Effects of calyculin A on tension and myosin phosphorylation in skinned smooth muscle of the rabbit mesenteric artery.

1. Using beta-escin and ionomycin-treated skinned smooth muscle strips of the rabbit mesenteric artery, the effects of calyculin A (CL-A, an inhibitor of type 1 and 2A phosphatases) on mechanical activities, phosphorylation of myosin light chain (MLC) and the relationship between the two were studied in Ca(2+)-free solution containing 4 mM EGTA and these effects were compared with those evoked by Ca2+. 2. The threshold concentration of Ca2+ required to increase either tension or MLC-phosphorylation was 0.1 microM and maximum effects were obtained at 10 microM. MLC was mainly monophosphorylated, rather than diphosphorylated, in the presence of Ca2+. ED50 value for Ca2+ was 0.54 microM for either tension or MLC-phosphorylation. The relationship between tension and MLC-phosphorylation is linear in the pCa range 7-5.5. 3. In Ca(2+)-free solution (containing either 20 mM EGTA or 4 mM EGTA with or without 4 mM BAPTA), 3 microM CL-A produced a contraction, the maximum amplitude of which was similar to that evoked by 10 microM Ca2+. CL-A (0.03-3 microM) concentration-dependently increased both tension and MLC-phosphorylation in Ca(2+)-free solution containing 4 mM EGTA. The threshold concentration of CL-A required for the increase in either tension or MLC-phosphorylation was 0.03 microM and maximum effects were obtained at 3 microM. In the presence of CL-A, MLC was not only monophosphorylated but also diphosphorylated. ED50 values for CL-A were 0.39 microM for tension, 0.44 microM for the monophosphorylated form of MLC and 0.54 microM for all phosphorylated (mono + di) forms. The relationship between tension and the monophosphorylated form of MLC was linear over the concentration range studied and was similar to that for Ca2+. 4. H-7 (3 microM, an inhibitor of protein kinase C) inhibited neither the tension nor phosphorylation of MLC induced by 10 microM Ca2+ or 3 microM CL-A. At a high concentration (30 microM), H-7 slightly inhibited both the tension and phosphorylation of MLC induced by either stimulant without a change in the tension-MLC-phosphorylation relationship. KN-62, an inhibitor of Ca(2+)-calmodulin-dependent protein kinase II, did not modify either the tension or the phosphorylation of MLC induced by 10 microM Ca2+ or 3 microM CL-A. CK-II, another inhibitor of Ca(2+)-calmodulin-dependent protein kinase II, did not inhibit the contraction induced by 3 microM CL-A.(ABSTRACT TRUNCATED AT 400 WORDS)     

Vasodilator action of cromakalim on human mesenteric artery

Human mesenteric artery rings (1–3 mm diameter obtained from bowel resections), precontracted with KCl 80 mM, were relaxed by cromakalim (IC₅₀ = 0.39 ± 0.04 μM, maximum inhibition 69 ± 2%). Cromakalim was more effective at inhibiting KCl 40 mM than KCl 80 mM. Cromakalim also inhibited contraction produced by noradrenaline, and was a more potent inhibitor of the second phase of the noradrenaline contraction than of the first phase.     

Effects of nifedipine derivatives on smooth muscle cells and neuromuscular transmission in the rabbit mesenteric artery

The effects of nifedipine and its derivatives, nisoldipine, nimodipine and nitrendipine, on smooth muscle cells and neuromuscular transmission were investigated in the rabbit mesenteric artery. These agents in concentrations of up to 2 X 10(-7) M modified neither the membrane potential nor the membrane resistance, yet did inhibit the spike potential evoked by direct muscle stimulation in the presence of TTX or by perivascular nerve stimulation. The inhibitory action of nitrendipine was weaker than that of the other derivatives. These agents had no effect on the miniature excitatory junction potentials (m.e.j.ps) and e.j.ps evoked by the first stimuli and after completion of the facilitation in a train stimulation. Nifedipine and its derivatives had no effect on the K-induced depolarization but did have a marked effect on the K-induced contraction. Nisoldipine showed the highest inhibitory potency for the K-induced contraction [IC50 was 1.2 X 10(-9) M for the 128 mM (K)o-induced contraction]. Noradrenaline depolarized the membrane (greater than 5 X 10(-7 M) and produced contraction (greater than 3 X 10(-7) M). The contraction evoked by high concentrations of noradrenaline was inhibited by these agents to a greater extent than that evoked by low concentrations. The contraction evoked by perivascular nerve or direct muscle stimulation was partly inhibited by nifedipine and its derivatives. The contraction elicited by Na-free solution was inhibited by these agents but the noradrenaline- or caffeine-induced contraction in Ca-free solution was not. These results indicate that in smooth muscle cells of the rabbit mesenteric artery, nifedipine and its derivatives inhibit the voltage dependent Ca-influx which occurs during the spike potential and in response to K-, electrically- or noradrenaline-induced depolarization. These derivatives appear to have no effect on the adrenoceptor operated Ca increase in myoplasm which occurs in the absence of depolarization at low noradrenaline concentrations. The derivatives act as Ca antagonists with a quantitative difference in potency, i.e. the strongest action was observed with nisoldipine and the weakest with nitrendipine.     

Structure-related blockage of calcium channels by vasodilator alkamides in mice mesenteric artery

The development of new calcium channel blockers is still relevant for the understanding of their physiological role and pharmacological and therapeutic purposes. For this task, natural products represent a relevant source of new drugs. The present work investigated the mechanism and the structural relationship of the vasodilator effect of riparins I, II and III in mouse small mesenteric artery. Riparins I, II and III induced an endothelium-independent and concentration-dependent vasodilator effect in mesenteric arteries. Riparins II and III were more potent than riparin I, suggesting a structural relationship of the effect of these drugs. All riparins inhibited the contractile effect of KCl, similarly to nifedipine. However, the inhibitory profile was different for the contractile responses to phenylephrine and caffeine, passing from similar to nifedipine with riparin I, for similar to SKF-96365 with riparin III. A comparable effect was observed for the increase in the intracellular calcium concentration induced by caffeine and phenylephrine. These results suggest that the higher hydroxylation provides the alkamides the ability to inhibit non-selective cation channels in addition to the inhibition of L-type calcium channels in mouse mesenteric arteries. These observations may give support to the development of new selective inhibitors of non-selective cation channels using alkamides as leading compounds.     

A vasodilator innervation to the central artery of the rabbit ear

1 The possibility of a vasodilator innervation to the isolated and perfused central artery of the rabbit ear was examined.2 Stimulation of the periarterial nerves in the presence of noradrenaline or other agonist used to maintain a partial constriction of the ear artery, led to a decrease in intraluminal flow followed after the cessation of stimulation by an increase in flow beyond the pre-stimulation level.3 After blockade of adrenergic transmission with bretylium or guanethidine or of the alpha- and beta-adrenoceptors with phentolamine and propranolol, stimulation of the periarterial nerves in the presence of a background tone, led to a clearly detectable vasodilation. This dilatation was not blocked by treatment with atropine or mepyramine; nor was it enhanced by physostigmine.4 Pretreatment of rabbits with reserpine (2 mg/kg) to deplete catecholamine stores, eliminated both the vasoconstrictor and vasodilator responses to nerve stimulation. However, a lower dose of reserpine (0.2 to 0.5 mg/kg) selectively eliminated the vasoconstrictor component of periarterial nerve activation.5 The ear artery dilated in response to low concentrations of prostaglandin E(1), and E(2), in the presence of noradrenaline, but treatment with inhibitors of prostaglandin synthesis, indomethacin, aspirin or eicosa-5,8,11,14-tetraynoic acid did not reduce the vasodilator response. Attempts to extract a prostaglandin in the bathing medium were unsuccessful.6 The involvement of a purine nucleotide appeared unlikely since the ear artery dilated only in response to fairly high concentrations of adenosine 5'-triphosphate (ATP), adenosine 5'-diphosphate (ADP) and adenosine 5'-monophosphate (AMP). Furthermore, dipyridamole, an inhibitor of adenosine uptake, enhanced dilation due to exogenous ATP but not to periarterial nerve stimulation.7 It is concluded that the central artery of the rabbit ear has a vasodilator innervation but the identity of the transmitter remains to be established.     

Actions of FRC-8653 on smooth muscle cells of the rabbit mesenteric artery.

In ring preparations of the rabbit mesenteric artery, the Ca-contraction, but not the noradrenaline (NA)-contraction, was inhibited by FRC-8653 (10(-9)-10(-5) M) in a concentration-dependent manner, although with a potency 50-100 times weaker than that of nicardipine. The actions of FRC-8653 on Ca-contraction appeared more slowly (over 1 hr) than those of nicardipine. FRC-8653 (up to 10(-5) M) and nicardipine (up to 10(-7) M) did not change the resting membrane potential of smooth muscles. The amplitude of the evoked excitatory junction potential (e.j.p.) was inhibited by FRC-8653, but not by nicardipine, with no alteration in the facilitation process of the e.j.p.s. The inhibition by FRC-8653 of the e.j.p. appeared rapidly and was reversible. FRC-8653 inhibited the membrane depolarization of smooth muscles elicited by ATP, but not by NA or high [K+]o solution. ATP-induced contractions were also inhibited by FRC-8653. The amplitudes of action potentials evoked by current stimuli were decreased by FRC-8653, with no significant change in the electrotonic potentials. Thus, FRC-8653 has properties similar to those of the dihydropyridine Ca-antagonists, but differs from them in that 1) its inhibitory actions on Ca influx appear slowly and 2) sympathetic transmission is inhibited, possibly by inhibition of the postjunctional events for e.j.p. generation.     

Mechanisms involved in the vasodilator effect induced by diosgenin in rat superior mesenteric artery

The aim of this study was to investigate the vasorelaxant effect induced by diosgenin in superior mesenteric rings. In rings pre-contracted with phenylephrine (10 microM), diosgenin caused concentration-dependent relaxations [EC(50) = (3.3 +/- 1.2) x 10(- 4)M, E(max) = 94.2 +/- 2.6 %]. Vascular relaxation induced by diosgenin was significantly inhibited after removal of the endothelium (E(max) = 46 +/- 8.8%, p < 0.001) or after pre-treatment of the rings with N-nitro-L-arginine methyl esther (l-NAME) 100 or 300 microM (E(max) = 35.3 +/- 4%; 28.1 +/- 3.3%, respectively, p < 0.001), atropine 1 microM (E(max) = 24.6 +/- 3.4%, p < 0.001), hydroxocobalamin 30 microM (E(max) = 54.0 +/- 9.6%, p < 0.001), 1H-[1,2,4]oxadiazolo-[4,3-a]quinoxalin-1-one (ODQ) 10 microM (E(max) = 46.0 +/- 8.0%, p < 0.001) or indomethacin 1 microM (E(max) = 22.6 +/- 11.8%, p < 0.001). Vasorelaxation evoked by diosgenin was significantly inhibited after pre-treatment of preparations with both selective and non-selective inhibitors of large conductance Ca(2+)-activated K(+) (BK(Ca)) channels, iberiotoxin 100 nM or tetraethylammonium (TEA) 1mM, respectively (E(max) = 62.5 +/- 9.1%; 65.7 +/- 1.1%, p < 0.001). Conversely, in endothelium-denuded vessels, none of BK(Ca) channel blockers modified the relaxant effect induced by diosgenin. In mesenteric endothelial cells loaded with FURA-2 diosgenin was able to increase intracellular calcium concentrations, which were significantly decreased by atropine 1 microM. In addition, in isolated mesenteric rings, diosgenin induced marked increase in nitric oxide (NO) levels, which was completely abolished after functional endothelium removal. The results obtained here demonstrated that diosgenin-induced relaxation appears to involve endothelial muscarinic receptor activation with increase in intracellular calcium concentrations and consequent release of endothelium-derived relaxing factors (EDRFs), mainly NO and cyclooxygenase derivatives, which activate BK(Ca) channels. Nevertheless, further studies are necessary to clearly elucidate residual endothelium-independent relaxation induced by diosgenin.     

The action of tyramine on the rabbit ear artery

1. The vasoconstrictor potency of extraluminal tyramine on the isolated perfused rabbit ear artery is considerably greater than that of intraluminal tyramine.2. Chronic denervation, which caused the noradrenergic storage structures in the medial-adventitial border of the artery to disappear, reduces the potency of extraluminal tyramine more than that of intraluminal tyramine so that the difference in potency for the two routes of administration tends to disappear. Cocaine exerts a greater inhibitory effect on responses to extraluminal tyramine than on those to intraluminal tyramine.3. It is concluded that the indirect component plays a more prominent part in the responses to extraluminal tyramine than in those to intraluminal tyramine. This conclusion is supported by analysis of the diphasic response of the artery to intraluminal injection of tyramine under perfusion conditions which permit intraluminal fluid to mix with the extraluminal fluid. Evidence is presented that the first phase of the response is mediated by intraluminal tyramine, and the second phase by extraluminal tyramine.     

3H-spiroperidol binding sites in the rabbit superior mesenteric artery. A histoautoradiographic study

The distribution of 3H-spiroperidol binding sites within rabbit superior mesenteric artery was studied in normal as well as 6-hydroxydopamine (6-OHDA) sympathectomized animals using a histoautoradiographic technique. The labelled drug was located in the three layers of the artery (adventitia, media and intima), with the greater density in the media. In the adventitia the radiolabelled drug was located at the level of fibrous and connective cells. In the media 3H-spiroperidol was bound by smooth muscle cells and is found in the cellular membrane of the same cells. 6-OHDA administration causes an increase in the number of 3H-spiroperidol binding sites in the adventitia and as well as a 20-25% increase in the media. The possible existence of a direct dopaminergic innervation of the superior mesenteric artery is discussed.     

Mechanisms of hydrogen peroxide-induced relaxation in rabbit mesenteric small artery

The effects of hydrogen peroxide were studied on isolated rabbit mesenteric small artery; rabbit superior mesenteric artery and mouse aorta were also studied as reference tissues. For mesenteric small artery, hydrogen peroxide (1 to 100 microM) relaxed a norepinephrine-stimulated artery in a concentration-dependent manner. The relaxation was not significantly affected by removal of the endothelium and was less pronounced in arteries contracted with high-KCl solution plus norepinephrine than in those contracted with norepinephrine alone. The relaxation response to hydrogen peroxide was increased by isobutylmethylxanthine and zaprinast, inhibited by diclofenac, methylene blue and dithiothreitol and unaffected by atropine, tetraethylammonium, superoxide dismutase, deferoxamine, dimethyl sulfoxide or the Rp stereoisomer of adenosine cyclic monophosphothioate. Hydrogen peroxide shifted concentration-contractile response curves for norepinephrine to the right and downwards. Norepinephrine and caffeine elicited a transient, phasic contraction of the mesenteric small artery exposed for 0.5, 1 and 2 min to a Ca2+-free solution. Hydrogen peroxide inhibited the norepinephrine-induced contraction, and to a lesser extent the caffeine-induced contraction, and verapamil did not alter the contraction to norepinephrine. These pharmacological properties of hydrogen peroxide were similar to those of 8-bromo cGMP; 8-bromo cGMP inhibited more potently the norepinephrine-induced than the KCl-induced contraction and the contraction elicited by norepinephrine in Ca2+-free solution. The present results suggest that hydrogen peroxide induces endothelium-independent relaxation of the rabbit mesenteric small artery precontracted with norepinephrine. The effects of hydrogen peroxide may be at least in part mediated by cGMP and cyclooxygenase products in the vascular smooth muscles now used.     

Effects of oxodipine on isolated rabbit aorta and mesenteric resistance vessels.

The inhibitory effects of the dihydropyridine Ca2+ antagonist, oxodipine, on contractions and 45Ca2+ influx stimulated by noradrenaline (NA) and high K+ in rabbit aorta were compared to the same parameters measured in mesenteric resistance arteries. In aortic rings oxodipine, 10(-11)-10(-6) M, inhibited in a concentration-dependent manner the contractions induced by high K+ (IC50 = 9.0 +/- 4.0 x 10(-10) M) or by Ca2+ in high K+ solution (IC50 = 6.2 +/- 2.4 x 10(-9) M), while responses to NA were only slightly affected (IC50 greater than 10(-6) M). In mesenteric resistance vessels oxodipine inhibited the contractions induced by high K+ and NA but was more effective against NA- than high K(+)-induced contractions (IC50 = 5.2 +/- 3.1 x 10(-10) and 1.2 +/- 1.8 x 10(-8) M, respectively). The concentration-inhibition curves for high K(+)-induced contraction and 45Ca2+ influx in aorta were almost superimposable (I50 = 2.2 +/- 2.0 x 10(-9) M), whereas NA-induced contractions were inhibited less than 45Ca2+ influx (I50 = 8.2 +/- 2.6 x 10(-8) M). In mesenteric resistance vessels the curves for contraction and 45Ca2+ influx stimulated by high K+ and NA were also superimposable, but 45Ca2+ influx stimulated by NA was more sensitive to oxodipine than that stimulated by high K+ (I50 = 3.9 +/- 2.0 x 10(-10) and 2.2 +/- 1.2 x 10(-8) M, respectively). It is concluded that the effects of oxodipine can be attributed to its ability to inhibit Ca2+ entry through both potential- and receptor-operated pathways.(ABSTRACT TRUNCATED AT 250 WORDS)     

Human interleukin-1 induces a rapid relaxation of the rabbit isolated mesenteric artery.

1. Strips of rabbit superior mesenteric artery, precontracted with phenylephrine, relaxed when exposed to human recombinant interleukin-1 (IL-1) of the alpha or beta types. The effect was observed within 10 min, was optimal 32 min after the application of the cytokines and concentration-dependent (12-290 pM). 2. IL-1 alpha and IL-1 beta were equipotent in relaxing the rabbit mesenteric artery. A synthetic fragment corresponding to IL-1 beta 163-171 was approximately one million fold less active than IL-1 beta. The tripeptide Lys-D-Pro-Thr, an analogue of IL-1 beta 193-195, was inactive as an antagonist of IL-1 beta on the preparation. 3. Indomethacin (2.8 microM) prevented or acutely reversed IL-1-induced relaxations in the rabbit mesenteric artery. Purified haemoglobin (10 microM) or the removal of endothelium had no effect on relaxations elicited by IL-1 beta. 4. The preparation exhibited some selectivity for IL-1 as recombinant human tumour necrosis factor-alpha (TNF-alpha), IL-2 or IL-6 failed to influence it. TNF-alpha was not synergistic with a subthreshold concentration of IL-1 beta. 5. Immunoreactive 6-keto-prostaglandin F1 alpha and prostaglandin E2 were increased in the bathing fluid of isolated mesenteric arteries exposed to IL-1 beta as compared to controls. 6. A supernatant of lipopolysaccharide-stimulated human monocytes produced a relaxation of the preparation with a profile similar to that produced with IL-1s and there was a good quantitative agreement between the extent of the relaxation and the enzyme immunoassay measurements of IL-1 alpha and IL-1 beta in the supernatant.(ABSTRACT TRUNCATED AT 250 WORDS)     

Effects of BRL 38227 on potassium currents in smooth muscle cells isolated from rabbit portal vein and human mesenteric artery.

1. Single smooth muscle cells were isolated from the rabbit portal vein and the human mesenteric artery and whole cell currents recorded at room temperature from either cell type by the whole cell voltage clamp technique. 2. In the rabbit portal vein cells addition of 10 microM BRL 38227 induced a quasi-instantaneous, voltage-insensitive and time-independent current which had a reversal potential of -75 mV under experimental conditions where the calculated EK was -83 mV. 3. Cells were held at 0 mV and BRL 38227 was added cumulatively to construct a dose-response relationship. BRL 38227 (0.03-10 microM) caused a dose-dependent outward shift in the holding current with an EC50 of 1.3 microM. 4. BRL 38227 (10 microM) had no effect on the delayed rectifier K+ current measured in the presence of 5 mM tetraethylammonium and no effect on the Ca(2+)-activated K+ current measured in the presence of 5 mM 4-aminopyridine. Similarly BRL 38227 had no effect on the Ca2+ current. 5. The BRL 38227-induced current was blocked by glibenclamide (10 microM) and phentolamine (100 microM), specific blockers of the ATP-sensitive K+ current in single cells. 6. In human isolated mesenteric artery cells, BRL 38227 (10 microM) induced a glibenclamide-sensitive current similar to, but smaller than, that observed in the rabbit portal vein. 7. We conclude that in these cells, BRL 38227 activates a potassium conductance which has the electrophysiological and pharmacological characteristics of ATP-sensitive K+ channels.     

Identification of the neuroeffector transmitter in jejunal branches of the rabbit mesenteric artery

Summary Vasoconstriction or excitatory junction potentials (e.j.ps) evoked by nerve stimulation (15 field pulses at 2 Hz every 3 min) were recorded in rabbit isolated jejunal arteries. The resting diameter of the arteries and its decrease in response to stimulation was measured by a photoelectric method. Vasoconstriction was insensitive to prazosin 0.1 or 1 mol/l. Yohimbine 1 mol/l considerably enhanced, whereas ,-methylene ATP (,-meATP) 1 mol/l abolished the contractile response. In order to test the effect of exogenously applied transmitter candidates, noradrenaline (0.1–1 mol/l) and ATP (10–30 mol/l) were added in concentrations which evoked a vasoconstriction comparable to that induced by electrical stimulation. The action of noradrenaline was prevented by prazosin 0.1 mol/l, but was unaffected by both yohimbine 1 mol/l and ,-meATP 1 mol/l. ,-meATP 1 mol/l depressed the effect of ATP. The e.j.ps evoked by a train of 15 pulses showed facilitation up to the third response and thereafter depression; a partial summation was also observed. Prazosin 0.1 mol/l did not change the e j.p. amplitudes. By contrast, when yohimbine 0.1 or 1 mol/l was added to the prazosin-containing medium, both the late e j.ps in the train and the summation were enhanced in a concentration-dependent manner. ,-meATP 1 mol/l almost abolished the e.j.ps. In conclusion, in rabbit jejunal arteries, stimulation of postganglionic sympathetic nerves may release noradrenaline together with ATP which is probably the sole neuroeffector transmitter under our conditions. Transmitter release seems to be modulated by the activation of presynaptic ₂-adrenoceptors. Under the stimulation conditions of the present experiments the released transmitter does not activate postsynaptic ₁-adrenoceptors. Send offprint requests to P. Illes     

Effects of H2O2 on membrane potential of smooth muscle cells in rabbit mesenteric resistance artery

The effects of H(2)O(2) on the membrane potential of smooth muscle cells of rabbit mesenteric resistance arteries were investigated. H(2)O(2) (3-30 microM) concentration-dependently hyperpolarized the membrane; this was inhibited by catalase but not by superoxide dismutase or the hydroxyl-radical scavenger dimethylthiourea. The cyclooxygenase inhibitor diclofenac partly inhibited the responses; the subsequent addition of the 5-lipoxygenase inhibitor 2-(12-hydroxydodeca-5,10-diynyl)-3,5,6-trimethyl-p-benzoquinone (AA-861) (but not the cytochrome P(450) inhibitor 17-octadecynoic acid) further attenuated H(2)O(2)-induced hyperpolarizations. The sarcolemmal ATP-sensitive K(+) (K(ATP)) channel inhibitor 1-[5-[2-(5-chloro-o-anisamido)ethyl]-2-methoxyphenylsulfonyl]-3-methylthiourea, sodium salt (HMR-1098), blocked the H(2)O(2)-induced hyperpolarization in the absence and presence of diclofenac. H(2)O(2) increased the production of prostaglandin E(2) and prostacyclin (estimated from its stable metabolite 6-keto-prostaglandin F(1alpha)), both of which produce a HMR-1098-sensitive hyperpolarization in the smooth muscle cells. It is concluded that, in smooth muscle cells of rabbit mesenteric artery, H(2)O(2) increases the synthesis of vasodilator prostaglandins and possibly 5-lipoxygenase products, which produce a hyperpolarization by activating sarcolemmal K(ATP) channels.     

Effects of dopamine on neuromuscular transmission in the guinea-pig mesenteric artery

The effects of dopamine on neuromuscular transmission in the guinea-pig mesenteric artery were investigated using a microelectrode method. Dopamine did not modify the membrane potential or the membrane resistance of the smooth muscle, but did reduce the amplitude of excitatory junction potentials (e.j.p.) and enhance the facilitation of e.j.p. produced by repetitive stimulation. Phentolamine (10(-7) M) enhanced the amplitude and the facilitation of the e.j.p., and with the addition of dopamine (10(-6) M) there was a reduction in the amplitude of e.j.p. but not in the facilitation. Haloperidol and sulpiride (greater than 10(-6) M) increased the amplitude of e.j.p. without altering the postjunctional membrane properties. Haloperidol and sulpiride did not increase the facilitation of e.j.p. produced by repetitive stimulation. In the presence of haloperidol or sulpiride (10(-5) M), dopamine (10(-6) M) did not suppress the amplitude of the e.j.p. These results indicate that in the guinea-pig mesenteric artery, dopamine inhibits the release of transmitter at the presynaptic membrane.     

Facilitating interaction between rauwolscine and angiotensin in the mesenteric artery of the rabbit

Summary The interaction between rauwolscine and angiotensin II was investigated in the isolated mesenteric artery of the rabbit. Rauwolscine, known as an antagonist at ₂-adrenoceptors, did not induce contraction itself but interacted with angiotensin to produce a facilitated response of the vascular tissue. In the presence of rauwolscine, the contractile response of the tissue to angiotensin was markedly enhanced. The degree of facilitation appeared to be dependent on the rauwolscine concentration used rather than that of angiotensin. Moreover, rauwolscine induced a concentration-dependent increase in tension (pD₂=6.8) in the presence of even subcontractile concentrations of angiotensin (10^–10 mol/l). This effect was not attributable to an indirect action involving presynaptic catecholamines, as revealed by the use of tissue strips from animals pretreated with reserpine or after chemical sympathectomy. Furthermore, an interaction via the prostaglandin system was excluded by negative results obtained with indomethacin. The agonistic effect of rauwolscine was significantly attenuated by phentolamine (₁/₂) but not by prazosin (₁) or phenoxybenzamine when applied for only a short time. The ₂-antagonist BDF 6143 behaved like rauwolscine whereas the ₁-antagonist corynanthine, a stereoisomer of rauwolscine, did not. The results indicate that the rauwolscine effect is mediated by a receptor with ₂-characteristics. In general, angiotensin appears to interfere with some process which determines the expression of a drug's intrinsic effect.This study was supported by a grant of the Deutsche Forschungsgemeinschaft