共查询到20条相似文献,搜索用时 15 毫秒
1.
Ghasemi M Sadeghipour H Mani AR Tavakoli S Hajrasouliha AR Ebrahimi F Dehpour AR 《European journal of pharmacology》2006,544(1-3):138-145
The purpose of this study was to investigate the effect of the endogenous cannabinoid anandamide on the nonadrenergic noncholinergic (NANC) relaxant responses to electrical field stimulation in isolated rat corpus cavernosum. The corporal strips were mounted under tension in a standard oxygenated organ bath with guanethidine sulfate (5 microM) and atropine (1 microM) (to produce adrenergic and cholinergic blockade). The strips were precontracted with phenylephrine hydrochloride (7.5 microM) and electrical field stimulation was applied at different frequencies to obtain NANC-mediated relaxation. The expression of CB1, CB2 and vanilloid receptor proteins within the rat corpus cavernosum was evaluated using western blot analysis. The results showed that the relaxant responses to electrical stimulation were significantly enhanced in the presence of anandamide at 1 and 3 microM. The potentiating effect of anandamide (1 microM) on relaxation responses was significantly attenuated by either the selective cannabinoid CB1 receptor antagonist N-(piperidin-1-yl)-5-(4-iodophenyl)-1-(2, 4-dichlorophenyl)-4-methyl-1H-pyrazole-3-carboxamide (AM251; 1 microM) or the vanilloid receptor antagonist capsazepine (3 microM), but not by the selective cannabinoid CB2 receptor antagonist 6-iodo-2-methyl-1-[2-(4-morpholinyl) ethyl]-1H-indol-3-yl (4-methoxyphenyl)methanone (AM630; 1 microM). Neither of these antagonists had influence on relaxation responses. Indomethacin (20 microM) had no effect on NANC-mediated relaxation in the presence or absence of anandamide (1 microM). Preincubation with Nw-Nitro-L-Arginine Methyl Ester (L-NAME; 1 microM) significantly inhibited the relaxation responses in the presence or absence of 1 microM anandamide. Although at 30 nM, L-NAME did not cause a significant inhibition of relaxant responses individually, it significantly inhibited the potentiating effect of anandamide (1 microM) on relaxation responses. Anandamide (1 microM) had no influence on concentration-dependent relaxant responses to sodium nitroprusside (10 nM-1 mM), a nitric oxide (NO) donor. The western blotting of corporal tissues demonstrated the existence of both vanilloid and CB1 receptors in corporal strips. In conclusion, our results showed that anandamide has a potentiating effect on NANC-mediated relaxation of rat corpus cavernosum through both CB1 and vanilloid receptors and the NO-mediated component of the NANC relaxant responses to electrical stimulation is involved in this enhancement. 相似文献
2.
Changes in nonadrenergic noncholinergic (NANC)-mediated relaxation of the anococcygeus muscle have been demonstrated in cholestasis. Cholestasis is also associated with accumulation of endogenous opioid peptides and nitric oxide (NO) overproduction. This study was therefore undertaken to investigate the effect of cholestasis on the NANC-mediated relaxation of corpus cavernosum in bile duct-ligated rats and to examine the possible roles of the opioid system and nitric oxide in the cholestasis-associated alterations of corpus relaxation. Bile duct-ligated and sham-operated rats were treated for 2 weeks with either normal saline, N (omega)-nitro L-arginine methylester (L-NAME) (3 mg/kg/day, i.p.) or naltrexone (20 mg/kg/day, i.p.). On the 14th day, the strips of corpus cavernosum were mounted under tension in a standard oxygenated organ bath with guanethidine sulfate (5 microM) and atropine sulfate (1 microM) (to produce adrenergic and cholinergic blockade). The strips were precontracted with phenylephrine hydrochloride (7.5 microM) and electrical field stimulation was applied at different frequencies to obtain NANC-mediated frequency-dependent relaxant responses. The results showed that the amplitudes of relaxation responses at each frequency in bile duct-ligated rats were greater than the responses of sham-operated animals. This increase in relaxation responses in bile duct-ligated rats was inhibited by chronic L-NAME administration for 2 weeks so it seemed that it might be due to the nitric oxide overproduction in cholestatic states. Chronic administration of naltrexone for 2 weeks to bile duct-ligated rats had the same inhibitory effect on the relaxation responses. Our results demonstrated that in cholestasis, there was an increase in NANC-mediated relaxation of corpus cavernosum and both opioid and nitric oxide systems were involved in this increase. 相似文献
3.
Dehghani M Sadeghipour H Shafaroodi H Honar H Riazi K Ebrahimkhani MR Hajrasouliha AR Tavakoli S Dehpour AR 《European journal of pharmacology》2004,496(1-3):181-187
The endothelium-dependent relaxation of corpus cavernosum smooth muscle and the roles of nitric oxide (NO) and arachidonic acid products of cyclooxygenase were investigated in non-operated, SHAM-operated, and bile duct-ligated rats. We further investigated the time-dependent alterations of corpus cavernosum relaxation in 2-, 7-, and 14-day bile duct-ligated animals. Acetylcholine produced concentration-dependent relaxation in phenylephrine-precontracted strips of corpus cavernosum. A significant reduction in the acetylcholine-induced relaxation was observed 2 days after bile duct ligation, and a greater reduction was observed on subsequent days. Incubation with 20 microM indomethacin reduced the acetylcholine-induced relaxation of the corpus cavernosum of unoperated rats while it had no effect in the corpus cavernosum of bile duct-ligated rats. Chronic treatment with Nomega-Nitro-L-Arginine Methyl Ester (L-NAME, 3 mg/kg/day, intraperitoneally) reduced the relaxation responses in the unoperated group while it had no effect in the bile duct-ligated group. These results show that acetylcholine-induced corporal relaxation is impaired in cholestatic rats, and this may be related to deficient nitric oxide production by the endothelium. The involvement of prostaglandins in this impairment seems unlikely. 相似文献
4.
Dehpour AR Seyyedi A Rastegar H Namiranian K Moezi L Sadeghipour H Dehghani M Jorjani M Roushanzamir F Ahmadiani A 《European journal of pharmacology》2002,445(1-2):31-36
Previous studies have shown the naloxone-induced withdrawal syndrome and the development of tolerance in the tissues of cholestatic animals. Increased neuronal nitric oxide synthase (nNOS) expression is reported to exist in morphine-tolerant animals. This, together with evidence for nitric oxide (NO) overproduction in cholestasis, suggested the possibility of an alteration of nonadrenergic noncholinergic (NANC) relaxation of anococcygeus muscles of cholestatic rats. To study this, we used three main groups of animals: unoperated, sham-operated and bile duct-ligated. Electrical field stimulation, in the presence of atropine and guanethidine, caused NANC relaxation in the anococcygeus muscle which was enhanced in bile duct-ligated animals. N(G)-nitro-L-arginine methyl ester (L-NAME), a NOS blocker, caused a dose-dependent inhibition of the NANC relaxation. The IC(50)'s of L-NAME in 7-day (7.30+/-0.87 microM), 14-day (6.98+/-0.70 microM) and 21-day (8.25+/-1.40 microM) bile duct-ligated groups were significantly different from those of unoperated (1.69+/-0.30 microM) and sham-operated groups (1.90+/-0.27 microM). L-NAME (100 microM) completely inhibited the NANC relaxation response, suggesting that NANC relaxation in the rat anococcygeus muscle is mediated mainly via NO. The contraction response of the intact muscle to phenylephrine, an alpha(1)-adrenoceptor agonist, and the relaxation response of the phenylephrine-contracted muscle to sodium nitroprusside, an NO donor, were not different in unoperated, sham-operated and 7-day bile duct-ligated groups. These results showed that the smooth muscle component of NANC relaxation is not altered in anococcygeus muscles of bile duct-ligated rats. It can thus be concluded that the NANC relaxation in the anococcygeus of cholestatic rats is more resistant to a NOS blocker, providing evidence for increased nitrergic neurotransmission in the anococcygeus muscles of cholestatic rats. 相似文献
5.
Relaxation of corpus cavernosum during penile erection is mediated by a non-adrenergic non-cholinergic (NANC) neurotransmission and by the endothelium via the release of nitric oxide. Hydrogen sulfide (H(2)S) is an endogenous gaseous mediator which is a potent vasodilator and a neurotransmitter. This study was initiated to characterize the role of H(2)S in NANC neurogenic transmission in rat corpus cavernosum. The expression of H(2)S producing enzymes was assessed using RT-PCR as well as Western blotting and showed the expression of cystathionine γ-lyase (CSE) in rat corporal tissue. Homogenates from rat corpus cavernosum convert l-cysteine to H(2)S and this was partially inhibited by a CSE inhibitor, propargylglycine. Electrical stimulation of corporal tissue strips caused NANC relaxation. This neurogenic relaxation was significantly enhanced by inhibition of CSE by propargylglycine indicating that endogenously produced H(2)S may have a negative regulatory role in neurogenic relaxation of rat corpus cavernosum. To investigate this further we used physiologically relevant concentrations of exogenous NaHS, and showed that nanomolar concentrations could inhibit corporal relaxation induced by a nitroxyl (HNO) donor (Angeli's salt) but not with nitrosonium (NO(+)) or NO donors. This suggests that an interaction between endogenously produced H(2)S and nitroxyl (HNO) might be involved in erectile function. 相似文献
6.
1. We investigated the effects of chronic pravastatin treatment on the impaired endothelium-dependent relaxation seen in aortae from established streptozotocin (STZ)-induced diabetic rats. Starting at 6 weeks of diabetes, pravastatin (10 mg kg(-1)) was administered to STZ-induced diabetic rats for 4 weeks. 2. The increased total cholesterol and low-density lipoprotein (LDL) cholesterol levels seen in STZ-induced diabetic rats were not restored to normal by pravastatin. Aortae from pravastatin-treated diabetic rats did not show an impaired endothelium-dependent relaxation to acetylcholine. The expression of the mRNA for endothelial nitric oxide synthase was unaffected by diabetes or pravastatin. 3. The enhanced level of malondialdehyde (MDA)-modified LDL seen in STZ-induced diabetic rats was normalized by pravastatin treatment. The resistance of LDL to oxidation was assessed by measuring the amount of MDA or conjugated dienes generated by incubation with copper ions. LDL isolated from diabetic rats, but not those from pravastatin-treated diabetics, showed enhanced the susceptibility to oxidation, but incubation in vitro with pravastatin had no effect on LDL oxidation. 4. Following incubation of control aortae for 6 h with LDL (0.1 mg protein ml(-1)) isolated from diabetic rats, the endothelium-dependent relaxation to acetylcholine or A23187 was impaired, but LDL isolated from control or pravastatin-treated rats had no such effect. This inhibitory effect of diabetic LDL was prevented by superoxide dismutase (SOD), a superoxide scavenger. 5. These results suggest that pravastatin preserves endothelial function in aortae from STZ-induced diabetic rats without lowering plasma cholesterol, and its effect may be due to decreased LDL oxidation. 相似文献
7.
Ghasemi M Sadeghipour H Shafaroodi H Nezami BG Gholipour T Hajrasouliha AR Tavakoli S Nobakht M Moore KP Mani AR Dehpour AR 《British journal of pharmacology》2007,151(5):591-601
BACKGROUND AND PURPOSE: Relaxation of corpus cavernosum, which is mediated by nitric oxide (NO) released from non-adrenergic non-cholinergic (NANC) neurotransmission, is critical for inducing penile erection and can be affected by many pathophysiological conditions. However, the peripheral effect of liver cirrhosis on erectile function is as yet unknown. The aim of the present study was to investigate the effect of biliary cirrhosis on NANC-mediated relaxation of rat corpus cavernosum and the possible roles of endocannabinoid and nitric oxide systems in this model. EXPERIMENTAL APPROACH: Cirrhosis was induced by bile duct ligation. Controls underwent sham operation. Four weeks later, strips of corpus cavernosum were mounted in a standard organ bath and NANC-mediated relaxations were obtained by applying electrical field stimulation. KEY RESULTS: The NANC-mediated relaxation was enhanced in corporal strips from cirrhotic animals. Anandamide potentiated the relaxations in both groups. Either AM251 (CB(1) antagonist) or capsazepine (vanilloid VR(1) antagonist), but not AM630 (CB(2) antagonist), prevented the enhanced relaxations of cirrhotic strips. Either the non-selective NOS inhibitor L-NAME or the selective neuronal NOS inhibitor L-NPA inhibited relaxations in both groups, but cirrhotic groups were more resistant to the inhibitory effects of these agents. Relaxations to sodium nitroprusside (NO donor) were similar in tissues from the two groups. CONCLUSIONS AND IMPLICATIONS: Cirrhosis potentiates the neurogenic relaxation of rat corpus cavernosum probably via the NO pathway and involving cannabinoid CB(1) and vanilloid VR(1) receptors. 相似文献
8.
Pharmacological characterization of rabbit corpus cavernosum relaxation mediated by the tissue kallikrein-kinin system. 总被引:1,自引:0,他引:1
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R A Lopes-Martins E Antunes M L Oliva C A Sampaio J Burton G de Nucci 《British journal of pharmacology》1994,113(1):81-86
1. The roles of the tissue kallikrein-kinin system and nitric oxide (NO) release in Phoneutria nigriventer venom-induced relaxations of rabbit corpus cavernosum (RbCC) smooth muscle have been investigated by use of a bioassay cascade. 2. Phoneutria nigriventer venom (10-30 micrograms), porcine pancreatic kallikrein (100 mu), rabbit urinary kallikrein (10 mu), bradykinin (BK, 0.3-3 nmol), acetylcholine (ACh, 0.3-30 nmol) and glyceryl trinitrate (GTN, 0.5-10 nmol) caused relaxations of the RbCC strips. Captopril (1 microM) substantially potentiated Phoneutria nigriventer venom- and BK-induced RbCC relaxations without affecting those elicited by GTN. 3. The bradykinin B2 receptor antagonist, Hoe 140 (D-Arg-[Hyp3,Thi5,D- Tic7,Oic8]-BK, 50 nM), aprotinin (10 micrograms ml-1) and the tissue kallikrein inhibitor, Pro-Phe-Aph-Ser-Val- Gln-NH2 (KIZD-06, 1.3 microM) significantly inhibited Phoneutria nigriventer venom-induced RbCC relaxations, without affecting those provoked by GTN and ACh. The B1 receptor antagonist, [Leu9]des Arg10BK (0.5 microM) and soybean trypsin inhibitor (SBTI, 10 micrograms ml-1) had no effect on Phoneutria nigriventer venom-induced RbCC relaxations. 4. The relaxations induced by Phoneutria nigriventer venom, porcine pancreas kallikrein, BK and ACh were significantly inhibited by N omega-nitro-L-arginine methyl ester (L-NAME, 10 microM) but not by D-NAME (10 microM). L-NAME did not affect GTN-induced relaxations. L-Arginine (300 microM), but not D-arginine (300 microM), significantly reversed the inhibitory effect of L-NAME. 5. Our results indicate that Phoneutria nigriventer venom activates the tissue kallikrein-kininogen-kinin system in RbCC strips leading to NO release and suggest a functional role for this system in penile erection. 相似文献
9.
The presence of neuronal nicotinic acetylcholine receptors in rabbit corpus cavernosum tissue and possible mechanisms underlying the potentiation of electrical field stimulation induced relaxation by nicotine were analyzed. In corpus cavernosum tissue strips nicotine (3 x 10(-5) M) and acetylcholine (10(-3) M) produced potentiation on electrical field stimulation (amplitude 50 V; frequency 4 Hz; width 0.8 ms) induced relaxation responses. This nicotine-induced potentiation was not altered by atropine (10(-6) M), guanethidine (5 x 10(-6) M) and indomethacin (10(-5) M), but abolished by hexamethonium chloride (10(-5) M) and L-nitro arginine methyl ester (10(-5) M). Nicotine did not cause any alteration on a single dose of carbachol (3 x 10(-5) M) and sodium nitroprusside (10(-5) M) induced relaxation responses. The results suggest that, nicotine-induced potentiation is NO and nicotinic acetylcholine receptor dependent but independent from prostaglandin synthesis, activation of muscarinic receptors and does not require intact adrenergic neurons. Nicotine did not affect smooth muscle and endothelium directly. In conclusion, in this study we showed for the first time that, nicotine acts on the nicotinic acetylcholine receptors located on the nitrergic nerves, thereby evoking the release of NO from these nerve terminals inducing relaxation response in rabbit corpus cavernosum tissue. 相似文献
10.
We investigated whether Cd2+ intake (in drinking water, 15 ppm) for 30 days can affect the nitrergic relaxations of the mouse corpus cavernosum (CC) and whether Zn2+ (25 mg kg(-1) via a stomach tube at 48-h intervals) or sodium selenate (8 microg kg(-1) day(-1) intraperitoneally) has a restorative action on the impairment in the response. Relaxant responses of the CC obtained from Cd2+-treated mice to electrical field stimulation (neurogenic) or acetylcholine (endothelium dependent) were significantly inhibited. A partial restoration was observed in the nitrergic relaxation of the CC obtained from Zn2+- or sodium selenate-co-treated animals. Neither agent exhibited any significant action on the responses of the tissue from control mice. There was no significant difference between Cd2+-treated and control mice in respect of the relaxation amplitude induced by sodium nitroprusside or papaverine. These results suggest that Cd2+ intake may impair the nitrergic relaxation of the mouse CC, and, co-treatment with Zn2+ or sodium selenate may partially improve the nitrergic mechanisms in the tissue. 相似文献
11.
We investigated whether bacterial lipopolysaccharide treatment causes any neuronal and vascular hyporeactivity in mouse cavernous tissue and also whether melatonin has any restorative effect on this possible neuronal and vascular hyporesponsiveness. Lipopolysaccharide treatment attenuated contractions in response to phenylephrine. Treatment with the inducible nitric oxide synthase inhibitor aminoguanidine or melatonin restored the hypocontractility of the cavernous smooth muscle to phenylephrine. Relaxant responses of corpus cavernosum precontracted by phenylephrine to acetylcholine or electrical field stimulation were significantly impaired in mice treated with bacterial lipopolysaccharide. Treatment with aminoguanidine or melatonin could prevent the impairment of the neuronal and endothelial relaxations. There was no significant difference between control and lipopolysaccharide-treated groups in the contractile response to high-dose KCl and in the relaxant response to papaverine. In conclusion, bacterial lipopolysaccharide treatment caused a neuronal and endothelial dysfunction in the mouse corpus cavernosum. A possible increased oxidative activity in the cavernous tissue may be a major reason for the impairment of relaxant responses and hypocontracility of tissue. The restorative effects of melatonin on this hyporeactivity may depend on its antioxidant properties and partly on its inhibitory action on the inducible nitric oxide synthase production. 相似文献
12.
Enzyme activities of the nitric oxide-cGMP pathway in corpus cavernosum isolated from middle-aged rats 总被引:2,自引:0,他引:2
Cyclic guanosine-3',5'-monophosphate (cGMP)-mediated mechanisms play an important role in vasodilation and blood pressure regulation. We investigated basal activity of the nitric oxide (NO)-cGMP signal transduction pathway in corpus cavernosum from both middle-aged and young rats, and the electrical field stimulation-induced relaxation in the organ was also evaluated. In middle-aged rats, nitric oxide synthase (NOS) and cGMP-phosphodiesterase activities were significantly decreased; however, guanylate cyclase activity was similar. cGMP concentration, a secondary messenger of NO, remained almost the same level as compared with young rats. These results suggest that decrease in cGMP-phosphodiesterase activity is likely to account for the maintenance of cGMP concentration. In isolated corpus cavernosum from middle-aged rats, electrical field stimulation-induced relaxation was partially impaired. These results suggest that downregulation of the NOS and cGMP-phosphodiesterase activities are early events in the pathogenesis of erectile dysfunction. 相似文献
13.
André E Malheiros A Cechinel-Filho V Yunes RA Calixto JB 《Journal of cardiovascular pharmacology》2003,41(2):300-306
This study examines the relaxation produced by the sesquiterpene polygodial and compares its action with those caused by acetylcholine (ACh) and sodium nitroprusside (SNP) in the rabbit corpus cavernosum (RbCC) in vitro. RbCC was set up in a 5-ml bath containing Krebs solution at 37 degrees C, at pH 7.2, and under 2 g of tension. Polygodial, ACh, and SNP elicited graded relaxation in RbCC with mean EC50 values of 46.70 microM, 0.38 microM, and 0.30 microM, respectively. The nitric oxide (NO) synthase inhibitor L-NOARG and the guanylate cyclase inhibitors LY 83583 and ODQ markedly inhibited the relaxation induced by polygodial (% of inhibition of 79, 48, and 51, respectively) and those caused by ACh (% of inhibition of 100, 49, and 32, respectively). Tetraethylammonium (TEA) and glibenclamide inhibited the relaxation induced by polygodial (52% and 43%, respectively), but only TEA caused shift to the right on ACh-mediated relaxation. In contrast, apamin, charybdotoxin, and 4-aminopyridine or the protein kinase A inhibitor KT 5720 all failed to affect either polygodial or ACh-mediated relaxation in these preparations. The authors concluded that polygodial produced graded relaxation in the RbCC in vitro via a mechanism that was partially dependent on the release of NO or a NO-derived substance through an activation of guanylate cyclase but was independent of adenylate cyclase mechanism. In addition, the opening of K+ channels sensitive to TEA and glibenclamide, but not those sensitive to apamin, 4-aminopyridine, or charybdotoxin, also contributed to the relaxant action produced by polygodial in the RbCC. 相似文献
14.
This study was designed to examine the pharmacological properties of evodiamine in isolated rabbit corpus cavernosum. In phenylephrine-precontracted cavernosal strips, evodiamine (0.01-10 microM) induced a concentration-dependent relaxation. Endothelium removal, N(G)-nitro-L-arginine methyl ester (L-NAME), or 1-H-[1,2,4]oxadiazolo [4,3-alpha] quinoxalin-1-one (ODQ) treatment did not affect this effect. In endothelium-denuded preparations, evodiamine-evoked response was significantly reduced in 60 mM KCl-precontracted strips and by charybdotoxin treatment, but not by glibenclamide. Higher-concentration evodiamine (> or =10 microM)-induced relaxation was also accompanied by an increase in cAMP and cGMP levels, but this effect was not affected by cis-N-(2-phenylcyclopentyl)-azacyclotridec-1-en-2-amine mono-hydrochloride (MDL-12,330A, an adenylyl cyclase inhibitor) or ODQ (a guanylyl cyclase inhibitor), respectively. Evodiamine significantly augmented both the corporal relaxation and the accumulation of cyclic nucleotides to sodium nitroprusside and forskolin, respectively. Evodiamine also enhanced electrical field stimulation-evoked relaxation, and this additive effect was significantly counteracted by zaprinast. In preparations obtained from aged rabbits, evodiamine still elicited complete relaxation; in contrast, acetylcholine- and sodium nitroprusside-evoked maximal response was significantly blunted. In summary, evodiamine possesses a potent corporal relaxing effect which is attributable to endothelium-independent properties probably linked to charybdotoxin-sensitive K(+) channel activation in the cavernosal vasculature and by nonselective interfering phosphodiesterase to prevent cyclic nucleotide degradation. Furthermore, the physiological effects of evodiamine on the aged animals may implicate a potential for the treatment of erectile dysfunction. 相似文献
15.
Göçmen C Seçilmiş A Kumcu EK Ertuğ PU Onder S Dikmen A Baysal F 《European journal of pharmacology》2000,406(1):93-98
The 5-?4-[4-(diethylamino)butyl]-1-piperidinyl?acetyl-5H-dibenz[b, f]-azepine (MF 10058) is a new potent and selective muscarinic M(2) receptor antagonist. The hemodynamic effects of MF 10058 were investigated in conscious freely moving dogs. Placebo and three doses of MF 10058 (2, 4 and 8 mg/kg) were orally administered according to a randomised four-way crossover design. Heart rate, cardiac conduction times, systolic and diastolic blood pressure were telemetrically recorded for 12-24 h after dosing. After placebo administration, a consistent reduction over time in heart rate was observed during the night-time period (-15%, P=0.019). MF 10058 administration antagonised the nocturnal bradycardia and shortened QT interval. The effect of the drug reached statistically significance, compared to placebo, with the highest dose of 8 mg/kg (+19% on heart rate, P=0.013; -4% on QT interval, P=0.049). The effect on heart rate lasted for the entire 24-h observation period (+16%, P=0.030). Nocturnal systolic and diastolic blood pressure were not significantly affected by MF 10058. No other signs of peripheral or central cholinergic block were observed at any dose. The results of this study demonstrated that oral administration of MF 10058 produces long-lasting hemodynamic effects in the conscious dog. The drug has a therapeutic potential for the treatment of bradycardic disorders. 相似文献
16.
Nitric oxide (NO)-mediated responses were investigated in corpora cavernosa isolated from 8-week diabetic rats. Relaxations to field stimulation were abolished by N(G)-nitro-L-arginine (NOARG, 100 microM). Responses to stimulation and sodium nitroprusside were reduced in tissues from diabetic rats compared to control rats, when data were expressed as g tension, but not when expressed as g/g tissue. The endothelium-dependent vasodilator, acetylcholine, failed to relax tissues. Stimulation-induced contractions were smaller in the diabetic group compared to the control group when data were expressed as g tension, but not g/g tissue. Contractions were enhanced by NOARG, and inhibited by acetylcholine (300 microM), by a similar degree in both groups. NOARG reduced the inhibitory effect of acetylcholine in tissues from control, but not diabetic rats. The results suggest diabetes caused a general impairment in responsiveness of rat corpus cavernosum, which may be a consequence of tissue weight change. A role for endothelium-dependent NO could not be identified; however, NO-mediated modulation of noradrenergic transmission by acetylcholine, may be defective in diabetes. 相似文献
17.
Altered relaxant responses to adenosine and adenosine 5'-triphosphate in the corpus cavernosum from men and rats with diabetes 总被引:1,自引:0,他引:1
The present study was aimed at investigating the effects of diabetes on the cavernosal smooth muscle relaxations mediated by adenosine and adenosine triphosphate (ATP) in tissues obtained from men and rats. Adenosine- and ATP-induced relaxant responses showed an enhanced sensitivity with an unaltered effectiveness in diabetic men. Adenosine-elicited relaxation in diabetic rat corporeal tissues exhibited enhanced effectiveness with unaltered sensitivity, whereas ATP-induced relaxations were decreased in diabetic animals when compared to control animals. Tetraethylammonium pretreatment, but not glibenclamide, L-NAME and 8-phenyltheophylline, normalized enhanced apparent affinity to adenosine in tissue from diabetic men and effectiveness (E(max)) to adenosine in diabetic rats. These results suggest that adenosine-elicited relaxation in diabetes is controlled at the receptor level events including K(+) channels in men whereas in rats postreceptor-related events including K(+) channels control the adenosine-induced relaxation. These relaxations to adenosine and ATP in men and rats with and without diabetes may be nitric oxide-independent mechanisms. Our results also suggest that ATP-induced relaxation did not involve K(ATP) channels and Ca-activated K(+) channels. 相似文献
18.
Mumtaz FH Lau DH Siddiqui EJ Thompson CS Morgan RJ Mikhailidis DP 《In vivo (Athens, Greece)》2006,20(2):243-246
BACKGROUND: Endothelin (ET-1) may play a role in the regulation of erection but this has not been conclusively demonstrated. Augmented cavernosal smooth muscle (CSM) contraction in the rat occurs following exposure to both ET-1 and phenylephrine (PE; alpha-1 agonist). The aim of this study was to assess the effect of ET-1 and its possible role in the alpha1-adrenergic pathway during the erectile process. MATERIALS AND METHODS: Organ bath studies were performed on CSM strips of penises obtained from 12 age-matched New Zealand White rabbits. The effect of ET-1 and PE alone on CSM tone in the absence and presence of ETA (BQ123) and ETB (BQ788) antagonists was assessed. Tissue responses were measured as tension (newton, N). EC50 values are expressed as mean +/- S.E.M. RESULTS: PE (10(8) - 10(-4) M) and ET-1 (10(-10) - 10(-6) M) produced a concentration-dependent contraction in rabbit CSM strips. The EC50 values were 1.7 x 10(-7) M +/- 1.1 and 3.4 x 10(-9) M +/- 1.5, respectively. BQ123 10(-5) M significantly inhibited ET-1-mediated CSM contractions more than BQ788 10(-5) M (both ANOVA p<0.01). The EC50 were 1.3 x 10(-6) M +/- 2.6 and 2.0 x 10(-7) M +/- 2.1, respectively. Neither the ETA or ETB receptor antagonist had a significant influence on alpha1-adrenergic receptor-mediated CSM contraction. CONCLUSION: ETA receptors may play a greater role than ETB receptors in ET-1-induced rabbit CSM contraction and the detumescence process. The a1-adrenergic-dependent pathway does not involve the ETA or ETB receptors. 相似文献
19.
Değim T Dündaröz R Sizlan A Yaşar M Denli M Gökçay E 《International journal of pharmaceutics》2002,238(1-2):105-109
Certain molecules, in particular steroids, have been observed to be outliers to quantitative structure-permeability relationships (QSPRs) for skin permeability (k(p)). Recently, however, many of the historical skin permeability data for these compounds have been found not to be consistent with more modern data. In this study QSPRs were re-analysed replacing the originally published steroid permeability data with those from more recent studies. A highly significant QSPR describing skin permeability in terms of the octanol-water partition coefficient (logP) and molecular weight (MW) was derived (log k(p)=0.74 logP-0.0091MW-2.39). This model is similar to those published previously. Statistical analysis of the residuals from the QSPR determined that the steroids are no longer outliers to this model. Thus, they may be considered to penetrate the skin by the same means as the majority of exogenous chemicals in this model. 相似文献
20.
Ulrich Diener Hans-Volker Tuczek Christine Fischer Karlernst Maier Ulrich Klotz 《Naunyn-Schmiedeberg's archives of pharmacology》1984,326(3):278-282
Summary In rat experiments and a clinical trial we have examined the suspected nephrotoxic potential of 5-amino-salicylic acid (5-ASA), the biological active metabolite of sulfasalazine (SZ). Male Wistar rats were treated orally for 4 weeks daily with 30 and 200 mg 5-ASA/kg and 75 and 500 mg SZ/kg. The two renal marker enzymes N-acetyl--D-glucosaminidase (NAG; EC 3.2.1.30), alanineaminopeptidase (AAP; EC 3.4.11.2) and creatinine were monitored in urine. At the end of the experiment rats were sacrificed, the removed kidneys histologically examined and drugs, their metabolites and creatinine measured in plasma and urine. In 9 patients treated chronically for their Crohn's disease with 3×0.5 g 5-ASA daily in form of suppositories and an oral preparation urinary excretions of NAG, AAP and serum creatinine were also monitored before and during therapy. Neither the animal experiments nor the observations in patients gave any evidence of nephrotoxic lesions induced by 5-ASA. Thus, our data show that in the doses applied, 5-ASA was devoid of altering renal excretion in rats and man. 相似文献