Erectile Dysfunction: Key Role of Cavernous Smooth Muscle Cells

Abstract

Erectile dysfunction is increasingly affecting men, from the elderly to young adults, being a sexual disorder related to the inability to generate or maintain a penile erection. This disorder is related to psychosocial factors such as anxiety, depression, and low self-esteem, to organic factors such as the presence of preexisting conditions like hypertension, diabetes and dyslipidemia. The pathophysiology of the disease is related to changes in the neurotransmission of the autonomic or the non-cholinergic non-adrenergic nervous system, as well as the release of local mediators, such as thromboxane A₂ and endothelin, and hormonal action. These changes lead to impaired relaxation of cavernous smooth muscle, which reduces local blood flow and impairs penile erection. Currently, therapy is based on oral vasodilation, such as sildenafil, tadalafil, vardenafil and iodenafil, or by direct administration of these agents into the corpus cavernosum or by intraurethral route, such as alprostadil and papaverine. Despite this, studies that consolidate the understanding of its pathophysiological process contribute to the discovery of new more efficient drugs for the treatment of erectile dysfunction. In this sense, in the present work an extensive survey was carried out of the mechanisms already consolidated and the most recent ones related to the development of erectile dysfunction.

Keywords: NANC; authonomic nervous system; corpus cavernous; endothelin; erection; flacity; smooth muscle.

FIGURE 1

Electromechanical coupling of cavernous smooth muscle contraction during rest (A) and after increase in [K⁺]_e (B).

FIGURE 2

Pharmacomechanical mechanism of contraction in the cavernous smooth muscle by activation of G_q/11-PLCβ₁ pathway. NA: noradrenaline; Ca_V: voltage-dependent Ca²⁺ channels; PLCβ₁: phospholipase Cβ₁; PIP₂: phosphatidylinositol 4,5-bisphosphate; DAG: diacylglycerol; IP₃: inositol 1,4,5-trisphosphate; IP₃R: IP₃ receptors; RyR: ryanodine receptors; SR: sarcoplasmic reticulum; SERCA: Ca²⁺-ATPase of SR; PKC: Ca²⁺-dependent protein kinase; MLCK: myosin light chain kinase; CaM: calmodulin protein.

FIGURE 3

Mechanism of maintenance of contraction in the cavernous smooth muscle by activation of G_12/13/ROCK pathway. PLCβ₁: phospholipase Cβ₁; PIP₂: phosphatidylinositol 4,5-bisphosphate; DAG: diacylglycerol; IP₃: inositol 1,4,5-trisphosphate; SR: sarcoplasmic reticulum; PKC: Ca²⁺-dependent protein kinase; RhoA: small GTP binding protein G; PLD: phospholipase D; PC: phosphatidylcholine; PA: phosphatidic acid; RhoGEF: RhoA guanine nucleotide exchange factor; ROCK: kinase of RhoA; CPI-17: PKC-dependent phosphatase inhibitor of 17 kDa; ZIPK: zipper-interacting protein kinase; MLCP: myosin light chain phosphatase; MYPT1: regulatory subunit of MLCP; PP1c: catalytic subunit of MLCP.

FIGURE 4

Pharmacomechanical mechanism of relaxation in the cavernous smooth muscle by activation of NO-sGC-PKG and G_s-AC-PKA pathways. NANC: non-adrenergic non-cholinergic transmission; [Ca²⁺]_i: intracellular Ca²⁺ concentration; CaM: calmodulin protein; nNOS: neuronal nitric oxide synthase; NO: nitric oxide; Ca_V: voltage-dependent Ca²⁺ channels; eNOS: endothelial nitric oxide synthase; PGI₂: prostacyclin; PGE_1/2: prostaglandins E types 1 and 2; AC: adenylyl cyclase; ATP: adenosine triphosphate; cAMP: cyclic adenosine monophosphate; PKA: cAMP-dependent protein kinase; AMP: adenosine monophosphate; sGC: soluble guanylyl cyclase receptor; GTP: guanosine triphosphate; cGMP: cyclic guanosine monophosphate; PKG: cGMP-dependent protein kinase; GMP: guanosine monophosphate; IP₃: inositol 1,4,5-trisphosphate; SR: sarcoplasmic reticulum; SERCA: Ca²⁺-ATPase of sarcoplasmic reticulum; Ca_V: voltage-dependent Ca²⁺ channels; MLCK: myosin light chain kinase; NCX: Na⁺/Ca²⁺ exchanger; PMCA: Ca²⁺-ATPase of plasma membrane; PDE: phosphodiesterase enzyme.