Sildena®l (0.1 ± 30 mM), a cyclic GMP phosphodiesterase 5 (PDE 5) inhibitor, induced inhibition of electrically evoked contractions of ring segments of human vas deferens from 34 vasectomies. Zaprinast (0.1 ± 100 mM), another PDE 5 inhibitor, and the nitric oxide (NO) donor sodium nitroprusside (SNP) (0.1 ± 100 mM) had no e ect on neurogenic contractions. The inhibition induced by sildena®l was not modi®ed by the inhibitor of guanylate cyclase 1H-[1,2,4]oxadiazolo [4,3-a] quinoxaline-1-one (ODQ) (1 ± 30 mM) but it was abolished by the K + channel blockers tetraethylammonium (TEA, 1 mM), iberiotoxin (0.1 mM) and charybdotoxin (0.1 mM). Sildena®l, zaprinast and SNP did not a ect the contractions induced by noradrenaline. SNP (10 mM) caused elevation of cyclic GMP levels that was potentiated by sildena®l (10 mM) and zaprinast (100 mM). ODQ (10 mM) inhibited the increase in cyclic GMP. Sildena®l inhibits adrenergic neurotransmission in human vas deferens. The inhibition is not related to accumulation of cyclic GMP but is probably due to activation of prejunctional large-conductance Ca 2+ -activated K + channels.
The effects of deamino-8-D-arginine vasopressin (desmopressin), a V 2 receptor antidiuretic agonist, were studied in isolated rings from branches of renal arteries obtained from 22 patients undergoing nephrectomy. The rings were suspended in organ bath chambers for isometric recording of tension. In precontracted rings with norepinephrine (10 ؊6 to 3 ؋ 10 ؊6 mol/L), desmopressin (10 ؊11 to 3 ؋ 10 ؊7 mol/L) caused endothelium-dependent relaxation (81% ؎ 4% reversal of the initial contraction in arteries with endothelium; 20% ؎ 4% in arteries without endothelium; P < . A rginine vasopressin promotes reabsorption of water in renal tubular cells through V 2 receptors coupled to adenylate cyclase activation and acts directly on human vascular smooth muscle to produce constriction through V 1 receptor stimulation.1-4 The specific V 2 receptor agonist deamino-8-d-arginine vasopressin (desmopressin) is a synthetic analogue of the natural hormone vasopressin with a strong V 2 antidiuretic effect and minimal V 1 pressor activity.5 Extrarenal actions of desmopressin include coagulation responses such as the release of factor VIIIc and von Willebrand factor, 6 -8 and cardiovascular effects such as increase in heart rate, decrease in mean arterial blood pressure, facial flushing, and increase in forearm blood flow. 9 -11 Whether these effects are mediated by receptors is not clearly established, but studies in humans demonstrate that an extrarenal V 2 receptor could be responsible for the coagulation and hemodynamic responses to desmopressin. 10 -12 Experiments in isolated arteries show that desmopressin induces concentration-dependent relaxation in human cerebral and mesenteric arteries that is prevented by the mixed V 1 -V 2 receptor antagonist desGly-d(CH 2 ) 5 -d-Tyr(Et)ValAVP but not
The results demonstrate that L-NMMA and ADMA reduce basal and stimulated nitric oxide activity in human renal arteries. An increase in the plasma concentrations of methylarginines associated with renal disease should be considered as a risk factor for endothelial dysfunction and abnormal vasomotor tone in human renal arteries.
OBJECTIVESThe present study was designed to evaluate the role of K ϩ channels in the adrenergic responses of human vas deferens as well as the intervention of dihydropyridine-sensitive Ca 2ϩ channels on modulation of adrenergic responses by K ϩ channel inhibitors. METHODSRing segments of the epididymal part of the vas deferens were taken from 32 elective vasectomies and mounted in organ baths for isometric recording of tension. We then studied the effects of K ϩ channel blockers on neurogenic and norepinephrine-induced contractile responses. RESULTSAddition of tetraethylammonium (TEA, 10 Ϫ3 M), a nonspecific K ϩ channel blocker, or charybdotoxin (10 Ϫ7 M), a nonselective inhibitor of large-and intermediate-conductance Ca 2ϩ -activated K ϩ channel, increased the contractile responses to norepinephrine and electrical field stimulation-induced contractions (P Ͻ .01), whereas iberiotoxin (10 Ϫ7 M), a selective blocker of large-conductance Ca 2ϩ -activated K ϩ channels, apamin (10 Ϫ6 M), a blocker of small-conductance Ca 2ϩ -activated K ϩ channels, or glibenclamide (10 Ϫ5 M), an inhibitor of ATP-sensitive K ϩ channels, were without effect. TEA-and charybdotoxin-induced potentiation of contractions elicited by electrical field stimulation and norepinephrine was blocked by L-type Ca 2ϩ channel blocker nifedipine (10 Ϫ6 M). CONCLUSIONSThe results suggest that charybdotoxin-sensitive, but iberiotoxin-insensitive, K ϩ channels are activated by stimulation with norepinephrine and electrical field stimulation to counteract the adrenergic-induced contractions of human vas deferens. Thus, inhibition of these channels increases significantly the contraction, an effect that appears to be mediated by an increase in Ca 2ϩ entry through L-type voltage-dependent Ca 2ϩ channels. UROLOGY 76: 1518.e7-1518.e12, 2010.
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