benzofurans and Erectile-Dysfunction

Topics: Animals; Benzofurans; Diabetes Mellitus; Erectile Dysfunction; Humans; Indoles; Male; Penile Erection; Rats

The development of novel therapeutic options is imperative in patients with erectile dysfunction, especially those non-responsive to phosphodiesterase type 5 inhibitors. LDD175, a potent BKCa channel opener, has a relaxation effect on the in vitro cavernosal smooth muscle strip.. To investigate the effect of LDD175 on erectile function using in vivo animal disease model.. Male Sprague-Dawley rats were assigned to a normal control group and seven diabetic groups: diabetic control, sildenafil (1 and 5 mg/kg), LDD175 (5 and 10 mg/kg), LDD175 5 mg/kg plus sildenafil 1 mg/kg, and LDD175 10 mg/kg plus tetraethylammonium.. Intracavernosal pressure (ICP), ratio of ICP to mean arterial pressure (MAP), and the area under curve of ICP/MAP of eight groups were compared using in vivo pelvic nerve stimulation.. The ICP, ICP/MAP ratio, and area under curve of the ICP/MAP ratio of the normal control rats increased with an increase in electrical field stimulation voltage. All parameters in the diabetic control group were significantly lower than those in the normal control rats, with an electrical field stimulation ranging from 1 to 5 V (P < .05). LDD175 improved the erectile response in diabetic rats in a dose-dependent manner. The combination of sildenafil (1 mg/kg) and LDD175 (5 mg/kg) showed a significant additive effect (P < .05) on the improvement of erectile function compared with sildenafil (1 mg/kg) alone. The enhancement of erectile function by LDD175 was completely blocked by tetraethylammonium.. The results showed that the BKCa channel opener LDD175 improved erectile function in an in vivo diabetic rat model. Furthermore, combination therapy of LDD175 and sildenafil had an additive effect on the improvement of erectile function in diabetic rats. LDD175 could be a new candidate for the treatment of erectile dysfunction.

Topics: Animals; Benzofurans; Diabetes Mellitus, Experimental; Disease Models, Animal; Erectile Dysfunction; Indoles; Male; Muscle, Smooth; Penile Erection; Phosphodiesterase 5 Inhibitors; Rats; Rats, Sprague-Dawley; Sildenafil Citrate

The BKCa channel has been reported to play an important role in erectile function. Recently, novel BKCa channel activator, LDD175, was introduced.. This study aims to investigate whether LDD175 relaxes corporal smooth muscle (CSM) via BKCa channel activation.. After isolation of CSM strip from a male rabbit model, contraction studies using organ bath was performed. Isolating human tissue and cell cultures, electrophysiological studies were done via whole-cell patch-clamp recording.. Vasodilatory effects of LDD175 were evaluated by cumulative addition ranging from 10(-7) to 10(-4) M in corpus cavernosal strips after precontraction with 10(-5) M phenylephrine via organ bath system. Using cultured human CSM cells, patch-clamp recording was performed. Erectile function was measured by in vivo rat cavernous nerve stimulation.. LDD175 caused an endothelium-independent relaxation of corporal tissues, and this effect was abolished by pretreatment with iberiotoxin. The relaxation effect of 10(-4) M LDD175 was greater than that of 10(-6) M udenafil (54.0 ± 3.1% vs. 34.5 ± 3.9%, P < 0.05); 10(-5) M LDD175 with 10(-6) M udenafil caused a greater relaxation effect on strips than 10(-5) M LDD175 or 10(-6) M udenafil alone (50.7%, 34.1%, vs. 20.7%, respectively, P < 0.001). In patch-clamp recordings, LDD175 increased K(+) currents in a dose-dependent manner, and washout of LDD175 or the addition of iberiotoxin fully reversed the increase. Intravenous LDD175 improved erectile function measured by area under the curve (AUC) of the intracavernosal pressure (ICP)/arterial blood pressure (ABP) ratio (1,612.1 ± 135.6 vs. 1,093.7 ± 123.1, P < 0.05). There was no difference between 10 mg/kg LDD175 and 1 mg/kg udenafil regarding maximal ICP, maximal ICP/ABP ratio, and the AUC of the ICP/ABP ratio (P > 0.05).. LDD175 leads to an endothelium-independent relaxation of erectile tissue, primarily through the opening of BKCa channels. The results suggest that LDD175 might be a new candidate treatment for erectile dysfunction.

Topics: Animals; Benzofurans; Erectile Dysfunction; Humans; Indoles; Male; Muscle Relaxation; Muscle Tonus; Muscle, Smooth; Patch-Clamp Techniques; Penile Erection; Phenylephrine; Rabbits

Amiodarone and a metabolite, desethylamiodarone, were measured in plasma of 55 patients and in both plasma and red blood cell (RBC) in 28 patients who received chronic amiodarone treatment. The assay for amiodarone and desethylamiodarone was performed by high-pressure liquid chromatography. During chronic treatment, median plasma concentration of amiodarone was 2.80 micrograms/ml and desethylamiodarone was 2.20 micrograms/ml. In matched samples, plasma amiodarone concentration exceeded RBC amiodarone concentration (p less than 0.001) and the RBC-to-plasma concentration ratio averaged 0.31. The plasma desethylamiodarone concentration was not significantly different from its RBC concentration, and the RBC-to-plasma concentration ratio averaged 1.29. There was a linear correlation between plasma concentrations of amiodarone and desethylamiodarone (r = 0.82) and between RBC concentrations of drug and metabolite (r = 0.71). Drug or metabolite concentrations in plasma and RBCs correlated directly with daily dosage of amiodarone. Adverse side effects during chronic amiodarone therapy were related most strongly to RBC drug and metabolite concentrations. The group with adverse side effects had a significantly higher RBC concentration of amiodarone, 150 vs 0.75 micrograms/ml (p less than 0.001), than did patients free of adverse effects. After dosage reduction, side effects abated and plasma and RBC concentrations of drug and metabolite decreased. These data indicate that there is an expected range of amiodarone and desethylamiodarone concentrations during chronic treatment and that adverse side effects correlate best with RBC concentrations of drug and metabolite. Red cell concentrations may reflect the amount of unbound, free amiodarone and desethylamiodarone in plasma.

Topics: Amiodarone; Anorexia; Benzofurans; Erectile Dysfunction; Erythrocytes; Humans; Male; Nausea; Saliva; Tachycardia; Ventricular Fibrillation