Endothelial IK and/or SK channels play an important role in the control of vascular tone by participating in endothelium-dependent relaxation. Whether β-AR antagonists, mainly used in hypertension, affect endothelial K channel function is unknown. In this study, we examined the effect of the β2-AR antagonist and inverse agonist ICI 118,551 on the IK /SK channel activity by assessing functional relaxation responses to several agonists that stimulate these channels. Mesenteric arterial rings isolated from male Sprague Dawley mounted to organ baths. Acetylcholine elicited IK - and SK -mediated relaxations that were abolished by TRAM-34 and apamin, respectively. ICI 118,551, which did not dilate the arteries per se, increased the IK -mediated relaxations, whereas SK -mediated relaxations remained unaltered. Same potentiating effect was also detected on the IK -mediated relaxations to carbachol and A23187, but not to NS309. Neither acetylcholine-induced nitric oxide-mediated relaxations nor SNP relaxations changed with ICI 118,551. The PKA inhibitor KT-5720, the selective β2-AR agonist salbutamol, the selective β2-AR antagonist butoxamine, the non-selective β-AR antagonist propranolol, and the inverse agonists carvedilol or nadolol failed to affect the IK -mediated relaxations. ICI 118,551-induced increase was not reversed by salbutamol or propranolol as well. Besides, low potassium-induced relaxations in endothelium-removed arteries remained the same in the presence of ICI 118,551. These data demonstrate a previously unrecognized action of ICI 118,551, the ability to potentiate endothelial IK channel-mediated vasodilation, through a mechanism independent of β2-AR antagonistic or inverse agonistic action. Instead, the enhancement of acetylcholine relaxation seems likely to occur by a mechanism secondary to endothelial calcium increase.
Aim: Although little is known about the mechanisms, varicocele is considered as one of the factors leading to male infertility. Since reduced motility of the vas deferens was shown to contribute to male infertility, in this study we aimed to investigate the effect of varicocele on electrical field stimulation (EFS)-induced biphasic contractions of the vas deferens in order to evaluate the effect of varicocele on the motility of the vas deferens. Material and Methods: A total of 26 Sprague-Dawley rats (200–250 g) were assigned randomly into two groups: sham (n = 10) and varicocele (n = 16). Varicocele was produced by partial obstruction of the left renal vein. Four weeks after the surgical procedure, vasa deferentia were harvested and EFS-induced responses were recorded from the strips prepared from ipsilateral and contralateral sides via Grass isometric force displacement transducers. Exogenous α-β methyl ATP was applied at the concentration of 10–5M to the vasa deferentia strips, and exogenous noradrenalin was applied cumulatively at the concentrations between 10–7 and 10–4M. At the end of each experiment, 80 mM KCl was applied to induce contractions. All contractions were expressed as the percentage of the 80 mM KCl-induced contractions. Results: Varicocele significantly inhibited both phases of EFS-induced biphasic contractions in the ipsilateral side, whereas in the contralateral site it did not produce any change. However, there was no change in exogenously applied α-β methyl ATP, noradrenalin and KCl-evoked contractions of the vasa deferentia obtained from both sides. Conclusions: These results suggest that varicocele affects the ipsilateral vas deferens motility by reducing neurotransmitter release.
The vascular action of trimethylamine-N-oxide (TMAO)-the gut microbiota-derived metabolite-in contributing cardiovascular disease is a controversial topic. A recent study has shown that acute exposure of TMAO at moderate concentrations inhibits endothelium-dependent hyperpolarization (EDH)-type relaxations selectively in rat isolated femoral arteries, but not in mesenteric arteries. Here we determined the efficacy of higher TMAO concentrations with longer exposure times on vascular reactivity in rat isolated superior mesenteric arteries. Acetylcholine-induced EDH-type relaxations were examined before and after incubation with TMAO (0.1-10 mM) at increasing exposure times (1-24 h). One-and 4-h-incubations with TMAO at 0.1-3 mM did not cause any change in EDH-type relaxations. However, when the incubation time was increased to 24 h, responses to acetylcholine were reduced in arteries incubated with 1-3 mM TMAO. In addition, at higher TMAO concentration (10 mM) the decrease in EDH relaxations could be detected both in 4-h-and 24-h-incubations. The EDH-relaxations were preserved in rings incubated with 10 mM TMAO for 24 h in the presence of SKA-31 (10 µM), the small (SKCa)-and intermediate (IKCa)-conductance calciumactivated potassium channel activator. Contractile responses to phenylephrine increased in arteries exposed to 10 mM TMAO for 24 h. Interestingly, nitric oxide (NO)-mediated relaxations remained unchanged in arteries treated for 24 h at any TMAO concentration. Our study revealed that TMAO selectively disrupted EDH-type relaxations time-dependently without interfering with NO-induced vasodilation in rat isolated mesenteric arteries. Disruption of these relaxations may help explain the causal role of elevated TMAO levels in certain vascular diseases.
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