Protein Inhibitor of Nitric Oxide Synthase (NOS) and the N-Methyl-d-Aspartate Receptor Are Expressed in the Rat and Mouse Penile Nerves and Colocalize with Penile Neuronal NOS1

Magee, Thomas R.; Ferrini, Mónica G.; Davila, Hugo H.; Zeller, Cynthia B.; Vernet, Dolores; Sun, Junhui; Lalani, Rukhsana; Burnett, Arthur L.; Rajfer, Jacob; González‐Cadavid, Néstor F.

doi:10.1095/biolreprod.102.007310

Cited by 38 publications

(38 citation statements)

References 31 publications

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“…Although these nNOS modulators have been shown to be expressed in the penis [57,58] their role in the regulation of penile erection remain to be established.…”

Section: Genital Tract and Nitrergic Neurotrans-missionmentioning

confidence: 99%

Point of NO Return for Nitrergic Nerves in Diabetes: A New Insight into Diabetic Complications

Cellek

2004

CPD

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Aberrations in nitrergic neurotransmission, due to a decrease in neuronal nitric oxide (NO) synthase (nNOS) protein, play an important role in the pathogenesis of autonomic neuropathy in diabetes. Until recently the mechanism of the decrease in nNOS protein content in nitrergic nerves during diabetes was debated. Two different views were prevailing, one attributing the nNOS decrease to nitrergic nerve degeneration, the other to an alteration in nNOS expression. Our recent study in which we showed that nitrergic nerves undergo a degenerative process in two phases might bring a solution to this debate. Our model suggests that, in the early stages of diabetes, nNOS expression is decreased in the nitrergic axons while nNOS levels are unaffected in the cell bodies, most probably due to a defect in axonal transport. This decrease is reversible with insulin treatment. As the diabetes progresses, nNOS starts to accumulate in the cell bodies since it cannot be transported down to the axons. Increased nNOS protein and NO production coincide with accumulation of advanced glycation endproducts (AGEs) in the blood and tissues. Synergistic action of AGEs and endogenous NO leads to increased oxidative stress within the cell bodies, resulting in apoptosis. This degenerative phase of nitrergic neuropathy is not reversible with insulin treatment. This suggests a point of no return for autonomic nerves after which the degenerative changes become irreversible. Future therapeutic approaches could target the defective axonal transport and prevention of AGEs accumulation before this point of no return. In the later stages, reduction of AGEs, replenishment of lost nitrergic neurons and restoration of function are putative therapeutic targets.

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“…Although these nNOS modulators have been shown to be expressed in the penis [57,58] their role in the regulation of penile erection remain to be established.…”

Section: Genital Tract and Nitrergic Neurotrans-missionmentioning

confidence: 99%

Point of NO Return for Nitrergic Nerves in Diabetes: A New Insight into Diabetic Complications

Cellek

2004

CPD

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“…With the advent of molecular biological techniques, a number of researchers have demonstrated that selectively altering the expression of a targeted gene in the penile vasculature can influence the erectile response. Gene transfer of therapeutic genes has been shown to be highly efficacious in improving the diminished erectile responses in a number of experimental animal models [32,[52][53][54][55][56][57][58][59][60][61][62][63][64][65][66][67][68][69][70][71]. In general, these studies increase the amount of an endogenous vasomodulator of the erectile response or alter the sensitivity of the corporal vasculature to any given relaxatory stimulus.…”

Section: Gene Therapy For the Treatment Of Erectile Dysfunctionmentioning

confidence: 99%

“…Importantly, all three NOS enzymes (eNOS, nNOS, and iNOS) have been utilized to improve endogenous NO production in the penis [53][54][55][56][57][62][63][64][65]. Overexpression of any of the three NOS isoforms in the penis will improve a diminished erectile response in animal models of ED [53][54][55][56][57][62][63][64][65]. Both eNOS and nNOS are the most likely therapeutic gene targets to improve NO synthesis in the penis, because both isoforms are tightly regulated and produce physiological relevant levels of NO in the endothelial cells and cavernous nerves.…”

Section: Gene Therapy For the Treatment Of Erectile Dysfunctionmentioning

confidence: 99%

Endothelial Nitric Oxide Synthase Gene Therapy for Erectile Dysfunction

Bivalacqua¹,

Musicki²,

Usta³

et al. 2005

CPD

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Basic science research on erectile physiology has been devoted to investigating the pathogenesis of erectile dysfunction (ED) and has led to the conclusion that ED is predominately a disease of vascular origin. It is well recognized that the incidence of ED dramatically increases in men who suffer from diabetes mellitus, hypercholesterolemia, and cardiovascular disease. Endothelial nitric oxide synthase (eNOS) is an important factor in cardiovascular homeostasis, angiogenesis, and erectile function. Given the impact of endothelial-derived nitric oxide (NO) in vascular biology, a great deal of research over the past decade has focused on the role of NO synthesis from the endothelium in normal erectile physiology as well as in disease states. Loss of the functional integrity of the endothelium and subsequent endothelial dysfunction plays an integral role in the occurrence of ED. Therefore, a likely target of gene therapy for the treatment of ED is eNOS. This communication reviews the role of eNOS in erectile physiology and discusses the alterations in eNOS expression in various vascular diseases of the penis. Putative gene therapy interventions to restore eNOS expression and subsequent endothelial function may represent an exciting new therapeutic strategy for the future treatment of ED.

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“…PnNOS is thought to be responsible for triggering the nitrergic mechanism responsible for cavernosal relaxation. 26,27 A similar variant, nNOSu, is present in the neuromuscular plates of skeletal muscles, 28 including the perineal muscles involved in erectile rigidity and ejaculation in rats. 29 The control of NO synthesis in the cavernosal nerve, whether due to sexual stimulation emanating centrally from the brain, or peripherally by means of the dorsal nerve spinal reflex, is assumed to be exerted through the activation of PnNOS activity.…”

Section: Synthesis Of Nomentioning

confidence: 99%

“…PIN, NMDAR subunits, and a truncated variant of the NMDAR subunit 1mRNA (NMDAR1-T) have been located in the peripheral penile nerves and pelvic ganglion. 27 The nitrergic activation of penile erection is not restricted to peripheral nerves of the corpora cavernosa but is also dependent on central nervous system control. Copulatory behavior and ejaculation are also central nervous system (CNS) regulated.…”

Section: Synthesis Of Nomentioning

confidence: 99%

Nitric oxide–cyclic GMP pathway with some emphasis on cavernosal contractility

Ghalayini

2004

Int J Impot Res

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Nitric oxide (NO) is formed from the conversion of L-arginine by nitric oxide synthase (NOS), which exists in three isoforms: neuronal (nNOS), endothelial (eNOS), and inducible (iNOS). nNOS is expressed in penile neurons innervating the corpus cavernosum, and eNOS protein expression has been identified primarily in both cavernosal smooth muscle and endothelium. NO is released from nerve endings and endothelial cells and stimulates the activity of soluble guanylate cyclase (sGC), leading to an increase in cyclic guanosine-3 0 ,5 0 -monophosphate (cGMP) and, finally, to calcium depletion from the cytosolic space and cavernous smooth muscle relaxation. The effects of cGMP are mediated by cGMP dependent protein kinases, cGMP-gated ion channels, and cGMP-regulated phosphodiesterases (PDE). Thus, cGMP effect depends on the expression of a cell-specific cGMPreceptor protein in a given cell type. Numerous systemic vasculature diseases that cause erectile dysfunction (ED) are highly associated with endothelial dysfunction, which has been shown to contribute to decreased erectile function in men and a number of animal models of penile erection. Based on the increasing knowledge of intracellular signal propagation in cavernous smooth muscle tone regulation, selective PDE inhibitors have recently been introduced in the treatment of ED. Phosphodiesterase 5 (PDE5) inactivates cGMP, which terminates NO-cGMP-mediated smooth muscle relaxation. Inhibition of PDE5 is expected to enhance penile erection by preventing cGMP degradation. Development of pharmacologic agents with this effect has closely paralleled the emerging science.

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Protein Inhibitor of Nitric Oxide Synthase (NOS) and the N-Methyl-d-Aspartate Receptor Are Expressed in the Rat and Mouse Penile Nerves and Colocalize with Penile Neuronal NOS1

Cited by 38 publications

References 31 publications

Point of NO Return for Nitrergic Nerves in Diabetes: A New Insight into Diabetic Complications

Point of NO Return for Nitrergic Nerves in Diabetes: A New Insight into Diabetic Complications

Endothelial Nitric Oxide Synthase Gene Therapy for Erectile Dysfunction

Nitric oxide–cyclic GMP pathway with some emphasis on cavernosal contractility

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