Role of Ca(2+)-activated K(+) channels and Na(+),K(+)-ATPase in prostaglandin E(1)- and E(2)-induced inhibition of the adrenergic response in human vas deferens.

We studied the role of K(+) channels and Na(+),K(+)-ATPase in the presynaptic inhibitory effects of prostaglandin E(1) (PGE(1)) and PGE(2) on the adrenergic responses of human vas deferens. Furthermore, we determined the effects of increasing extracellular K(+) concentrations ([K(+)](o)) and inhibition of Na(+),K(+)-ATPase on neurogenic and norepinephrine-induced contractile responses. Ring segments of the epididymal part of the vas deferens were taken from 45 elective vasectomies and mounted in organ baths for isometric recording of tension. The neuromodulatory effects of PGEs were tested in the presence of K(+) channel blockers. PGE(1) and PGE(2) (10(-8) to 10(-6)M) induced inhibition of adrenergic contractions. The presence of tetraethylammonium (10(-3)M), charybdotoxin (10(-7)M), or iberiotoxin (10(-7)M), prevented the inhibitory effects of PGE(1) and PGE(2) on the adrenergic contraction. Both glibenclamide (10(-5)M) and apamin (10(-6)M) failed to antagonize PGE(1) and PGE(2) effects. Raising the [K(+)](o) from 15.8mM to 25.8mM caused inhibition of the neurogenic contractions. Ouabain at a concentration insufficient to alter the resting tension (10(-6)M) increased contractions induced by electrical stimulation but did not alter the contractions to norepinephrine. The inhibition of neurogenic responses induced PGE(1), PGE(2) and increased extracellular concentration of K(+) was almost completely prevented by ouabain (10(-6)M). The results demonstrate that PGE(1) and PGE(2) inhibit adrenergic responses by a prejunctional mechanism that involves the activation of large-conductance Ca(2+)-activated K(+) channels and Na(+),K(+)-ATPase.

Modulation of adrenergic responses of human vas deferens by K+ channel inhibitors.

OBJECTIVES: The present study was designed to evaluate the role of K(+) channels in the adrenergic responses of human vas deferens as well as the intervention of dihydropyridine-sensitive Ca(2+) channels on modulation of adrenergic responses by K(+) channel inhibitors. METHODS: Ring 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(+) channel blockers on neurogenic and norepinephrine-induced contractile responses. RESULTS: Addition of tetraethylammonium (TEA, 10(-3) M), a nonspecific K(+) channel blocker, or charybdotoxin (10(-7) M), a nonselective inhibitor of large- and intermediate-conductance Ca(2+)-activated K(+) channel, increased the contractile responses to norepinephrine and electrical field stimulation-induced contractions (P < .01), whereas iberiotoxin (10(-7) M), a selective blocker of large-conductance Ca(2+)-activated K(+) channels, apamin (10(-6) M), a blocker of small-conductance Ca(2+)-activated K(+) channels, or glibenclamide (10(-5) M), an inhibitor of ATP-sensitive K(+) channels, were without effect. TEA- and charybdotoxin-induced potentiation of contractions elicited by electrical field stimulation and norepinephrine was blocked by L-type Ca(2+) channel blocker nifedipine (10(-6) M). CONCLUSIONS: The results suggest that charybdotoxin-sensitive, but iberiotoxin-insensitive, K(+) 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(2+) entry through L-type voltage-dependent Ca(2+) channels.

Increased contraction to noradrenaline by vasopressin in human renal arteries.

OBJECTIVE: Arginine vasopressin (AVP) not only acts directly on blood vessels through vasopressin V1 receptor stimulation but also may modulate adrenergic-mediated responses in animal experiments. The aim of the present study was to assess whether subpressor concentrations of AVP could contribute to an abnormal adrenergic contractile response of human renal arteries. METHODS: Renal artery rings were obtained from 27 patients undergoing nephrectomy. The rings were suspended in organ bath chambers for isometric recording of tension. RESULTS: AVP (10(-10) mol/l) and the vasopressin V1 receptor agonist [Phe2, Orn8]-vasotocin (10(-10) mol/l) produced a leftward shift of the concentration-response curve to noradrenaline (half-maximal effective concentration decreased from 1.1 x 10(-6) mol/l to 3.1 x 10(-7) mol/l). The enhancement of noradrenaline-induced contractions was inhibited by the vasopressin V1 receptor antagonist d(CH2)5Tyr(Me)AVP (10-8 mol/l) and unaffected by endothelium removal or pretreatment with the inhibitor of nitric oxide (NO) synthase NG-monomethyl-l-arginine (l-NMMA). The vasopressin V2 receptor agonist 1-desamino-8-D-arginine vasopressin (dDAVP) (10(-10)-10(-8) mol/l) did not modify contractile responses to noradrenaline. In the presence of the dihydropyridine calcium antagonist nifedipine (10(-6) mol/l), vasopressin failed to enhance the contractile response to noradrenaline. CONCLUSIONS: The results demonstrate that subpressor concentrations of vasopressin potentiate the contractile effects of noradrenaline without intervention of the NO system. The effects appear to be mediated by vasopressin V1 receptor stimulation, which brings about an increase in calcium entry through dihydropyridine-sensitive calcium channels.