Recent studies have revealed a significant relationship between erectile dysfunction (ED) and lower urinary tract symptoms (LUTS), both of which commonly affect middle-aged and older men. These conditions share underlying causes, particularly endothelial dysfunction, atherosclerosis, and chronic pelvic ischemia (CPI). This study investigated the therapeutic potential of LDD175, a large-conductance Ca 2+ -activated K + channel (BKCa channel) opener, in simultaneously treating both conditions using a CPI animal model of male Sprague Dawley rats. Our study investigated the induction of CPI through surgical endothelial damage combined with a high-cholesterol diet. We assessed erectile and voiding functions by measuring intracavernosal pressure (ICP) and intraurethral pressure (IUP), respectively, after nerve stimulation. We performed histological examinations of vascular changes and western blot analyses of cavernous and prostate tissues to understand the underlying mechanisms. This study evaluated the effectiveness of LDD175 compared to standard treatments, such as sildenafil for ED and tamsulosin for LUTS. Therefore, the CPI model successfully demonstrated ED and LUTS symptoms with decreased ICP and increased IUP. Analysis revealed elevated levels of hypoxia-inducible factor-1α, transforming growth factor-β1 and β2 in cavernous tissue, and increased α1A-adrenoceptor expression in prostate tissue. LDD175 administration showed promising results, with dose-dependent improvements in ICP and IUP, and therapeutic effects comparable to those of established treatments. Our findings suggest a novel therapeutic approach that can simultaneously address ED and LUTS, opening new possibilities for clinical application in the treatment of these interconnected conditions.
Male ; Animals ; Erectile Dysfunction/etiology* ; Rats, Sprague-Dawley ; Lower Urinary Tract Symptoms/etiology* ; Ischemia/drug therapy* ; Rats ; Tamsulosin ; Hypoxia-Inducible Factor 1, alpha Subunit/drug effects* ; Sildenafil Citrate/therapeutic use* ; Penis/blood supply* ; Disease Models, Animal ; Transforming Growth Factor beta1/metabolism* ; Pelvis/blood supply* ; Prostate/metabolism* ; Sulfonamides/therapeutic use* ; Large-Conductance Calcium-Activated Potassium Channels/agonists*

The aim of the present study was to study the effect of β-estradiol (β-E(2)) on the large-conductance Ca(2+)-activated potassium (BK(Ca)) channel in mesenteric artery smooth muscle cells (SMCs). The mesenteric arteries were obtained from post-menopause female patients with abdominal surgery, and the SMCs were isolated from the arteries using an enzymatic disassociation. According to the sources, the SMCs were divided into non-hypertension (NH) and essential hypertension (EH) groups. Single channel patch clamp technique was used to investigate the effect of β-E(2) and ICI 182780 (a specific blocker of estrogen receptor) on BK(Ca) in the SMCs. The results showed the opening of BK(Ca) in the SMCs was voltage and calcium dependent, and could be blocked by IbTX. β-E(2) (100 μmol/L) significantly increased open probability (Po) of BK(Ca) in both NH and EH groups. After β-E(2) treatment, NH group showed higher Po of BK(Ca) compared with EH group. ICI 182780 could inhibit the activating effect of β-E(2) on BK(Ca) in no matter NH or EH groups. These results suggest β-E(2) activates BK(Ca) in mesenteric artery SMCs from post-menopause women via estrogen receptor, but hypertension may decline the activating effect of β-E(2) on BK(Ca).
Aged ; Estradiol ; analogs & derivatives ; pharmacology ; Female ; Humans ; Hypertension ; physiopathology ; Large-Conductance Calcium-Activated Potassium Channels ; agonists ; metabolism ; physiology ; Mesenteric Arteries ; metabolism ; physiology ; Middle Aged ; Muscle, Smooth, Vascular ; cytology ; metabolism ; physiology ; Patch-Clamp Techniques ; Postmenopause ; physiology ; Receptors, Estrogen ; antagonists & inhibitors

Trigeminal neuralgia is a paroxysmal disorder with severely disabling facial pain and thus continues to be a real therapeutic challenge. At present there are few effective drugs for treatment of this pain. The present study was aimed to explore the involvement of BK(Ca) channels and Kv channels in the mechanical allodynia in a rat model of trigeminal neuropathic pain. Here the effectiveness of drug target injection at the trigeminal ganglion through the infraorbital foramen was first evaluated by immunofluorescence and animal behavior test. Trigeminal neuropathic pain model was established by chronic constriction injury of the infraorbital nerve (ION-CCI) in rats. BK(Ca) channel agonist and Kv channel antagonist were administered into the trigeminal ganglion in ION-CCI rats and sham rats by the above target injection method, and the facial mechanical pain threshold was measured. The results showed that the drug could accurately reach the trigeminal ganglion by target injection which was more effective than that by the normal injection around infraorbital foramen. Rats suffered significant mechanical allodynia in the whisker pad of the operated side from 6 d to 42 d after ION-CCI. BK(Ca) channel agonist NS1619 significantly and dose-dependently attenuated the facial mechanical allodynia and increased the facial mechanical pain threshold in ION-CCI rats 15 d after operation. Kv antagonist 4-AP was able to reduce the threshold in ION-CCI rats when facial mechanical threshold was partly recovered and relatively stable on the 35th day after operation. These results suggest that BK(Ca) channel agonist NS1619 and Kv channel antagonist 4-AP can significantly affect the rats' facial mechanical pain threshold after ION-CCI. Activation of BK(Ca) channels may be related to the depression of the primary afferent neurons in trigeminal neuropathic pain pathways. Activation of Kv channels may exert a tonic inhibition on the trigeminal neuropathic pain.
4-Aminopyridine ; administration & dosage ; Animals ; Benzimidazoles ; administration & dosage ; Constriction ; Facial Pain ; physiopathology ; Injections, Intralesional ; Kv1.4 Potassium Channel ; antagonists & inhibitors ; Large-Conductance Calcium-Activated Potassium Channels ; agonists ; Male ; Orbit ; innervation ; Pain Threshold ; physiology ; Rats ; Rats, Sprague-Dawley ; Trigeminal Ganglion ; drug effects ; Trigeminal Neuralgia ; drug therapy ; physiopathology

There are some evidences that K+ efflux evoked by muscarinic stimulation is not mainly mediated by large conductance K+ (BK) channels in salivary gland. In this experiment, we therefore characterised non BK channels in rat submandibular gland acinar cells and examined the possibility of agonist effect on this channel using a patch clamp technique. Two types of K+ channels were observed in these cells. BK channels were observed in 3 cells from total 6 cells and its average conductance was 152+/- 7 pS (n=3). The conductance of the another types of K+ channel was estimated as 71+/-7 pS (n=6). On the basis of the conductance of this channel, we defined this channel as intermediate conductance K+ (IK) channels, which were observed from all 6 cells we studied. When we increased Ca2+ concentration of the bath solution in inside-out mode, the IK channel activity was greatly increased, suggesting this channel is Ca2+ sensitive. We next examined the effect of carbachol (CCh) and isoproterenol on the activity of the IK channels. 10(-5) M isoproterenol significantly increased the open probability (Po) from 0.08+/-0.02 to 0.21+/-0.03 (n=4, P<0.05). Application of 10(-5) M CCh also increased Po from 0.048+/-0.03 to 0.55+/-0.33 (n=5, P<0.05) at the maximum channel activity. The degree of BK channel activation induced by the same concentration of CCh was lower than that of IK channels; Po value was 0.011+/-0.003 and 0.027+/-0.005 in control and during CCh stimulation (n=3), respectively. The result suggests that IK channels exist in salivary acinar cells and its channel activity is regulated by muscaricinic and beta- adrenergic agonist. We conclude that IK channels also play a putative role in secretion as well as the BK channels in rat submandibular gland acinar cells.
Acinar Cells* ; Adrenergic Agonists ; Animals ; Baths ; Carbachol ; Isoproterenol ; Large-Conductance Calcium-Activated Potassium Channels ; Rats ; Salivary Glands ; Submandibular Gland*