Experimental erectile dysfunction in experimental diabetes and aging has been studied in the rat (40-42). Rat studies typically consist a measurement of intracavernous pressure in response to electrical stimulation of the cavernous nerve in normal and diabetic rats (43). The pathophysiology of erectile dysfunction in DAN appears to mimic the human condition wherein it is vasculogenic resulting in engorgement of corpora cavernosa and is because of a deficiency of nitric oxide (40,44-46). In the penile corpora cavernosa, nitric oxide is produced mainly by the activation of the neuronal nitric oxide synthase (NOS) in the nerve terminals and, to a lesser extent, by endothelial NOS in the lacunar and vascular endothelium (40,46). Nitric oxide stimulates guanylate cyclase ^ cGMP ^ activation of phosphokinase G ^ reduction of intracellular Ca2+ ^ relaxation of the smooth muscle cells ^ penile engorgement. Support for this concept in the rat derives from a number of observations. Nitric oxide downregulation in the vasculature and penile corpora is associated with erectile dysfunction (46). Chronic treatment with the nitric oxide inhibitor L-NAME leads to abolition of the erectile response (46,47).
Structural changes in corpora are also considered important. There is impaired compliance of the corpora cavernosa and the penile arteries (40,48) because of alterations in the smooth muscle and an increase in collagen deposition in the corporal tissue (40,49). Corporal fibrosis results in tissue stiffness and venous leakage. Smooth muscle function is important in that its relaxation results in an increase in intracorporeal pressure, sufficient to compress veins against tunica albuginea. Impaired smooth muscle relaxation results in insufficient pressure ^ insufficient venous compression ^ venous leakage (50).
Urological investigators have used the rat model to develop and evaluate novel approaches to treatment (51). In addition to standard approaches such as the evaluation of novel phosphodiesterase inhibitors, investigators have additionally used novel gene therapy with different genes and vectors and ex vivo gene therapy, combining gene transfer with stem cell implants (42). Considerable success has been encountered using gene transfer with the large conductance, Ca-sensitive K channel subtype (i.e., hSlo). The mechanism of action was presumably related to the importance of K channel hyperpolarizing currents to relaxation of corporal smooth muscle and penile erection. A single intracavernous injection of the "naked" pcDNA-hSlo (100 ^g), which encodes the a-subunit of the human maxi-K channel, was associated with physiologically significant increases in the magnitude of the cavernous nerve-stimulated intracorporeal pressure response that lasts for up to 6 months after a single intracavernous injection (52). Gene transfer prevented an age-related decrease in resting intracavernous pressure and a physiologically relevant, significant effect on normalizing erection in vivo (53). Recently, the efficacy of this gene in the treatment of experimental diabetic erectile dysfunction has been reported (51). The ability of gene transfer with this pore-forming subunit of the human maxi-K channel (hSlo) to ameliorate the decline in erectile capacity commensurate with 12-24 weeks of STZ-diabetes examined in 181 Fischer-344 rats.
Erectile capacity was evaluated by measuring the intracavernous pressure response to cavernous nerve stimulation (ranging from 0.5 to 10 mA). In the first series of experiments, ANOVA revealed increased engorgement pressure in treated animals. A second series of experiments further examined the dose dependence and duration of gene transfer. The intracavernous pressure response to submaximal (0.5 mA) and maximal (10 mA) nerve stimulation was evaluated 3 or 4 months postinjection of a single dose of pcDNA-hSlo ranging from 10 to 1000 ^g. ANOVA again revealed that hSlo overexpression was associated with increased nerve-stimulated pressure responses compared with responses in corresponding control animals. Histological studies revealed no immune response to the presence of hSlo. Polymerase chain reaction analysis documented that expression of both plasmid and transcript were largely confined to the corporal tissue. In the third series of pharmacological experiments, hSlo gene transfer in vivo was associated with iberiotoxin-sensitive relaxation responses to sodium nitroprusside in corporal tissue strips in vitro. The latter data indicate that gene transfer produces functional maxi-K-channels that participate in the modulation of corporal smooth muscle cell tone. Taken together, these observations suggest a fundamental diabetes-related change in corporal myocyte maxi-K-channel regulation, expression, or function that may be corrected by expression of recombinant hSlo. Another gene that has been evaluated has been through intracavernosal gene therapy with PnNOS cDNA, which is reported to correct the aging-related erectile dysfunction for at least 18 days (54).
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