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AC/cAMP/PKA

Decrease

Relaxation

CSM, corporal smooth muscle; EC, endothelial cells; IP3, inositol triphoshate; DAG, diacylglycerol; PKC, protein kinase C; ACH, acetylcholine; CHOL, cholinergic; M, muscarinic; NO, nitric oxide; VIP, vasoactive intestinal polypeptide; PGE1, prostaglandin E1; NANC, nonadrenergic, noncholinergic; GC, guanylate cyclase; AC, adenylate cyclase; PKA, protein kinase A.

CSM, corporal smooth muscle; EC, endothelial cells; IP3, inositol triphoshate; DAG, diacylglycerol; PKC, protein kinase C; ACH, acetylcholine; CHOL, cholinergic; M, muscarinic; NO, nitric oxide; VIP, vasoactive intestinal polypeptide; PGE1, prostaglandin E1; NANC, nonadrenergic, noncholinergic; GC, guanylate cyclase; AC, adenylate cyclase; PKA, protein kinase A.

activates PKC, leading to phosphorylation of further downstream targets (e.g., target proteins and ion channels). IP3 induces the release of calcium from the sarcoplasmic reticulum, leading to corporal smooth muscle cell depolarization and contraction (penile flaccidity). IP3 also interacts with membrane-bound calcium channels, which further contribute to calcium influx. Several groups have demonstrated that ET and a-adrener-gic agents induce smooth muscle contraction via activation of these inhibitory signaling pathways (8,69-71).

Role of Potassium Channels in Corporal Smooth Muscle

Activation of potassium (K+) channels leads to the efflux of K+ down its electrochemical gradient, leading to corporal smooth muscle cell hyperpolarization and relaxation. Hyperpolarization results in a decrease in membrane potential (more negative charge) and prevents the opening of L-type voltage-dependent calcium channels (72). Four distinct types of K+ channels have been identified in corporal smooth muscle: the Ca2+-sen-sitive potassium (KCa) channel (e.g., Maxi-K or Slo); the metabolically regulated KATP channel; the voltage-regulated, delayed rectifier K channel (e.g., KDR); and the fast transient A-type K current (69,73-75).

The Maxi-K and KATP channels appear to be the most physiologically relevant in modulating human corporal smooth muscle tone. Studies have indicated that the Maxi-K channel mediates the major K+ current on cultured human and rat corporal smooth muscle cells. The activity ofthis channel is increased after NOS and cGMP activation, leading to smooth muscle relaxation. Moreover, Maxi-K expression is altered in response to aging and disease-related states, as demonstrated in the rat. Christ et al. (76) showed that intracorporal injection of the Maxi-K complementary DNA ameliorated the age-related decrease in erectile function in an in vivo rat model. The same group also demonstrated that Maxi-K/hSlo gene transfer restored erectile capacity in diabetic rats (77). Recent

Corpus Cavernosum Injection

Fig. 8. Electron photomicrographs of the corpora showing the presence of gapjunctions. (A) Electron micrograph of corpus cavernosum, sectioned longitudinally to show more electron dense smooth muscle cells separated by lighter straining connective tissue. Scale bar = 5 mm. (B) Electron micrograph of corpus cavernosum shows region of contact between smooth muscle cells. This region is enlarged in insert to show gap junction. Scale bars represent 5 mm in main portion of B and 0.125 mm in insert. (C) Electron micrograph of corporeal smooth muscle cells in culture shows larger gap junction between cells. Scale bar = 0.25 mm. (Reproduced with permission from ref. 284.)

Fig. 8. Electron photomicrographs of the corpora showing the presence of gapjunctions. (A) Electron micrograph of corpus cavernosum, sectioned longitudinally to show more electron dense smooth muscle cells separated by lighter straining connective tissue. Scale bar = 5 mm. (B) Electron micrograph of corpus cavernosum shows region of contact between smooth muscle cells. This region is enlarged in insert to show gap junction. Scale bars represent 5 mm in main portion of B and 0.125 mm in insert. (C) Electron micrograph of corporeal smooth muscle cells in culture shows larger gap junction between cells. Scale bar = 0.25 mm. (Reproduced with permission from ref. 284.)

studies have also demonstrated that activation of Na+/K+ ATPase by NO is involved in corporal smooth muscle relaxation (3,78). Activation ofthe Na+/K+ ATPase leads to cell membrane hyperpolarization , preventing influx of calcium via voltage-dependent Ca2+ channels.

Gap Junctions (Connexins; see Fig. 8)

Smooth muscle cell responses are coordinated through gap junctions, which are intercellular communications that allow for the transmission of electrical or chemical signals between adjacent cells (Fig. 8; refs. 43-45, 51, 69, 79, and 80). Neighboring cells each contribute a hemichannel (connexon) composed of a hexamer of connexin proteins that constitute the pore-forming units of these aqueous, intercellular channels. Electron microscopic studies have shown that these gap junctions are prominent at areas of membrane apposition between adjacent corporal smooth muscle cells (Fig. 7). Therefore, current-carry-ing ions and second messenger molecules are able to diffuse between adjacent myocytes (44). The connexin family is composed of more than 16 members; however, connexin 43 appears to be the predominant protein found within corporal smooth muscle.

Table 6

Penile Erection and Flaccidity: Neurochemical Regulation

Neurogenic control Cholinergic mechanism (acetylcholine) Adrenergic mechanism (norepinephrine)

Nonadrenergic, noncholinergic (NANC) system (neuronal NO and VIP) Endothelial control Nitric oxide (endothelial NO) Endothelin (ET-1) Prostaglandins (PGEj, PGE2, PGI2)

Histological studies on corporal tissue sections have revealed that the autonomic innervation of the human corpus cavernosum consists of widely distributed nerve fibers. Therefore, adjacent myocytes do not receive individual innervation; rather, they are linked by gap junctions that allow for the synchronization of smooth muscle tone. Con-nexin-43-derived gap junctions appear to modulate the a1-adrenergic and ET-1-induced contractility as well as NO-induced relaxation responses of corporal smooth muscle (42). Finally, there is significant heterogeneity in connexin 43 expression among corporal tissues excised from patients with organic erectile dysfunction (81-86).

Cholinergic Mechanisms (ACh; see Fig. 6; Table 6)

ACh is the main neurotransmitter of the parasympathetic nervous system. For many years, the parasympathetic nervous system was believed to be the sole effector of physiological erections (87); the action of pre- and postganglionic parasympathetic neurons was believed to be mediated in many tissues through the release of ACh (88). However, cholinergic nerve fibers are found in limited numbers within the corpora cavernosa. In humans, intravenous administration or intracavernosal injection of the antimuscarinic blocking agent atropine does not prevent penile erection. In vitro, transmural stimulation of corpus cavernosal strips causes a frequency-dependent neurogenic relaxation that is both resistant to adrenergic and cholinergic blockers and blocked by administration of the neurotoxin tetrodoxin (89). Although cholinergic fibers do not directly mediate relaxation via postjunctional receptors in the corporal smooth muscle, they do act as modulators for other neuroeffector systems. Within the corpus cavernosum, adrenergic nerves receive inhibitory interneuronal modulation from cholinergic nerves. Cholinergic nerves also facilitate nonadrenergic noncholinergic smooth muscle relaxation. Specifically, ACh acting via prejunctional muscarinic receptors inhibits the release of noradrenaline from adrenergic fibers (90,91) and facilitates the release of NO from the endothelium via postjunctional muscarinic receptors as well as the release of additional vasoactive peptides.

Nonadrenergic Noncholinergic Nervous System Neuroeffector Systems (Peptidergic, Including Vipergic, and Nitrergic)

The finding that corporal smooth muscle relaxation also occurred in the presence of both parasympathetic and sympathetic blockers led to the search for a nonadrenergic, noncholinergic neurotransmitter responsible for penile erection (89,92-94). This additional pathway is attenuated by pathways interfering with the synthesis and/or the effects ofNO.

Immunohistochemical studies have demonstrated the presence of NOS in the autonomic nerves (nitrergic) innervating penile blood vessels and corporal smooth muscle (95-97). The synthesis of NO occurs as a byproduct of the conversion of L-arginine to

L-citrulline by the enzyme NOS. NOS exists as three different isoforms. Neuronal NOS and endothelial NOS are the constitutive isoforms and require calcium and calmodulin for activity. The third isoform, inducible NOS, does not require calcium for activation. Notably, NO is not stored in synaptic vesicles within nerve terminals but is synthesized on demand. Therefore, in the flaccid state, NOS activity is minimal.

Experimentally, transmural electrical stimulation of nerves within human corpus caver-nosum tissue induces NO production and relaxation (98,99), which are attenuated by the administration ofNOS inhibitors. These inhibitors (e.g., NG-nitro-L-arginine) also diminish the erectile response to pelvic nerves in vivo (95,100,101). NO production via neuronal NOS is currently believed to be responsible for the initiation of erection, whereas endothelial NOS facilitates and maintains a full erection. Additionally, recent studies have demonstrated a novel pathway that does not require calcium for NOS activation. In response to shear stress within the penile vasculature, there is activation of phosphatidylinositol-3-kinase, which activates PKB. Once activated, PKB phosphorylates endothelial NOS, leading to the production and release of NO by the endothelium (102,103).

Nitric Oxide

It is well-established that NO is the major regulator of corporal smooth muscle relaxation. This molecule was initially found to be released by endothelial cells and was later found to be synthesized and released by neurons (104-106). These findings have also been demonstrated in the corpus cavernosum (66,98,107-112). Intracavernosal injection of NO donors elicits penile erection in humans (113-116). In vitro, many experiments have shown a relaxant effect of NO on strips of corpora cavernosa and helicine arteries that have been precontracted by noradrenaline (107,110,117,118). Furthermore, smooth muscle relaxation is elicited by NO donors and is inhibited by NO scavengers or NOS inhibitors (119). However, NO activity in response to ACh or bradykinin in penile arteries is only partially reversed following administration of NOS inhibitors. Therefore, the endothelium-relaxing mechanisms appear to differ from those in the corporal smooth muscle.

cGMP is hydrolyzed to GMP by different PDEs, and several PDE isoenzymes (i.e., PDE2, PDE3, PDE4, and PDE5) are localized to the human corpora cavernosum. Some of these PDEs degrade both cGMP and cAMP, whereas others are specific for cGMP or cAMP. Spontaneous contractile activity and noradrenaline-induced contractions are opposed by different PDE inhibitors; quazinone (PDE3 inhibitor) is the most potent. Presently, administration of select PDE inhibitors (i.e., PDE5 inhibitors) is known to facilitate penile erection, an effect expected from a physiological response that depends on the NO-cGMP pathway. Pharmacological inhibition ofNOS suppresses penile erection induced by cavernous nerve stimulation in the rat (95,120). NO also mediates ACh- and bradykinin-induced relaxation of corpus cavernosum strips (90,121). Finally, NO-mediated relaxation also appears to be regulated by androgens, because castration reduces NO S expression in the corpora cavernosa of rats (122,123).

NO derived from nitrergic nerve fibers or the endothelium diffuses into adjacent corporal smooth muscle cells (98,116,121), thus activating soluble guanylate cyclase, which results in the generation of cGMP (107,124). As previously mentioned, this cGMP activates second messengers—that is, PKG (or cGK). Following activation, PKG1 (the predominant isoform in smooth muscle) activates K+ channels and the Na+/K+-ATPase pump and inhibits calcium influx, leading to an overall decrease in intracellular calcium and to corporal smooth muscle relaxation (4,8,125). PKG1 appears to play a critical role in the NO-cGMP pathway, because PKG knockout mice can not obtain normal erections in response to activation of the NO-cGMP pathway (126). Moreover, PKG1 has been shown to phosphorylate and inactivate the RhoA/ROK pathway, providing a regulatory link between these opposing pathways.

Vasoactive Intestinal Polypeptide

Vasoactive intestinal polypeptide (VIP) is a 28-residue polypeptide originally isolated from the porcine gastrointestinal tract. It is a potent vasodilator acting with NO as a possible comediator ofpenile erection (127-129). This is supported by the observation that a large percentage of corporal trabecular and perivascular nerve fibers stain for both VIP and NOS (130-132). Unlike NO, which acts via cGMP, VIP receptor binding leads to smooth muscle relaxation through an increase in cAMP and PKA activation, resulting in the closure of Ca+ channels and an opening of K+ channels (133). Whereas NO is believed to initiate penile erection because of its very short half-life, VIP has been proposed to be responsible for maintenance of relaxation because its half-life lasts 10 min (134). Moreover, conversely to NOS, which has been suggested to be an androgen-dependent neurotransmitter, chemical castration does not influence VIP immunostaining ofhuman corpora cavernosa (135).

VIP fibers also follow the same anatomical course as cholinergic fibers. Cotransmission of VIP and ACh is suggested by the ultrastructural examination of human penile tissue, which demonstrates colocalization ofVIP- and ACh-containing vesicles (136-138). Additionally, VIP-induced relaxation is completely abolished by pretreatment with atropine or VIP antibody (137,139). Intracorporal injection of exogenous VIP alone failed to produce erections in many impotent men, indicating that other modulators must be involved in corporal smooth muscle relaxation (140,141). The concentration of VIP has been shown to increase in men during pharmacologically or psychogenically induced erections. Diminished VIP levels may play a role in diabetes- and age-related erectile dysfunction.

Adrenergic Mechanisms

Cavernosal and helicine arteries, as well as corporal smooth muscle cells, receive adrenergic innervation that mediates penile detumescence. Adrenergic fibers outnumber cholinergic nerve fibers within the penis. Penile tissue contains a1- and a2-adrenoreceptors. a1 -receptors are the principle mediators ofarterial and trabecular smooth muscle contraction; a2-receptors apparently play a less significant role (18,21). a1-adrenoreceptors are activated by the local release of noradrenaline (NA or NE) as well as by circulating catecholamines. Recent studies have revealed the presence of multiple a1 -adrenoreceptor subtypes (a1A, a1B, a1D) within human corporal tissue, indicating that NA-induced contraction likely is mediated by more than one receptor subtype (68,142,143). a1D and a1A are the predominant subtypes expressed in the corporal smooth muscle.

Intracavernous drug injection has demonstrated the importance of adrenergic mechanisms in the modulation ofpenile erection. a-blockers (phenoxybenzamine and phentol-amine) induce erection, whereas a-agonists induce shrinkage of both the erect and flaccid penis (144), suggesting that within the flaccid penis, corporal smooth muscle tone is maintained by continuous a-adrenoreceptor stimulation. P-adrenoreceptors also are present within the corpus cavernosum; however, they mediate smooth muscle relaxation and appear to be of little physiological significance (93). Radioligand binding studies have demonstrated that a-adrenoreceptors outnumber P-adrenoreceptors by roughly 9:1 in corporal smooth muscle cells (145). Furthermore, there is an increase in a-adrenergic tone with aging and disease states (40). Therefore, a-adrenergic vasoconstriction may be the predominant response over P-adrenergic vasodilation resulting from sympathetic nerve stimulation.

a2-adrenoreceptors (a2A, a2B, a2C) are present on cholinergic nerve terminals in human penile tissue. This is important in maintaining penile flaccidity, because prejunctional NA inhibits nonadrenergic, noncholinergic transmitter release in addition to production of postjunctional vasoconstriction of vascular smooth muscle (146-148). Conversely, activation of muscarinic receptors in addition to a2-receptors on adrenergic nerve terminals decreases the release ofNA in human corporal tissue (147). Therefore, intercommunication exists between adrenergic and cholinergic systems in modulating penile erection.

Finally, a2-adrenoreceptors distant from adrenergic nerve terminals may be stimulated by circulating catecholamines, suggesting a possible mechanism for impotence associated with high anxiety.

Other Neurotransmitters

Calcitonin gene-related peptide is a potent vasodilator that has been shown to be localized within the cavernous nerves, cavernous arteries, and corporal smooth muscle (149). In sharp contrast to VIP, calcitonin gene-related peptide injection induces a dosage-related increase in penile flow, possibly through the release ofNO. Intracavernous injection induces penile erections in humans (150,151).

Neuropeptide Y has both direct and indirect vasoconstrictor actions, and it has been localized with NE in adrenergic postganglionic neurons (152,153). Electrical field stimulation of human cavernosal arteries and corpus cavernosal muscle strips in vitro elicits a biphasic contractile response (154). The second component ofthe evoked contraction can be abolished adrenergic antagonists; however, the initial contractile component remains refractory, suggesting that contractile neurotransmitters other than noradrena-line are released from these nerve terminals.

Arginine vasopressin contracts human corporal strips and cavernosal artery rings in a concentration-dependent manner. As demonstrated by radio-immunoassay, the concentration of arginine vasopressin is 10-fold higher within human corporal tissue than within plasma.

Substance P has been shown to have an inhibitory effect on cavernosal smooth muscle; however, it is found at smaller concentrations and is localized mainly in the nerves around the corpuscular receptors beneath the epithelium of the glans penis (138).

Angiotensin II has been found within human corpus cavernosum at physiological levels. Moreover, angiotensin II levels are increased during detumescence in humans and have been shown to terminate erections in anesthetized dogs (155,156). Administration of an angiotensin type 1 receptor antagonist was recently shown to restore erectile function in normotensive aged rats, suggesting a role for the renin-angiotensin system in age-related erectile dysfunction (157).

Endothelin-1

ETs are a family of three peptides: ET-1, ET-2, and ET-3. ET-1 is a potent vasoconstrictor and a mitogenic factor that stimulates fibroblasts, smooth muscle, and endothelial cells (87,116,157-159). It is synthesized by the lacunar endothelium and elicits strong, sustained contractions of the corpus cavernosum smooth muscle in vitro. ET-2 and ET-3 also evoke contractions in corporal smooth muscle; however, they have a lower potency than ET-1 (160). In addition to its vasoconstrictive properties, ET-1 acts as a vasodilator at low doses. ET-3 mainly has vasodilator effects on corporal tissue. This has led to the speculation that ET may contribute to the maintenance of penile flaccidity by providing sustained tone. ET-1-induced contractions are believed to depend on intracellular calcium, whether by influx via voltage-gated or receptor-mediated Ca channels, release from intracellular stores, calcium sensitization, or a combination of these (161). ET also has been shown to potentiate the effect of catecholamines on corporal smooth muscle (162).

Two types of ET receptors have been identified: ETA and ETB. ETA is expressed in the vascular smooth muscle and mediates vasoconstriction, whereas the ETB receptor predominates in the endothelium and leads to vasodilation via local release of NO (163). Animal studies using ET-selective receptor antagonists have demonstrated enhanced corporal smooth relaxation; however, these agents have failed to show any improvement in erectile response in human clinic trials (164).

Prostanoids

Prostaglandins are synthesized from arachidonic acid via the cyclooxygenase pathway (65). The corpus cavernosum synthesizes PGE (PGE1 and PGE2), PGF2a, PGD2, prostacyclin (PGI2), and thromboxane A2. These agents act via G protein-coupled receptors that lead to corporal smooth muscle contraction or relaxation. PGE1 is the only endogenous prostaglandin shown to elicit human corporal smooth muscle relaxation. However, depending on specific receptor subtype (EP 1-4) interactions, PGE can also lead to smooth muscle constriction. Specifically, the EP2, EP3II, and EP4 receptors have been shown to mediate smooth muscle relaxation, whereas the EP1 and EP3I receptors elicit contraction (165). PGE1 also acts to inhibit the release of NE by binding to prejunctional EP3 receptors, thus offsetting corporal sympathetic tone (140,165). Additionally, PGE1 induces a 3- to 10-fold increase in intracellular cAMP levels (4,63,166), which, in turn, results in the activation of PKA and a decrease in intracellular calcium levels, leading to smooth muscle relaxation (167). Relaxation also occurs through the activation of KCa channels by PGEj via a PKA-mediated mechanism (168).

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