The Ca2+-sensitive K+ channel (maxi-K+) is an important modulator of corporal smooth muscle tone. The goal of these studies was twofold: 1) to determine the feasibility of transfecting corporal smooth muscle cells in vivo with the hSlo cDNA, which encodes for the human smooth muscle maxi-K+channel, and 2) to determine whether transfection of the maxi-K+channel would affect the physiological response to cavernous nerve stimulation in a rat model in vivo. Intracorporal microinjection of pCMVβ/Lac Z DNA in 10-wk-old rats resulted in significant incorporation and expression of β-galactosidase activity in 10 of 12 injected animals for up to 75 days postinjection. Moreover, electrical stimulation of the cavernous nerve revealed that, relative to the responses obtained in age-matched control animals ( N = 12), intracavernous injection of naked pcDNA/ hSlo DNA was associated with a statistically significant elevation in the mean amplitude of the intracavernous pressure response at all levels of current stimulation (range 0.5–10 mA) at both 1 mo ( N= 5) and 2 mo ( N = 8) postinjection. Furthermore, qualitatively similar observations were made at 3 mo ( N = 2) and 4 mo ( N = 2) postinjection. These data indicate that naked hSlo DNA is quite easily incorporated into corporal smooth muscle and, furthermore, that expression is sustained for at least 2 mo in corporal smooth muscle cells in vivo. Finally, after expression, hSlo is capable of measurably altering nerve-stimulated penile erection. Taken together, these data provide compelling evidence for the potential utility of gene therapy in the treatment of erectile dysfunction.
In patients who recover erectile function after radical prostatectomy (with preservation of at least 1 neurovascular bundle), a recovery time of 6 to 18 months is not uncommon. As this is also the usual time required for regeneration of spinal nerves, we believe that regeneration of cavernous nerves, partially damaged inadvertently, may be responsible. In a rat model, we examined the long-term effect of unilateral and bilateral cavernous nerve transection on the nonadrenergic/noncholinergic (NANC) nervous system and erectile function. In 31 rats, nitric oxide synthase (NOS), the enzyme that catalyzes nitric oxide production, was identified in penile nerve fibers from a mid-shaft segment with nicotinamide adenine dinucleotide phosphate (NADPH) diaphorase staining and antibody to neuronal NOS. Animals were divided into three groups: 5 rats underwent pelvic exploration without transection of cavernous nerves (sham group); 13 rats underwent unilateral neurotomy of a 5-mm. segment of the cavernous nerve; and 13 rats underwent bilateral neurotomy. After bilateral ablation, the NOS-positive nerve fibers were significantly decreased at 3 weeks and remained so at 6 months; no erectile response could be elicited by pelvic nerve stimulation. After unilateral ablation, the NOS-positive nerve fibers were similarly decreased on the side of the neurotomy at 3 weeks, but by 6 months the number had increased significantly and approximated the level on the contralateral side. Furthermore, electrostimulation of the intact side induced a greater intracavernous pressure response at 6 months than at 3 weeks (N.B. the rat has an incomplete septum). Fibers positive for NOS were also identified in the dorsal nerve. The staining pattern diminished as rapidly and significantly on the side of neurotomy as in tissue from the corpus cavernosum. However, regeneration was not seen. To our knowledge, this is the first demonstration of regeneration of NOS-containing nerves after cavernous nerve neurotomy. Our findings support the reports by others that unilateral nerve-sparing is sufficient to preserve erectile function.
The rapid spread of locally restricted neural and hormonal signals among the vast array of largely inexcitable corporal smooth muscle cells is an absolute prerequisite to normal erectile function. And yet the mechanism(s) responsible for this phenomenon is not well understood. As a first step toward a more integrative understanding of erectile physiology and/or dysfunction, an 8- to 12-wk period of experimental diabetes was induced in 2-mo-old male Fischer 344 rats by either intraperitoneal streptozotocin (STZ) injection (35 mg/kg; n = 22) or subtotal pancreatectomy (n = 11). Fourteen age-matched control animals received injection of vehicle only while nine others served as sham-operated control animals. Eight STZ-diabetic animals received insulin replacement. Erectile function was assessed by evaluation of penile reflexes and monitoring of intracavernous pressure responses to both electrical stimulation of the cavernous nerve and intracorporal papaverine or nitroglycerin injection. Intracavernous pressure responses to neurostimulation were significantly attenuated in both STZ-diabetic and subtotal pancreatectomy animals compared with age-matched control animals (P < 0.05). Penile reflexes were also significantly diminished (P < 0.05). Regression analysis revealed that diabetes-related decreases in neurostimulated intracavernous pressure responses were strongly correlated with diminished synaptophysin immunoreactivity in the corpora (P < 0.001; r = 0.88). However, there were no detectable diabetes-related differences in pharmacological erections induced by intracavernous papaverine or nitroglycerin injection. Northern analysis revealed a marked diabetes-related increase in the amount of connexin 43 mRNA measured in frozen corporal tissue. Insulin replacement partially restored (attenuated the loss of) synaptophysin immunoreactivity and maintained neurostimulated intracavernous pressure responses to control levels while having no effect on penile reflexes. These observations may have important implications to the understanding of erectile physiology as well as the etiology of diabetes-related erectile dysfunction.
For secondary ureteropelvic junction obstruction, laparoscopic pyeloplasty can be performed safely with a success rate comparable to that of standard open pyeloplasty. The patient benefits of laparoscopic ureteropelvic junction repair of secondary ureteropelvic junction obstruction are similar to the benefits of laparoscopic repair of primary ureteropelvic junction obstruction.
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