Antinociceptive Effect of Vardenafil on Carrageenan-Induced Hyperalgesia in Rat: involvement of Nitric Oxide/Cyclic Guanosine Monophosphate/Calcium Channels Pathway.

In this study, we aimed to investigate the peripheral antinociception effects of specific phosphodiesterase 5 (PDE-5) inhibitor vardenafil on carrageenan-induced nociception in rats, and the role of calcium besides the L-arginine- nitric oxide (NO)- cyclic guanosine monophophate (cGMP) pathway in these effects. Hyperalgesia was induced by the intraplantar injection of 0.1 mL fresh carrageenan solution to right hind-paw whereas, saline as a vehicle of carrageenan was injected to the left paw. This procedure was used for measuring mechanic nociception pressure via an analgesimeter. Pressure which produced nociception was measured before (0 minute) and after(15, 30, 60 and 120 minutes) carrageenan injection. Local administration of vardenafil produced a dose-dependent antinociceptive effect. Pretreatment with N(W)-nitro-L-arginine methyl ester (L-NAME, nitric oxide synthase inhibitor), oxadiazolo (4, 3, a) quinoxalin -1-one (ODQ, inhibitor of guanylyl cyclase) or A23187 (calcium ionophore) decreased the effect of vardenafil. In contrast, L-arginine (nitric oxide donor) seemed to potentiate the vardenafil-induced antinociception. Our results suggest that phosphodiesterase type-5 inhibitor vardenafil may offer a new therapeutic tool to treat pain. It's effect was probably result from L-arginine/NO-cGMP pathway activation and Ca + 2 channels are also involved.

An evaluation of vardenafil as a calcium channel blocker in pulmonary artery in rats.

OBJECTIVE: Vardenafil was reported to relax rat pulmonary artery through endothelium-dependent mechanisms. The aim of this in vitro study was to investigate other related mechanisms for this effect. MATERIALS AND METHODS: Endothelium-intact and denuded artery rings were suspended in order to record isometric tension. In the rings with or without endothelium, the concentration-response curves for vardenafil were generated. In the rings without endothelium the contractile response induced by phenylephrine (Phe) or KCl was assessed in the presence or absence of vardenafil. In the last set of experiments, pulmonary artery rings were exposed to calcium-free isotonic depolarizing solution and the contractile response induced by the addition of calcium was evaluated in the presence or absence of vardenafil, nifedipine, verapamil or 1H-[1,2,4] oxadiazolo[4,3-a] quinoxalin-1-one (ODQ). RESULTS: Vardenafil attenuated pulmonary artery contraction induced by phenylephrine in the presence and absence of endothelium. In addition, vardenafil attenuated both Phe or KCl-induced contraction but, it's effect on the KCl dose-response curve was more significant. Vardenafil also inhibited the contractile response induced by calcium in a dose-dependent manner. Addition of nifedipine or verapamil did not significantly alter this effect while ODQ incubation significantly inhibited vardenafil-induced relaxation. CONCLUSION: From these findings, it was proposed that vardenafil relaxed rat pulmonary artery through inhibiting calcium influx.

The achilles heel in melatonin: asthma.

Asthma is a clinical syndrome characterized by chronic airway inflammation, airway responsiveness, and expiratory airflow limitation. Nocturnal symptoms and decreases in lung function are common aspects of the asthma clinical syndrome. Nocturnal symptoms also appear to be associated with asthma-related mortality. In addition to its importance to the regulation of human circadian rhythms, an accumulating body of evidence also suggests that melatonin is also involved in the regulation of smooth muscle tone. For this reason, this study aimed to evaluate contraction and relaxation responses in tracheal smooth muscle rings obtained from rats treated with melatonin. Following administration of melatonin (50mg/kg/day) at the same time every day for 6 weeks, in vitro organ bath experiments were performed with rat tracheal preparations exposed to contractile (acetycholine and serotonin) and relaxant (theophylline and papaverine) agents. Melatonin treatment strengthened contraction responses, but did not affect relaxation responses in rat tracheal preparations. We think that melatonin might play a role in the pathogenesis of nocturnal asthma. Therefore, clinicians should be aware of the importance of melatonin to nocturnal exacerbation of asthma symptoms and alert asthmatic patients that use exogenous melatonin supplementation of its potential negative effects.

Acute effects of vardenafil on pulmonary artery responsiveness in pulmonary hypertension.

Phosphodiesterase type-5 (PDE-5) inhibitors are novel and important options for the treatment of pulmonary arterial hypertension (PAH). Therefore, we aimed to examine effects of vardenafil, a PDE-5 inhibitor, on the pulmonary arteries isolated from rats with monocrotaline- (MCT-) induced pulmonary hypertension. MCT (60 mg/kg) or its vehicle was administered by a single intraperitoneal injection to 6-week-old male Sprague Dawley rats. Rats were sacrificed 21 days after MCT injection, and the main pulmonary arteries were isolated and then mounted in 20 mL organ baths. Concentration-response curves for vardenafil (10(-10)-10(-5) M) were constructed in phenylephrine- (Phe-) precontracted rings. PAH caused marked rightward shift in the curves to vardenafil whereas maximal responses were not affected. Inhibition of NO synthase (L-NAME, 10(-4) M) or guanylyl cyclase (ODQ, 10(-5) M) caused similar attenuation in responses evoked by vardenafil. Moreover, contraction responses induced by CaCl(2) (3 × 10(-5)-3 × 10(-2) M) were significantly reduced in concentration-dependent manner by vardenafil. In conclusion, vardenafil induced pulmonary vasodilatation via inhibition of extracellular calcium entry in addition to NO-cGMP pathway activation. These results provide evidence that impaired arterial relaxation in PAH can be prevented by vardenafil. Thus, vardenafil represents a valuable therapeutic approach in PAH besides other PDE-5 inhibitors.

What may be happen after an organophosphate exposure: acute myocardial infarction?

The increase in accidental organophosphate poisoning as well as the rise in the number of cases of suicide attempts with organophosphate compounds is due to primarily to the widespread use of these compounds in agriculture. Organophosphates are anti-acetycholinesterase agents and their toxicity affects many organs, including the pancreas, liver and heart. Cardiac complications often accompany poisoning with these compounds and may be serious and often fatal. However, little is known about the myocardial infarction risk associated with exposure to pesticides. Herein, a rare case of acute myocardial infarction due to acute exposure to organophosphate compound is documented with electrocardiogram, enzyme and clinical characteristics in this report.