Influence of T-type Ca2+ (mibefradil) and Cl- (indanyloxyacetic acid 94) channel antagonists on α1-adrenoceptor mediated contractions in rat aorta

2000 ◽  
Vol 78 (9) ◽  
pp. 714-720 ◽  
Author(s):  
Jennifer A Duggan ◽  
Reza Tabrizchi
Keyword(s):  
Rat Aorta ◽  
Mechanical Activity ◽  
Maximal Response ◽  
Response Curves ◽  
Selective Activation ◽  
Contraction Coupling ◽  
Mechanical Responses ◽  
The Individual ◽  
The Right ◽  
Stimulation Of

The effects of the T-type and L-type Ca2+ channel antagonists, mibefradil and nifedipine, respectively, and those of a Cl- channel antagonist, indanyloxyacetic acid 94, on mechanical responses elicited by selective activation of α1-adrenoceptors using cirazoline were examined in rat isolated aortic rings. The presence of mibefradil (300 nM), indanyloxyacetic acid, 94 (30 µM) and nifedipine (300 nM) alone inhibited mechanical responses elicited by cirazoline. The concentration-response curves to cirazoline were displaced to the right with significant increases in the EC50 and significant depressions of the maximal responses in the presence of the individual agents mibefradil, indanyloxyacetic acid 94, or nifedipine. A combination of mibefradil and indanyloxyacetic acid 94 further inhibited the mechanical activity produced by cirazoline. The further reduction in the maximal response to cirazoline, in the presence of mibefradil and nifedipine, was insignificant when compared with the effects of nifedipine alone. In addition, maximal mechanical responses produced by cirazoline were not significantly affected by a combination of nifedipine and indanyloxyacetic acid 94 when compared with either nifedipine alone or mibefradil and indanyloxyacetic acid 94 combined. Our current findings indicate that mibefradil, indanyloxyacetic acid 94, and nifedipine can inhibit cirazoline-induced contractions to a varying degree. Moreover, based on our present data it would be reasonable to suggest that the contribution of T-type versus L-type Ca2+ channels to contractile responses obtained with cirazoline are approximately 21% and 35%, respectively, of the Emax. It would appear that L-type Ca2+ channels play a greater role in processes that are involved in excitation-contraction coupling subsequent to stimulation of α1-adrenoceptors. In addition, Cl- channels also appear to be involved in the process of contraction following α1-adrenoceptor activation.Key words: T-type Ca2+ channels, L-type Ca2+ channels, Cl- channels, isolated aortic rings.

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.

Antagonist properties of arylaminopyridazine GABA derivatives at the Ascaris muscle GABA receptor

1991 ◽  
Vol 159 (1) ◽  
pp. 149-164
Author(s):  
A. H. Duittoz ◽  
R. J. Martin
Keyword(s):  
Gabaa Receptor ◽  
Binding Sites ◽  
Gaba Receptor ◽  
Dissociation Constants ◽  
Ascaris Suum ◽  
Antagonistic Activity ◽  
Maximal Response ◽  
Response Curves ◽  
Gaba Derivatives ◽  
The Right

1. In a previous study, it was shown that the potency order for two arylamino-pyridazine derivatives, SR95531 and SR95103, was different in Ascaris suum when compared to vertebrate preparations. SR95531, the most potent analogue at the vertebrate GABAA receptor, was found to be very weak at antagonizing GABA responses in Ascaris, but SR95103, approximately 20 times less potent than SR95531 in vertebrate preparations, was more potent than SR95531 in Ascaris. These results suggested the existence of different accessory binding sites at the Ascaris GABA receptor. 2. To test this hypothesis, the effects of a series of arylaminopyridazine derivatives of GABA on the GABA response in Ascaris suum muscle were investigated using a two-microelectrode current-clamp technique. 3. The results showed that SR42627, a potent antagonist at the GABAA receptor, was one of the weakest analogues in Ascaris muscle. In contrast, SR95132, virtually inactive in vertebrate preparations, was equipotent to SR95103, the most potent analogue of the series in Ascaris muscle. 4. The three most potent analogues in Ascaris, SR95103, SR95132 and SR42666, displace GABA dose-response curves to the right without decreasing the maximal response. The modified Schild plots for these compounds are consistent with a competitive mechanism involving two molecules of GABA and only one molecule of antagonist interacting with the receptor. The estimated dissociation constants for SR95103, SR95132 and SR42666 are, respectively, 64, 65 and 105 mumol l-1. 5. Structure-activity relationships for this series of compounds were examined in Ascaris and compared to those in vertebrates. Substitution on the pyridazine ring in the 4-position, while detrimental for the antagonist potency at the vertebrate GABAA receptor, appears to be a prerequisite for antagonistic activity on the Ascaris muscle GABA receptor. These results are interpreted in terms of the accessory binding site theory of Ariens, and suggest the existence of different accessory binding sites on the Ascaris GABA receptor.

scholarly journals Changes in the sensitivity to glucagon of lipolysis in adipocytes from pregnant and lactating rats

1988 ◽  
Vol 254 (3) ◽  
pp. 661-665 ◽  
Author(s):  
V A Zammit
Keyword(s):  
Adipose Tissue ◽  
The Other ◽  
High Concentration ◽  
Response Curves ◽  
Pregnant Rats ◽  
Adipose Tissue Lipolysis ◽  
The Right ◽  
Peak Lactation ◽  
Stimulation Of

1. Rates of lipolysis were measured at different concentrations of glucagon in adipocytes prepared from parametrial adipose tissue of fed or starved rats in different reproductive states. All experiments were performed in the presence of a high concentration of adenosine deaminase (1 unit/ml). 2. Maximal rates of lipolysis (elicited by 25 nM-glucagon in each instance) were higher in adipocytes from peak-lactating rats than those from pregnant animals in both the fed and starved states. 3. Of adipocytes from fed animals, those from peak-lactating rats were the most sensitive to glucagon, whereas those from late-pregnant and early-lactating rats were 1-2 orders of magnitude less sensitive. 4. Adipocytes from 24 h-starved rats showed a much smaller stimulation of lipolysis by glucagon, making the assessment of sensitivity difficult. Therefore, rates of lipolysis were also measured in the presence of a maximally anti-lipolytic dose of insulin. The presence of insulin did not alter the relative sensitivities to glucagon of adipocytes from fed animals in different reproductive states, although all dose-response curves were shifted to the right. When lipolysis in adipocytes from starved animals was measured in the presence of insulin, it became evident that starvation for 24 h markedly increased the sensitivity of adipocytes from late-pregnant rats to glucagon, but did not affect that of cells from animals in the other reproductive states. 5. It is concluded that the large changes in sensitivity to glucagon that occurred during the reproductive cycle may enable the modulation of adipose-tissue lipolysis in vivo to satisfy the different metabolic requirements of the animal in the transition from pregnancy to peak lactation.

Mechanisms of airway hypercontractility in basenji-greyhound dogs

1987 ◽  
Vol 63 (5) ◽  
pp. 2008-2014 ◽  
Author(s):  
T. M. Murphy ◽  
N. M. Munoz ◽  
C. A. Hirshman ◽  
J. S. Blake ◽  
A. R. Leff
Keyword(s):  
Maximal Response ◽  
Adrenergic Blockade ◽  
Vagus Nerves ◽  
Response Curves ◽  
Bronchial Smooth Muscle ◽  
Muscarinic Response ◽  
Contractile Forces ◽  
Stimulation Of

The comparative effects of contractile agonists and physiological stimulation of the tracheal and bronchial smooth muscle (BSM) response were studied isometrically in situ in five Basenji-greyhound (BG) and six mongrel dogs. Frequency-response curves generated by bilateral stimulation of the vagus nerves (0–20 Hz, 15–20 V, 2-ms duration) elicited greater maximal contraction in mongrel trachea (36.8 +/- 8.1 vs. 26.9 +/- 4.0 g/cm; P less than 0.02) and exhibited greater responsiveness in mongrel BSM (half-maximal response to electrical stimulation 3.0 +/- 1.1 vs. 7.0 +/- 0.5 Hz; P less than 0.05) compared with BG dogs. However, muscarinic sensitivity to intravenous methacholine (MCh) was substantially greater in BG dogs; MCh caused contraction greater than 1.5 g/cm at a mean dose of 3.0 X 10(-10) mol/kg for BG dogs compared with 5.1 X 10(-9) mol/kg for mongrel controls (P less than 0.03, Mann-Whitney rank-sum test). In contrast to the muscarinic response, the contractile response elicited by intravenous norepinephrine after beta-adrenergic blockade was similar in trachea and bronchus for both mongrel and BG dogs. Our data confirm previous in vitro demonstration of tracheal hyporesponsiveness in BG dogs and demonstrate that the contraction resulting from efferent parasympathetic stimulation is less in the BG than mongrel dogs. However, postsynaptic muscarinic responsiveness of BG BSM is substantially increased. We conclude that a component of airway responsiveness in BG dogs depends directly on contractile forces generated postsynaptically that are nongeometry dependent, postjunctional, and agonist specific.

Adenosine participates in regulation of smooth muscle relaxation in aortas from rats with experimental hypothyroidism

2002 ◽  
Vol 80 (6) ◽  
pp. 507-514 ◽  
Author(s):  
G Baños ◽  
F Martínez ◽  
J I Grimaldo ◽  
M Franco
Keyword(s):  
Smooth Muscle ◽  
Adenosine Receptor ◽  
Adenosine Receptors ◽  
Muscle Relaxation ◽  
Rat Aorta ◽  
Smooth Muscle Relaxation ◽  
Vascular Relaxation ◽  
Response Curves ◽  
The Difference ◽  
The Right

The contribution of adenosine receptors was evaluated in vascular relaxation in experimental hypothyroidism. Hypothyroid aortic rings contracted less than normal controls with noradrenaline, phenylephrine, and KCl; the difference was maintained after incubation with 1,3-dipropyl-8-p-sulfophenylxanthine (an A1 and A2 adenosine receptor blocker). The vascular relaxation induced by acetylcholine or carbachol was similar in normal and hypothyroid aortic rings. However, adenosine, N6-cyclopentyladenosine (an A1 adenosine receptor analogue), and 5'-N-ethylcarbox amidoadenosine (an A2 and A3 adenosine analogue) induced vasodilation that was larger in hypothyroid than in normal aortas. Nω-nitro-L-arginine methyl ester shifted the dose-response curves of adenosine, N6-cyclopentyladenosine, or 5'-N-ethylcarboxamidoadenosine to the right in both normal and hypothyroid vessels. The blocker 1,3-dipropyl-8-p-sulfophenylxanthine significantly reduced adenosine-induced relaxation in the hypothyroid but not in the normal aortic vessels. These results suggest that in hypothyroid aortas, a larger adenosine-mediated vasodilation is observed probably due to an increase in receptor number or sensitivity.Key words: adenosine receptors, nitric oxide, hypothyroidism, smooth muscle, rat aorta.

scholarly journals Early Effects of Tetraethylammonium Chloride on the Contractile Properties of Isolated Rabbit Basilar Arteries

1987 ◽  
Vol 7 (2) ◽  
pp. 237-247 ◽  
Author(s):  
A. R. Young ◽  
H. Säveland ◽  
J. D. Pickard ◽  
S. Perry ◽  
L. Brandt ◽  
...  
Keyword(s):  
Potassium Conductance ◽  
Cerebrovascular Reactivity ◽  
Maximal Response ◽  
Induced Response ◽  
Response Curves ◽  
Vascular Effects ◽  
Extracellular Medium ◽  
Tetraethylammonium Chloride ◽  
Basilar Arteries ◽  
The Right

The acute vascular effects of tetraethylammonium chloride (TEA) were examined on annular segments of rabbit basilar arteries, Contractions induced by the potassium channel blocker were compared with those obtained for potassium chloride, 5-hydroxytryptamine (5-HT) and norepinephrine (NE), The greater magnitude of the contractions was of the following order: [K+] > 5-HT> TEA> NK High concentrations of TEA alone (10−2 M) generated spontaneous oscillatory contractions in cerebral vessels that were normally quiescent, Low concentrations of TEA (10−8-10−6 M), which had no vasomotor properties per se, enhanced the contractile response of submaximal concentrations of 5-HT (10−7 M) and NE (3 × 10−6 M) and attenuated the contraction produced by 60 m M [K+], An increased vascular response to the amines was still evident up to 3 h after the addition of TEA despite frequent rinsing with fresh buffer solutions. On arteries precontracted with TEA (10−2 M), but not high [K +], the subsequent addition of 5-HT (10−7 M) still induced a powerful constriction. Repeated concentration-response curves for [K+] were reproducible and, in the presence of TEA (10−8 or 10−6 M), the curve was displaced to the right in a competitive manner. A higher concentration of TEA (10−4 M) was devoid of any blocking properties on the [K+]-induced response whereas, at 10−3 M TEA, the response was potentiated, as evidenced by a shift of the curve to the left. Interactions between TEA and the cumulative response to 5-HT were difficult to interpret. Repeated exposures of the artery to 5-HT resulted in an increased maximal response with each determination (EAm = 127 ± 9% and 149 ±: 14% of control values following the second and third applications, respectively). With TEA (10−6 M), the increase in the maximal contractile effect noted previously was not observed. Contractions induced by single concentrations of TEA (10−2 M) or [K+] (60 m M) were calcium dependent, were abolished completely in a calcium-free medium, and were depressed by the calcium antagonist nimodipine. 5-Hydroxytryptamine-induced contractions (10−5 M) were less sensitive to withdrawal of calcium from the extracellular medium (31 ± 6% relative to the maximal response at 4 m M calcium). Hence, an acute reduction in potassium conductance in cerebrovascular smooth muscle produced by TEA has complex, concentration-dependent effects and reproduces only part of the spectrum of effects of cisternal injection of blood on cerebrovascular reactivity.

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.

Reproducible Measurement of Human Motoneuron Excitability With Magnetic Stimulation of the Corticospinal Tract

2009 ◽  
Vol 102 (1) ◽  
pp. 606-613 ◽  
Author(s):  
Peter G. Martin ◽  
Anna L. Hudson ◽  
Simon C. Gandevia ◽  
Janet L. Taylor
Keyword(s):  
Magnetic Stimulation ◽  
Corticospinal Tract ◽  
Motor Evoked Potentials ◽  
Compound Action Potential ◽  
Maximal Response ◽  
Response Curves ◽  
Stimulus Response ◽  
Maximal Output ◽  
Voluntary Contractions ◽  
Stimulation Of

It is difficult to test responses of human motoneurons in a controlled way or to make longitudinal assessments of adaptive changes at the motoneuron level. These studies assessed the reliability of responses produced by magnetic stimulation of the corticospinal tract. Cervicomedullary motor evoked potentials (CMEPs) were recorded in the first dorsal interosseus (FDI) on 2 separate days. On each day, four sets of stimuli were delivered at the maximal output of the stimulator, with the final two sets ≥10 min after the initial sets. Sets of stimuli were also delivered at different stimulus intensities to obtain stimulus-response curves. In addition, on the second day, responses at different stimulus intensities were evoked during weak voluntary contractions. Responses were normalized to the maximal muscle compound action potential ( Mmax). CMEPs evoked in the relaxed FDI were small, even when stimulus intensity was maximal (3.6 ± 2.5% Mmax) but much larger during a weak contraction (e.g., 26.2 ± 10.2% Mmax). CMEPs evoked in the relaxed muscle at the maximal output of the stimulator were highly reproducible both within (ICC = 0.83, session 1; ICC = 0.87, session 2) and between sessions (ICC = 0.87). ICCs for parameters of the input-output curves, which included measures of motor threshold, slope, and maximal response size, ranged between 0.87 and 0.62. These results suggest that responses to magnetic stimulation of the corticospinal tract can be assessed in relaxation and contraction and can be reliably obtained for longitudinal studies of motoneuronal excitability.

Endothelium dependence of effects of high PCO2 on agonist-induced contractility of rat aorta

1993 ◽  
Vol 264 (2) ◽  
pp. H512-H519 ◽  
Author(s):  
S. Fukuda ◽  
M. Morioka ◽  
T. Tanaka ◽  
K. Taga ◽  
K. Shimoji
Keyword(s):  
Response Curve ◽  
Thromboxane A2 ◽  
Rat Aorta ◽  
Cyclooxygenase Inhibitors ◽  
High Pco2 ◽  
Maximal Response ◽  
Thromboxane A2 Receptor ◽  
Aortic Smooth Muscle ◽  
The Right ◽  
Time Contraction

To investigate the modulation of CO2 and endothelium of vascular contraction induced by various agonists, we studied the influence of high PCO2 (PCO2 = 91 mmHg, pH = 6.99) on the response of endothelium-intact and -rubbed rat aortic preparations to KCl, phenylephrine (PE), and human-porcine endothelin-1 (ET-1). Response of endothelium-intact aortic preparations to KCl was not influenced by both high PCO2 and the pH-matched acidotic solution (7.00) with normal PCO2, whereas that of endothelium-rubbed preparations was attenuated solely by high PCO2. With cyclooxygenase inhibitors or a thromboxane A2 receptor antagonist, high PCO2 attenuated the respose of both preparations to KCl. The dose-response curve of endothelium-intact and -rubbed preparations to PE was shifted to the right by both high PCO2 and the pH-matched acidotic solution with normal PCO2. The maximal response of endothelium-intact preparation to PE was attenuated by high PCO2. Indomethacin augmented the inhibitory action of high PCO2 on the PE-induced contraction. Contractile responses of endothelium-intact and -rubbed preparations to ET-1 were not influenced by high PCO2. With indomethacin, high PCO2 also had no influence on the ET-1-induced contraction of endothelium-intact preparations. Endothelium modified the high PCO2 effects on the time-contraction responses to the three agonists. CO2 and endothelium may variously modify the responses of rat aorta to different agonists. Cyclooxygenase-related eicosanoid(s) may be involved in the effects of high PCO2 on the response of rat aortic smooth muscle cells to KCl and PE.

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+.

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