Clonidine and erectile dysfunction

[Pinkleton]

How can a central a2 agonist like clonidine cause erectile dysfunction? I thought it just reduces sympahetic outflow. I could see it causing an inability to ejaculate, but what's the mechanism for a lack of erection?

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[Phloston]

How can a central a2 agonist like clonidine cause erectile dysfunction? I thought it just reduces sympahetic outflow. I could see it causing an inability to ejaculate, but what's the mechanism for a lack of erection?

I had asked this at one point also but had never found a clear answer.

But here's what I found:

For erection:

J Urol. 1988 Apr;139(4):849-52.
Local suppressive effect of clonidine on penile erection in the dog.
Lin SN, Yu PC, Yang MC, Chang LS, Chiang BN, Kuo JS.
Source
Department of Surgery, Veterans General Hospital, Taipei, Taiwan, Republic of China.
Abstract
Dogs, 8.5 to 10 kg. in weight, were anesthetized with sodium pentobarbital (35 mg./kg.), intraperitoneally. Penile erection as indicated by an increase in the intracorporal pressure (ICP-increase) was produced by electrical stimulation of the right cavernous nerves. Drugs were administered into the internal pudendal artery (IPA) and femoral vein. A low dose (0.2 to 0.4 microgram/kg.) of clonidine, an alpha 2 adrenoceptor agonist, which could not affect either ICP or systemic arterial pressure (SAP) through an intravenous route, did suppress the ICP-increase markedly via direct injection into the IPA which supplies the penile blood flow. By intra-IPA injection, yohimbine (2.5 micrograms/kg.), an alpha 2 adrenoceptor antagonist, remarkably restored the ICP to the erection state. By intravenous injection, clonidine at a dose of 1.6 to 3.2 micrograms/kg. also profoundly reduced the ICP-increase, but only negligibly lowered the SAP. The IPA blood flow (IPAF) decreased coincidentally when the ICP-increase was effectively reduced by either intravenous or intra-IPA injection of clonidine. These findings suggest clonidine could act locally in the penile structure to suppress penile erection, possibly resulting from a penile vasoconstriction involving alpha 2 adrenoceptor. Whether this vasoconstriction is caused by a direct alpha 2 stimulating effect on the vascular smooth muscle or by an alpha 2 presynaptic inhibition of the vasodilator nerve (cavernous nerve) endings has been discussed.

For emission:

Neuroendocrinology. 1990 Mar;51(3):357-64.
Clonidine suppresses copulatory behavior and erectile reflexes in male rats: lack of effect of naloxone pretreatment.
Clark JT, Smith ER.
Source
Department of Physiology, Meharry Medical College, Nashville, Tenn.
Abstract
Adrenergic transmitters and opioid peptides are implicated in the regulation of male sexual behavior. In the present studies we examine a possible interaction between these two neurochemical systems in the regulation of components of male sexual behavior. In mating tests, clonidine (0.25 mg/kg, 6 min pretest) induced a profound deficit in intromissive and ejaculatory behavior whereas naloxone (5 mg/kg, 20 min pretest) evinced a facilitation of ejaculatory behavior, evidenced by decreases in the ejaculation latency in the initial copulatory series and by decreases in ejaculation latency and intercopulatory interval in the second copulatory series. Importantly, prior treatment with naloxone did not prevent or attenuate the copulatory suppression induced by clonidine. In ex copula penile reflex tests, clonidine (0.25 mg/kg, 6 min pretest) decreased the incidence of seminal emission and the number of penile responses (erections, cups and flips). Naloxone (5 mg/kg, 20 min pretest) was without effect on any of the parameters of penile reflex activity and, further, failed to prevent or attenuate the erectile suppression induced by clonidine. A final study evaluated the dose-response relationship of clonidine-induced erectile dysfunction. A similar degree of erectile dysfunction was observed after 0.005, 0.025 or 0.25 mg/kg clonidine, whereas 0.0005 mg/kg was without effect. Previous studies demonstrated a dose-dependent inhibition of mounting, intromissive and ejaculatory behavior, with 0.25 mg/kg selectively eliminating ejaculatory behavior in mating tests. These data demonstrate a dose-dependent inhibition of penile reflexes, with inhibition occurring at doses lower than those required to induce copulatory dysfunction. Further, we suggest that opioid receptors sensitive to naloxone blockade are not involved in the clonidine-induced suppression of copulatory or erectile function.

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Remember that SNS doesn't affect ejaculation. SNS is emission. Somatic is ejaculation.

 

[Pinkleton]

Thanks Phloston for such an elaborate response! So in the CNS clonidine acts presynaptically whereas it can act postsynaptically in the periphery, specifically the corpus cavernosum in this case.

Good call on the ejaculation being a somatic reflex. Forgot about that. The point and shoot mnemonic is not a very good one. It should be point and cock. Pun intended.

 

[Coug42]

If it helps, this is how I remember it:

Yohimbine does the opposite of Clonidine. Yohimbine is a "natural" aphrodisiac or remedy for ED, whch is really debatable, but that's besides the point. So if Clonidine does the opposite, it can increase ED in theory.

Yohimbine is an alpha-2 Antagonist on peripheral POST-synaptic alpha-2 receptors leading to smooth muslce relaxation in corpus cavernosa; it is also an Antagonist of PRE-synaptic alpha-2 receptors in the CNS leading to increased NT release (Dopamine, NO, etc.)

Clonidine does the exact opposite; it's an Agonist mostly in the CNS of PRE-synaptic alpha-2 receptors, decreasing NT release; and can also be an Agonist of peripheral POST-synaptic alpha-2 receptors leading to smooth muscle contraction in the corpus cavernosa --> ED.

Remember Yohimbine, and you'll remember Clonidine or the other way around. It helps me, so I thought I'd share.

 

[Pinkleton]

If it helps, this is how I remember it:

Yohimbine does the opposite of Clonidine. Yohimbine is a "natural" aphrodisiac or remedy for ED, whch is really debatable, but that's besides the point. So if Clonidine does the opposite, it can increase ED in theory.

Yohimbine is an alpha-2 Antagonist on peripheral POST-synaptic alpha-2 receptors leading to smooth muslce relaxation in corpus cavernosa; it is also an Antagonist of PRE-synaptic alpha-2 receptors in the CNS leading to increased NT release (Dopamine, NO, etc.)

Clonidine does the exact opposite; it's an Agonist mostly in the CNS of PRE-synaptic alpha-2 receptors, decreasing NT release; and can also be an Agonist of peripheral POST-synaptic alpha-2 receptors leading to smooth muscle contraction in the corpus cavernosa --> ED.

Remember Yohimbine, and you'll remember Clonidine or the other way around. It helps me, so I thought I'd share.

Nice! That is such a great way to remember it

 

[Phloston]

If it helps, this is how I remember it:

Yohimbine does the opposite of Clonidine. Yohimbine is a "natural" aphrodisiac or remedy for ED, whch is really debatable, but that's besides the point. So if Clonidine does the opposite, it can increase ED in theory.

Yohimbine is an alpha-2 Antagonist on peripheral POST-synaptic alpha-2 receptors leading to smooth muslce relaxation in corpus cavernosa; it is also an Antagonist of PRE-synaptic alpha-2 receptors in the CNS leading to increased NT release (Dopamine, NO, etc.)

Clonidine does the exact opposite; it's an Agonist mostly in the CNS of PRE-synaptic alpha-2 receptors, decreasing NT release; and can also be an Agonist of peripheral POST-synaptic alpha-2 receptors leading to smooth muscle contraction in the corpus cavernosa --> ED.

Remember Yohimbine, and you'll remember Clonidine or the other way around. It helps me, so I thought I'd share.

Solid post.