Norepinephrine-induced Contractile Responses Research Articles

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 15.8 mM to 25.8 mM 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

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. 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. 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). 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.

Effects of thromboxane A2 synthetase inhibitor, DP-1904 on the action of vasoactive substances in rabbit blood vessel smooth muscle preparations

Thromboxane A2 (TxA2) is a potent platelet aggregator as well as a vascular and bronchial constrictor. DP-1904, a newly synthesized imidazol TxA2 synthetase inhibitor, is a potent and long-acting agent. The present investigation was conducted to explore the effect of DP-1904 on the contractile responses in rabbit pulmonary artery and descending aorta strips induced by various vasoactive substances. Fourteen Japanese albino rabbits, weighing about 3 kg, were sacrificed. Rabbit pulmonary artery and descending aorta were removed, cut spirally, set up in bioassay glass jackets and superfused with Krebs-Henseleit solution at 37 degrees C, saturated with oxygen and carbon dioxide. Contraction of tissues was detected by an isotonic transducer and displayed on a polyrecorder. Arachidonic acid-induced contractile responses in rabbit pulmonary artery and descending aorta strips were attenuated significantly by the continuous infusion of DP-1904 in a dose-dependent fashion. Prostaglandin F2 alpha-induced contractile responses in rabbit pulmonary artery and descending aorta strips were attenuated significantly by the continuous infusion of DP-1904, dose-dependently. Angiotensin II-induced contractile responses in rabbit pulmonary artery and descending aorta strips were attenuated significantly by the continuous infusion of DP-1904, dose-dependently. Norepinephrine-induced contractile responses in rabbit pulmonary artery and descending aorta strips were attenuated significantly by the continuous infusion of DP-1904, dose-dependently. The above results suggest that DP-1904 might be a useful therapeutic agent for treatment of pulmonary hypertension in patients with chronic obstructive lung diseases.

Heterogeneity and complexity of α 1-adrenoceptors in the ovine uterine artery and umbilical vein

To understand the subtypes of α 1-adrenoceptors in the regulation of uterine and umbilical vascular function, the subtypes of α 1-adrenoceptors in the ovine uterine artery and umbilical vein were investigated pharmacologically. The use of the irreversible α 1B-adrenoceptor antagonist, chloroethylclonidine, revealed the heterogeneity of α 1-adrenoceptors in these two tissues. Chloroethylclonidine showed different patterns of action. While it depressed the maximal contraction to norepinephrine in the umbilical vein, it did not decrease the maximal response in the uterine artery. The α 1A-adrenoceptor antagonist, 2-(2,6-dimethoxyphenoxyethyl) aminomethyl-1,4-benzodioxane (WB 4101), competitively inhibited norepinephrine-induced contractile responses in the ovine uterine artery and umbilical vein with intermediate pA 2 values of 8.30 and 8.45, respectively. Combined use of chloroethylclonidine with either prazosin or WB 4101 produced an additive inhibition of norepinephrine-induced contractions in both tissues, suggesting an interaction of WB 4101 with a chloroethylclonidine-insensitive α 1-adrenoceptor. However, the chloroethylclonidine-insensitive α 1-adrenoceptor differed on the affinity for prazosin in the uterine artery and umbilical vein. The Ca 2+ channel blocker, nifedipine, inhibited contractions to both the chloroethylclonidine-sensitive α 1-adrenoceptor (α 1B subtype) and the chloroethylclonidine-insensitive α 1-adrenoceptor in both tissues. Prazosin, WB 4101 and chloroethylclonidine all inhibited norepinephrine-induced contraction due to the release of calcium from intracellular stores in both tissues. Our results suggest that there is heterogeneity and complexity of α 1-adrenoceptors in the ovine uterine artery and umbilical vein. Both the chloroethylclonidine-sensitive and -insensitive α 1-adrenoceptor may use both intracellular and extracellular Ca 2+ sources. © 1997 Elsevier Science B.V. All rights reserved.

Arterial size determines the enhancement of contractile responses after suppression of endothelium-derived relaxing factor formation.

We studied the effect of endothelium-derived relaxing factor (EDRF) on norepinephrine-induced contractile responses and on the tissue guanosine-3',5'-phosphate (cGMP) concentration of isolated rabbit arteries with an increasing endothelium to smooth muscle cell ratio (aorta, femoral and mesenteric arteries). After suppression of EDRF formation (either by NG-nitro-L-arginine or, in mesenteric arteries, by saponin), contractions elicited by cumulative doses of norepinephrine were unaltered in aorta but were enhanced by 22.5% in femoral arteries and by 44.3% in mesenteric arteries (at the highest norepinephrine concentration). The cGMP concentration (pmol/mg protein) of unstimulated, endothelium-intact vessels decreased after suppression of EDRF formation from 1.09 +/- 0.24 to 0.74 +/- 0.28 in aortic, from 2.86 +/- 0.4 to 0.61 +/- 0.19 in femoral and from 6.3 +/- 0.9 to 0.7 +/- 0.15 in mesenteric arterial segments. The basal cGMP concentration did not differ in endothelium-denuded segments of these arteries, suggesting a similar basal activity of soluble guanylate cyclase (sGC). A higher sensitivity of sGC may have contributed to the higher cGMP concentration observed in the smaller arteries, since in the presence of sodium nitroprusside the cGMP concentration of endothelium-denuded segments increased 1.8-fold in aortic, 2.9-fold in femoral and 2.4-fold in mesenteric arterial segments. However, these differences in sGC activation cannot be solely responsible for the high basal cGMP concentration in endothelium-intact mesenteric arteries. The greater ratio of endothelium to smooth muscle cell layers in the smaller arteries might result in a higher EDRF concentration in the vascular wall and subsequently in a higher cGMP concentration.(ABSTRACT TRUNCATED AT 250 WORDS)

Changes in extracellular Ca2+ over a physiologic concentration range differentially modulate reactivity of resistance arteries of spontaneously hypertensive and normotensive rats.

Norepinephrine-induced contractile responses of mesenteric resistance arteries of normotensive Wistar Kyoto (WKY) and spontaneously hypertensive (SHR) rats were examined in the presence of 1.25, 1.5, and 2.5 mM extracellular Ca2+. In endothelium-intact WKY segments, the three levels of extracellular Ca2+ had no effect on sensitivity to norepinephrine. However, the response of SHR vessels to low dose norepinephrine was significantly enhanced in the presence of 1.25 and 2.5 mM Ca2+ versus 1.5 mM Ca2+. After endothelial WKY vessels responded like SHR vessels, i.e. sensitivity to norepinephrine was enhanced in 1.25 mM Ca2+ compared with 1.5 mM Ca2+. This response to alterations in extracellular Ca2+ was also observed after blockade of the neuronal amine pump with cocaine. These results indicate that vascular smooth muscle of both SHR and WKY respond to small physiologic changes in extracellular Ca2+ with altered sensitivity to norepinephrine. This effect is independent of the neuronal amine pump. We conclude that the endothelium of the normotensive rat protects against Ca(2+)-induced changes in sensitivity to norepinephrine and this protection is absent in SHR.

Bay K 8644-like contractile effects of a peptide isolated from spontaneously hypertensive rats

The in vitro contractile effect of a peptide recently isolated from the blood of spontaneously hypertensive rats was assessed on rat aortic rings. Preincubation of aortic rings with the peptide had no effect on resting tension but significantly enhanced K+ or norepinephrine-induced contractile responses. Contractile effects were abolished by removal of extracellular calcium or by additions of the calcium channel antagonists, verapamil and nifedipine. The antagonism of peptide enhancement of contraction by verapamil was noncompetitive, whereas nifedipine blockade was competitive in nature. Moreover, preincubation of aortic rings with the peptide attenuated the contractile response to Bay K 8644, a newly described synthetic calcium channel agonist. We suggest that this peptide has similar effects to Bay K 8644 and may act as an endogenous modulator of voltage-dependent calcium channels.

Inhibition of norepinephrine-induced contractile responses of canine mesenteric artery by plant total saponins.

Inhibition of norepinephrine-induced contractile responses of canine mesenteric artery by plant total saponins.

P2B0402) - Influence of Ca antagonists on norepinephrine-induced contractile responses in isolated rabbit vascular smooth muscles

P2B0402) - Influence of Ca antagonists on norepinephrine-induced contractile responses in isolated rabbit vascular smooth muscles