Thursday, September 6, 2007

Mechanisms Of Erection

Intracavernosal smooth muscle tone is by far the most important determinant of intracavernosal blood flow. Approximately half of the cavernosal volume is composed of smooth muscle, with the remainder consisting of either lacunar spaces or collagen. Collagen fibers are largely responsible for the passive mechanical properties of cavernosal tissue. In contrast, active contraction of cavernosal smooth muscle is dependent upon a number of factors, including the level of agonists (neurotransmitters, hormones and endothelium-derived factors), adequate expression of receptors, integrity of transduction mechanisms, calcium homeostasis, interaction of contractile proteins, and intimate intracellular communication between smooth muscle cells (gap junctions).

Cavernosal smooth muscle cells contain abundant amounts of the contractile proteins, actin and myosin. Following phosphorylation of myosin by adenosine triphosphate (ATP), attachments (crossbridges) form between the light chains of these two proteins and these attachments provide the mechanism for contractile tone of smooth muscle. The expenditure of energy for maintaining this state of tone is almost zero, but there is an absolute requirement for a high concentration of cytoplasmic free calcium.

Adequate calcium homeostasis is, therefore, fundamental to the normal regulation of smooth muscle tone. Three major mechanisms are involved:

  1. Influx of extracellular calcium through voltageregulated channels.
  2. Activation of membrane-bound receptors which allow extracellular calcium to enter through receptor-operated channels.
  3. Activation of signal pathways which allow intracellular release of calcium from the sarcoplasmic reticulum.

Relaxation of cavernosal smooth muscle may be thought of as ‘resetting’ the contractile machinery. This is mainly accomplished by lowering intracellular calcium. There are a number of mechanisms by which this may be achieved but, in general, all pathways depend on either the accumulation of cyclic adenosine monophosphate (cAMP) or cyclic guanosine monophosphate (cGMP), or the activation of potassium channels with consequent hyperpolarization of the cellular membrane.

Nitric oxide, produced from its precursor L-arginine by nitric oxide synthase (NOS), appears to exert two effects within the corpora:

  1. Activation of potassium-channel ATPase, resulting in hyperpolarization of the smooth muscle cell membrane. This hyperpolarization prevents the opening of voltage-dependent calcium channels, thereby reducing intracellular calcium.
  2. Activation of guanylate cyclase which catalyzes the conversion of guanosine triphosphate (GTP) to cGMP. This triggers relaxation by lowering intracellular calcium.

Other muscle relaxants act via cAMP-dependent mechanisms and include prostaglandin (PG) E1 and vasoactive intestinal polypeptide (VIP). These substances react with membrane receptors coupled to a G protein which stimulates adenylate cyclase to produce cAMP, thus lowering intracellular calcium. The presence of two distinct and separate pathways to induce intracorporeal vasodilatation is probably a reflection of the importance of the erectile mechanism in the perpetuation of the species.

The breakdown of cGMP, accomplished mainly by phosphodiesterase type 5 (PDE5), raises cytoplasmic free calcium levels and reverses smooth muscle relaxation. Compounds such as papaverine and the recently discovered, more selective, molecule sildenafil inhibit intracorporeal PDE5, thereby increasing the intracellular half-life of cGMP and, thus, promoting and prolonging smooth muscle relaxation and erection.

Regulation Of Intracavernosal Smooth Muscle Contractility

Two principal mechanisms control the tone of penile smooth muscle cells:

  1. Neurogenic control, in which adrenergic, cholinergic and NANC fibers all play a role.
  2. Endothelial control, by neurotransmitter substances released by the endothelium lining the helicine arteries and lacunar spaces.

Adrenergic Vasoconstrictor Mechanisms

Catecholamine-containing adrenergic nerves have been demonstrated in the cavernosal and helicine arteries as well as in cavernosal smooth muscle of humans. Norepinephrine is released from dense-core vesicles of sympathetic nerve terminals to interact with α-adrenoceptors located on cavernosal smooth muscle membranes. The main mediator of penile smooth muscle contraction appears to be the α1-adrenoceptor, all three subtypes (αa1A, α1B and α1D) of which have been detected in the human corpus cavernosum. There is some evidence that the (α1A subtype is functionally predominant. The interaction of norepinephrine with the α1-adrenoceptor results in an increase in intracellular calcium via a guanidine nucleotide-binding protein (G protein) mechanism amplified through inositol phosphate (IP3) and diacylglycerol (DAG) pathways. Sympathetic nerve activity is therefore involved in both inducing detumescence and active maintenance of intracavernosal smooth muscle tone when the penis is in its normal flaccid state. This is the basis for the clinical effectiveness of drugs such as phentolamine (Vasomax®).

Cholinergic Mechanisms

Erection is initiated by increased neural activity in the parasympathetic nerves originating from the S2–S4 spinal segments. The preganglionic neurotransmitter is acetylcholine, but the postganglionic nerve endings mediating vasodilation are NANC. Acetylcholine may, however, modulate noradrenergic vasoconstrictor tone by acting upon prejunctional muscarinic receptors on adjacent sympathetic nerve endings.

Non-Adrenergic Non-Cholinergic Mechanisms

The principal neurotransmitter mediating trabecular smooth muscle relaxation is NANC. Originally, the 28 amino-acid peptide VIP was put forward as the candidate molecule, but it is now recognized that nitric oxide (NO) is the most important molecular mediator of erection. NO synthase is present in the pelvic nerves and in the peripheral autonomic nerve endings innervating the corpora. Release of NO leads to the accumulation of cGMP within trabecular smooth muscle cells and hyperpolarization of the cell membrane. The resultant reduction in intracellular calcium leads to smooth muscle cell relaxation which, as already mentioned, spreads rapidly from cell to cell through so-called gap junctions. Vasodilatory responses are terminated by degradation of cGMP, mainly by the enzyme PDE5.

Endothelial Mechanisms

Endothelium-derived relaxation factors were first described in the rabbit aorta by Furchgott in 1980. A similar mechanism in which lacunar endothelium releases a substance that relaxes trabecular smooth muscle also occurs in the corpora. Again, the main relaxing factor is NO, produced by NO synthase, which exerts an effect by stimulating the activity of guanylate cyclase, resulting in an accumulation of cGMP and a decrease in cytoplasmic free calcium.

Other molecules play a part in tumescence and detumescence, including endothelin-1, which has a powerful vasoconstrictory effect. In contrast, the action of PGE1 is to relax trabecular smooth muscle. Other prostaglandins, such as PGI2, may also play a role in preventing intracorporeal coagulation by their antiplatelet aggregation activity.

hemodynamics of erection

Penile erection is a hemodynamic response to a combination of humoral, neurogenic and local signals. Vasodilatory signaling coincides with reduced vasoconstrictor activity. The result is increased flow through the dilating cavernosal arteries. At the same time, the smooth muscle helicine arteries and lacunar spaces relax, thereby allowing blood to fill the intracorporeal space. Cavernosal filling compresses the obliquely running subtunical venules against the sturdy tunica albuginea, resulting in a hundred-fold increase in resistance to venous outflow. Intracavernosal blood pressure soon rises to approximate that of systolic blood pressure, thereby producing penile erection.

Orgasm And Ejaculation

Orgasm and ejaculation are the result of a sudden increase in sympathetic efferent activity. This has a number of effects: the prostate, seminal vesicles and vasa deferentia contract, emptying their contents into the prostatic urethra. The bladder neck closes tightly to prevent retrograde ejaculation, and the external urethral sphincter relaxes. Semen is ejaculated in a pulsatile fashion as a result of rhythmic contractions of the bulbocavernosus muscles.

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