الفهرس 
REVIEW OF LITERATUREOnly 14 pages are availabe for public view
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Abstract
Prostaglandins play an important role in lower genitourinary tract functions.
< They regulate bladder function, ejaculation and erectile process.
< The current study was conducted to investigate the differentialeffects of some PGs modulators on different tissues of the lower genitourinary tract in rats.
<Isolated rat urinary bladder, prostatic vas deferens and corpus cavernosum were used for in-vitro experiments. The effects of some PGs modulators (agonists, antagonists), and COX inhibitors on EFSand ACh or PE-induced reactivities were studied.
< The study also compared the potential deleterious effects of some nonselective COX inhibitors and selective COX-2 inhibitor on detrusor muscles in normal rat and in those suffering from CYP-induced hemorrhagic cystitis. Moreover, interaction between some effective PGs analogues and NO/cGMP pathway was also investigated.First, rat urinary bladder detrusor muscles-Alprostadil (synthetic PGE) and iloprost (PGIanalogue) potentiated both ACh and EFS-induced contraction of rat detrusor muscles.
Alprostadil showed higher degree of potentiation than iloprost. Both showed higherpotentiation of cholinergic-mediated contraction than neuronally-mediated one, indicating a greater extent of interaction between EP,EPand IPreceptors pathways and the similar Gq-coupled muscarinic receptors (Mand M). -Blocking of either EPreceptors by (SC51322) or IPreceptors by (RO118452) produced significant inhibition of AChand EFS-induced contraction.
< Blockade of IPreceptors lowered the potency of ACh on detrusor muscles with higher degree of inhibition at low frequencies. IPreceptor blocker increased logECvalue of ACh from -4.03±0.08 to -3.60±0.07,while EPblocker increased it to only -3.88±0.10, indicating a greater contribution for IPreceptors in the bladder physiology than EP.
<The potentiatory effect of alprostadil was significantly inhibited in presence of the PDE-5 inhibitor-sildenafil-indicating that PGEpathway may have a crosstalk with NO/cGMP pathway. Elevated level of cGMP by sildenafilinhibitsthe activity of PLC involved in the pathway ofalprostadil indetrusor muscles.-Nonselective COX inhibitors-indomethacin, ketoprofen and diclofenac-decreasedthe detrusor muscle activity as they inhibited both its cholinergic and neuronally-mediated contractions. Diclofenac was the most potentfollowed by indomethacin then ketoprofen.
This deleterious effect may be COX-1 dependent, as the highly selective COX-2 inhibitor (DFU) did not significantly affect detrusor muscle contractility.
<The inhibitory effect of indomethacin was significantly lowered in presence of atropine confirming the participation of muscarinic receptors (M) in urothelium involvedin the cholinergic activity of the bladder with its associated induction of the synthesis and releaseof the contractile PGs such as PGEfrom the urothelium.
<So, when indomethacin inhibits the synthesis of PGEin urothelium, a part of the cholinergic activity is lost.-Cyclophosphamide-injectioninduced hemorrhagic cystitis in rats. Histopathological examination showed high degree of inflammation, hemorrhage and edema, mild ulceration and urothelial proliferation in urinary bladder. Moreover, CYP-induced hemorrhagic.
Summary and Conclusionscystitis was found to be associated withhypoactivity of detrusor muscles, as the cholinergic (ACh) and neuronally (EFS)-mediated contractions were lowered by almost 60% and 75% respectivelycompared to control.
Such deleterious effect may be attributed to the reduction of PGErelease as a consequence of increased Mreceptors expression and NO release from urothelium as well as increased COX-2 isoenzyme expression which is responsible for the synthesis of the pro-inflammatory PGs. -In CYP-injected rats, the effect of alprostadil on detrusor muscles contraction was not different from control. Iloprost produced significantly less potentiation of ACh-induced contraction in cystitis compared to control.
Blocking of IPreceptors but not EPproduced significantly less inhibition of ACh-induced contraction in cystitis compared to control. On the other hand, although selective DPreceptor blocker (ONO-AE3-237) showed no significant effect on detrusor contractility in control, it potentiated both ACh and EFS-induced contraction in cystitis, suggesting that DPreceptors may be involved in the pathogenesis of CYP-induced hemorrhagic cystitis.-Cyclophosphamide-induced cystitis decreased the inhibitory effect of the nonselective COX inhibitors (indomethacin, ketoprofen and diclofenac) on ACh-induced contraction.
Such effect is not altered by atropine.
This effect may be attributed to the diminished release of PGEfrom urothelium as a result of increased NO synthesis.
The slight inhibition remained may be due to other mechanisms such as; inhibition of the release of ACh and ATP themselvesfrom urothelium and increased activity of acetylcholinesterase. Also, COX-2 inducible expression in cystitis may contribute to the noticeable damage as inhibiting its synthesis by selective COX-2 inhibitor (DFU)potentiatedthe contractile response of ACh. -Cyclophosphamide-induced cystitis potentiated the inhibitory effect of the nonselective COX inhibitors, especially indomethacin, on neuronally-mediated contraction compared to control rats, suggesting that this effect may be due to inhibition of the synthesis of contractile PGs which seem to have greater contribution to EFS-induced contraction in cystitis.
Second, rat prostatic vas deferens-Neither alprostadilnor iloprost significantly affected PE or EFS-induced contraction of prostatic vas deferens. -In contrast, indomethacin and diclofenac but not ketoprofen inhibited both PE and EFS-induced contractions in prostatic vas deferens probably by modulating Catransduction rather than by COX inhibition. -Under normal physiological conditions, prostatic vas deferens was the only responsive tissue to the effect of selective COX-inhibitor. DFUpotentiated PE-induced contraction of prostatic vas deferens.
However, it did not significantly affect neuronally-mediated one.
This could be explained by the fact that COX-2 isoenzyme is constitutively expressed in prostatic vas deferens under normal physiology.
Summary and ConclusionsThird, rat corpus cavernosum-Alprostadil, iloprost and selective EPagonist (L902688) showed concentration-dependent relaxation ofrat corpus cavernosum.
The later was proved to be the most potent relaxant among them indicating more participation of EPreceptors in erectile process. In contrast to EPagonist, the relaxant effect of alprostadil and iloprost was potentiated in presence of PDE-5 inhibitor and both potentiated EFS-induced relaxation suggesting that therelaxant pathwaysof alprostadil and iloprost but not EPagonistmay have a crosstalk with NO/cGMP pathway.
This could be explained by the enhanced activity of both PKG by sildenafil and PKA by alprostadil and iloprost which in turnactivate each other. -Selective COX-2 inhibitor (DFU) did not show any significant effect on corpus cavernosal relaxation. On the other hand, nonselective COX inhibitors potentiated the neuronal (EFS) and endothelial (ACh)-dependent relaxation of rat corpus cavernosum.
Indomethacin and ketoprofen did not potentiate SNP-induced relaxation suggesting that they may not have a direct interaction with NO/cGMP pathway.
The potentiatory effect may probably be mediated by inhibiting the synthesis of TXAwhich in turnlowers NO availability. This suggestion was confirmed by the masked potentiatory effect of indomethacin in presence of the TXAreceptor blocker (GR32191B).
Diclofenac was the only member which potentiated SNP-induced relaxation suggesting a direct interaction for the drug with NO/cGMP pathway. Conclusions and possible clinical implicationsfrom the current study, it can be concluded that: Prostaglandins by acting on specific PGs receptors in the rat urinary bladder detrusor muscles, corpus cavernosum and prostatic vas deferens were found to play an important role in lower genitourinarytract functions including; micturition, erection and to a lesser extent in ejaculation.
Both alprostadil and iloprost were more effective on rat corpus cavernosum than detrusor muscle, and they showed no important role in prostatic vas deferens contractility. Urinary bladder detrusor muscle was the most sensitive tissue to the effect of COX inhibitors. Nonselective COX inhibitors (indomethacin, ketoprofen and diclofenac) significantly inhibited detrusor muscle contractility through a COX-1 dependent pathway by inhibiting the synthesis and release of the contractile PGs as PGEfrom the urothelium which is a part of the cholinergic activity mediated via M-receptors activation. This inhibitory effect may contribute to the side effects of NSAIDson urinary bladder. Under normal physiological conditions, prostatic vas deferens was the only responsive tissue to the effect of selective COX-2 inhibitor among the tissues of genitourinary system studied. It potentiated adrenergic response of the prostatic vasdeferens through inhibition of COX-2 isoenzyme constitutively expressed in prostatic vas deferens with no significant effect on neuronally-mediated contraction.
Summary and ConclusionsCyclophosphamide-induced hemorrhagic cystitis in rats was associated with induced expression of COX-2 isoenzyme responsible for the synthesis of the pro-inflammatory PGs. Inhibiting COX-2 synthesis by DFU significantly potentiated the contractile response of ACh. Therefore, selective COX-2 inhibitors may be beneficial in improving detrusor muscle reactivity in patients with cystitis, while nonselective COX inhibitors may cause further worsening of the condition.
DPreceptors may have a role in the pathogenesis of CYP-induced cystitis, sotheir blockade may be beneficial in such condition.
EPreceptors may play an important role in erectile process.
Theiractivation could be implicated in mediating the relaxant effect of PGs in corpus cavernosum. Clinically, alprostadil is already used for management of erectile dysfunction and its combinationwith sildenafil is proved to be effective.
So, the use of EPagonist and iloprost as well as the combination of iloprost with sildenafil could be promising in this respect and worth further investigation. Alprostadil may also be beneficial particularly in patients suffering from bladder hypoactivity in addition to erectile dysfunction, as it may improve detrusor muscle reactivity as well.
Cyclooxygenase-1 isoenzyme is involved in erectile process, as nonselective COX inhibitors potentiated both the neuronal and endothelial-mediated relaxation. In contrast, selective COX-2 inhibitor may have no significant effect on erectile function.So, the use of COX inhibitors may be safe in patients suffering from erectile dysfunction.
The use of selective COX-2 inhibitor as well as ketoprofen may be appropriate in treating inflammatory conditions without affecting ejaculatory function. In contrast, indomethacin and diclofenac may not be recommended in patients with normal ejaculatory