The Catch a Feeling thread

Local control of penile erection:
Acetylcholine appears to be the neurotransmitter of the preganglionic parasympathetic neurons. The neurotransmitters for the short postganglionic neurons have not been fully defined. Acetylcholine does not appear to influence the contractility of the corporeal smooth muscle fibers directly, but does so through activation of cholinergic receptors on the endothelial cells (Fig. 3). Nitric oxide (NO) has been identified in the corporeal tissue (9) and is believed to be the endothelial-derived relaxation factor(s). NO is synthesized from its precursor, l-arginine, by the enzyme nitric oxide synthase (NOS). Both constitutive and inducible NOS isoforms are produced in the cavernosal tissues (10, 11). Constitutive NOS is produced by the endothelial cells and the nerve terminals, whereas the inducible NOS appears to be produced by the corporeal smooth muscle cells only.
NO produced by the sinusoidal endothelial cells and by the noncholinergic parasympathetic neurons diffuses into the adjacent smooth muscle cells and activates soluble guanylate cyclase to increase the intracellular cGMP concentration. The cGMP appears to be the major intracellular effector of the smooth muscle cell relaxation (12) via a biochemical cascade of protein kinases. A putative mechanism for cGMP-induced corporeal smooth muscle relaxation involves protein kinase phosphorylation of myosin light chains directly or as a consequence of lowering intracellular calcium stores (10). Although several types of phosphodiesterase (PDE) isoenzymes have been identified in the human corpora cavernosa, type 5 was found to be the predominant isoenzyme responsible for the inactivation of cGMP (13). Sildenafil (Viagra, Pfizer Inc., New York, NY) inhibits this PDE, which is also found in vascular smooth muscles and platelets (14). Sildenafil, to a lesser extent, also inhibits PDE type 6 in the retinal rod photoreceptors (responsible for metabolism of the light-stimulated cGMP) and has little or no effect on the calcium/calmodulin-dependent PDE-1 and the calcium/ calmodulin-independent PDE-3 isoenzymes in the cardiac muscles (responsible for metabolism of cGMP that is involved in regulation of cardiac contractility) (14). Phosphodiestrase inhibitors are emerging as an attractive physiological means for induction and/or prolongation of erection in man (15). In addition to stimulation of cGMP production, NO itself could directly influence the contractility of the corporeal smooth muscle fibers by altering the transcellular ion flux through activation of the sodium/potassium-adenosinetriphosphatase (16) and the potassium-conductive membrane hyperpolarization pathway (17).
Other noncholinergic parasympathetic neurotransmitters capable of promoting smooth muscle relaxation, and hence the erectile response, include vasoactive intestinal polypeptide (VIP), bradykinin, peptide histidine methionine, pituitary adenylate cyclase-activating polypeptide, helospectin, galanin, calcitonin gene-related peptide (CGRP), and prostaglandin E-1 (18, 19, 20, 21). Before the identification of NO in the penile tissue, VIP was thought to be the chief neuromediator of the erectile function; however, VIP was found to colocalize with NOS in penile neurons of rats and humans (22). Its relaxation effect on the corporeal smooth muscle fibers appears to be mediated by the NO-cGMP pathway (23) similar to bradykinin’s ability to stimulate the endothelial NOS pathway to generate NO (24). However, the exact mechanisms by which other neuropeptides participate in regulation of the erectile function remain to be determined.
Norepinephrine is responsible for regulation of corpus cavernosum smooth muscle tone via the interaction with α-1 and α-2 adrenergic receptors (25). Other neurotransmitters capable of promoting smooth muscle contraction, and hence detumescence, include endothelin-1, substance-P, PGF-2α, thromboxane A-2, angiotensin II, and calcium (18, 20, 26, 27, 28, 29, 30). Some of these agents exert their effect through modulation of the presynaptic α-2 adrenergic receptors. A role for sympathetic innervation of the penis in mediation of psychologically provoked erection has been suggested, but the validity of such a belief was disputed based upon the observation of a full retainment of erectile capacity in men who undergo bilateral complete sympathectomy (31, 32). However, the recent in vitro studies demonstrating the relaxation effect of the β-2 adrenergic receptor agonist isoproterenol on noradrenaline-precontracted human penile smooth muscle cells (33) suggest that, at least in some situations, β-adrenergic innervation could participate in the mediation of human erection.
α-1 Adrenergic receptors are the preponderant subtype in corporeal smooth muscles (34) and the deep dorsal penile vein (35), whereas α-2 receptors dominate in the cavernosal arteries (34). However, no quantitative differences in the prevalence of the two subtypes have been found in the circumflex veins of either potent or impotent men. Crowe and colleagues (36) found the greatest density of nerves supplying the deep dorsal vein and the vasa vasorum to be (in decreasing order) neuropeptide-Y (NPY), VIP, and dopamine-β-hydroxylase-containing nerves. These investigators proposed that NPY, by its prolonged vasoconstricting effect, may aid in penile erection, and the vasodilating effect of VIP may be involved in facilitating the drainage of penile blood during detumescence. A recent series of in vitro experiments by Segarra and colleagues (37) using ring segments of human penile dorsal vein has provided additional evidence for an active role of the deep dorsal vein in the total penile vascular resistance through the release of NO from both neural and endothelial elements.
The presence of a critical balance of smooth muscle to connective tissue has been suggested for the successful veno-occlusion and the manifestation of erectile response to occur. A potential role for transforming growth factor β-1 (TGF-β1) and PGE-1 in maintaining this critical balance of smooth muscle/connective tissue and a role for intracorporeal oxygen tension in regulation of synthesis of these regulatory factors have also been suggested (38). Thus, neuronal dysregulation or poor intrinsic compliance of the corporeal smooth muscle cells could be a significant factor in the pathogenesis of erectile dysfunction (Fig. 4) (39).
Another aspect of the control of corporeal smooth muscle cell function that has recently been described is the role played by the gap junction (18, 38, 39). Gap junction channels interconnect the corpus cavernosum smooth muscle cells and allow them to function as a coordinated network with synchronous myographic activity. Second messengers, such as calcium ion and inositol triphosphate (IP3), are transported between corporeal smooth muscle cells through these junctions. Therefore, cell-to-cell communication is a likely means for synchronization and integration of the corporeal smooth muscle activity that occurs despite the paucity of nerve supply to individual smooth muscle cells.

Erection is the ultimate response to multiple psychogenic and sensory stimuli from imaginative, visual, auditory, olfactory, gustatory, tactile, and genital reflexogenic sources, which effect several neurological and vascular cascades that lead to penile tumescence and rigidity sufficient for vaginal penetration. Further, erection is associated with significant psychological and physical changes, including heightened sexual arousal, full testicular assent and swelling, dilatation of the urethral bulb, an increase in glans and coronal size, cutaneous flush over the epigastrium, chest, and buttocks, nipple erection, tachycardia and elevation in blood pressure, hyperventilation, and generalized myotonia (40, 59). The local penile changes are effected by a vasodilating parasympathetic discharge subsequent to the central nervous system (CNS) inputs or as a result of reflex action in response to local afferent stimulation of the sacral parasympathetic nuclei.
New data implicating gonadal androgens in modulation of penile erection through local regulation of NO secretion and/or action need to be emphasized. Experiments that have shown castrated rats to have reduced penile tissue NOS content and androgen replacement to restore NOS production and action (60) have cast doubt on the older dogma that androgens act only centrally to modulate sexual libido. Data in which androgens were shown to influence the frequency of nonerotic or“ reflex” erection support a role for peripheral androgen actions in the human (61). Moreover, a recent study in rats by Lugg and colleagues (62) implicates dihydrotestosterone and not testosterone as the local modulating androgen of the NO-cGMP pathway. However, the fact that androgens can enhance NPT, but not erection in response to erotic stimuli (61), may suggest the presence of both androgen-sensitive and androgen-insensitive central pathways for erectile control.

The evidence reviewed above suggests that a fall of resistance within the corporeal vascular bed and the subsequent increase in arterial inflow are the major vascular events leading to erection of the penis (Figs. 4 and 5) (39, 63, 67). A dramatic increase in penile arterial blood flow to about 25 to 60 times that of the flaccid state occurs during the rapid period of tumescence (63). Pulse Doppler analysis studies with intracavernous vasoactive drug injections have established that a peak cavernosal artery systolic flow greater than 25 ml/sec is required for erection to occur (68, 69, 70, 71). At full rigidity, an increase in penile length of 7.5 cm usually requires the entrapment of 80–115 ml of blood. As the penile volume increases to near maximum (from <10 ml in the flaccid state to ∼60 ml in the erect state), the arterial influx declines and plateaus at a level that is sufficient to keep the penis in the rigid (full erection) state. Dynamic infusion cavernosometry and cavernosography (DICC) studies have shown that a fluid flow rate between 5 and 40 ml/min is required to maintain a normal penis in the erect state (72, 73). Further, at these minimum flow rates of full erection, the cavernosal artery occlusion pressure (CAOP) equilibrates with the intracavernous pressure.
The intracorporeal pressure during the flaccid state is between 10 to 15 mm Hg. Intrapenile pressure changes are modest during the initial phase of the sexual cycle and remain so until near-maximum changes in circumference and volume are attained. As the penis becomes erect, the penile body pressure increases rapidly to about 90 mm Hg. Perineal muscle contraction results in further increase in penile body pressure to greater than 120 mm Hg (suprasystolic pressure), which results in full rigidity and elevation of the penis to greater than 90 degrees from the plane of lower extremities (63, 67). After orgasm, penile body pressure declines rapidly and the penile volume returns to the flaccid size. The aforementioned DICC studies suggested that the intrapenile pressure normally drops at a rate of less than 1 mm Hg/sec during detumescence, as reflected by the rate of drop in intrapenile pressure when fluid infusion is discontinued.