Dissociation constants (KA) and relative efficacies of sympathomimetic amines in isolated atria during hypothermia-induced supersensitivity

1983 ◽  
Vol 61 (6) ◽  
pp. 572-580 ◽  
Author(s):  
Kenneth J. Broadley ◽  
John H. McNeill
Keyword(s):  
Dose Response ◽  
Dissociation Constants ◽  
Response Curves ◽  
Isolated Atria ◽  
Adrenoceptor Agonists ◽  
Dose Response Curves ◽  
The Right ◽  
Tension Curves ◽  
Noradrenaline And Adrenaline ◽  
Right Atria

Hypothermia increases the sensitivity of isolated cardiac muscle to stimulation by β-adrenoceptor agonists. The purpose of this study was to determine pharmacologically whether this supersensitivity is associated with a change in the affinity of agonists for the receptor. The positive inotropic and chronotropic responses of guinea-pig paced left and spontaneously beating right atria were recorded. Cumulative dose–response curves to noradrenaline (or adrenaline) were compared with isoproterenol in each tissue. At 38 °C, the rate curves were to the left of the tension curves, with lower mean effective concentration (EC50) values. However, this difference was less for noradrenaline and adrenaline which were therefore tension selective relative to isoproterenol. Lowering the temperature to 25 °C induced supersensitivity, all dose–response curves being displaced to the left. In the presence of carbachol the curves were shifted to the right with depression of the maxima. Dissociation constants (KA) were calculated from plots of reciprocals of equiactive concentrations obtained before and in the presence of carbachol. KA values for rate and tension responses of each agonist were identical at 38 °C, indicating that the rate selectivity was not due to affinity differences. The efficacies (er) of noradrenaline and adrenaline were greater than isoproterenol for tension, but smaller for rate responses, which may explain their relative tension selectivity. At 25 °C the KA values of all agonists were reduced approximately 10-fold. Hypothermia-induced supersensitivity is therefore associated with an increase in affinity for the cardiac β-adrenoceptor.

Competitive antagonism of pressor responses to angiotensin II and angiotensin III by the angiotensin II-1 receptor ligand losartan

1992 ◽  
Vol 70 (5) ◽  
pp. 716-719 ◽  
Author(s):  
Aly Abdelrahman ◽  
Catherine C. Y. Pang
Keyword(s):  
Angiotensin Ii ◽  
Dose Response ◽  
Dissociation Constants ◽  
Ang Ii ◽  
Receptor Ligands ◽  
Response Curves ◽  
Competitive Antagonism ◽  
Angiotensin Iii ◽  
Dose Response Curves ◽  
The Right

Losartan (DuP 753) and PD123177 are nonpeptide angiotensin (ANG) receptor ligands for subtypes of ANG II receptors ANG II-1 and ANG II-2, respectively. We examined the effects of losartan and PD123177 on dose – mean arterial pressure (MAP) response curves for ANG II and ANG III in eight groups (n = 6 each) of conscious rats. Saline (0.9% NaCl), losartan (1 × 10−6 and 9 × 10−6 mol/kg), and PD123177 (2 × 10−5 mol/kg) were i.v. bolus injected 15 min before the construction of ANG II dose–response curves in groups I, II, III, and IV, respectively. Groups V–VIII were treated similarly to I–IV except that ANG III was given in place of ANG II. Losartan dose dependently shifted the dose–response curves of ANG II and ANG III to the right with similar dissociation constants (−log KI of 6.6 ± 0.7 and 6.6 ± 0.1 mol/kg, respectively) and no change in the maxima. PD123177 affected neither maximum MAP nor ED50 values for ANG II or ANG III. Our results show that losartan but not PD123177 is a competitive antagonist of the MAP effects of ANG II and ANG III.Key words: nonpeptide angiotensin receptor antagonist, angiotensin II, angiotensin III, blood pressure, losartan.

Characterization of sulfidopeptide leukotriene responses in sheep tracheal smooth muscle in vitro

1991 ◽  
Vol 69 (6) ◽  
pp. 805-811 ◽  
Author(s):  
K. Tomioka ◽  
J. T. Jackowski ◽  
W. M. Abraham
Keyword(s):  
Smooth Muscle ◽  
Dose Response ◽  
Tracheal Smooth Muscle ◽  
Response Curves ◽  
Leukotriene Antagonist ◽  
Dose Response Curves ◽  
The Right ◽  
Glutamyl Transpeptidase

We have investigated the effects of leukotrienes (LTs) on isolated tracheal smooth muscle from sheep sensitive to Ascaris suum antigen. LTC4 and LTD4 produced dose-dependent contractions of sheep trachea, but LTE4 was virtually inactive. YM-17690, a non-analogous LT agonist, produced no contractile response up to 100 μM. Indomethacin (5 μM) had no effect on LTC4- and LTD4-induced contractions. L-Serine borate (45 mM), an inhibitor of γ-glutamyl transpeptidase, shifted the dose–response curve of LTC4 to the left by 161-fold, and L-cysteine (6 mM), an inhibitor of aminopeptidase, shifted the dose–response curves of LTC4 and LTD4 to the left by 67- and 23-fold, respectively. YM-16638 (1 μM), an LT antagonist, shifted the dose–response curves of LTC4 and LTD4 to the right with pKB values of 6.57 and 7.13, respectively. YM-16638 did not affect LTC4-induced contractions of L-serine borate-treated tissues, indicating that the compound acts only on LTD4 receptors in sheep trachea. LTE4 (1 μM) shifted the dose–response curves of LTC4 and LTD4 to the right with pKB values of 6.87 and 7.31, respectively. YM-17690 (10 μM) showed effects similar to LTE4, suggesting that the compound acts as an LTE4 agonist in sheep trachea. These results suggest that in sheep tracheal smooth muscle (a) LTC4 and LTD4 produce contractions, (b) these LT-induced contractions are not mediated by cyclooxygenase products, (c) LTC4 is converted to LTD4 and then to LTE4, and (d) the potency of the LTC4- and LTD4-induced contractions is increased when their conversion to LTE4 is inhibited. This potentiation may result from the inability of LTE4 to contract sheep trachea and (or) its antagonist actions.Key words: leukotriene antagonist, receptors, asthma.

scholarly journals Nifedipine-sensitive vascular reactivity of femoral arteries in WKY: the effect of pertussis toxin pretreatment and endothelium removal

2007 ◽  
pp. 663-666
Author(s):  
S Líšková ◽  
J Kuneš ◽  
J Zicha
Keyword(s):  
G Proteins ◽  
Pertussis Toxin ◽  
Dose Response ◽  
Vascular Reactivity ◽  
Response Curves ◽  
Femoral Arteries ◽  
Voltage Dependent ◽  
Dose Response Curves ◽  
Vasodilator Action ◽  
The Right

Maintenance of norepinephrine (NE)-induced contraction is dependent on Ca(2+) influx through L-type voltage-dependent Ca(2+) channels (VDCC), which is opposed by nitric oxide. Adrenergic receptors are coupled with different G proteins, including inhibitory G proteins (Gi) that can be inactivated by pertussis toxin (PTX). Our study was aimed to investigate the effects of endothelium removal, PTX pretreatment and acute VDCC blockade by nifedipine on the contractions of femoral arteries stimulated by norepinephrine. We used 12-week-old male WKY, half of the rats being injected with PTX (10 microg/kg i.v., 48 h before the experiment), which considerably reduced their blood pressure (BP). Contractions of isolated arteries were measured using Mulvany-Halpern myograph. NE dose-response curves determined in femoral arteries from PTX-treated WKY rats were shifted to the right compared to those from control WKY. On the contrary, removal of endothelium augmented NE dose-response curves shifting them to the left. Acute VDCC blockade by nifedipine (10(-7) M) abolished all differences in NE dose-response curves which were dependent on the presence of either intact endothelium or functional Gi proteins because all NE dose-response curves were identical to the curve seen in vessels with intact endothelium from PTX-treated animals. We can conclude that BP reduction after PTX injection is accompanied by the attenuation of NE-induced contraction of femoral arteries irrespective of endothelium presence. Moreover, our data indicate that both vasodilator action of endothelium and Gi-dependent vasoconstrictor effect of norepinephrine operate via the control of Ca(2+) influx through VDCC.

Pentobarbital and contraction of vascular smooth muscle

1975 ◽  
Vol 229 (6) ◽  
pp. 1635-1640 ◽  
Author(s):  
BT Altura ◽  
BM Altura
Keyword(s):  
Smooth Muscle ◽  
Vascular Smooth Muscle ◽  
Dose Response ◽  
Mechanical Activity ◽  
Response Curves ◽  
Aortic Smooth Muscle ◽  
Dose Response Curves ◽  
Portal Veins ◽  
The Right ◽  
Dose Dependent

This study, with isolated rat aortic strips and portal veins, was undertaken to : 1) study the effects, if any, of pentobarbital Na (PTB) (5 x 10(-5) to 2 X 10(-3) M) on reactivity to epinephrine, serotonin, and KCl; 2) determine whether certain concentrations of PTB induce direct actions on aortic strips and portal veins; and 3) gain some insight into how these effects are brought about. The results indicate that PTB can: a) inhibit development of spontaneous mechanical activity in these vessels in anesthetic concentrations; b) dose-dependently attenuate contractions induced by epinephrine, serotonin, and KC1; c) cause a noncompetitive type displacement of the dose response curves of these vasoactive agents; d) attenuate Ca2+- induced contractions of potassium-depolarized aortic strips and portal veins concomitant with a dose-dependent displacement of these dose-response curves to the right; and e) rapidly relax drug as well as Ca2+ -induced contractions of aortas and portal veins. In addition, the data indicate that rat portal venous smooth muscle is more sensitive to the inhibitory actions of PTB than rat aortic smooth muscle. Overall, these data suggest that concentrations of PTB used to induce surgical anesthesia can exert profound depressant effects on at least two different types of vascular smooth muscle that may be related to actions on movement and/or translocation of Ca2+.

Histamine dose-response curves in guinea pigs

1985 ◽  
Vol 58 (2) ◽  
pp. 625-634 ◽  
Author(s):  
W. C. Hulbert ◽  
T. McLean ◽  
B. Wiggs ◽  
P. D. Pare ◽  
J. C. Hogg
Keyword(s):  
Dose Response ◽  
Guinea Pigs ◽  
Response Curve ◽  
Dynamic Compliance ◽  
Dose Response Curve ◽  
Base Line ◽  
Response Curves ◽  
Mechanically Ventilated ◽  
Dose Response Curves ◽  
The Right

Histamine dose-response curves were performed on anesthetized tracheostomized guinea pigs that were paralyzed and mechanically ventilated at a constant tidal volume and breathing frequency. The dose was calculated by generating an aerosol of known concentration and measuring the volume delivered to the lung. Increasing the dose was accomplished by increasing the number of breaths of aerosol delivered. The response to each dose was determined by measuring the change in airway resistance (RL) and dynamic compliance (Cdyn) using the method of Von Neergaard and Wirz (Z. Klin. Med. 105: 51–82, 1927). With increasing doses of histamine, RL increased and reached a plateau at approximately five times the base-line value and Cdyn fell to approximately 20% of its initial value. The variability in the base-line and maximum response as well as the calculated sensitivity and reactivity was less than that previously reported. Propranolol pretreatment increased resting RL and shifted the dose-response curve for RL to the left of the controls, increasing reactivity but not sensitivity. Atropine shifted the dose-response curve to the right of the control, decreasing sensitivity but without changing reactivity. The data for Cdyn showed that atropine pretreatment caused a higher resting value and propranolol pretreatment a lower value at the highest histamine dose but no differences in either sensitivity or reactivity.

Relationship among sensitivity to adrenaline, plasma corticosterone level; and estrous cycle in rats

1995 ◽  
Vol 73 (5) ◽  
pp. 602-607 ◽  
Author(s):  
M. L. V. Rodrigues ◽  
F. K. Marcondes ◽  
R. C. Spadari-Bratfisch
Keyword(s):  
Estrous Cycle ◽  
Dose Response ◽  
Corticosterone Level ◽  
Plasma Corticosterone ◽  
Female Rats ◽  
Extraneuronal Uptake ◽  
Response Curves ◽  
Experimental Conditions ◽  
Dose Response Curves ◽  
Right Atria

The dose–response curves to the chronotropic effect of adrenaline obtained in right atria isolated from female rats indicated an order of increasing sensitivity to adrenaline, at the pD2 level, according to the estrous cycle, as follows: estrus ≤ metestrus ≤ diestrus ≤ proestrus. Inhibition of neuronal and extraneuronal uptake shifted the dose–response curves to adrenaline to the left only in right atria isolated from rats during estrus or metestrus. Moreover, under these experimental conditions, right atria were subsensitive to adrenaline during proestrus, in contrast to metestrus. Plasma corticosterone levels were lower during estrus and higher at proestrus. There was a positive correlation between right atria sensitivity to adrenaline and plasma corticosterone levels and estrous cycle phases. Our results also suggest that in the rat right atria during proestrus, as opposed to the other phases of the estrous cycle, there was an endogenous inhibition of extraneuronal uptake together with some alteration at the adrenoceptor level and (or) at intracellular mechanisms beyond receptors.Key words: adrenergic response, female, adrenaline, chronotropism, right atria.

scholarly journals Myorelaxant Effect of Essential Oil of Rhizome of Alpinia calcarata Rosc. on Rat Duodenal Smooth Muscle

2007 ◽  
Vol 2 (7) ◽  
pp. 1934578X0700200 ◽  
Author(s):  
Siddharth Pandey ◽  
Om Prakash ◽  
Anjum Zafar ◽  
Subrata K. Hore ◽  
Anil K. Pant ◽  
...  
Keyword(s):  
Smooth Muscle ◽  
Essential Oil ◽  
Dose Response ◽  
Response Curves ◽  
Competitive Antagonist ◽  
Rat Duodenum ◽  
Dose Response Curves ◽  
The Right ◽  
Dose Dependent

Analysis of the essential oil from the rhizome of Alpinia calcarata Rosc. (ACREO) by a combination of GC and GC-MS revealed the presence of 1,8-cineole (42.2%), endo-fenchyl acetate (14.7%), camphene (7.6%), β-pinene (6.9%), α-terpineol (5.3%) and camphor (5.0%). Twenty-three compounds were identified in the oil. ACREO showed dose dependent myorelaxant activity in rat duodenum. The dose response curves of acetylcholine (ACh) and CaCl2 were shifted by ACREO to the right with increases in EC50 values and decreases in Vmax. These findings suggest that ACREO is a non-competitive antagonist of ACh and calcium.

scholarly journals Comparison of the AT1-receptor blockers candesartan, irbesartan and losartan for inhibiting renal microvascular constriction

2001 ◽  
Vol 2 (1_suppl) ◽  
pp. S204-S210 ◽  
Author(s):  
William F van Rodijnen ◽  
Ton A van Lambalgen ◽  
Marco E van Teijlingen ◽  
Geert-Jan Tangelder ◽  
Piet M ter Wee
Keyword(s):  
Dose Response ◽  
Inhibitory Effect ◽  
At1 Receptor ◽  
Ang Ii ◽  
Response Curves ◽  
Receptor Blockers ◽  
Dose Response Curves ◽  
The Right ◽  
At1 Receptor Blockers ◽  
Slow Dissociation

Angiotensin II (Ang II) type 1 (AT1) receptor blockers differ in their affinity for the AT1-receptor, suggesting a dissimilar potency for inhibiting Ang II-induced vascular constriction. In the present study, we compared the effects of candesartan, irbesartan and losartan on the renal microvascular constriction to locally-formed Ang II, using isolated, perfused hydronephrotic rat kidneys. Addition of 1 nmol/L angiotensin I (Ang I, the precursor of Ang II) significantly reduced the diameters of interlobular arteries (ILAs; -47.6±2.6%), afferent arterioles (AAs; -43.6±2.3%) and efferent arterioles (EAs; -31.6±2.4%). Candesartan and irbesartan were more potent in antagonising the constriction to Ang I than losartan. By contrast, candesartan and irbesartan differed only slightly in potency. After a washing period of 60 minutes with drug-free medium, a second application of Ang I failed to induce vasoconstriction only in candesartan-treated kidneys. Pretreatment of hydronephrotic kidneys with candesartan, to further explore its antagonistic properties, shifted the dose-response curves of Ang II approximately 2 log units to the right without reducing the maximal Ang II-induced constriction of ILAs, AAs or EAs. Additionally, dose-response curves of Ang II were similar after short (10 minutes) and prolonged (60 minutes) preincubation with candesartan. Our findings indicate that candesartan and irbesartan are more potent inhibitors of renal microvascular constriction to locally-formed Ang II than losartan. The inhibitory effect of candesartan is more prolonged, suggesting a slow dissociation from the AT1-receptor. Additionally, candesartan was found to block the Ang II-induced constriction of renal microvessels in a surmountable manner.

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