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Definition
Pharmacomechanical coupling refers to the physiological mechanisms that regulate smooth muscle contraction independently of the membrane potential.1 In cavernous smooth muscle it is triggered by the binding of agonists to G protein-coupled receptors.2 It is distinguished from electromechanical coupling, in which the contractile response follows membrane depolarisation.2 A classic example is the release of Ca2+ from the sarcoplasmic reticulum by the chemical messenger inositol 1,4,5-trisphosphate (IP3), which is initiated not by depolarisation but by agonist-receptor interaction.1 The concept also covers changes in the Ca2+ sensitivity of the contractile apparatus. Sensitisation to Ca2+ is attributed to inhibition of myosin phosphatase, most likely dominated by activation of the small GTP-binding protein RhoA and its effector Rho-kinase, whereas cyclic nucleotide-activated kinases can desensitise the muscle.1 Ca2+ sensitivity reflects the balance between myosin light-chain kinase and phosphatase activities and is a major regulated determinant of smooth muscle function.3 In the penis, these mechanisms control the tone of corpus cavernosum smooth muscle and thus the balance between flaccidity and erection.2
Clinical Context
The balance between contractant and relaxant factors controls the degree of contraction of the smooth muscle of the corpora cavernosa and determines the functional state of the penis. Noradrenaline contracts both the corpora cavernosa and penile vessels via α1-adrenoceptors.4 Sympathetic stimulation is the primary mechanism that keeps the penis flaccid. Electromechanical coupling contributes to cavernous smooth muscle contraction, but flaccidity arises mainly from pharmacomechanical coupling: agonists bind G protein-coupled receptors and activate the Gq/11-phospholipase Cβ1 cascade, which generates diacylglycerol and IP3; IP3 releases Ca2+ from the sarcoplasmic reticulum.2 Contractile agonists such as endothelin-1 and angiotensin II also activate RhoA through G12/13 proteins. Rho-kinase then phosphorylates the regulatory subunit of myosin light-chain phosphatase, inactivating it and maintaining contraction, while protein kinase C adds to this effect by phosphorylating the phosphatase inhibitor CPI-17.2
Erection depends on the reverse process. Neurogenic nitric oxide (NO) is considered the most important factor for relaxation of the penile vessels and corpora cavernosa.4 NO stimulates soluble guanylate cyclase to produce cyclic guanosine monophosphate (cGMP), which activates cGMP-dependent protein kinase. This kinase lowers intracellular Ca2+ in several ways, including activation of K+ channels, inhibition of voltage-dependent Ca2+ channels and increased sequestration and extrusion of Ca2+.2 Ca2+ desensitisation also involves antagonism between the cGMP-activated kinase and the RhoA/Rho-kinase pathway.3
These pathways explain how erectile dysfunction (ED) can develop and how drugs act. Deregulation of any step in these signalling pathways may compromise penile function and contribute to ED. In the penis the predominant phosphodiesterase isoform is PDE5, which acts specifically on cGMP. PDE5 inhibitors raise intracellular cGMP and promote relaxation of the corpus cavernosum, but prior sexual stimulation is essential to increase NO levels and generate cGMP.2 Four selective PDE5 inhibitors have been approved by the European Medicines Agency for the treatment of ED.5 In rats, pharmacological antagonism of Rho-kinase stimulated penile erection independently of NO, which introduces a potential alternative avenue for ED treatment.6