Lead acetate versus cadmium sulfate in the modulation of main physiological pathways controlling detrusor muscle contractility in rat.

Heavy metals have a deleterious effect on lower urinary tract functions. Scant data has been reported about metals' effect on altering detrusor muscle contractility. Rats were given lead acetate (3, 30 mg/kg), cadmium sulfate (0.1, 1 mg/kg) or ferrous sulfate-iron overload-(3, 30 mg/kg), in a subacute toxicity study (21 days, ip). In-vitro tension experiments were conducted using isolated rat detrusor muscle. Measurement of heavy metal concentrations in blood and tissue homogenates was performed, as well as histopathological examinations. Subacute toxicity induced by treatment with lead and cadmium was manifested as a decrease in EFS, ACh, and ATP-mediated contraction of isolated detrusor muscle. Iron overload only decreased EMAX of EFS and ACh-mediated contraction. Lead (30 mg/kg) caused an upward shift in the dose response curve of isoprenaline-induced relaxation, with a significant decrease in EMAX. Lead (30 mg/kg) or cadmium (1 mg/kg) inhibited adenosine (10-5 M)-induced relaxation. Comparisons to control tissues showed a selective accumulation of metals in the detrusor muscle. Histopathological examinations revealed edema and inflammation in the urinary bladder. Directly added lead (10 mM) inhibited detrusor muscle contraction in-vitro, and its effect was decreased in presence of atropine, and potentiated in presence of TEA, L-NAME, or MB. Cadmium's (0.1 mM) inhibitory effect was reduced in presence of nifedipine or trifluoperazine. In conclusion, lead, cadmium, or iron induce detrusor hypoactivity: The inhibitory effect of lead may be mediated by modulating muscarinic receptors but not the K+/NO/cGMP pathway, whereas cadmium inhibitory effect may be mediated by inhibiting the Ca2+/calmodulin pathway.

Evaluation of l-arginine on kidney function and vascular reactivity following ischemic injury in rats: protective effects and potential interactions.

BACKGROUND: There is an interaction between many cell types involved in the pathophysiology of ischemic acute renal failure. Nitric oxide (NO) precursors, especially l-arginine, may have protective effects on tissue ischemia/reperfusion injury (IRI); however, their molecular mechanisms are unclear. In the present study, the interaction between l-arginine, cyclo-oxygenase (COX)-2 and reactive oxygen species (ROS) in the pathogenesis of ischemic acute renal failure was investigated. METHODS: Ischemia/reperfusion injury model in rats was used and various biochemical parameters examined. The rat isolated aortic rings served as model for hypoxia/reoxygenation where endothelium dependent and independent relaxations were exerted. RESULTS: Pre-treatment of rats subjected to IRI with l-arginine (125mg/kg) significantly reduced kidney MDA levels, elevated kidney SOD activity, GSH level and total NO levels at 24 and 48h after reperfusion. Kidney COX-2 level was only different in the l-arginine-treated group 48h after reperfusion compared to the IRI group. Pre-treatment with l-arginine (10(-2)M) alone or in combination with celecoxib significantly potentiated the acetylcholine (Ach)-induced relaxations in control and hypoxic rings. The effect of the combination was synergistic only in hypoxic rings. Addition of ascorbic acid to the celecoxib-arginine combination did not produce further potentiation. Sodium nitroprusside-induced relaxations in control and hypoxic rings were potentiated by l-arginine or celecoxib-arginine combination but not by ascorbic acid. CONCLUSIONS: The protective effect of l-arginine may result from the interaction between NO and ROS and increased NO bioavailability. The protective effects of combined celecoxib and l-arginine against IRI could be attributed to their antioxidant activity which exceeded that of ascorbic acid.

Combined effect of sildenafil and guanethidine, propranolol or verapamil on erectile function in rats.

OBJECTIVES: This study aims to further elucidate the role of adrenergic transmission in erection and to highlight whether adrenergic transmission in the penis modulates sildenafil's action. METHODS: Measurement of intracavernosal pressure in the anesthetized rat model. KEY FINDINGS: Guanethidine (3 and 6 mg/kg) potentiated intracavernosal pressure/mean arterial pressure (ICP/MAP) rises in response to cavernous nerve stimulation by 4.375 ± 0.425 and 18.375 ± 1.085% respectively. Propranolol did the opposite. In presence of guanethidine, sildenafil (0.01, 0.1 and 1 mg/kg) potentiated ICP/MAP responses by 81.571 ± 4.918%, 147.83 ± 10.864% and 279.285 ± 23.053% at 1 Hz compared to 22.277 ± 2.139%, 123.571 ± 8.443% and 186.25 ± 13.542% respectively in the absence of guanethidine. Propranolol inhibited the effect sildenafil at all frequencies of stimulation. Verapamil exhibited a pro-erectile action and potentiated the effect of sildenafil (0.01, 0.1 and 1 mg/kg) on erectile responses corresponding to 85.25 ± 6.716%, 146 ± 11.288% and 221.571 ± 19.032% respectively compared to 26.011 ± 1.911%, 87.142 ± 8.73% and 182.2 ± 16.921% in its absence. CONCLUSIONS: This study provides functional evidence that inhibition of sympathetic tone peripherally results in enhancement of erectile function. ß-adrenergic receptors seem to play an important role in erection. The combination of sildenafil and guanethidine or verapamil could have a potential advantage on erectile function but propranolol may mask the effect of sildenafil on erectile function.

Peripheral modulation of dopaminergic receptors affects erectile responses in rats.

Clinical observations have suggested that dopaminergic mechanisms are involved in the regulation of male sexual responses, including erection. Apomorphine was initially reported to exert its erectogenic effects by modifying central dopaminergic activity. This study aimed primarily at evaluating and investigating the effect of apomorphine on erectile functions in rats and its potential effects on the cardiovascular system, as well as the possible role of dopaminergic stimulation in the peripheral control of erection. Measurement of intracavernosal pressure changes elicited by electrical stimulation of the cavernosal nerve in anaesthetized rats and mating tests were used. SCH23390, the D1 receptor antagonist, attenuated penile response to electrical stimulation. Intravenous administration of apomorphine in low dose (100 microg/kg), but not in high dose, significantly potentiated erectile responses to electrical stimulation. Intracavernosally injected apomorphine (50 microg/kg) significantly potentiated the filling rate of the corpora cavernosa 5 min. after injection, and did not induce erection in absence of electrical stimulation. In addition, apomorphine amplified the male sexual and copulatory behaviour by reducing ejaculation, mount and intromission latencies, and significantly increasing the number of ejaculations per session. However, apomorphine produced rapid and long-lasting hypotension and potentiated the hypotension and tachycardia associated with nerve-stimulated penile erection. Our results suggest that D1-dopaminergic receptors may be functionally involved in the peripheral mediation of penile erection. Apomorphine may amplify sexual and copulatory behaviour and may also, by a complementary role, amplify neurogenically mediated erections by acting in the periphery.

The role of the NO/NMDA pathways in the development of morphine withdrawal induced by naloxone in vitro.

The effect of nitric oxide (NO)/N-methyl-d-aspartate (NMDA) pathways on naloxone-induced withdrawal contracture was studied in vitro in a model of acute morphine dependence in the isolated guinea pig ileum. Exposure of the isolated guinea pig ileum to morphine (10(-5) M) for 5 min resulted in acute dependence, characterized by a strong withdrawal contracture induced by naloxone (5x10(-5) M). The NO synthase (NOS) inhibitor N(G)-nitro-L-arginine methyl ester (L-NAME; 5x10(-4) M) as well as the soluble guanylate cyclase inhibitor methylene blue (MB; 10 microM) were found to significantly attenuate the naloxone-induced withdrawal contracture. In addition, the NO precursor L-arginine (5x10(-4) M) as well as the NO donors sodium nitroprusside (SNP; 1 microM) and sodium azide (NaZ; 10 microM) were able to revert the effect of L-NAME returning the amplitude of naloxone-induced contracture to the same level in control morphine-dependent ilea. We also demonstrated that the competitive NMDA receptor antagonist DL-2-amino-5-phosphonovaleric acid (AP-5; 50 microM) potently reduced the amplitude of naloxone-induced contracture in the same model, an effect that was reversed by co-administration of the excitatory amino acid L-glutamate (40 microM). This in vitro study confirms the implication of the NO/NMDA pathways in morphine dependence.