Penile erection is a complex physiologic process that occurs through a coordinated cascade of neurologic, vascular, and humoral events.

The mechanisms of erection and flaccidity are shown in the upper and lower inserts, respectively. During erection, relaxation of the trabecular smooth muscle and vasodilatation of the arterioles results in a severalfold increase in blood flow, which expands the sinusoidal spaces to lengthen and enlarge the penis. The expansion of the sinusoids compresses the subtunical venular plexus against the tunica albuginea. In addition, stretching of the tunica compresses the emissary veins, thus reducing the outflow of blood to a minimum. In the flaccid state, inflow through the constricted and tortuous helicine arteries is minimal, and there is free outflow via the subtunical venular plexus.

Mechanics of erection. (A) In the flaccid state, arterial vessels are constricted and venous vessels are noncompressed. (B) On erection, smooth muscle relaxation in the trabeculae and arterial vasculature results in increased blood flow, which rapidly fills and dilates the cavernosal spaces. Venous outflow drops as the expanding cavernosal spaces compress the venous plexus and the larger veins passing through the tunica albuginea.

Erection
With sexual arousal through imaginative, visual, auditory, tactile, olfactory, and other erotic stimuli, nitric oxide (NO) is released by nonadrenergic, noncholinergic (NANC) neurons. Originally termed endothelial-derived relaxing factor, NO is known to be the most important physiologically occurring vasoactive molecule in the entire cardiovascular system. This also applies to corpus cavernosum function, where local smooth muscle relaxation, and in turn erection, is mediated predominantly by NO release.

On arousal, parasympathetic activity triggers a series of events starting with the release of nitric oxide and ending with increased levels of the intracellular mediator cyclic guanosine monophosphate (cGMP). Increases in cGMP cause penile vascular and trabecular smooth muscle relaxation. Blood flow into the corpora cavernosa increases dramatically. The rapid filling of the cavernosal spaces compresses venules resulting in decreased venous outflow, a process often referred to as the corporeal veno-occlusive mechanism. The combination of increased inflow and decreased outflow rapidly raises intracavernosal pressure resulting in progressive penile rigidity and full erection

1: Mechanism of erection

Non-adrenergic, non-cholinergic nerves and vascular endothelium release nitric oxide in response to sexual arousal, which activates cytoplasmic guanylate cyclase, converting GTP into cGMP. The increased levels of cGMP alter transmembrane calcium ion flux, resulting in cavernosal smooth muscle relaxation, dilatation of cavernosal and helicine arteries and engorgement of lacunar spaces. The expanding lacunar spaces compress the subtunical venous plexus against the tunica albuginea, decreasing cavernosal venous outflow, increasing intracavernosal pressure, with resulting penile rigidity. Cyclic nucleotides, such as cGMP, are hydrolysed by cyclic nucleotide phosphodiesterases.

GTP=guanosine triphosphate; GMP=guanosine monophosphate; cGMP=cyclic guanosine monophosphate.

Through membrane-bound G proteins, NO activates guanylate cyclase, which induces cleavage of guanosine triphosphate to 3',5'-cyclic guanosine monophosphate (3',5'-cGMP).The smooth muscle-relaxing effects of NO are mediated by this second messenger (cGMP).

Cyclic GMP activates protein kinase G (PKG), which phosphorylates proteins at the so-called maxi-potassium channels. This results in an outflow of potassium (K+) ions into the extracellular space with subsequent hyperpolarization, with inhibition or blockade of voltage-dependent calcium (Ca++) channels and therefore a decrease in intracellular Ca++ ion concentrations.

Molecular Mechanism of Penile Smooth-Muscle Relaxation.

Cyclic AMP (cAMP) and cyclic GMP (cGMP), the intracellular second messengers mediating smooth-muscle relaxation, activate their specific protein kinases, which phosphorylate certain proteins to cause opening of potassium channels, closing of calcium channels, and sequestration of intracellular calcium by the endoplasmic reticulum. The resultant fall in intracellular calcium leads to smooth-muscle relaxation. Sildenafil inhibits the action of phosphodiesterase (PDE) type 5, thus increasing the intracellular concentration of cGMP. Papaverine is a nonspecific phosphodiesterase inhibitor. GTP denotes guanosine triphosphate, and eNOS endothelial nitric oxide synthase.

The intracellular decline in Ca++ ions suppresses the activity of myosin light chain (MLC) kinase and thus increases the intracellular content of dephosphorylated MLC, which enables the smooth muscle cell to relax. It is well established that NO and cGMP are the most important transmitters for onset and maintenance of erection. In physiologic terms, 3',5'-cGMP is permanently broken down to the biologically inactive 5'-GMP by the enzyme PDE5.

Cyclic adenosine monophosphate (cAMP), a further second messenger in erectile function, plays an inferior role when compared with cGMP. When erection occurs, vasoactive intestinal polypeptide (VIP) is released at parasympathetic NANC nerve terminals, as is similarly the case with NO release. Both NO and VIP are in colocalization at the respective NANC nerve terminals and are released simultaneously with sexual arousal. VIP activates membrane-bound adenylate cyclase, which promotes cleavage of adenosine triphosphate to 3'5'-cAMP. cAMP activates protein kinase A, which phosphorylates proteins adjacent to the maxi-potassium channels, resulting in K+ ion outflow and hyperpolarization. In turn, the same biochemical actions take place as were described for 3'5'-cGMP.

The NO does not have a specific receptor on the cellular membrane. Rather it crosses the plasma membrane of smooth muscle cells and binds to the heme component of soluble guanylate cyclase. The resulting change in conformation increases guanylate cyclase activity, stimulating the conversion of guanosine-5'-triphosphate (GTP) to guanosine 3',5'-cyclic monophosphate (cGMP), an intracellular messenger for transducing extracellular signals. The binding of cGMP to cGMP-dependent protein kinases and ion channels and/or to cGMP phosphodiesterases results in the reduction of intracellular calcium and, in turn, to diminution of smooth muscle contractility. Finally, cGMP is metabolized to GMP via phosphodiesterase, of which four isoforms (types 2, 3, 4, and 5) have been identified in human penile tissue. Phosphodiesterase type 5 (PDE 5) is the predominant isoform in human corporal smooth muscle.

Several neurotransmitters are involved in penile erection. A principal neural mediator of penile smooth muscle relaxation, and therefore of erection, is nitric oxide. Nitric oxide accounts for the biological activity of endothelial derived relaxing factor. It is formed from its precursor, L-arginine, by nitric oxide synthase. Nitric oxide activates guanil cyclase to form intracellular guanosine monophosphate, a potent second messenger molecule for smooth muscle relaxation. The importance of this pathway is shown by the clinical finding that selective inhibitors of phosphodiesterase-5 (which breaks down cyclic guanosine monophosphate) facilitate erection.

Detumescence and return to the Flaccid state
Detumescence.After ejaculation or cessation of erotic stimuli, sympathetic tonic discharge resumes, resulting in contraction of the smooth muscles around sinusoids and arterioles. Arterial flow is diminished to flaccid levels, much of the blood from the sinusoidal spaces is expelled, and the venous channels reopen

Detumescence of the erect penis is mediated by adrenergic nerve terminals whose neurotransmitter, norepinephrine, activates adrenergic receptors. It has been proposed that contraction of human cavernous arteries that follows the stimulation of the adrenergic nerves is mediated mainly by alpha-2 adrenoreceptors, whereas neurogenic contraction in trabecular muscle is largely mediated by alpha-1 adrenoreceptors.

Adrenergic stimulation causes vasoconstriction of the penile arteries and contraction of the trabecular muscle, resulting in reduction of arterial inflow and collapse of lacunar spaces, respectively. Contraction of the trabecular muscle causes decompression of the drainage venules from the cavernous bodies, thus allowing venous drainage of the lacunar spaces.

During the return to the flaccid state, cyclic GMP is hydrolyzed to GMP by phosphodiesterase type 5. Other phosphodiesterases are also found in the corpus cavernosum, but they do not appear to have an important role in erection. Communication among smooth-muscle cells takes place through gap junctions in the membranes of adjacent cells, which allow the passage of ions and second messengers to synchronize muscle activity.

Molecular Mechanism of Penile Smooth-Muscle Contraction.
Norepinephrine from sympathetic nerve endings, and endothelins and prostaglandin F₂ from the endothelium, activate receptors on smooth-muscle cells to initiate the cascade of reactions that results in elevation of intracellular calcium concentrations and smooth-muscle contraction. Protein kinase C is a regulatory component of the calcium-independent, sustained phase of agonist-induced contractile responses.

Other neurotransmitters that may play a role in the erectile mechanism include:

Smooth Muscle

The key to the entire system is smooth muscle. The percent of smooth muscle dictates the ability to achieve and maintain erections. Roughly 45 percent of the cavernosal body is made up of smooth muscle.The common mechanism of these agents may be via regulation of smooth muscle calcium.

Penile erection or flaccidity is determined by the state of relaxation or contraction of trabecular and arteriolar smooth muscle, which is influenced, in turn, by several factors, including:

Trabecular muscle tone is controlled and penile blood vessel smooth muscle tone may be influenced by three neuroeffector systems.

Local Penile Smooth Muscle Physiologic Mechanisms.

Apart from these proerectile mechanisms, other biological pathways are important either for inducing or inhibiting erection. In particular, activation of the sympathetic nervous system, which occurs, for example, with performance anxiety, results in inhibition of erection. With increased sympathetic tone, norepinephrine is released at alpha1-adrenoceptors located on the cavernous smooth muscle cell. Norepinephrine activates membrane-bound phospholipase C, which induces cleavage of phosphoinositol diphosphate to inositol triphosphate and diacylglycerol. Both inositol triphosphate and diacylglycerol cause an increase in intracellular Ca++, which in turn activates MLC kinase and leads to an increase in phosphorylated MLC. This enables the smooth muscle cell to contract and thus prevent erection. In addition, endothelial vasoactive compounds, such as endothelin 1, angiotensin II, and thromboxane A2, which have smooth muscle contractile properties, can also interfere with smooth muscle relaxation and prevent erection.

To sum up
In the flaccid state, the smooth muscle cells of the penile arteries and the corpora cavernosa are in a state of tone (contraction). Relaxation of the smooth muscle (arterial and cavernosal) causes increased inflow of blood into the lacunar spaces of the corpora cavernosa. The arterial pressure expands the relaxed trabecular walls, thus expanding the tunica albuginea with subsequent elongation and compression of the draining venules. This mechanism of veno-occlusion restricts the outflow of blood through these channels. After ejaculation or cessation of the erotic stimuli, the smooth muscle surrounding the arteries and the lacunar spaces contracts. The inflow of blood is reduced and the venous drainage of the corporeal spaces is opened, returning the penis to the flaccid state. Erection of the penis is thus a haemodynamic event under the control of the autonomic nervous system. Coordination of the neuronal activity from psychogenic stimuli occurs in the hypothalamus while reflexogenic erection involves a polysynaptic coordination in the sacral parasympathetic centres.