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]

Negative chronotropic and parasympatholytic effects of alinidine on canine sinus node and AV junction

1985 ◽  
Vol 248 (3) ◽  
pp. H324-H330
Author(s):  
G. R. Hageman ◽  
B. H. Neely ◽  
F. Urthaler ◽  
T. N. James
Keyword(s):  
Sinus Node ◽  
Stellate Ganglion ◽  
Stimulus Frequency ◽  
Response Curves ◽  
Sinus Node Artery ◽  
Sinus Rate ◽  
Before And After ◽  
Anesthetized Dogs ◽  
Selective Perfusion ◽  
Chronotropic Effects

The direct effects of alinidine (N-allyl-clonidine) on the sinus node and atrioventricular (AV) junction were studied in 18 anesthetized dogs. Stimulus frequency-response curves to right stellate ganglion and right cervical vagus stimulations as well as responses to norepinephrine or acetylcholine were determined before and after selective perfusion of alinidine into the sinus node artery. Alinidine (1 microgram/ml) had no effect on spontaneous sinus rate [148 +/- 5 (SE) beats/min]. However, alinidine concentrations of 5, 10, and 25 micrograms/ml produced significant (P less than 0.05) sinus slowing to 138, 127, and 121 beats/min, respectively. Recovery to control rate was dose dependent and took from 4 to 33 min. Sinus rate increases with right stellate stimulations were not affected by alinidine. However, sinus rate decreases with right vagal stimulations were significantly (P less than 0.01) attenuated by alinidine. The negative chronotropic effects of acetylcholine were not influenced by alinidine. Alinidine (1-100 micrograms/ml into AV node artery) had no effect on the A-H interval of the His bundle electrogram. However, alinidine (10 and 25 micrograms/ml) diminished the AV block produced by stimulation of the left vagus in electrically paced hearts but not the negative dromotropic actions of directly administered acetylcholine. Thus alinidine has direct negative chronotropic effects, no effect on sinus node responses to sympathetic stimulation, ability to diminish sinus node and AV junctional responses to vagal stimulations without interference at the cholinergic muscarinic receptor, and 4) no effect on AV nodal conduction.

Sympathetic neural effects on regional atrial recovery properties and cardiac rhythm

1981 ◽  
Vol 240 (4) ◽  
pp. H590-H596
Author(s):  
F. A. Kralios ◽  
C. K. Millar
Keyword(s):  
Left Atrial ◽  
Sinus Node ◽  
Stellate Ganglion ◽  
Sympathetic Nerves ◽  
Substantial Effect ◽  
Cardiac Nerve ◽  
Anesthetized Dogs ◽  
Functional Distribution ◽  
The Right ◽  
Stimulation Of

The functional distribution of the cardiac sympathetic nerves to the atria and their arrhythmiogenic effects were determined in 16 open-chest pentobarbital-anesthetized dogs. Shortening of refractory periods at four right and two left atrial sites during stimulation of the nerves was taken as a criterion of their distribution. Stimulation of right stellate ganglion, craniovagal, and right stellate cardiac nerves produced localized shortening on the right atrium, particularly at the sinus node area, and invariably induced sinus tachycardia. The recurrent cardiac nerve produced little shortening at all sites and less arrhythmiogenic effect. The left stellate ganglion and ventrolateral cardiac nerve affected only left atrial sites and induced atrioventricular junctional rhythm. The ventromedial cardiac nerve affected all sites and had no consistent arrhythmiogenic effect. The innominate nerve had no substantial effect. We concluded that the functional distribution of the cardiac sympathetic nerves is localized, and that rate, rhythm, and refractory period changes induced by stimulation of these nerves are characteristic of the area of distribution.

Regional coronary vasoconstriction in response to stimulation of stellate ganglia

1982 ◽  
Vol 243 (3) ◽  
pp. H410-H415 ◽  
Author(s):  
L. E. Rinkema ◽  
J. X. Thomas ◽  
W. C. Randall
Keyword(s):  
Left Ventricle ◽  
Regional Variations ◽  
Coronary Vasoconstriction ◽  
Blocking Agents ◽  
Anesthetized Dogs ◽  
Significant Change ◽  
The Right ◽  
Adrenergic Blocking ◽  
Beta Adrenergic Blocking Agents ◽  
Adrenergic Blocking Agents

Recent experiments have demonstrated that direct and reflex sympathetic stimulation elicit coronary vasoconstriction when the inotropic and chronotropic effects are blocked with beta-adrenergic blocking agents. This vasoconstriction can be blocked with alpha-adrenergic blocking agents. Regional variations in the flow reduction produced by right (RSS) vs. left (LSS) stellate stimulation were delineated in this study. Open-chest pentobarbital-anesthetized dogs were given propranolol (1 mg/kg iv). Hearts were neurally decentralized and paced just above the spontaneous heart rate. Radiolabeled microspheres (15 +/- 2 micrometers) were injected into the left atrium before and during RSS (n = 11) or LSS (n = 11). RSS produced relatively little vasoconstriction confined to anterior left ventricle. In contrast, LSS produced significant vasoconstriction in all areas of the right and left ventricles. In the endocardial half of the left ventricle the flow decrease was uniformly distributed among the regions studied. In the epicardial half of the flow decrease was more pronounced in posterior than in anterior regions. No significant change occurred in the endo-epi ratios with RSS, but with LSS there was a significant change in three areas. The changes were related to regional variations in the degree of epicardial constriction. Thus RSS and LSS have differential effects (quantitatively) on regional coronary blood flow.

Myocardial catecholamines and stimulation of the stellate ganglion in hemorrhagic shock

1965 ◽  
Vol 209 (4) ◽  
pp. 751-756 ◽  
Author(s):  
Vincent V. Glaviano ◽  
Mary Ann Klouda
Keyword(s):  
Blood Pressure ◽  
Hemorrhagic Shock ◽  
Stellate Ganglion ◽  
Myocardial Contraction ◽  
Cardiac Contraction ◽  
Cardiac Responses ◽  
Left Stellate Ganglion ◽  
Anesthetized Dogs ◽  
The Right ◽  
Stimulation Of

Cardiac responses to electrical stimulation of the right or left stellate ganglion were recorded from 16 open-chest anesthetized dogs in hemorrhagic shock. Shock was induced by bleeding the animals to a mean blood pressure of 40 mm Hg. This level of pressure was maintained for 4 hr, during which time blood pressure, heart rate, force of myocardial contraction, and intraventricular pressures were recorded. Stimulation of the stellate ganglion for 15–40 sec every 30 min after hemorrhage showed a gradual decrease in these parameters to levels below control. The reinfusion of blood and the infusion of exogenous l-norepinephrine did not restore an increase in force of cardiac contraction to stellate stimulation. Myocardial epinephrine and norepinephrine levels in shock were found not to differ from those in 14 normal dog hearts. In contrast to almost complete myocardial refractoriness to stellate stimulation in hemorrhagic shock, stimulation of the vagus nerve elicited bradycardia and eventual cardiac arrest. The decrease observed in force of cardiac contraction to stimulation of the stellate ganglion in hemorrhagic shock may be due to depletion of norepinephrine stores in the heart.

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.

ANG II- and TxA2-induced mesenteric vasoconstriction in rats is mediated by separate cell signaling pathways

1999 ◽  
Vol 277 (1) ◽  
pp. H1-H7 ◽  
Author(s):  
Johannes Bauer ◽  
Cécile Dau ◽  
Alessandro Cavarape ◽  
Franz Schaefer ◽  
Heimo Ehmke ◽  
...  
Keyword(s):  
Signaling Pathways ◽  
Dose Response ◽  
Ang Ii ◽  
Response Curves ◽  
Intracellular Ca ◽  
The Right ◽  
Activate Protein Kinase ◽  
Cell Signaling Pathways

Studies in vitro have demonstrated that vasoconstrictor agents increase intracellular Ca2+ and activate protein kinase C (PKC) to elevate vascular tone. The aim of the present study was to determine the importance of these signaling pathways for angiotensin II (ANG II) and thromboxane A2(TxA2) in regulating mesenteric blood flow (MBF) in vivo. In anesthetized rats increasing doses of ANG II or the TxA2 agonist U-46619 were administered into the superior mesenteric artery to reduce MBF. Intra-arterial infusion of inhibitors served to examine the contribution of different pathways: 8-(diethylamino)octyl 3,4,5-trimethoxybenoate hydrochloride (TMB-8) to inhibit intracellular Ca2+ release, nifedipine to block transmembrane Ca2+ influx through the L-type Ca2+ channel, and staurosporine to inhibit PKC. Each of the inhibitors attenuated ANG II-induced reductions in MBF, and all dose-response curves were shifted to the right to an approximately threefold higher ANG II dose. Combinations of the inhibitors revealed that their effects were additive; together they abolished the vasoconstrictor action of ANG II completely. In contrast, the dose-response curve for U-46619 was not affected by any of the inhibitors infused either separately or together. The results demonstrate that a rise in intracellular Ca2+ and activation of PKC are major mediators of the vasoconstrictor effect of ANG II in mesenteric circulation, but they play a subordinate role, if any, for the effects of TxA2. Because TxA2 plays a major role only under pathological conditions, the uncontrolled vasoconstriction appears to be associated with the recruitment of novel signal transduction pathways.

scholarly journals Dose-Response Curves for Alcuronium and Pancuronium Alone and in Combination

1982 ◽  
Vol 10 (3) ◽  
pp. 248-251 ◽  
Author(s):  
C. A. Shanks
Keyword(s):  
Nitrous Oxide ◽  
Effective Dose ◽  
Dose Response ◽  
Electrical Response ◽  
Surgical Patients ◽  
Simultaneous Administration ◽  
Response Curves ◽  
Twitch Response ◽  
The Mean ◽  
The Right

Simultaneous administration of pancuronium and alcuronium was used in surgical patients during nitrous oxide — narcotic — barbiturate anaesthesia in order to determine the intensity of neuromuscular blockade. When compared with the results obtained when each of the drugs was given alone, the effect was not greater than the additive. The mean effective dose of pancuronium to produce 95% paralysis was 76 μg per kg for the mechanical twitch response and 70 μg per kg for the electrical response. The respective mean doses of alcuronium producing that degree of paralysis were 285 and 244 μg per kg. Usually the curve derived for the mechanical twitch response was to the right of, and roughly parallel to, that for the electrical response.

Short-term cholinergic desensitization of rat pancreatic secretory response

1987 ◽  
Vol 252 (3) ◽  
pp. G392-G397
Author(s):  
J. Asselin ◽  
L. Larose ◽  
J. Morisset
Keyword(s):  
Dose Response ◽  
Recovery Period ◽  
Ionophore A23187 ◽  
Muscarinic Agonists ◽  
Short Term ◽  
Response Curves ◽  
Amylase Release ◽  
Pancreatic Acini ◽  
Cholinergic Agent ◽  
The Right

Dispersed pancreatic acini were first exposed to carbamylcholine (10(-7)-10(-4) M) for 60 min, washed, and reexposed to this same agonist (10(-8)-10(-3) M) for 15 min. During this second incubation, the functional secretory capacity of these acini was evaluated by measuring amylase release. Acini preexposed to concentrations of carbamylcholine of 10(-6) M or greater showed shifts to the right in the subsequent carbamylcholine dose-response curves of amylase release. A 3-h recovery period (without carbamylcholine) did not restore the altered carbamylcholine dose-response curve. Ca2+ concentrations of 10(-7) M or 2.5 X 10(-3) M instead of 0.5 X 10(-3) M during the 60-min preincubation did not affect the desensitization process. With use of N-[3H]methylscopolamine to evaluate muscarinic receptors, the only changes observed after desensitization were a significant decrease in the high-affinity and an equivalent increase in that of the low-affinity receptors. After cholinergic exposure amylase release stimulated by caerulein was only slightly modified, whereas amylase release in response to a phorbol ester 12-O-tetradecanoylphorbol-13-acetate and to the ionophore A23187 was not altered. These data indicate that short-term desensitization with a cholinergic agent is relatively specific to muscarinic agonists, causes changes in the muscarinic receptor high- and low-affinity concentration but does not alter intracellular steps after calcium mobilization or protein kinase C activation known to be involved in the secretion process.

Effects of repetitive bursts of vagal activity on atrioventricular junctional rate in dogs

1979 ◽  
Vol 237 (3) ◽  
pp. H275-H281 ◽  
Author(s):  
D. W. Wallick ◽  
M. N. Levy ◽  
D. S. Felder ◽  
H. Zieske
Keyword(s):  
Cardiac Cycle ◽  
Sinus Node ◽  
Critical Time ◽  
Large Change ◽  
Vagal Activity ◽  
Vagus Nerves ◽  
Pacemaker Cells ◽  
Chronotropic Response ◽  
Sinus Node Artery ◽  
The Mean

A stable atrioventricular (AV) junctional rhythm was produced in open-chest dogs by injecting pentobarbital into the sinus node artery. When the cervical vagus nerves were stimulated repetitively, the junctional pacemaker cells tended to become synchronized with the vagal activity. During such synchronization, the junctional rate varied directly rather than inversely with the frequency of vagal stimulation. The magnitude of the chronotropic response depended on the timing of the vagal stimuli within the cardiac cycle. In 9 dogs, when the mean heart periods were plotted as a function of the R-st intervals (i.e., the time from the beginning of ventricular depolarization to the beginning of the stimulus burst), the mean heart periods varied from a maximum of 1,815 ms to a minimum of 1,160 ms, depending on the R-st interval. A small change in the R-st interval was capable of evoking a relatively large change in cycle length. Therefore, the impulses from various efferent vagal fibers to the AV junction must arrive almost synchronously, the released acetylcholine must be removed rapidly, and the sensitivity of the pacemaker cells to acetylcholine must change rapidly at some critical time during the cardiac cycle.

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