Erectile Dysfunction commonly known as ED or Impotence, affects a large segment of the male population that results in impaired relaxation of the smooth muscle cells in the corpus cavernosum and in the penile arteries. It is an age-related problem that is increasingly common in men aged over 40 years. In the past, ED was often assumed to be either a psychological problem or a normal part of the ageing process, to be tolerated with other signs of aging. However, ED is now known to be primarily organic resulting from vascular, hormonal or neurological complications. The corpus cavernosum (cavernous space) contains sinusoids that are surrounded by trabecular smooth muscle (Ref.1). Upon sexual stimulation, the increase in parasympathetic activity results in dilatation of the cavernosal arteries and increased blood flow into these vascular spaces. At the same time, relaxation of the trabecular smooth muscle increases the compliance of the cavernous spaces, which facilitates entry of the blood. The increase in blood volume and the compression of the relaxed trabecular muscle against the tunica albuginea (a fibrous coat surrounding the penis) results in collapse of the venules and obstruction of venous outflow. Once this occurs, blood ceases to flow in through the cavernosal arteries, and a rigid erection occurs. The major mediator of relaxation of the smooth muscle cells in the cavernosal arteries and the trabecular muscle is nitric oxide (NO) (Ref.2).
Once sexual stimulation is under way, nitric oxide, the natural vasodilator, required for erection is produced by NOS (Nitric Oxide Synthase) in the endothelium of the penile and cavernosal arteries (eNOS) and by an isoform of this enzyme in the NANC (Non-Adrenergic/Non-Cholinergic) nerve terminals (nNOS) that densely innervate the corpus cavernosum. Nitric oxide is thus derived from both vascular and neuronal sources. Sexual stimulation also enables the release of neurotransmitters, hormones and ANP (Atrial Natriuretic Peptide). These compounds along with nitric oxide regulate the smooth muscle tone (periodic contraction and relaxation) by altering cellular Ca2+ (Calcium) levels. Nitric oxide activates sGC (Soluble Guanylate Cyclase) where as ANP activates mGC (Membrane Guanylate Cyclase) which in turn cause an increase in the levels of cGMP (Cyclic Guanosine 3,5-Monophosphate) (Ref.3 & 4). In a similar manner neurotransmitters and hormones dependent activation of G-Proteins like GN-AlphaS (GN-AlphaS Complex Locus) and bicarbonate ions (that pass through Anion Transporters) activate mAC (Membrane Adenylate Cyclase) and sAC (Soluble Adenylate Cyclase), respectively to increase the intracellular cAMP (Cyclic Adenosine 3,5-Monophosphate) levels. G-Proteins also stimulates PLC (Phospholipase-C) that generates IP3 (Inositol 1,4,5-trisphosphate) production through PIP2 (Phosphatidylinositol 4,5-bisphosphate) cleavage. IP3, upon IP3R (IP3 Receptor) activation, modulates release of Ca2+ from intracellular calcium stores. These compounds (cAMP, cGMP and Ca2+) cause smooth muscle relaxation through a variety of mechanisms, including protein phosphorylation and gating of ion channels (Ref.4).
Smooth muscle tone is regulated by cellular Ca2+, which activates the Ca2+/Calm (Calmodulin)-dependent enzyme MLCK (Myosin Light Chain Kinase), which leads to MLC (Myosin Light Chain) phosphorylation and contraction. The active Ca2+/Calm/MLCK enzyme complex phosphorylates a Serine residue on positon 2 (Ser2) of the MLC (Myosin Light Chain) (P-chains or LC2 chains) associated with each Myosin head (thick filament head). This phosphorylation requires one ATP and high ATPase activity. But activation of MLC PPtase (MLC Phosphatase) reverses this process to activate Actin-Myosin cross bridging (Actinomyosin) and in turn smooth muscle relaxation of corpus cavernosum resulting in penile erection (Ref.4 & 5). The levels of cGMP and cAMP in the cell reflect the dynamic balance between muscle relaxation and contraction. cAMP activates MLCK activity by increase in Ca2+ influx through CNG (Cyclic-Nucleotide Gated Ion Channels) and CaCn (Calcium Channels) activation whereas cAMP-dedendent PKA (Protein Kinase-A) activation inhibits MLCK function. Similarly levels of cGMP reflect a balance between production of nitric oxide by NOS and degradation of cGMP by cyclic nucleotide PDEs (Phosphodiesterases). cGMP causes smooth muscle relaxation through a variety of mechanisms that includes phosphorylation and opening of KCn (Potassium Channels); activation of PKG (cGMP-Dependent Protein Kinase); and interactions with PDEs. Opening of potassium channels leads to hyperpolarization, closure of L-Type Calcium channels and decreased Ca2+ levels that results in vasodilation. Activation of PKG leads to inhibition of IP3R, Ca2+ export and activation of MLC PPtase resulting in smooth muscle relaxation. However, cGMP interacts with PDEs in different aspects. It activates PDE1, PDE2 and PDE4 but inhibits PDE3 function to regulate degradation of cAMP to 5’AMP. Binding of cGMP to PDE5 is of outmost importance as it is vital for regulation of cGMP levels and ultimately controls vasodilation and penile erection. PDE5 degrades cGMP to 5’GMP enhancing muscle contraction rather than relaxation (Ref.6 & 7).
Aging along with vascular, hormonal or neurological irregularities, alters production of nitric oxide by NOS and disturbs the balance between synthesis and degradation of cGMP causing ED. Although ED is multifactorial, impaired relaxation of the smooth muscle cells in the corpus cavernosum and in the penile arteries is a common denominator in most cases. The most common anti-impotence drug Sildenafil or Sildenafil Citrate under the trade name such as Viagra, Cialis, Levitra, etc acts as a relatively specific vasodilator of the penile circulation that enhances prolonged muscle relaxation/vasodilation by inhibiting the action of PDE5 to increase cGMP levels and in turn its subsequent functions. The introduction of Sildenafil as vasodilator has revolutionized the treatment of impotence, because it can be taken orally, rather than use of mechanical and prosthetic devices. But intake of this drug is often associated with few side effects like headache, Dyspepsia, nasal congestion, urinary tract infection, abnormal vision, Diarrhea, dizziness and rashes (Ref.8 & 9). Several risk factors are common to Erectile Dysfunction and cardiovascular disease (such as age, hypertension, Atherosclerosis, smoking and Diabetes) and as the two conditions frequently occur together, proper clinical pharmacology of Sildenafil and the potential for interaction between Sildenafil with other drugs should be analyzed to avoid health complications (Ref.10).