Changes in Endothelial Function and Microcirculation

–฀and฀by฀the฀progressive฀decline฀in฀red฀cell฀deformability฀ [132,฀133] .฀The฀supply฀of฀O 2 ฀to฀ the฀tissues฀is฀thus฀also฀reduced.฀In฀addition,฀the฀following฀variables฀are฀elevated฀in฀smok- ers:฀leucocyte฀count฀ [134–136] ,฀CO-induced฀platelet฀aggregability฀ [41] ,฀and฀factor฀XIII฀ and฀von฀Willebrand฀factor฀activity฀ [136–138] .฀All฀these฀smoking-induced฀reactions฀tend฀to฀ normalise฀following฀smoking฀cessation฀andor฀nicotine฀substitution฀Table฀ 6.2 . Previous฀thinking฀concerning฀the฀important฀vasoconstrictor฀effect฀of฀nicotine฀in฀terms฀ of฀the฀evolution฀of฀vascular฀disease฀should฀be฀revised฀to฀take฀account฀of฀the฀very฀much฀ greater฀part฀played฀by฀CO฀and฀CO-haemoglobin฀and฀by฀glycoproteins฀in฀bringing฀about฀ changes฀in฀the฀vessels฀and฀the฀microcirculation฀Fig.฀ 6.1 ,฀Table฀ 6.2 ฀ [8] . Based฀on฀experimental฀animal฀work,฀it฀has฀been฀reported฀that฀nicotine฀stimulates฀new฀ blood฀vessel฀formation฀angiogenesis,฀and฀this฀is฀associated฀with฀endothelial฀proliferation฀ [139] .฀Overall,฀this฀study฀attributes฀tumorigenic฀activity฀to฀nicotine฀ [139] . Further฀research฀is฀required฀to฀conirm฀whether฀these฀results฀can฀be฀transposed฀to฀the฀ situation฀in฀man.฀To฀date,฀at฀least,฀there฀is฀no฀evidence฀to฀show฀that฀nicotine฀displays฀such฀ properties฀in฀humans.

6.2.3 Microcirculation and O

2 Supply Smoking-induced฀damage฀to฀the฀microcirculation,฀including฀the฀skin฀and฀O 2 ฀supply,฀has฀been฀ studied฀in฀humans฀and฀in฀experimental฀animals฀ [140–143] .฀In฀particular,฀dramatic฀reactions฀ have฀ been฀ demonstrated฀ in฀ smokers฀ undergoing฀ revascularisation฀ procedures฀ [144,฀ 145] .฀ Likewise,฀skin฀necroses฀have฀been฀described฀in฀smokers฀following฀cosmetic฀facial฀surgery฀ [141,฀146,฀147] .฀These฀harmful฀effects฀were฀elicited฀by฀the฀toxic฀constituents฀of฀cigarette฀ smoke฀and฀by฀CO,฀and฀to฀a฀very฀much฀smaller฀extent฀by฀nicotine฀ [9] .฀In฀smokers,฀skin฀laps฀ also฀show฀delayed฀healing฀or฀fail฀to฀survive฀at฀all฀see฀ Chap.฀7.8 ฀ [144,฀148,฀149] . Variables Smoking Nicotine Reference฀nos Plasma฀ibrinogen฀concentration Ý Û [71,฀128–130,฀136,฀137,฀ 157,฀203–205] Platelet฀aggregation฀CO-induced Ý Û [41] Haematocrit Ý Û [71,฀130,฀131] Leucocyte฀count Ý Û [135–137] von฀Willebrand฀factor Ý Û [136,฀137] Factor฀XIIa Ý Û [141] Plasminogen ß Û [128,฀129] Vascular฀permeability฀for฀ibrinogen Ý Û [206–208] Red฀cell฀deformability ß Û [132,฀133,฀173] Viscosity฀plasma,฀blood Ý Û [71,฀128,฀130,฀131] CO-haemoglobin Ý Û [95] Catecholamines฀in฀blood฀and฀urine Ý Ý ,฀Û [179,฀195] Table 6.2 ฀฀฀Differences฀between฀cigarette฀smoking฀and฀nicotine฀administration฀on฀haemorheological฀ variables฀ [8] Results฀from฀clinical฀studies.฀Ý:฀elevated,฀ß:฀low฀or฀reduced,฀Û:฀unchanged฀or฀normal Dalla฀et฀al฀studies฀in฀2004฀the฀effects฀of฀acute฀and฀chronic฀smoking฀on฀skin฀microvas- cular฀properties฀of฀young฀healthy฀subjects.฀In฀this฀observational฀study,฀using฀a฀totally฀non- invasive฀approach,฀employing฀continuous฀palmar฀microvascular฀low฀laser฀Doppler฀and฀ arterial฀pressure฀measurements,฀a฀total฀of฀20฀healthy฀male฀subjects฀nine฀habitual฀smokers฀ and฀11฀non-smokers;฀aged฀27฀±฀1฀and฀29฀±฀2฀years,฀respectively฀were฀examined฀ [150] .฀ Measures฀were฀obtained฀at฀baseline฀and฀after฀iontophoretic฀administration฀of฀acetylcholine฀ ACh,฀ an฀ endothelium-dependent฀ vasodilator฀ and฀ of฀ sodium฀ nitroprusside฀ NP,฀ an฀ endothelium-independent฀vasodilator.฀The฀study฀showed฀that฀smokers฀showed฀signiicant฀ lower฀baseline฀microvascular฀resistive฀Z0฀and฀oscillatory฀impedance,฀i.e.฀ZC฀properties฀ than฀non-smokers.฀In฀the฀non-smokers฀group,฀ACh฀and฀NP฀iontophoresis฀induced฀a฀signii- cant฀ decrease฀ of฀ both฀ Z0฀ and฀ ZC,฀ before฀ and฀ after฀ smoking฀ one฀ cigarette฀ p฀ ฀ 0.02.฀ Conversely,฀in฀the฀smokers฀group,฀both฀Z0฀and฀ZC฀were฀not฀affected฀by฀ACh฀iontophoresis฀ before฀acute฀smoking,฀while,฀after฀smoking,฀a฀signiicant฀decrease฀of฀both฀Z0฀and฀ZC฀p฀฀ 0.02฀was฀detected฀after฀ACh฀challenge.฀The฀study฀indicates฀that฀smokers฀have฀a฀complex฀ disruption฀of฀peripheral฀microcirculatory฀regulation,฀including฀inappropriate฀resting฀vaso- dilation,฀ impaired฀ endothelium-dependent฀ and฀ independent฀ vasodilation,฀ paradoxical฀ recovery฀of฀endothelium-dependent฀vasodilation฀in฀response฀to฀acute฀smoking฀ [151] . In฀a฀further฀study,฀the฀acute฀effects฀of฀smoking฀on฀microvascular฀function฀in฀healthy฀ smokers฀was฀studied฀using฀measures฀of฀HR,฀blood฀pressure,฀capillary฀recruitment฀during฀ peak฀reactive฀hyperaemia฀and฀endothelium-dependent฀and฀endothelium-independent฀vaso- dilatation฀ of฀ the฀ skin฀ microcirculation฀ with฀ iontophoresis฀ of฀ acetylcholine฀ and฀ sodium฀ nitroprusside฀respectively฀combined฀with฀laser฀Doppler฀luxmetry฀ [151] ฀It฀was฀found฀that฀ in฀comparison฀with฀sham฀smoking,฀acute฀smoking฀caused฀increases฀in฀HR฀smoking,฀9.3฀±฀ 4.1฀beatsmin;฀sham,฀−1.3฀±฀3.0฀beatsmin;฀p฀฀0.001฀and฀systolic฀blood฀pressure฀smok- ing,฀6.3฀±฀8.8฀mmHg;฀sham,฀0.8฀±฀4.4฀mmHg;฀p฀฀0.05.฀Also,฀decreases฀in฀absolute฀smok- ing,฀−4.9฀±฀6.9฀per฀mm 2 ;฀sham,฀0.8฀±฀2.1฀per฀mm2;฀p฀=฀0.01฀and฀relative฀smoking,฀−13.8฀±฀ 21.4;฀sham,฀1.9฀±฀6.9;฀p฀=฀0.02฀capillary฀recruitment฀during฀peak฀reactive฀hyperaemia;฀ and฀decreases฀in฀absolute฀[smoking,฀-62.4฀±฀47.7฀perfusion฀units฀PU;฀sham,฀−30.8฀±฀32.6฀ PU;฀p฀=฀0.04]฀and฀relative฀smoking,฀−147฀±฀163;฀sham,฀32฀±฀225;฀p฀=฀0.07฀vasodilata- tion฀caused฀by฀acetylcholine฀were฀demonstrated.฀From฀this฀study฀it฀can฀be฀concluded฀that฀ acute฀ smoking฀ is฀ associated฀ with฀ impaired฀ capillary฀ recruitment฀ during฀ peak฀ reactive฀ hyperaemia฀ and฀ impaired฀ microvascular฀ endothelium-dependent฀ vasodilatation.฀ These฀ indings฀may฀also฀explain฀the฀increased฀blood฀pressure฀and฀decreased฀insulin฀sensitivity฀ that฀have฀been฀observed฀after฀acute฀smoking฀ [151] . Vascular฀response฀and฀O 2 ฀supply฀of฀the฀skin฀and฀deeper฀tissue฀layers฀can฀be฀measured฀ by฀laser฀Doppler฀lowmetry฀and฀by฀determining฀transcutaneous฀partial฀O2฀pressure฀with฀ platinum฀electrodes,฀as฀our฀own฀research฀has฀demonstrated฀ [9] .฀Attention฀was฀drawn฀long฀ ago฀to฀the฀differences฀between฀the฀reactions฀produced฀by฀cigarette฀smoke฀and฀by฀nicotine฀ [152] .฀Reactive฀hyperaemia฀occurring฀after฀1–3฀min฀occlusion฀of฀the฀upper฀arm฀with฀a฀ blood฀pressure฀cuff฀and฀its฀normalisation฀have฀been฀found฀to฀differ฀between฀smokers฀and฀ non-smokers฀ [9,฀153,฀154] ,฀with฀reactive฀hyperaemia฀in฀smokers฀being฀less฀than฀that฀in฀ non-smokers฀see฀Fig.฀ 6.6 :฀the฀reasons฀for฀this฀are฀certainly฀to฀be฀sought฀in฀vasorespon- siveness฀NO฀production฀and฀in฀the฀viscosity฀of฀the฀blood,฀which฀inluences฀its฀low฀prop- erties฀ [9] .฀ The฀ differences฀ in฀ vasoreactivity฀ were฀ still฀ detectable฀ even฀ after฀ a฀ 6-month฀ observation฀period฀Fig.฀ 6.7 ฀ [8] .฀For฀a฀summary฀of฀the฀indings฀on฀this฀topic,฀readers฀are฀