Contractions Of Rat Portal Vein Research Articles

Adenosine affects the calcium dynamics of rat portal vein.

1. The present study was carried out to characterize the effect of adenosine on calcium dynamics in the rat portal vein. Isolated portal vein of male albino rats was used as the experimental model as it exhibits autorhythmicity. 2. Adenosine and its analogues 2-CAD, N6-CHA and NECA were used to characterize the type of adenosine receptor involved and 2-CAD was used along with adenosine throughout the other part of study to characterize the effect of adenosine on Ca2+ dynamics. Adenosine and its analogues were found to inhibit the spontaneous contractions of rat portal vein in a concentration-related manner. The order of potency was NECA > 2-CAD > N6-CHA > adenosine. Incubation of the tissue with CGS-15943A, an adenosine receptor antagonist, had a per se enhancing effect on autorhythmicity. Adenosine and 2-CAD failed to reverse the contractile response produced by hypertonic KCl (80 or 30 mM). Whereas adenosine and 2-CAD effectively relaxed the tissues contracted with phenylephrine (10(-5) m). 3. Preincubation of the tissue with 2-CAD (10(-4), 10(-5) or 10(-6) m) for 5 min raised the threshold concentration of CaCl2 to evoke contractile response and also significantly increased the mean EC50 values of CaCl2. Nifedipine was found to be more potent than 2-CAD on Ca2+ channels. 4. The results of the present study suggest that the endogenous adenosine plays a significant role in producing vascular relaxation through the participation of A2 receptor subtype. This effect may be due to its inhibitory effect on release of Ca2+ from the intracellular stores. Further to this effect, 2-CAD had a major inhibitory effect on voltage-operated Ca2+ channels compared with receptor-operated Ca2+ channels. 5. It can be concluded that adenosine through its A2 receptor produces vasorelaxant effect by interfering with the release of Ca2+ from the intracellular stores coupled with influx of Ca2+ from the extracellular sources.

In vitro and in vivo biological activities of SR140333, a novel potent non-peptide tachykinin NK 1 receptor antagonist

( S)1- {;2-[3-(3,4-dichlorophenyl)-1-(3-isopropoxyphenylacetyl)piperidin-3-yl]ethyl };-4-phenyl-1-azoniabicyclo[2.2.2]octane chloride (SR140333) is a new non-peptide antagonist of tachykinin NK 1 receptors. SR140333 potently, selectively and competitively inhibited substance P binding to NK 1 receptors from various animal species, including humans. In vitro, it was a potent antagonist in functional assays for NK 1 receptors such as [Sar 9,Met(O 2) 11]substance P-induced endothelium-dependent relaxation of rabbit pulmonary artery and contraction of guinea-pig ileum. Up to 1 μM, it had no effect in bioassays for NK 2 ([βAla 8]neurokinin A-induced contraction of endothelium-deprived rabbit pulmonary artery) and NK 3 ([MePhe 7]neurokinin B-induced contraction of rat portal vein) receptors. The antagonism exerted by SR140333 toward NK 1 receptors was apparently non-competitive, with pD' 2 values (antagonism potency evaluated by the negative logarithm of the molar concentration of antagonist that produces a 50% reduction of the maximal response to the agonist) between 9.65 and 10.16 in the different assays. SR140333 also blocked in vitro [Sar 9,Met(O 2) 11]substance P-induced release of acetylcholine from rat striatum. In vivo, SR140333 exerted highly potent antagonism toward [Sar 9,Met(O 2 11]substance P-induced hypotension in dogs ( ED 50 = 3 μg/kg i.v., bronchoconstriction in guinea-pig (ED 50 = 42 μg/kg i.v.) and plasma extravasation in rats (ED 50 = 7 μg/kg i.v.). Finally, it also blocked the activation of rat thalamic neurons after nociceptive stimulation (ED = 0.2 μg/kg i.v.).

Ammonium ion increases the tone of rat portal vein

1. 1. The effect of ammonium ion on vascular tone was investigated using the portal vein isolated from rat. 2. 2. Ammonium chloride at 10–90 mM induced a contractile response. 3. 3. Spontaneous twitch contraction of portal strips was augmented by ammonium chloride at 10–60 mM. 4. 4. Ammonium chloride-induced contraction was abolished in calcium-free solution or in the presence of 1 μM nifedipine. 5. 5. Methylamine (60 mM) also induced a contractile response and augmented the spontaneous twitch contraction in rat portal vein. 6. 6. After withdrawal of ammonium chloride or methylamine from the organ bath solution, the spontaneous twitch contraction was strongly inhibited. 7. 7. These results suggest that ammonium compounds increase vascular tone by causing influx of extracellular calcium through the voltage-dependent calcium channel and intracellular alkalinization is involved in this process.

Antihypertensive and vasodilator effect of A-80b, a new pyridazino indole derivative

The hypotensive and antihypertensive activities of a A-80b, a newly synthesized pyridazino[4,5-b]indole derivate were investigated in anaesthetized rats. In vitro studies were also done to examine the possible mechanism of its vasodilator action. A 80b (3–15 mg/kg i.p.) showed potent and long-lasting antihypertensive activity in spontaneous hypertensive rats. In normotensive rats, A-80b (7.5–30 mg/kg i.p.) also lowered blood pressure but less than in hypertensive rats. The decrease in diastolic pressure was greater than the decrease in systolic pressure and cardiac frequency was not modified significantly. Contractile responses induced in isolated rat thoracic aorta by K+ and noradrenaline were inhibited by A-80b. In K+-depolarized rat aorta, A-80b showed dose-dependent inhibition of the Ca2+-induced contraction. Also, A-80b inhibited spontaneous contractions of rat portal vein. The vasodilator action seemed to be endothelium-independent. These results suggest that A-80b is a new chemical entity which exerts a hypotensive and antihypertensive effect, possibly attributable to vasodilator activity via interference with Ca2+ influx and probably Ca2+ mobilization from intracellular stores.

Patent Evaluation: Novel Tetralones as Potassium Channel Activators

SummaryNovelty: Novel tetralones are disclosed which are said to be potassium channel activators. These are potentially useful in the treatment of hypertension and asthma.Biology: In vitro activity was determined by measuring the compounds' ability to inhibit noradrenaline-induced contractions of rat portal vein, and resting tension of guinea-pig trachea. In vivo activity was determined by measuring the reduction of blood-pressure in SHR rats. Data are given for twenty-four compounds. 1,2-Dihydro-4-(1,2-dihydro-2-oxo-1-pyridyl)-2,2-dimethyl-1-oxonaphthalene-6-carbonitrile had IC50s of 0.6 and 0.1 μM, respectively, and produced a 97 mmHg decrease in blood pressure at 1 mg/kg po.Chemistry: The syntheses of sixty-five examples and fifty-five intermediates are detailed. The compounds are prepared by the epoxidation of dihydronaphthalene-ones followed by amine-induced epoxide opening. Fourteen compounds are specifically claimed.Structure:

FR 113680: a novel tripeptide substance P antagonist with NK1 receptor selectivity.

1. We have discovered a novel tripeptide substance P (SP) antagonist, FR 113680 [N alpha-[N alpha-(N alpha-acetyl-L-threonyl)-N'-formyl-D- tryptophyl]-N-methyl-N-phenylmethyl-L-phenylalaninamide]. In binding experiments, FR 113680 inhibited [3H]-SP binding to guinea-pig lung membranes (NK1) in a competitive manner but had not effect on [3H]-SP binding to rat cerebral cortical membranes (NK1), [3H]-neurokinin A ([3H]-NKA) binding to rat duodenum smooth muscle membranes (NK2) and [3H]-eledoisin (Ele) binding to rat cerebral cortical membranes (NK3). 2. In bioassay experiments, FR 113680 dose-dependently inhibited SP-induced guinea-pig ileum contraction (NK1), but did not inhibit either NKA-induced rat vas deferens contraction (NK2) or neurokinin B (NKB)-induced contraction of rat portal vein (NK3). According to Schild plot analysis, the inhibitory effect of FR 113680 on SP-induced guinea-pig ileum contraction is competitive and the pA2 value is 7.53. 3. The inactivity of FR 113680 on NK1 receptors in rat compared to guinea-pig may represent species-specific forms of the NK1 receptor. 4. These findings suggest that FR 113680 interacts selectively with the NK1 neurokinin receptor.

Comparison of the effects of several potassium‐channel openers on rat bladder and rat portal vein in vitro

1. The ability of several K-channel openers to inhibit KCl-induced contractions of rat bladder detrusor and spontaneous mechanical activity in rat portal vein was examined. 2. Lemakalim, pinacidil, Ro 31-6930, RP 49356, P1060 and S 0121 dose-dependently relaxed rat detrusor, precontracted with 20 mM KCl. With the exception of pinacidil, concentrations of these agents below 30 microM did not inhibit 80 mM KCl-included contractions. Pinacidil (10 microM) produced a small, but significant (P < 0.05) relaxation of 80 mM KCl-induced mechanical activity. Minoxidil sulphate and BRL 38226 produced some relaxation of 20 mM but not 80 mM KCl-induced contractions. 3. Glibenclamide (0.3-3 microM) antagonized the relaxant effects of lemakalim, pinacidil, Ro 31-6930, RP 49356, P1060 and S 0121 in a competitive manner (pA2 values 6.3-6.6). The effects of minoxidil sulphate and BRL 38226 were fully antagonized by 3 microM glibenclamide. 4. Lemakalim, pinacidil, S 0121, BRL 38226 and minoxidil sulphate were each approximately 8 times more potent as inhibitors of the spontaneous contractions of rat portal vein than KCl-induced contractions of the rat detrusor. Minoxidil sulphate was approximately 30 times more potent in the rat portal vein than in the bladder. This may indicate that either minoxidil sulphate is acting at different recognition sites in these two tissues, or that this compound has an additional mechanism of action in the portal vein. 5. With the exception of minoxidil sulphate, all the compounds tested stimulated 86Rb efflux and 42K efflux from preloaded rat detrusor strips. The stimulated 86Rb efflux was qualitatively but not quantitatively similar to the stimulated 42K efflux. Minoxidil sulphate stimulated 42K efflux from rat portal vein but not from rat bladder. 6. It is concluded that all the compounds tested cause relaxation of rat detrusor predominantly by Kchannel opening. Selectivity for bladder rather than vascular smooth muscle was not shown by any compound.

Caffeine-induced contraction of rat portal vein and effects of K-depolarization, Na-removal and low temperature.

Contribution of Ca influx from extracellular pool and Ca-release from store sites in caffeine-induced contraction of rat portal vein longitudinal muscle were examined. At 37 degrees C caffeine induced a phasic contraction and the contraction was inhibited by verapamil or in the absence of Ca. Under low temperature, it was not decreased remarkably by verapamil or by the removal of extracellular Ca. Na-removal potentiated caffeine-induced contraction in the absence of Ca. Caffeine-induced contraction was also potentiated by high-K-depolarization. These contractions were at both temperature inhibited greatly by ryanodine. Caffeine induced the burst of the action potential at 37 degrees C but it was not remarkable at 17 degrees C. These results indicate that both extracellular Ca influx and release of stored Ca are involved in the caffeine-induced contraction. However, dependence of the contraction on Ca sources are influenced by temperature, extracellular Na and membrane potential.

O-129 - Effects of caffeine and ryanodine on the contraction of rat portal vein.

O-129 - Effects of caffeine and ryanodine on the contraction of rat portal vein.

Effects of calcium entry blockers on calcium-dependent contractions of rat portal vein.

1 The effects of six calcium entry blockers belonging to the dihydropyridine (isradipine or PN 200-110, nifedipine, nicardipine), verapamil (D888 or desmethoxyverapamil, D600 or gallopamil) and diltiazem classes were investigated on isometric spontaneous contractions and contractions induced by high-K+ solutions, noradrenaline, acetylcholine and caffeine. 2 The rank order of potency was PN 200-110 greater than nicardipine = nifedipine = D888 greater than D600 greater than diltiazem from experiments on spontaneous contractions and high-K+ induced contractions. With depolarized preparations, the concentration-response curves for nicardipine, PN 200-110, nifedipine and D600 were significantly shifted to the left indicating that the calcium entry blockers show voltage-dependent inhibitory properties. This effect was not significant with D888 and diltiazem. 3 All the calcium entry blockers strongly reduced the noradrenaline (NA)- and acetylcholine (ACh)-induced contractions at concentrations which produced complete inhibition of spontaneous contractions. They had a slight effect on caffeine-induced contractions. 4 In Ca2+-free, EGTA-containing solutions, both ACh, NA and caffeine produced transient contractions, the amplitude of which could be taken as a measurement of the amount of internal calcium present in a drug-sensitive calcium store. The filling of the calcium store was maximal after 10-12 min of calcium loading in 2.1 mM Ca2+, while the depletion was complete after 4-6 min of perfusion in Ca2+-free solution. 5 At concentrations which abolished spontaneous contractions, PN 200-110, nifedipine, D888 and D600 had no appreciable effect on contractions evoked in Ca2+-free solutions by ACh, NA and caffeine. When added in Ca2+-containing solutions diltiazem and, to a lesser extent, nicardipine strongly reduced the contractions evoked in Ca2 -free solutions, suggesting that they inhibited the filling of the internal calcium store. 6. These results indicate that the six calcium entry blockers are potent inhibitors of calcium influx through voltage-dependent calcium channels. Two of them (diltiazem and nicardipine) may exert an additional effect to depress contractions dependent on intracellular calcium release.

Calcium pools for noradrenaline and potassium-induced contractions of rat portal vein.

The contractile responses of isolated normal and Ca-depleted rat portal veins to varying concentrations of noradrenaline (NA) and K+ have been studied with a view to further clarifying the sources of Ca for contraction using both agents. The comparably rapid times-to-peak of NA and K+ contractions of normal (Ca-containing) strips suggest mobilization of a common Ca pool, perhaps superficial: whereas, following Ca-depletion. NA appears to mobilize a superficial pool more readily than K+. Following K+ depolarization in Ca-free medium, NA produced a contraction sensitive to ryanodine, suggesting Ca release from an intracellular pool.

Tris does not inhibit isolated vascular or intestinal smooth muscle contraction.

There are conflicting reports on the effect of tris(hydroxymethyl)aminomethane (Tris) on smooth muscle contraction. Therefore, the effect of substitution of Tris for bicarbonate in physiological saline solution on smooth muscle contractility was investigated. Tris (25 mM) increased the amplitude without changing the frequency of spontaneous contractions in rat portal vein. Tris did not inhibit either norepinephrine-induced contractions in rat portal vein and aorta or histamine-induced contractions in taenia coli. When the pH of the Tris-buffered solution was lowered from the control value of 7.4 to 7.0, spontaneous contractions in portal vein as well as agonist-induced contractions in all of the above preparations were inhibited. Tris did not inhibit contractions induced by calcium in potassium-depolarized smooth muscle preparations if the Tris-buffered solution contained sufficient amounts of sodium ion (as did bicarbonate-buffered solution). These results suggest that Tris does not inhibit contractile responses of isolated vascular and intestinal smooth muscle preparations provided that the conditions other than the buffer system (especially pH of solution) are similar to those in bicarbonate-buffered solutions.

Artificial buffers do not inhibit contractile responses in the smooth muscle of rat portal vein and guinea pig taenia coli.

Effects of substitution for NaHCO3 (and 5% CO2) in the physiological solution with equimolar N-2-hydroxyethylpiperazine-N'-2-ethanesulfonic acid (HEPES) or morpholinopropane sulfonic acid (MOPS) (and 100% O2) at various pH levels on the contractility of smooth muscle were examined. At pH 7.4, spontaneous contraction in rat portal vein was not inhibited by the artificial buffer solutions, as compared to findings in the case of bicarbonate buffer solution. Norepinephrine-dose response curve in the case of rat portal vein and the histamine-dose response curve in cases of guinea pig taenia coli remained unchanged in the artificial buffer solutions. At pH 7.2 and 7.0, the spontaneous contraction in portal vein was reversibly inhibited either in artificial or in bicarbonate buffer solutions. The norepinephrine- and histamine-dose response curve shifted downwards and/or to the right in these low pH solutions. Thus, HEPES and MOPS had no inhibitory effect on the smooth muscle contractility. Since low pH strongly inhibited the contractility, attention should be directed to the temperature-dependent decreases in pKa of the artificial buffers (i.e., if pH of the solution is adjusted at room temperature and then warmed, pH decreases).

ARTIFICIAL BUFFERS DO NOT INHIBIT CONTRACTILE RESPONSES IN THE SMOOTH MUSCLE OF RAT PORTAL VEIN AND GUINEA PIG TAENIA COLI

AbstractEffects of substitution for NaHCO3 (and 5% CO2) in the physiological solution with equimolar N-2-hydroxyethylpiperazine-N’-2-ethanesulfonic acid (HEPES) or morpholinopropane sulfonic acid (MOPS) (and 100% O2) at various pH levels on the contractility of smooth muscle were examined. At pH 7.4, spontaneous contraction in rat portal vein was not inhibited by the artificial buffer solutions, as compared to findings in the case of bicarbonate buffer solution. Norepinephrine-dose response curve in the case of rat portal vein and the histamine-dose response curve in cases of guinea pig taenia coli remained unchanged in the artificial buffer solutions. At pH 7.2 and 7.0, the spontaneous contraction in portal vein was reversibly inhibited either in artificial or in bicarbonate buffer solutions. The norepinephrine- and histamine-dose response curves shifted downwards and/or to the right in these low pH solutions. Thus, HEPES and MOPS had no inhibitory effect on the smooth muscle contractility. Since low pH strongly inhibited the contractility, attention should be directed to the temperature-dependent decreases in pKa of the artificial buffers (i.e., if pH of the solution is adjusted at room temperature and then warmed, pH decreases).