Effects of a specific bradycardic agent (AQ-A39) and verapamil on β-adrenergic responses in isolated guinea pig atria

1987 ◽  
Vol 65 (2) ◽  
pp. 146-151 ◽  
Author(s):  
Peter K. S. Siegl ◽  
George Morgan
Keyword(s):  
Heart Rate ◽  
Guinea Pig ◽  
Channel Blocker ◽  
Cardiac Contractility ◽  
Force Of Contraction ◽  
Bradycardic Agent ◽  
Inotropic Responses ◽  
Right Atria ◽  
Guinea Pig Atria ◽  
Elevated Heart Rate

AQ-A39 (5,6-dimethoxy-2-{3-[(α-(3,4-dimethoxy)phenylethyl)methylamino]propyl}-phthalimidine), a specific bradycardic agent, and verapamil, a calcium channel blocker, were studied for their ability to alter rate and force of contraction in the presence and absence of isoproterenol, a β-adrenergic stimulant, using isolated guinea pig atria. Both compounds (10−7–10−4 M) produced dose-related decreases in frequency of spontaneously beating right atria. Verapamil decreased, while AQ-A39 increased, the force of contraction of electrically stimulated (1.0 Hz) left atria. At equal negative chronotropic concentrations, AQ-A39 was more effective than verapamil in reducing the maximum isoproterenol-induced tachycardia. Verapamil, but not AQ-A39, antagonized positive inotropic responses to isoproterenol. Therefore, AQ-A39 differed from verapamil in that (i) AQ-A39 was a more selective bradycardic agent in both β-adrenergically stimulated and nonstimulated preparations and (ii) AQ-A39 was more effective in reducing isoproterenol-elevated heart rate compared with basal heart rate. This profile of activities suggests that AQ-A39 will be beneficial in cardiac pathologies where sympathetic nervous system activity is elevated and a lowering of heart rate without a reduction in cardiac contractility is desired.

Characterization of the effects of AHN 086, an irreversible ligand of "peripheral" benzodiazepine receptors, on contraction in guinea-pig atria and ileal longitudinal smooth muscle

1989 ◽  
Vol 67 (2) ◽  
pp. 126-134 ◽  
Author(s):  
G. T. Bolger ◽  
A. H. Newman ◽  
K. C. Rice ◽  
H. W. M. Lueddens ◽  
A. S. Basile ◽  
...  
Keyword(s):  
Smooth Muscle ◽  
Guinea Pig ◽  
Calcium Channels ◽  
Benzodiazepine Receptors ◽  
Significant Inhibition ◽  
Bay K 8644 ◽  
Longitudinal Smooth Muscle ◽  
Peripheral Benzodiazepine Receptors ◽  
Inotropic Responses ◽  
Guinea Pig Atria

The effects of AHN 086 and its reversibly acting structural analogue Ro 5-4864 were studied in the spontaneously beating guinea-pig atria and field-stimulated guinea-pig ileal longitudinal smooth muscle in the presence and absence of dihydropyridine calcium channel modulators. The treatment of guinea-pig atria with AHN 086 followed by extensive washing did not alter contraction. However, AHN 086 (0.5 μM) potentiated (88%) the positive inotropic responses by BAY K 8644, an effect that was not reversed by extensive washing of the tissue. Higher concentrations of AHN 086 (> 2 μM) irreversibly inhibited the intropic, but not the chronotropic responses to BAY K 8644, nifedipine, and isoproterenol. Ro 5-4864 (10 μM) produced a reversible enhancement of the inotropic responses and block of the chronotropic responses to BAY K 8644. In guinea-pig ileal longitudinal smooth muscle, both AHN 086 and Ro 5-4864 reversibly inhibited field-stimulated contractions. Neither Ro 5-4864 nor AHN 086 affected the ability of nifedipine to inhibit field-stimulated contractions of ileal longitudinal smooth muscle. Treatment of intact atria with 5 μM AHN 086 followed by extensive washing resulted in a significant inhibition (30–50%) of [3H]Ro 5-4864 binding to peripheral benzodiazepine receptors and of [3H]nitrendipine binding to voltage-operated calcium channels, but did not affect [3H]dihydroalprenolol binding to β-adrenergic receptors on atrial membranes. The same treatment applied to intact ileal longitudinal smooth muscle affected neither [3H] (−)-quinuclidinyl benzilate binding to muscarine receptors nor [3H]nitrendipine binding, but did result in a significant inhibition (30–50%) of [3H]Ro 5-4864 binding to ileal longitudinal smooth muscle membranes. The pharmacology of AHN 086 suggests that there is a different relationship between peripheral benzodiazepine receptors and voltage-operated calcium channels in guinea-pig atria and ileal longitudinal smooth muscle.Key words: calcium channels, peripheral benzodiazepine receptors, dihydropyridines, benzodiazepines, dihydropyridine binding sites.

Interaction between adenosine and inotropic interventions in guinea pig atria

1983 ◽  
Vol 245 (3) ◽  
pp. H475-H480
Author(s):  
J. G. Dobson
Keyword(s):  
Electrical Stimulation ◽  
Guinea Pig ◽  
Blocking Agent ◽  
Depressant Effect ◽  
Force Development ◽  
Contraction Frequency ◽  
Contractile Parameters ◽  
Inotropic Responses ◽  
Adrenergic Blocking ◽  
Guinea Pig Atria

Isolated guinea pig atria stimulated to contract isometrically were used to determine whether adenosine at a concentration that does not cause a direct depressant effect on peak contractile force, rate of force development, and rate of relaxation was capable of influencing the elevation in these contractile parameters caused by an increase in preload, paired electrical stimulation, an increase in contraction frequency, and catecholamine stimulation in K+-depolarized and nondepolarized atrial muscle. Adenosine had no effect on the contractile parameters that were enhanced by an increase in preload or paired electrical stimulation. The nucleoside reduced the increases in the contractile parameters produced by isoproterenol stimulation, an increase in contraction frequency, and isoproterenol-induced contractions in depolarized atria. All adenosine reductions were inhibited by theophylline, an antagonist of adenosine actions. The adenosine reduction of the elevated contractile parameters caused by increasing contraction frequency was not prevented by atropine (a muscarinic antagonist) or propranolol (a beta-adrenergic blocking agent). These results suggest that adenosine at a concentration that does not produce direct negative inotropic responses is capable of attenuating the elevation in contractility elicited by catecholamine stimulation, an increase in contraction frequency, and catecholamine-induced contractions in depolarized atria. However, the reduction by adenosine of the contractile responses elicited by an increase in contraction frequency appears to be independent of catecholamines.

Dose-Response Effects of Adrenergic and Cholinergic Stimulation on Atrial Natriuretic Peptide Secretion from Beating Isolated Guinea-Pig Atria

1993 ◽  
Vol 85 (1) ◽  
pp. 5-12 ◽  
Author(s):  
P. F. Speake ◽  
S. C. Pirie ◽  
J. D. Kibble ◽  
A. Muneer ◽  
D. Taylor ◽  
...  
Keyword(s):  
Guinea Pig ◽  
Atrial Natriuretic Peptide ◽  
Natriuretic Peptide ◽  
Secretory Response ◽  
Force Of Contraction ◽  
Absolute Change ◽  
The Absolute ◽  
Peptide Secretion ◽  
Guinea Pig Atria ◽  
Atrial Natriuretic

1. The possible role of autonomic neurotransmitters in atrial natriuretic peptide secretion was investigated using spontaneously beating guinea-pig atria in vitro. Dose responses were determined for adrenaline, noradrenaline and acetylcholine and the selective α- and β-adrenoceptor agonists phenylephrine and isoprenaline, respectively. Adrenoceptor effects were further studied using the selective α- and β-adrenoceptor antagonists prazosin and propranolol, respectively, in conjunction with maximal adrenaline challenge. Results for rate and force of contraction and atrial natriuretic peptide secretion are expressed as a ratio (mean ± SEM) of a 15 min treatment period (stage 2) to a corresponding pretreatment period (stage 1). 2. Adrenaline and noradrenaline caused dose-dependent increases in the rate and force of contraction and in atrial natriuretic peptide secretion with a peak secretory response at 2 × 10−6 mol/l of 1.54 ± 0.08 (P <0.01) and 1.34 ± 0.08 (P <0.01) for adrenaline and noradrenaline, respectively. Acetylcholine decreased the rate and force of contraction, and ANP secretion was reduced to 0.47 ± 0.06 at 3 × 10−5 mol/l (P <0.01). Isoprenaline increased the rate and force of contraction and atrial natriuretic peptide secretion with a peak secretory response of 152 ± 0.22 at 2 × 10−6 mol/l (P <0.01). Phenylephrine increased the force but had no effect on the rate of contraction, and stimulated atrial natriuretic peptide secretion to 1.13 ± 0.09 at 2 × 10−5 mol/l (P <0.05). After both α- and β-adrenoceptor blockade, adrenaline was still able to significantly stimulate atrial natriuretic peptide secretion and positive inotropy. There was no chronotropic effect of adrenaline in the presence of propranolol. Simultaneous α- and β-adrenoceptor blockade inhibited all the effects of adrenaline. 3. A significant correlation was observed between the absolute change in rate of contraction and the absolute change in atrial natriuretic peptide secretion upon stimulation with each of the drugs (r = 0.63, P < 0.001). A similar relationship between developed tension and atrial natriuretic peptide secretion could not be demonstrated. 4. In conclusion, secretion of atrial natriuretic peptide from guinea-pig atria was stimulated by adrenergic and inhibited by cholinergic agonists. The adrenergic response was mediated by both α- and β-adrenoceptor stimulation. The observed changes in the rate of contraction showed a significant correlation with atrial natriuretic peptide secretion.

Age-dependent biochemical and contractile properties in atrium of transgenic mice overexpressing junctin

2004 ◽  
Vol 287 (5) ◽  
pp. H2216-H2225 ◽  
Author(s):  
Uwe Kirchhefer ◽  
Hideo A. Baba ◽  
Gabriela Hanske ◽  
Larry R. Jones ◽  
Paulus Kirchhof ◽  
...  
Keyword(s):  
Heart Rate ◽  
Transgenic Mice ◽  
Ryanodine Receptor ◽  
Transmembrane Protein ◽  
Force Of Contraction ◽  
Stress Tests ◽  
Age Dependent ◽  
Beating Rate ◽  
Right Atria ◽  
Junctional Sarcoplasmic Reticulum

Junctin is a transmembrane protein of the cardiac junctional sarcoplasmic reticulum (SR) that binds to the ryanodine receptor, calsequestrin, and triadin 1. This quaternary protein complex is thought to facilitate SR Ca2+ release. To improve our understanding of the contribution of junctin to the regulation of SR function, we examined the age-dependent effects of junctin overexpression in the atrium of 3-, 6-, and 18-wk-old transgenic mice. The ratio of atrial weight and body weight was unchanged between junctin-overexpressing (JCN) and wild-type (WT) mice at all ages investigated ( n = 6–8). The protein expression of triadin 1 was decreased starting in 3-wk-old JCN atria (by 69%), whereas the expression of the ryanodine receptor was diminished in 6- (by 48%) and 18-wk-old (by 57%) JCN atria compared with age-matched WT atria. Force of contraction was decreased by 35% in 18-wk-old JCN compared with age-matched WT left atrial muscle strips, which was accompanied by a prolonged time of relaxation (48.1 ± 0.9 vs. 44.2 ± 0.8 ms, respectively, n = 6–8, P < 0.05). The spontaneous beating rate of isolated right atria was higher in 18-wk-old JCN mice compared with age-matched WT mice (389 ± 10 vs. 357 ± 6 beats/min, respectively, n = 6–8, P < 0.05). Heart rate was lower by 9% in telemetric ECG recordings in 18-wk-old JCN mice during stress tests. Three-week-old JCN atria exhibited a higher potentiation of force of contraction at rest pauses of 30 s (by 13%) and of 300 s (by 35%), suggesting increased SR Ca2+ content. This was consistent with the higher force of contraction in 3-wk-old JCN atria (by 29%) compared with age-matched WT atria (by 10%) under the administration of caffeine. We conclude that in 3-wk-old atria, junctin overexpression was associated with a reduced expression of triadin 1 resulting in a higher SR Ca2+ load without changes in contractility or heart rate. In 6-wk-old JCN atria, the compensatory downregulation of the ryanodine receptor may offset the effects of junctin overexpression. Finally, the progressive decrease in ryanodine receptor density may contribute to the decreased atrial contractility and lower heart rate during stress in 18-wk-old JCN mice.

Does endogenous adenosine have a role in the cardiac responses to isoprenaline and in the rapid fade of the inotropic response of perfused heart?

1994 ◽  
Vol 72 (2) ◽  
pp. 152-160 ◽  
Author(s):  
Kenneth J. Broadley ◽  
Andrew N. A. Wilson
Keyword(s):  
Guinea Pig ◽  
Adenosine Deaminase ◽  
Papillary Muscles ◽  
Inotropic Response ◽  
Force Of Contraction ◽  
Depressant Effect ◽  
Response Curves ◽  
Endogenous Adenosine ◽  
Left And Right ◽  
Right Atria

The role of endogenous adenosine during the β-adrenoceptor responses to isoprenaline of guinea-pig isolated cardiac preparations was examined. Insignificant effects of adenosine deaminase (0.3 U∙mL−1) on cumulative concentration–response curves for isoprenaline on isolated left and right atria and papillary muscles indicated a negligible depressant effect of endogenous adenosine during these responses. The increase in force of contraction to an infusion of isoprenaline (14 nM) in perfused spontaneously beating hearts rapidly waned while the infusion continued, whereas the increase in rate of contraction remained constant throughout the infusion. The degree of fade was less in paced preparations (5 Hz), indicating that it was only in part due to the rate increase exerting some mechanical constraint on the force of contraction. The P1-purinoceptor antagonist 8-phenyltheophylline (12 μM) and adenosine deaminase (0.3 U∙mL−1) did not enhance the peak responses to the isoprenaline infusion. The fade of the inotropic response in both spontaneous and paced hearts was also not attenuated by the presence of 8-phenyltheophylline or adenosine deaminase. The fade was not, therefore, due to release of endogenous adenosine exerting a depressant effect. Whether this declining inotropic response represents a form of rapid desensitization remains to be determined.Key words: guinea-pig perfused hearts, left and right atria, papillary muscles, β-adrenoceptor agonist, endogenous adenosine.

Effect of mersalyl on isolated perfused guinea pig atria

1960 ◽  
Vol 199 (3) ◽  
pp. 460-462 ◽  
Author(s):  
Edward Stein ◽  
John Magin ◽  
Morris Kleinfeld
Keyword(s):  
Heart Rate ◽  
Guinea Pig ◽  
Left Atrium ◽  
Mechanism Of Action ◽  
Right Atrium ◽  
Transmembrane Potential ◽  
Cysteine Hydrochloride ◽  
The Right ◽  
Guinea Pig Atria ◽  
Electrical And Mechanical Activities

The effects of mersalyl in concentrations of 0.4–2 x 10–4 m were studied on isolated perfused guinea pig atria. Mersalyl produced a moderate slowing of the heart rate, an enhanced repolarization of the transmembrane potential and a decrease in contractility of both right and left atrium. The atria eventually developed asystole which usually occurred earlier in the left than in the right atrium. Administration of 6.3 x 10–4 m cysteine hydrochloride as a constant perfusion reversed the asystole. The improvement in both the electrical and mechanical activities occurred gradually. The mechanism of action of mersalyl is attributed to inhibition of certain protein sulfhydryls in the cell; the reactivation of function by cysteine is postulated to be due to the formation of mersalyl cysteinate.

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