Regulation of human penile smooth muscle tone by prostanoid receptors

Abstract

We have characterized the prostanoid receptors involved in the regulation of human penile arterial and trabecular smooth muscle tone. Arachidonic acid induced relaxation of human corpus cavernosum strips (HCCS) that was blocked by the cyclo-oxygenase inhibitor, indomethacin, and augmented by the thromboxane receptor (TP) antagonist, SQ29548, suggesting that endogenous production of prostanoids regulates penile smooth muscle tone. TP-receptors mediate contraction of HCCS and penile resistance arteries (HPRA), since the agonist of these receptors, U46619, potently contracted HCCS (EC50 8.3+/-2.8 nM) and HPRA (EC50 6.2+/-2.2 nM), and the contractions produced by prostaglandin F(2alpha) at high concentrations (EC50 6460+/-3220 nM in HCCS and 8900+/-6700 nM in HPRA) were inhibited by the selective TP-receptor antagonist, SQ29548 (0.02 microM). EP-receptors are responsible for prostanoid-induced relaxant effects in HCCS because only prostaglandin E1 (PGE1), prostaglandin E2 and the EP2/EP4-receptor agonist, butaprost, produced consistent relaxation of this tissue (EC50 93.8+/-31.5, 16.3+/-3.8 and 1820+/-1284 nM, respectively). In HPRA, both prostacyclin and PGE1 (EC50 60.1+/-18.4 and 109.0+/-30.9 nM, respectively) as well as the selective IP receptor agonist, cicaprost, and butaprost (EC50 25.2+/-15.2 and 7050+/-6020 nM, respectively) caused relaxation, suggesting co-existence of IP- and EP-receptors (EP2 and/or EP4). In summary, endogenous production of prostanoids may regulate penile smooth muscle contractility by way of specific receptors. TP-receptors mediate contraction in HCCS and HPRA, while the relaxant effects of prostanoids are mediated by EP2- and/or EP4-receptors in HCCS and by EP- and IP-receptors in HPRA.

Figure 1

Effects of the treatment with indomethacin (10 μM) or SQ29548 (0.02 μM) on loss in tone induced by the addition of arachidonic acid (AA; 100 μM) in human trabecular smooth muscle strips contracted with phenylephrine. Data are expressed as mean±s.e.mean of the percentage of total relaxation induced by 0.1 mM papaverine. n indicates the number of patients from whom the tissues were collected for the experiments. ^***Indicates P<0.005 vs control responses by a two-factors ANOVA test.

Figure 2

Contractile responses induced by the thromboxane analogue, U46619, by prostaglandin F_2α (PGF_2α), by the FP receptor agonist, fluprostenol, and by the agonist for EP₁ and EP₃ receptors, sulprostone, in human trabecular smooth muscle strips. Data are expressed as mean±s.e.mean of the percentage of contraction induced by 125 mM K⁺ (KPSS). n indicates the number of patients from whom the tissues were collected for the experiments.

Figure 3

Effects of the treatment with the TP receptor antagonist, SQ29548 (0.02 μM), on the contractile responses elicited by the thromboxane analogue, U46619 (A), by prostaglandin F_2α (PGF_2α) (B), and by the FP receptor agonist, fluprostenol (C), in human trabecular smooth muscle strips. Data are expressed as mean±s.e.mean of the percentage of maximum contraction obtained in absence of SQ29548. n indicates the number of patients from whom the tissues were collected for the experiments. ^***Indicates P<0.005 vs control responses by a two-factors ANOVA test.

Figure 4

Contractile responses induced by the thromboxane analogue, U46619, by prostaglandin F_2α (PGF_2α), by the FP receptor agonist, fluprostenol, and by the agonist for EP₁ and EP₃ receptors, sulprostone, in human penile resistance arteries. Data are expressed as mean±s.e.mean of the percentage of contraction induced by 125 mM K⁺ (KPSS). n indicates the number of patients from whom the tissues were collected for the experiments.

Figure 5

Effects of the treatment with the TP receptor antagonist, SQ29548 (0.02 μM), on the contractile responses elicited by the thromboxane analogue, U46619 (A) and by prostaglandin F_2α (PGF_2α) (B) in human penile resistance arteries. Data are expressed as mean±s.e.mean of the percentage of maximum contraction obtained in absence of SQ29548. n indicates the number of patients from whom the tissues were collected for the experiments. ^***Indicates P<0.005 vs control responses by a two-factors ANOVA test.

Figure 6

Responses elicited by vehicle, prostaglandin D₂ (PGD₂), prostacyclin (PGI₂), prostaglandin E₁ (PGE₁), prostaglandin E₂ (PGE₂) and the selective EP₂ receptor agonist, butaprost, on human trabecular smooth muscle strips contracted with phenylephrine. Data are expressed as mean±s.e.mean of the percentage of total relaxation induced by 0.1 mM papaverine. n indicates the number of patients from whom the tissues were collected for the experiments.

Figure 7

(A) Shows the responses elicited by prostaglandin D₂ (PGD₂), prostacyclin (PGI₂) and prostaglandin E₁ (PGE₁) on human penile resistance arteries contracted with norepinephrine. (B) shows the relaxations induced by the vehicle, by the selective DP receptor agonist, BW245C, by the selective IP receptor agonist, cicaprost and the selective EP₂ receptor agonist, butaprost, on human penile resistance arteries contracted with norepinephrine. Data are expressed as mean±s.e.mean of the percentage of total relaxation induced by 0.1 mM papaverine. n indicates the number of patients from whom the tissues were collected for the experiments.

Figure 8

Cyclic AMP (A) and cyclic GMP (B) tissue content of human corpus cavernosum after exposure to prostaglandin E₁ (PGE₁). Data are expressed as mean±s.e.mean of pmol cyclic AMP or cyclic GMP per mg of tissue protein content. n indicates the number of patients from whom the tissues were collected for the determinations. ^**P<0.01, ^***P<0.005 vs control. (Student-Newmann-Keuls post hoc test).