Neuronal NOS activity by nonadrenergic noncholinergic
neurons is known to be decreased in both
in vitro
in vivo
models of smoking (Xie
et al.
, 1997). Compo-
nents of burned, but not unburned, tobacco are in part
responsible for the loss of neuronal NO through enzy-
matic blockade (Demady
et al.
, 2003). It has been well
smoke damages the endothelium and impairs eNOS-
mediated vasodilation (Fig. 1) (Celermajer
et al.
, 1993;
et al.
, 2001).
Furthermore, in addition to cigarettes’ effect on enzy-
matic synthesis, superoxide anions produced by the
metabolites from smoke directly decrease the level of free
NO in the corpora cavernosa. This is partially mediated
via activation of the NADH oxidase enzyme family
et al.
, 2007). Superoxide anions are increased in
smokers, and their presence shunts NO into a peroxyni-
trite pathway that lessens the vasoactive availability of
NO (Peluffo
et al.
, 2009).
The Rho-associated kinase (ROK), which regulates sen-
sitivity to calcium contractility in the smooth muscle cell,
is known to maintain the ±accid state, and, as such, ROK
inhibitors can be theorised to induce erection (Mills
et al.
, 2001). Intracellular NO functions to inhibit ROK
allowing for vasodilation. Similarly, decreases in NO lev-
els secondary to smoking disinhibit ROK and act to fur-
ther worsen ED (Chitaley
et al.
, 2001). Furthermore,
smokers have decreased ROK activity in peripheral leuco-
cytes correlating to poor nitroglycerin vasodilation further
hinting at a connection between ROK signalling and
smoking (Hidaka
et al.
, 2010).
Smoking also causes intrinsic damage to vessels pre-
venting elastic dilation despite strong paracrine signals.
Smoking alters the elastin of the extracellular matrix and
induces calci²cation of medial elastic ²bres producing
arterial stiffness (Guo
et al.
, 2006).
Epidemiological associations between ED and
There have been numerous cross-sectional studies that
have established a correlation between cigarette smoking
and ED (Austoni
et al.
, 2005; Kupelian
et al.
, 2007; Chew
et al.
, 2009; Ghalayini
et al.
, 2010; Wu
et al.
, 2012). The
studies have included populations from China, the Mid-
dle East, Europe and the Americas. Each study exhibited
a variable baseline smoking prevalence. The odds ratio of
smokers with ED has ranged between 1.4 and 3.1 with
statistically signi²cant con²dence intervals in the vast
majority of these studies. Typically, populations were
selected to minimise other known causes of ED such as
psychotropic medications and prostate cancer due to
treatment effects. In a speci²c cohort of young men
40 years of age, smoking was a signi²cant risk factor for
ED. In these men, the multivariate analysis did not show
signi²cance in other vascular risk factors strongly indicat-
ing a role for smoking in the pathogenesis of ED in
younger men (Elbendary
et al.
, 2009). While the majority
of these studies accounted for other vascular risk factors
(i.e. age, hypertension, obesity and diabetes), it was dif²-
cult to determine signi²cance of any isolated risk factors
as many existed together and were impossible to separate.
To address the inherent bias in cross-sectional studies,
a series of long-term cohorts were created in the 1990s to
determine possible links between smoking and ED. In the
Male Health Professionals Study, of the 22 086 men with-
out baseline ED, the relative risk that smokers developed
ED over a follow-up of 14 years was 1.4 (95% CI
1.6) (Bacon
et al.
, 2006). Likewise in Minnesota
cohort, the odds ratio of smokers to develop ED was 1.42
after adjusting for age (95% CI 1.00
2.02). The strength
of the association was greatest in men under the age of
70 years, and this association decreased with progressively
older age groups. The investigators felt this may have
been due to survivorship bias or the exclusion of men
from the study who had undergone prostate surgery or
who had prostate cancer (Gades
et al.
, 2005). The Massa-
chusetts Male Aging Study followed 513 middle-aged men
with good erectile function and excluded diabetics and
patients with baseline cardiac disease. Cigarette smokers
Fig. 1
Interplay of neuronal and endothelial effects on vascular relax-
ation. The main mediator of penile arterial relaxation is nitric oxide
(NO). NO is released directly from neurons and indirectly via endothe-
lial production. Cigarette smoke has been shown to directly inhibit
both neuronal and endothelial isoforms of nitric oxide synthase (NOS).
In addition, superoxide anions from cigarette smoke directly degrade
NO. Rho-kinase (ROK) is upregulated in men who smoke, thus activat-
ing myosin light-chain (MLC) phosphatase that prevents NO-induced
2014 Blackwell Verlag GmbH
, 1087–1092
Smoking and male erectile function
J. R. Kovac
et al.