Effects of inotropic agents on isolated guinea pig heart under conditions that modify calcium pools involved in contractile activation

1986 ◽  
Vol 64 (7) ◽  
pp. 947-953 ◽  
Author(s):  
Kyosuke Temma ◽  
Tai Akera ◽  
Yuk-Chow Ng
Keyword(s):  
Guinea Pig ◽  
Heart Muscle ◽  
Isolated Heart ◽  
Bay K 8644 ◽  
Inotropic Effect ◽  
Common Mechanism ◽  
Primary Role ◽  
Guinea Pig Heart ◽  
Inotropic Effects ◽  
Contractile Activation

Positive inotropic effects of strophanthidin were compared with those of isoproterenol, BAY K 8644, grayanotoxin, veratridine, and monensin in electrically stimulated left atrial muscle preparations of guinea pig heart under conditions in which the calcium pool, playing a primary role in contractile activation, was altered. In concentrations that caused similar degrees of increase in developed tension under 1 Hz stimulation, grayanotoxin and strophanthidin caused a relatively large increase in potentiated postrest contraction compared with that caused by isoproterenol, whereas the effect of BAY K 8644 on the postrest contraction was the smallest. The effect of high concentrations of grayanotoxin or strophanthidin, however, resembled that of isoproterenol. The sensitivity of the isolated heart muscle to these agents was compared under conditions in which utilization of various calcium pools contributing to contractile activation was suppressed. Mn2+, which reduces contribution of very superficial Ca2+, reduced sensitivity of heart muscle to the positive inotropic effect of isoproterenol and enhanced the inotropic effect of monensin or veratridine. Verapamil, nifedipine, diltiazem, or ryanodine did not have marked effects on the positive inotropic action of Ca2+, monensin, veratridine, or strophanthidin. These results suggest that the positive inotropic actions of veratridine, grayanotoxin, and strophanthidin share a common mechanism and that low concentrations of strophanthidin may increase loading of Ca2+ pool, which plays an important role in potentiated postrest contraction.

Roles of PKA, PI3K, and cPLA2 in the NO-mediated negative inotropic effect of β2-adrenoceptor agonists in guinea pig right papillary muscles

2008 ◽  
Vol 294 (1) ◽  
pp. C106-C117 ◽  
Author(s):  
Fabien A. Faucher ◽  
François E. Gannier ◽  
Jacques M. Lignon ◽  
Pierre Cosnay ◽  
Claire O. Malécot
Keyword(s):  
Guinea Pig ◽  
Positive Inotropic Effect ◽  
Negative Inotropic Effect ◽  
Inotropic Effect ◽  
Papillary Muscles ◽  
Guinea Pig Heart ◽  
Inotropic Effects ◽  
Inotropic State ◽  
No Release ◽  
High Concentrations

Although β2-adrenoceptors represent 15–25% of β-adrenoceptors in the guinea pig heart, their functionality is controversial. We assessed the inotropic effects of β2-adrenoceptor partial agonists in right papillary muscles. Salbutamol induced a small but significant concentration-dependent negative inotropic effect (NIE, −5% at 60 nM) followed by a moderate positive inotropic effect (+36% at 6 μM) due to activation of β1-adrenoceptors. In the presence of 4 μM atenolol, the concentration-dependent NIE (−12% at 6 μM) was biphasic, best described by a double logistic equation with respective EC50 values of 3 and ∼420 nM, and was insensitive to SR59230A. In muscles from pertussis toxin-treated guinea pigs, the salbutamol-induced positive inotropic effect was sensitive to low concentrations of ICI-118551 in an unusual manner. Experiments in reserpinized animals revealed the importance of the phosphorylation-dephosphorylation processes. PKA inhibition reduced and suppressed the effects obtained at low and high concentrations, respectively, indicating that its activation was a prerequisite to the NIE. The effect occurring at nanomolar concentrations depended upon PKA/phosphatidylinositol 3-kinase/cytosolic phospholipase A2 (cPLA2) activations leading to nitric oxide (NO) release via the arachidonic acid/cyclooxygenase pathway. NO release via PKA-dependent phosphorylation of the receptor was responsible for the inotropic effect observed at submicromolar concentrations, which is negatively controlled by cPLA2. The possibility that these effects are due to an equilibrium between different affinity states of the receptor (Gs/Gi coupled and Gi independent with different signaling pathways) that can be displaced by ICI-118551 is discussed. We conclude that β2-adrenoceptors are functional in guinea pig heart and can modulate the inotropic state.

Relationship between the Effect on Calcium Turnover and Early Cardiotoxicity of Doxorubicin and 4'-EPI-Doxorubicin in Guinea Pig Heart Muscle

1980 ◽  
Vol 66 (6) ◽  
pp. 689-697 ◽  
Author(s):  
Fabrizio Villani ◽  
Luigia Favalli ◽  
Francesco Piccinini
Keyword(s):  
Guinea Pig ◽  
Heart Muscle ◽  
Myocardial Contractility ◽  
Negative Inotropic Effect ◽  
Experimental Models ◽  
Inotropic Effect ◽  
General Mechanism ◽  
Guinea Pig Heart ◽  
Membrane Bound ◽  
Guinea Pig Atria

Doxorubicin and 4'-epi-doxorubicin, two anthracycline derivatives with different cardiotoxic effects in experimental models, were found to decrease myocardial contractility in isolated guinea pig atria by significantly modifying calcium turnover. This effect seems to be mainly localized on the fast exchanging membrane-bound calcium, while these drugs do not significantly influence the intracellular stores of calcium. 4'-epi-doxorubicin, which induces a less negative inotropic effect than doxorubicin, produces a smaller inhibition of calcium turnover. This supports the hypothesis that the inhibition of calcium turnover and particularly of the fast exchanging calcium compartment is a general mechanism involved in the early anthracycline-induced cardiotoxicity.

Functional and autoradiographic characterization of dopamine D2-like receptors in the guinea pig heart

2002 ◽  
Vol 80 (6) ◽  
pp. 578-587 ◽  
Author(s):  
María de Jesús Gómez ◽  
Guy Rousseau ◽  
Réginald Nadeau ◽  
Roberto Berra ◽  
Gonzalo Flores ◽  
...  
Keyword(s):  
Guinea Pig ◽  
Western Blot ◽  
Dopamine Receptors ◽  
Negative Inotropic Effect ◽  
Cyclase Activity ◽  
Inotropic Effect ◽  
Receptor Subtypes ◽  
Guinea Pig Heart ◽  
Additional Information ◽  
The Right

Dopamine receptors include the D1- (D1 and D5 subtypes) and D2-like (D2, D3, and D4 subtypes) families. D1-like receptors are positively and D2-like receptors negatively coupled to the adenylyl cyclase. Dopamine D2-like (D4 subtype) receptors have been identified in human and rat hearts. However the presence of D2 and D3 receptor subtypes is unclear. Furthermore, their role in cardiac functions is unknown. By autoradiographic studies of guinea pig hearts, we identified D3 and D4 receptors, using the selective radioligands [3H]-7-OH-DPAT and [3H]emonapride (YM-09151-2 plus raclopride). Western blot analysis confirmed D3 and D4 receptors in the right and left ventricle of the same species. Selective agonists of D3 and D4 receptors (±)-7-OH-DPAT and PD 168 077 (10–9 to 10–5 M, respectively) induced a significant negative chronotropic and inotropic effect in the isolated guinea pig heart preparation. Negative inotropic effect induced by PD 168 077 was associated with an inhibition in cyclase activity. No changes in cyclase activity were found with (±)-7-OH-DPAT. The aim of this study is to support the presence of D3 and D4 receptors in the heart. Although our results suggest that D3 and D4 receptors are functionally active in the heart, we need additional information with an antagonist and an agonist of improved potency and selectivity to understand the respective roles of D3 and D4 receptors in the cardiac functions.Key words: Dopamine receptors (D2, D3, D4 subtypes), autoradiography, Western blot, cAMP, heart.

Positive inotropic effects of low concentrations of leukotrienes C4 and D4 in rat heart

1990 ◽  
Vol 259 (4) ◽  
pp. H1239-H1246 ◽  
Author(s):  
M. Karmazyn ◽  
M. P. Moffat
Keyword(s):  
Calcium Channel ◽  
Positive Inotropic Effect ◽  
Negative Inotropic Effect ◽  
Bay K 8644 ◽  
Inotropic Effect ◽  
Receptor Interaction ◽  
Inotropic Effects ◽  
Coronary Pressure ◽  
Low Concentrations ◽  
Rat Hearts

We examined the effects of leukotrienes (LT) B4, C4, D4, and E4 (0.010-2.5 ng/ml) on contractile and coronary function in isolated rat hearts. Concentration-dependent effects were examined either by the cumulative addition of LTs or by addition of specific concentrations to individual preparations. Neither LTB4 nor LTE4 produced myocardial or coronary effects at any concentration, irrespective of addition protocol. At 0.010 ng/ml, both LTC4 and LTD4 produced an increase in force that was associated with a 30% elevation in coronary pressure. Further cumulative addition of either leukotriene resulted in a negative inotropic effect and a further increase in coronary pressure. In contrast, following single additions of LTC4 or LTD4 (0.01-0.50 ng/ml) a positive inotropic effect and an increased coronary pressure were observed. LTC4 or LTD4 at 0.5 ng/ml produced a negative inotropic effect in hearts pretreated with 0.01 ng/ml of LTD4 or LTC4, respectively. Reversal of this addition protocol resulted in a negative inotropic effect of either 0.01 ng/ml LTD4 or LTC4. Verapamil and nifedipine significantly attenuated the positive inotropic and coronary constricting effect of 0.5 ng/ml LTC4 and LTD4. The addition of either LT following BAY K 8644 resulted in a negative inotropic effect, in contrast to the positive inotropic influence seen with leukotriene alone. Our results demonstrate a positive inotropic effect of low concentrations of LTC4 and LTD4 concomitant with coronary artery constriction, a phenomenon determined by leukotriene addition protocols and suggestive of LTC4/LTD4 receptor interaction. The effects of calcium channel antagonists and BAY K 8644 on the inotropic response suggest a leukotriene-mediated activation of the calcium channel resulting in increased intracellular calcium concentrations.

Reduced glutathione modulates the arachidonic acid induced coronary reactions

1984 ◽  
Vol 62 (10) ◽  
pp. 1261-1267 ◽  
Author(s):  
Jaime Talesnik ◽  
James N. Tsoporis
Keyword(s):  
Arachidonic Acid ◽  
Guinea Pig ◽  
Reduced Glutathione ◽  
Isolated Heart ◽  
Prostaglandin E ◽  
Guinea Pig Heart ◽  
Rat Hearts ◽  
Resistance Vessels ◽  
Vasodilator Action ◽  
Perfused Hearts

Coronary flow was recorded from spontaneously beating isolated perfused hearts of rats and guinea pigs. Arachidonic acid (AA), in single bolus doses, produced a fast short lasting coronary constriction followed by a slow developing but persisting vasodilation. These reactions (biphasic type) were characteristic of the guinea pig heart. In about 50% of the rat hearts the vasoconstrictor action predominated while the biphasic response was obtained in the rest of the experiments. Pretreatment of rats with aspirin prevented the responses to AA in the isolated heart. The administration of reduced glutathione (GSH) (about 1 mM to the rat or 0.5–0.75 mM to the guinea pig hearts) produced a marked development and (or) enhancement of the vasodilator action of AA. Repeated or single large doses of AA produced a change of pattern of responses from biphasic to constrictor type; the addition of GSH restored the vasodilator phase. Since GSH directs the endoperoxide metabolism towards the synthesis of prostaglandin E2 (PGE2), we postulate that the coronary dilatation of resistance vessels produced by AA would be due to a great extent to PGE2.

Dissociation between adenosine release, MVO2, and energy status in working guinea pig hearts

1997 ◽  
Vol 272 (1) ◽  
pp. H371-H381 ◽  
Author(s):  
U. K. Decking ◽  
S. Arens ◽  
G. Schlieper ◽  
K. Schulze ◽  
J. Schrader
Keyword(s):  
Guinea Pig ◽  
Isolated Heart ◽  
Adenosine Kinase ◽  
Energy Status ◽  
Perfusion Medium ◽  
Guinea Pig Heart ◽  
Atp Formation ◽  
Fluorocarbon Emulsion ◽  
Cardiac Energy ◽  
Arterial Po2

Rapid adaptation of ATP formation and coronary flow is required when cardiac work is altered. Cardiac energy status was proposed to control both oxygen consumption (MVO2) and release of vasoactive adenosine (AR). To investigate the hypothesis of a linear relation between free AMP and AR, we employed 31P nuclear magnetic resonance (NMR) in a newly elaborated guinea pig heart performing pressure-volume work. Under basal conditions, MVO2 was 7.8 +/- 1.0 mumol.min-1.g-1, free AMP 297 +/- 189 nM and AR 226 +/- 179 pmol.min-1.g-1 (n = 29). Decreasing arterial PO2 by 50% reduced MVO2 and increased free AMP by 29%; however, AR rose threefold (n = 5). Doubling oxygen content of the perfusion medium (fluorocarbon emulsion) did not alter MVO2, free AMP, or AR (n = 6). When afterload was doubled, MVO2 increased (+45%) and AR decreased (-60%) despite no change in ADP or AMP (n = 6). Dobutamine increased MVO2 (+50%) and AMP (-98%); however, AR rose more than five times (n = 8). Switching substrates from glucose + pyruvate to glucose diminished MVO2 and increased ADP twofold and AMP fourfold, whereas AR remained constant (n = 6). Our findings demonstrate that cardiac energy status is also not the prime regulator of oxidative phosphorylation in the isolated heart. Changes in the oxygen supply-to-demand ratio induced a rise in AR that exceeded by far the increase in free AMP. Thus, additional factors, possibly inhibition of adenosine kinase, influence the release of vasoactive adenosine.

Blockade of Cardiac Histamine Receptors by Promethazine

1974 ◽  
Vol 52 (1) ◽  
pp. 23-27 ◽  
Author(s):  
John H. McNeill ◽  
Subhash C. Verma
Keyword(s):  
Cyclic Amp ◽  
Guinea Pig ◽  
Histamine Receptors ◽  
Inotropic Effect ◽  
Guinea Pig Heart ◽  
Chronotropic Effects ◽  
Non Equilibrium

The inotropic and chronotropic effects of histamine on the isolated perfused guinea pig heart were antagonized by promethazine over a concentration range 4 × 10−6 – 16 × 10−6 M. Promethazine (4 × 10−6 M) decreased the ability of histamine (1 μg) to elevate cardiac cyclic AMP. A higher dose of histamine could not overcome the promethazine blockade. Promethazine (4 × 10− 6 M) did not block the inotropic effect of noradrenaline. Higher concentrations of promethazine, particularly 16 × 10−6 M did decrease the noradrenaline response. The data indicate that promethazine can interact with cardiac histamine receptors but the interaction is either noncompetitive or competitive non-equilibrium in nature.

scholarly journals Photoaffinity labelling of the cardiac calcium channel. (−)-[3H]azidopine labels a 165 kDa polypeptide, and evidence against a [3H]-1,4-dihydropyridine-isothiocyanate being a calcium-channel-specific affinity ligand

1987 ◽  
Vol 243 (1) ◽  
pp. 127-135 ◽  
Author(s):  
D R Ferry ◽  
A Goll ◽  
H Glossmann
Keyword(s):  
Guinea Pig ◽  
Calcium Channel ◽  
Polyacrylamide Gel Electrophoresis ◽  
Dimethyl Ester ◽  
High Capacity ◽  
Bay K 8644 ◽  
Channel Blockers ◽  
Guinea Pig Heart ◽  
Affinity Ligand ◽  
Heart Membranes

The arylazide 1,4-dihydropyridine (-)-[3H]azidopine binds to a saturable population of sites in guinea-pig heart membranes with a dissociation constant (KD) of 30 +/- 7 pM and a density (Bmax.) of 670 +/- 97 fmol/mg of protein. This high-affinity binding site is assumed to reside on voltage-operated calcium channels because reversible binding is blocked stereoselectively by 1,4-dihydropyridine channel blockers and by the enantiomers of Bay K 8644. A low-affinity (KD 25 +/- 7 nM) high-capacity (Bmax. 21.6 +/- 9 pmol/mg of protein) site does not bind (-)- or (+)-Bay K 8644, but is blocked by high concentrations (greater than 500 nM) of dihydro-2,6-dimethyl-4-(2-isothiocyanatophenyl)-3,5-pyridinedicarboxy lic acid dimethyl ester (1,4-DHP-isothiocyanate) or, e.g., (+/-)-nicardipine. (-)-[3H]Azidopine was photoincorporated covalently into bands of 165 +/- 8, 39 +/- 2 and 35 +/- 3 kDa, as determined by SDS/polyacrylamide-gel electrophoresis. Labelling of the 165 kDa band is protected stereoselectively by 1,4-dihydropyridine enantiomers at low (nM) concentrations and by (-)- and (+)-Bay K 8644, whereas the lower-Mr bands are not. Thus, only the 165 kDa band is the calcium-channel-linked 1,4-dihydropyridine receptor. Photolabelling of the 39 or 35 kDa bands was only blocked by 10 microM-1,4-DHP-isothiocyanate or 50 microM-(+/-)-nicardipine but not by 10 microM-(-)-Bay K 8644. [3H]-1,4-DHP-isothiocyanate binds to guinea-pig heart membranes with a KD of 0.35 nM and dissociates with a k-1 of 0.2 min-1 at 30 degrees C. [3H]-1,4 DHP-isothiocyanate irreversibly labels bands of 39 and 35 kDa which are protected by greater than 10 microM-(+/-)-nicardipine or unlabelled ligand but not by 10 microM-(-)-Bay K 8644. Thus, [3H]-1,4-DHP-isothiocyanate is not an affinity probe for the calcium channel.

Sign in / Sign up

Export Citation Format

Share Document