Female reproductive organs—Animal studies demonstrate a role for PGE2 and PGF2α in early reproductive processes such as ovulation, luteolysis, and fertilization. Uterine muscle is contracted by PGF2α, TXA2, and low concentrations of PGE2; PGI2 and high concentrations of PGE2 cause relaxation. PGF2α, together with oxytocin, is essential for the onset of parturition. PGI2 also assists in promoting uterine smooth muscle cell maturation. The effects of prostaglandins on uterine function are discussed below (see Clinical Pharmacology of Eicosanoids).
2.
Male reproductive organs—Despite the discovery of prostaglandins in seminal fluid, the role of prostaglandins in semen is still conjectural. The major source of these prostaglandins is the seminal vesicle; the prostate, despite the name “prostaglandin,” and the testes synthesize only small amounts. The factors that regulate the concentration of prostaglandins in human seminal plasma are not known in detail, but testosterone does promote prostaglandin production. Thromboxane and leukotrienes have not been found in seminal fluid. Men with a low seminal fluid concentration of prostaglandins are relatively infertile.
Smooth muscle-relaxing prostaglandins such as PGE1 enhance penile erection by relaxing the smooth muscle of the corpora cavernosa (see Clinical Pharmacology of Eicosanoids).
E. Central and Peripheral Nervous Systems 1.
Fever—PGE2 increases body temperature, predominantly via EP3, although EP1 also plays a role, especially when administered directly into the cerebral ventricles. Exogenous PGF2α and PGI2 induce fever, whereas PGD2 and TXA2 do not. Endogenous pyrogens release interleukin-1, which in turn promotes the synthesis and release of PGE2. This synthesis is blocked by aspirin, other antipyretic NSAIDs, and acetaminophen.
2.
Sleep—When infused into the cerebral ventricles, PGD2 induces natural sleep (as determined by electroencephalographic analysis) via activation of DP1 receptors and secondary release of adenosine. PGE2 infusion into the posterior hypothalamus causes wakefulness.
3.
Neurotransmission—PGE compounds inhibit the release of norepinephrine from postganglionic sympathetic nerve endings. Moreover, NSAIDs increase norepinephrine release in vivo, suggesting that the prostaglandins play a physiologic role in this process. Thus, vasoconstriction observed during treatment with COX inhibitors may be due, in part, to increased release of norepinephrine as well as to inhibition of the endothelial synthesis of the vasodilators PGE2 and PGI2. PGE2 and PGI2 sensitize the peripheral nerve endings to painful stimuli. PGE2 acts via EP1 and EP4 receptors to potentiate excitatory cation channel activity and inhibit hyperpolarizing K+ channel activity, thereby increasing membrane excitability. Prostaglandins also modulate pain centrally. Both COX-1 and COX-2 are expressed in the spinal cord and release prostaglandins in response to peripheral pain stimuli. PGE2, and perhaps also PGD2, PGI2, and PGF2α, contribute to so-called central sensitization, an increase in excitability of spinal dorsal horn neurons, that augments pain intensity, widens the area of pain perception, and results in pain from normally innocuous stimuli. PGE2 acts on the EP2 receptor to facilitate presynaptic release of excitatory neurotransmitters and block inhibitory glycinergic neurotransmission as well as postsynaptically to enhance excitatory neurotransmitter receptor activity.
F. Inflammation and Immunity