecellproliferation.ByreducingNO
formation, smoking counteracts these preventive processes [106]
. Where dysfunctional NOSIIIactivityisassociatedwithinhibitionofNOproduction,supplementaryadministra-
tion of THB improves endothelium-dependent vasodilatation in chronic smokers [107]
. Glyceryltrinitrateorsodiumnitroprussideinluencetheseprocessesbecausetheyhavea
vasodilatoractioninresponsetoNOproduction.TheinterplayofLDLoxidationandNOS dysfunctionissupportedbyin-vitroexperimentsinsaphenousveinringsandplatelets
[108, 109]
,showingthatimpairedendothelium-dependentrelaxationisattributabletoinadequate THBsynthesisresultingfromtheharmfuleffectsofcigarettesmokeconstituentsFig.
6.5
[108,110] .Inhypercholesterolaemiatheadverseeffectonvascularfunctionresultsfrom
theoxidationofLDLtooxo-LDL [111]
.Asanantioxidant,ascorbicacidisreportedto improvesmoking-inducedvascularresponses
[112] .Smoking-relatedendothelialdamage
Smoking free radicals
shear stress
chemoattractants
developing plaque containing monocytes
macrophages and smooth muscle cells
NO synthesis leucocyte adhesion
molecules monocyte
activation injured
endothelium oxo-
oxo-
cytokines to recruit smooth
muscle cells monocyte
adhesion
LDL LDL
Fig. 6.5
Smokingstimulatesmonocyteadhesion,migrationandactivation.Increasedshearforces altertheendothelialsurfaceandincreasetheproductionoftheadhesionmoleculesICAM-1and
VCAM-1onvascularendothelium.Inaddition,chemicaladhesivesarereleasedfrommonocytes, and the reduction in NO synthesis increases monocyte adhesion to the endothelial cells. The
endotheliumbecomesporous,withtheresultthatoxo-LDLmoleculesareabletopassthrough. Theseinturnactivatemonocytesmacrophageswhichreleasecytokinesandgrowthfactors–a
startingpointforatheroscleroticchangesinthevessel [209]
ispartiallyreversibleifsmokingcessationismaintainedforatleast12months [113,114]
. Disturbedprostacyclinsynthesisisassociatedwiththeincreasedproductionofvasocon-
strictorthromboxanes [115]
.