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VOL. 73 (4), 963-985, 2007 PHISIOLOGY OF PENILE VASCULATURE...

through both voltage-dependent L-type and receptor-operated Ca2+
channels (ROCs), with a minor role for either intracellular Ca2+
mobilization or store-operated Ca2+ (SOC) entry (36, 37). A
capacitative Ca2+ entry through SOCs not coupled to contraction but

probably related to non-contractile functions of vascular smooth

muscle cells, such as protein and gene expression, is also present in
penile small arteries. Despite the large extracellular Ca2+ dependence
of penile vasoconstriction, there are also potent mechanisms of Ca2+

sensitization of the contractile proteins involving several kinases such

as protein kinase C (PKC), tyrosine kinases (TKs) and Rho kinase
(RhoK) (37), which suggests that Ca2+ entry and Ca2+ sensitization

may cooperate to elicit vasoconstriction upon a1-adrenergic receptor
stimulation. Rho A is a member of the Ras superfamily of small

GTP-binding proteins and Rho kinase (RhoK) is a serine-threonine

kinase which is activated by RhoA (33) and has been shown to play

a key role in the physiology of erection. Thus, inhibition of RhoK in

a rat in vivo model markedly increases intracavernosal pressure and

leads to erection (38) and adeno-associated viral gene transfer of

dominant negative RhoA mutant enhances erectile function (39). In
human CC, RhoA-mediated Ca2+ sensitization contributes to smooth

muscle contraction and flaccidity (40). Interestingly, we have recently
shown that RhoK is involved not only in the Ca2+ sensitization of the
contractile apparatus but also in the regulation of Ca2+ entry through

ROC channels upon a1-adrenoceptor activation in rat penile small
arteries (41). These findings suggest that RhoK and other kinases
involved in Ca2+ homeostasis of penile arteries represent potential

therapeutic targets for the treatment of organic ED (Figure 1).

REGULATION OF PENILE VASODILATATION
AND ERECTION

Accumulating experimental evidence for more than a decade now
has supported nitric oxide (NO) as a central component of the major
signal transduction pathway mediating penile erectile responses.
Wheras the role of NO as a neurotransmiter in the reflex arc that
initiates erection was early established, endothelial-derived NO is
becoming increasingly recognized as a key factor in the vascular
homeostasis and physiology of penile erection.

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