Chronotropic response to (±)-CGP12177 in right atria of stressed rats

2001 ◽  
Vol 79 (5) ◽  
pp. 393-399 ◽  
Author(s):  
I N Santos ◽  
R C Spadari-Bratfisch
Keyword(s):  
Response Curve ◽  
Response Curves ◽  
Stimulant Effect ◽  
Chronotropic Response ◽  
Stress Changes ◽  
Random Intervals ◽  
The Right ◽  
Right Atria ◽  
Concentration Response Curve ◽  
Shock Stress

Foot-shock stress changes the sensitivity of the rat right atria to β1- and β2-adrenoceptor (AR) agonists. We investigated whether the same stress protocol also changes the atrial sensitivity to the non conventional agonist, (±)-CGP12177. Concentration-response curves to (±)-CGP12177, a β1- and β2-adrenoceptor antagonist with agonist properties at the putative β4-adrenoceptors, were obtained in the absence and presence of propranolol (200 nM or 2 µM), CGP20712A 10 nM plus ICI118,551 50 nM, or CGP20712A (1 µM or 3 µM), in right atria from rats submitted to three daily foot-shock sessions (120 mA pulses of 1.0 s duration applied at random intervals of 5-25 s over 30 min) and killed after the third session. The pD2 for (±)-CGP12177 was not influenced by foot-shock stress. The stimulant effect of (±)-CGP12177 was resistant to blockade by 200 nM and 2 µM (±)-propranolol, and to combined blockade by CGP20712A and ICI118,551. However, in right atria from stressed rats given 200 nM propranolol, the concentration-response curve to the agonist was shifted 2.0-fold to the right. CGP20712A shifted the concentration-response curve to (±)-CGP12177 to the right by 4.6- (1 µM) and 19-fold (3 µM) in atria of control rats, and by 2.2- (1 µM) and 43-fold (3 µM) in atria of stressed rats. Maximum response to CGP12177 was not affected by propranolol or CGP20712A in concentrations ranging from 0.1 nM to 10 µM. These results show that the chronotropic effect of (±)-CGP12177 is mediated by atypical β4-adrenoceptors. In constrast with to β1-and (or) β2-AR, this receptor is resistant to the effects of foot-shock stress, suggesting that the putative β4-AR is a different receptor from a low affinity state of β1-adrenoceptor, as previously proposed, unless both proposed isoforms of β1-adrenoceptor show independent stress-induced behavior.Key words: putative β4-adrenoceptor, low affinity β1-adrenoceptor isoform, stress, right atria, chronotropic response.

Pharmacological evidence for β2-adrenoceptor in right atria from stressed female rats

1999 ◽  
Vol 77 (6) ◽  
pp. 432-440 ◽  
Author(s):  
R C Spadari-Bratfisch ◽  
I N Santos ◽  
LCM Vanderlei ◽  
F K Marcondes
Keyword(s):  
Estrous Cycle ◽  
Model Equation ◽  
Female Rats ◽  
Cycle Phase ◽  
Response Curves ◽  
Chronotropic Response ◽  
Site Model ◽  
Stressed Female ◽  
Right Atria ◽  
Shock Stress

The purpose of the present study was to demonstrate a physiological response to TA2005, a potent β2-adrenoceptor (β2-AR) selective agonist, in right atria isolated from stressed female rats under the influence of the estrous cycle. We obtained concentration-response curves to the agonist in the presence and in the absence of selective antagonists in right atria isolated from female rats submitted to three daily foot-shock sessions (30 min duration, 120 pulses of 1.0 mA, 1.0 s, applied at random intervals of 5-25 s) and sacrificed at estrus or diestrus. Our results showed that the pD2 values of TA2005 were not influenced by estrous cycle phase or foot-shock stress. However, in right atria from stressed rats sacrificed during diestrus, the concentration-response curve to TA2005 was biphasic, with a response being obtained at concentrations of 0.1 nM, whereas during estrus no response was observed at doses lower than 3 nM. ICI118,551, a β2-AR antagonist, abolished the response to nanomolar concentrations of TA2005 in right atria from stressed rats at diestrus, with no changes in agonist pD2 values in right atria from control rats (7.47 ± 0.09, p > 0.05) but a 3-fold decrease in pD2 values of TA2005 in right atria from foot shock stressed rats (7.90 ± 0.07, p [Formula: see text] 0.05). Concentration-response curves to TA2005 in the presence of ICI118,551 were best fitted by a one-site model equation. The β1-AR antagonist, CGP20712A, shifted to the right only the second part of the concentration-response curves to the agonist, unmasking the putative β2-AR-mediated response to the agonist in tissues isolated from stressed rats at diestrus. Under this condition, concentration-response curves to the agonist were best fitted by a two-site model equation. pD2 and maximum response of TA2005 interaction with β1- and putative β2-adrenoceptor components were calculated. Schild analyses gave a pKB value for CGP20712A that was typical for the interaction with β1-AR in each experimental group. pKB values for ICI118,551 could not be obtained in stressed rats sacrificed at diestrus since Schild plot slopes were lower than 1.0. In right atria from control rats, ICI118,551 pKB values were similar to reported values for the interaction of the antagonist with β1-AR. These results confirm that a heterogenous β-AR population mediating the chronotropic response to catecholamines can be demonstrated in right atria from foot shock stressed female rats sacrificed at diestrus. The stress-induced response seems to be mediated by the β2-AR subtype. Right atria from rats sacrificed during estrus are protected against stress-induced alterations on the homogeneity of β-AR population.Key words: foot-shock stress, TA2005, ICI118,551, CGP20712A, estrus, diestrus.

The β-adrenoceptor site activated by CGP12177 varies in behavior according to the estrous cycle phase and stress

2003 ◽  
Vol 81 (5) ◽  
pp. 459-468 ◽  
Author(s):  
I N Santos ◽  
F K Marcondes ◽  
R C Spadari-Bratfisch
Keyword(s):  
Estrous Cycle ◽  
Stress Hormones ◽  
Serum Levels ◽  
Female Rats ◽  
Cycle Phase ◽  
Response Curves ◽  
Chronotropic Response ◽  
The Right ◽  
Right Atria ◽  
Group Serum

The aim of this work was to assess whether stress and estrous cycle phases affected the β-adrenoceptor (β-AR) site activated by CGP12177 in the right atria of rats. The chronotropic response to CGP12177 in the absence or presence of antagonists was determined in atria from rats submitted to one daily foot-shock session for 3 consecutive days. Blood was collected for hormonal assays. The pD2 for CGP12177 in atria from females was lower than in atria from males and was unaltered by stress or the estrous cycle. Propranolol (200 nM) or CGP20712A (3 μM) shifted the concentration–response curves to CGP12177 to the right in control and stressed estrus or control diestrus rats. Atria from stressed diestrus rats were resistant to blockade by propranolol or CGP20712A, indicating that the effect of β-adrenoceptor antagonists on the response to CGP12177 is influenced by estrous cycle phases. The stress-induced increase in serum corticosterone levels was independent of the estrous cycle or gender, but the estradiol/progesterone ratio was affected differently in the two groups of female rats. In the diestrus group, serum estradiol levels decreased after the first foot-shock session and remained low until the day of sacrifice, whereas in the estrus group the serum levels of estradiol did not decrease after stress and peaked on the second day, which corresponded to proestrus. These data do not indicate whether there is a direct or indirect effect of stress hormones and (or) sex steroids on cardiac β-AR sensitivity. However, they do show that the classic and low-affinity binding sites of the β-AR are independently regulated and that the β-AR atypical site affinity for antagonists depends on the estrous cycle.Key words: allosterism, β-adrenoceptor, β-adrenoceptor, receptor active site, steroid hormones, stress.

Evaluation of β-Adrenerglc Blocking Agents in Presence of Adrenergic Tone

1972 ◽  
Vol 50 (5) ◽  
pp. 381-388
Author(s):  
Victor Elharrar ◽  
Reginald A. Nadeau
Keyword(s):  
Dose Response ◽  
Sinus Node ◽  
Stellate Ganglion ◽  
Sodium Pentobarbital ◽  
Response Curves ◽  
Chronotropic Response ◽  
Blocking Agents ◽  
Sinus Node Artery ◽  
Anesthetized Dogs ◽  
The Right

The importance of the level of adrenergic tone in the determination of the dose–response curve to noradrenaline (NA) and in the evaluation of β-adrenergic blocking agents was studied in open-chest sodium pentobarbital anesthetized dogs by injecting drugs directly into the sinus node artery. Changes in the level of adrenergic tone by stimulating the right stellate ganglion resulted in variation of the observed chronotropic response to NA and of its ED50. The chronotropic responses were corrected by taking into account the underlying adrenergic tone. The negative chronotropic effect of dl-propranolol (1 and 10 μg) appeared to be related to its β-blocking properties and not to its quinidine-like effects as shown by the lack of effect of d-propranolol injected at the same doses. The magnitude of the negative chronotropic effects of 10 μg of propranolol and 100 μg of practolol, oxprenolol, and sotalol was shown to be related to the initial heart rate and consequently to the level of adrenergic tone. The comparison of these four β-blocking agents was carried out on corrected dose-response curves to NA. Their relative potencies were found to be: propranolol > oxprenolol > practolol > sotalol, corresponding to ratios of 1, [Formula: see text], [Formula: see text], and [Formula: see text]

II. Pharmacology of Angiotensin Antagonists

1973 ◽  
Vol 51 (2) ◽  
pp. 114-121 ◽  
Author(s):  
D. Regoli ◽  
W. K. Park ◽  
F. Rioux
Keyword(s):  
Slow Rate ◽  
Response Curve ◽  
Receptor Site ◽  
Maximal Response ◽  
Pharmacological Properties ◽  
Response Curves ◽  
Onset Of Action ◽  
Competitive Antagonist ◽  
Long Acting ◽  
The Right

The pharmacological properties of three antagonists of angiotensin II (ATII) have been characterized on the rat isolated stomach strip.(8-Gly)-ATII, a newly synthesized antagonist of ATII, as well as (8-Leu)-ATII and (1-Sar-8-Leu)-ATII displace to the right the dose–response curve of ATII and the displacement is proportional to the dose of antagonist.Dose–response curves of ATII remain parallel to that of the control in the presence of (8-Gly)-ATII and (8-Leu)-ATII, while parallelism is lost with (1-Sar-8-Leu)-ATII. This antagonist also depresses the maximal response to ATII.All data presented in this paper indicate that (8-Gly)-ATII and (8-Leu)-ATII are competitive antagonists of ATII with different affinities for the receptors, (8-Gly)-ATII being about 12 times less potent than (8-Leu)-ATII. This compound competes with ATII on a one to one basis: pA2 of (8-Leu)-ATII has the same value as pD2 of ATII.(1-Sar-8-Leu)-ATII does not fulfil the criteria of a competitive antagonist. This compound is very potent and the onset of action is as rapid (5 min) as for the other two compounds. All data obtained with (1-Sar-8-Leu)-ATII are consistent with the assumption that this compound is competitive in the sense that it acts on the same receptor site as ATII, but owing probably to slow rate of inactivation by tissue aminopeptidases, it dissociates slowly from the receptors and it acts as a specific long-acting antagonist.

Role of Endothelial K + Channels in NO-Dependent Vasorelaxant Responses to Acetylcholine in Rat Aorta.

Hypertension ◽  
2000 ◽  
Vol 36 (suppl_1) ◽  
pp. 698-698
Author(s):  
John Quilley ◽  
Yue Qiu
Keyword(s):  
Dose Response ◽  
Response Curve ◽  
Rat Aorta ◽  
Dose Response Curve ◽  
Response Curves ◽  
K Channels ◽  
Voltage Dependent ◽  
The Right ◽  
Stimulation Of

P30 Endothelium-dependent vasorelaxant responses to acetylcholine (Ach) in rat aorta are mediated solely by NO. Rings precontracted with U46619 were used to investigate the role of endothelial K + channels. Thus, any effect of K + channel inhibitors on Ach responses in the absence of an effect on those to nitroprusside (NP) can be attributed to interference with Ach-induced stimulation of NO. Vasorelaxant responses to Ach (log EC 50 -7.29M) were abolished by removal of the endothelium or inhibition of NO synthesis with nitroarginine (100μM) which potentiated responses to NP (log EC 50 -9.41M vs -8.47M for control). In the presence of TEA (10mM) to inhibit K + channels, the dose-response curve for Ach, but not NP, was shifted to the right (log EC 50 -6.06). Elevation of extracellular K + (25mM KCl)also shifted the dose-response curve for Ach to the right. Inhibitors of specific types of K + channels: BaCl 2 (30μM), apamin (100nM), glibenclamide (10μM), charybdotoxin (50nM) and iberiotoxin (100nM) were without effect on dose-response curves to either Ach or NP. However, the combination of apamin (100nM) and charybdotoxin (50nM) but not apamin plus iberiotoxin, reduced relaxant responses to Ach (log EC 50 -6.95M) without affecting those to NP.These results confirm that Ach-induced relaxation of rat aorta is mediated entirely by endothelium-derived NO, the release of which apparently involves hyperpolarization of the endothelium. This effect is dependent on activation of a K + channel that is blocked by a combination of apamin/charybdotoxin but neither agent alone, possibly indicating characteristics of both Ca 2+ - activated and voltage-dependent K + channels.

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.

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.

Reduction of intrinsic sinoatrial frequency and norepinephrine response of the exercised rat

1977 ◽  
Vol 55 (4) ◽  
pp. 813-820 ◽  
Author(s):  
Richard L. Hughson ◽  
John R. Sutton ◽  
J. Desmond Fitzgerald ◽  
Norman L. Jones
Keyword(s):  
Sinoatrial Node ◽  
Parasympathetic Nervous System ◽  
Control Group ◽  
Response Curves ◽  
Chronotropic Response ◽  
In Vitro Measurements ◽  
The Right

Physical training is associated with a reduction of intrinsic sinoatrial activity; the present study examined the role of the parasympathetic nervous system in this reduction. Six groups of rats were studied for 10 weeks: inactive control; treadmill exercised; parasympathetic receptor blockade with atropine; exercise plus atropine; parasympathetic receptor stimulation with carbachol; and exercise plus carbachol. In vivo ISF (cardiac frequency 20 min after injection of propranolol and atropine) was measured at 3-week intervals. At the end of 10 weeks the right atrium was excised, in vitro measurements were made of ISF, and chronotropic dose–response curves to acetylcholine and norepinephrine were established. In vivo, ISF was reduced with time, the greatest reduction being found in the exercise plus atropine group; the treadmill-exercised and the atropine-treated groups also had a greater reduction than the control group. In vitro, no differences were observed in acetylcholine responses. The maximum norepinephrine chronotropic response was reduced in the treadmill-exercised and the exercise plus atropine groups. The maximum norepinephrine-induced frequency correlated with the in vitro ISF (r = 0.75). Thus, ISF was reduced with training, but this effect was independent of parasympathetic activity. The properties of the sinoatrial node which set ISF also influenced the maximum norepinephrine response.

Existence of two types of postjunctional α-adrenoceptors in the isolated canine internal carotid artery

1988 ◽  
Vol 66 (5) ◽  
pp. 655-659 ◽  
Author(s):  
Yasuaki Kawai ◽  
Shigeaki Kobayashi ◽  
Toshio Ohhashi
Keyword(s):  
Response Curve ◽  
Carotid Arteries ◽  
Internal Carotid ◽  
The Other ◽  
Low Concentrations ◽  
Selective Agonists ◽  
High Concentrations ◽  
The Right ◽  
Internal Carotid Arteries ◽  
Concentration Response Curve

The pharmacological characteristics of postjunctional α-adrenoceptors in isolated canine internal carotid arteries were investigated by the use of selective agonists and antagonists for α1 and α2-adrenoceptors. Norepinephrine, phenylephrine, and xylazine caused concentration-dependent contractions in the helical strips. The contraction induced by 10−4 M xylazine was significantly smaller than that produced by 10−4 M norepinephrine or 10−4 M phenylephrine. The contraction induced by 10−4 M phenylephrine was almost the same value as that induced by 10−4 M norepinephrine. Phentolamine (10−8 and 10−7 M) caused a parallel shift to the right of the concentration–response curve to norepinephrine. The contractile responses to low concentrations of norepinephrine were significantly suppressed by pretreatment with an α2-antagonist such as yohimbine (10−9 and 10−8 M) or DG 5128(10−7 and 10−6 M). On the other hand, the responses to higher concentrations of norepinephrine were mainly reduced by low concentrations of an α1-antagonist, prazosin (3 × 10−10 and 3 × 10−9 M). These results suggest that both α1- and α2-adrenoceptors are located on the plasma membrane of smooth muscle cells in canine internal carotid arteries and that the norepinephrine-induced contractions at low and high concentrations are mainly mediated by activation of α2- and α1-adrenoceptors, respectively.

Effects of Lidocaine and Procaine on Canine Nasal Blood Vessels

1988 ◽  
Vol 97 (4) ◽  
pp. 409-413 ◽  
Author(s):  
Hsing-Won Wang ◽  
Richard T. Jackson
Keyword(s):  
Blood Vessels ◽  
Nasal Mucosa ◽  
Dose Response ◽  
Response Curve ◽  
Smooth Muscle Contraction ◽  
Dose Response Curve ◽  
Maximal Response ◽  
Field Stimulation ◽  
Response Curves ◽  
The Right

The effects of lidocaine and procaine on contractile responses of isolated canine nasal mucosal blood vessels to field stimulation and methoxamine were investigated. Analysis of cumulative dose-response curves showed that the two local anesthetics antagonized methoxamine and inhibited the field-stimulation response. The latter effect was interpreted as due to the blockade of Na+channels. This would inhibit nerve conduction induced by field stimulation. The former effect on methoxamine is probably caused by the effect of these anesthetics on the mobilization of Ca++ needed for smooth muscle contraction. Preincubation of the nasal mucosa with low doses of procaine or lidocaine shifts the methoxamine dose-response curve to the right. With higher doses, the maximal response is also reduced. The shift of the dose-response curve showed that procaine or lidocaine can change the α-adrenergic receptor affinity. Commercial 1% lidocaine with 1:100,000 epinephrine also inhibits field stimulation and antagonizes methoxamine contractions. Lidocaine can increase the basal tone of nasal mucosa, while procaine cannot. From these results, we conclude that procaine and lidocaine have common mechanisms in blocking Na+ channels but differ in their ability to modify Ca++ stores or channels.

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