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  • Adenosine  (3)
  • Papaverine  (3)
  • Negative inotropic effect  (2)
  • [3H]prazosin binding  (2)
  • 1
    Digitale Medien
    Digitale Medien
    Springer
    Naunyn-Schmiedeberg's archives of pharmacology 306 (1979), S. 241-248 
    ISSN: 1432-1912
    Schlagwort(e): Papaverine ; Isoprenaline ; Carbachol ; Cyclic AMP ; Cyclic GMP ; Ventricular contraction
    Quelle: Springer Online Journal Archives 1860-2000
    Thema: Medizin
    Notizen: Summary In the isolated ventricular myocardium of the dog the effects of papaverine on the contractile force and on the cyclic nucleotide levels were studied. Furthermore the interaction between papaverine and the adrenergic β-or cholinergic stimulation was investigated. 1. Papaverine (3×10−5 M) induced a positive inotropic action and increased the cyclic AMP level in the majority of preparations. Ventricular muscles isolated from certain dogs showed only a negative inotropic response to papaverine. As a whole, a significant correlation was found between the tension developed and the cyclic AMP level after the administration of papaverine. The cyclic GMP level was not changed or decreased by papaverine. 2. The positive inotropic action of papaverine and elevation of the cyclic AMP level in response to papaverine were not inhibited by a β-adrenoceptor blocking drug, pindolol (3×10−8 M), indicating that these effects are not caused by catecholamine release. 3. In muscles, in which papaverine failed to cause the positive inotropic action, contractile as well as cyclic AMP responses to isoprenaline were significantly enhanced by papaverine. 4. Carbachol (3×10−6M) diminished the positive inotropic actions of isoprenaline and papaverine, abolished the accumulation of cyclic AMP produced by these agents, and increased significantly the cyclic GMP level. The elevation of cyclic GMP level by carbachol in the presence of papaverine was especially marked and amounted to 4-fold the corresponding control value. These results indicate that papaverine inhibits the break down of the intracellular cyclic AMP and GMP in the intact myocardial cells and may thereby interact functionally with the autonomic nervous system.
    Materialart: Digitale Medien
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  • 2
    ISSN: 1432-1912
    Schlagwort(e): Chlorethylclonidine ; Alpha1-adrenoceptors ; Positive inotropic effect ; [3H]prazosin binding ; Phosphoinositide hydrolysis ; Rabbit papillary muscle
    Quelle: Springer Online Journal Archives 1860-2000
    Thema: Medizin
    Notizen: Summary The influence of the alphalb-adrenoceptor-selective antagonist chlorethylclonidine on the alpha1-adrenergic positive inotropic effect and the phosphoinositide hydrolysis induced by phenylephrine was investigated in the rabbit ventricular myocardium. Pretreatment of membrane fractions derived from the rabbit ventricular muscle with 10−5 mol/l chlorethylclonidine decreased the specific binding of [3H]prazosin (at a saturating concentration of 10−9 mol/l) from the control value of 11.27±0.48 to 4.18±1.87 fmol/mg protein. The inhibition by adrenaline of the binding of [3H]prazosin (slope factor and affinity) was not affected by chlorethylclonidine. The positive inotropic effect of phenylephrine (in the presence of 3 × 10−7 mol/l bupranolol) was inhibited by chlorethylclonidine in a concentration-dependent manner (10−7−10−5 mol/l) and abolished by 10−5 mol/l chlorethylclonidine. The concentration of chlorethylclonidine to inhibit the phenylephrine-induced maximum response to 50% was 2.4 × 10−6 mol/l. The accumulation of [3H]inositol monophosphate and [3H]inositol trisphosphate induced by 10−5 mol/l phenylephrine was inhibited by chlorethylclonidine in the same concentration range. These findings indicate that the myocardial alpha1-adrenoceptors mediating a positive inotropic effect in the rabbit ventricular myocardium may belong to the chlorethylclonidine-sensitive alpha1b-subtype, and that the subcellular mechanism of action involve phosphoinositide hydrolysis.
    Materialart: Digitale Medien
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  • 3
    ISSN: 1432-1912
    Schlagwort(e): Adenosine ; Phenylisopropyladenosine ; Negative inotropic effect ; Cyclic AMP ; Ventricular myocardium of the dog
    Quelle: Springer Online Journal Archives 1860-2000
    Thema: Medizin
    Notizen: Summary Experiments were carried out to characterize the adenosine-induced negative inotropic effect in relation to the extent of β-adrenoceptor activation in the isolated dog left ventricular myocardium. Adenosine and R-N6-phenylisopropyladenosine inhibited the positive inotropic effect of isoprenaline (10−7 mol/1 and lower) about 20% of its maximal response, which was antagonized by an A1 adenosine receptor antagonist 1,3-dipropyl-8-cyclopentylxanthine in a concentration-dependent manner. The negative inotropic effect of adenosine disappeared and that of R-N6-phenylisopro-pyl-adenosine decreased when the isoprenaline concentration was elevated to the level higher than 10−7 mol/1. Adenosine deaminase (1.5 U/ml) that abolished the negative inotropic effect of adenosine enhanced the effect of R-N6-phenylisopropyladenosine, indicating that endogenous adenosine released by high isoprenaline concentration (10−6 mol/1) modulates the interaction. The maximal response to adenosine and R-N6-phenylisopro-pyladenosine determined in the presence of 10−7 mol/1 isoprenaline was 50% of that of carbachol which elicited the maximal inhibition even in the presence of 10−6 mol/1 isoprenaline. The negative inotropic effects of R-N6-phenylisopropyladenosine and carbachol were additive to the maximal response equivalent to that of carbachol. The difference in the efficiency between the adenosine and muscarinic receptor agonists may be partly ascribed to the difference in densities of the respective receptors in the dog ventricular myocardium. The negative inotropic effect of R-N6-phenylisopropyladenosine in the presence of isoprenaline was associated with decrease in cyclic AMP levels elevated previously by isoprenaline. The elevation of cyclic AMP levels caused by isoprenaline (3 × 10−7 mol/1) was abolished by R-N6-phenylisopro-pyladenosine (10−4 mol/1), while the contractile response was reduced only by 30% with R-N6-phenylisopro-pyladenosine. In the absence of β-adrenoceptor stimulation R-N6-phenylisopropyladenosine elicited a negative inotropic effect without changes in cyclic AMP levels, but this effect was less than 10% of the basal force of contraction. It is concluded that in the dog ventricular myocardium adenosine receptors play a role for the inhibitory regulation of contractility, which is influenced markedly by the pre-existing level of β-adrenoceptor activation.
    Materialart: Digitale Medien
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  • 4
    ISSN: 1432-1912
    Schlagwort(e): α-Adenoceptors ; β-Adrenoceptors ; Phenylephrine ; cAMP ; Papaverine ; Rabbit papillary muscle
    Quelle: Springer Online Journal Archives 1860-2000
    Thema: Medizin
    Notizen: Summary The time course of changes of the level of 3′,5′-cyclic AMP (cAMP) and of the tension developed under stimulation of α- and β-adrenoceptors by phenylephrine was investigated in the isolated rabbit papillary muscle. Furthermore the doseresponse relationships for increases of cAMP and of developed tension elicited by phenylephrine were determined. 1. A submaximally effective concentration of phenylephrine (10−5 M) increased significantly the level of cAMP of the papillary muscle at 15 and 30 s by 45 and 36%, respectively; the level of cAMP returned to the control value at 60 s after the administration. The developed tension increased significantly not before 45 s and reached its maximal level at 180 s. 2. When α-adrenoceptors were blocked by phentolamine (10−6 M), the positive inotropic effect of phenylephrine was decreased significantly but the increase of cAMP induced by phenylephrine was not reduced. In the presence of phentolamine the increase of cAMP induced by phenylephrine lasted longer than in the control experiments. 3. The effects of phenylephrine (10−5 M) both on the level of cAMP and the developed tension mediated via stimulation of β-adrenoceptors in the presence of phentolamine were enhanced by the phosphodiesterase inhibitor papaverine throughout the course of responses. 4. Phenylephrine produced an increase in developed tension as well as in cAMP. The corresponding dose-response curves run parallel to each other but differed by about 1.5 log units whereby the developed tension was evoked by lower concentrations. Phentolamine (10−6 M) shifted the curve for the positive inotropic action by about 1.5 log units but did not affect that for increase in cAMP. Therefore, in the presence of the α-adrenolytic drug phentolamine the difference between both curves became smaller so that both curves were superimposed. Papaverine (10−5 M) shifted the whole curve for cAMP upwards and enhanced the maximal contractile response to phenylephrine mediated by stimulation of β-adrenoceptors. 5. The present results indicate that the positive inotropic action of phenylephrine in lower concentrations (〈10−5 M) induced by stimulation of α-adrenoceptors is independent of the level of cAMP. The positive inotropic action of the higher concentrations of phenylephrine induced via stimulation of β-adrenoceptors was preceded by an accumulation of cAMP; the inhibition of the cAMP phosphodiesterase activity by papaverine enhanced the actions of phenylephrine both on the level of cAMP and on the contractile force.
    Materialart: Digitale Medien
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  • 5
    Digitale Medien
    Digitale Medien
    Springer
    Naunyn-Schmiedeberg's archives of pharmacology 337 (1988), S. 169-176 
    ISSN: 1432-1912
    Schlagwort(e): Phorbol ester ; Protein kinase C ; alphaAdrenoceptors ; beta-Adrenoceptors ; Positive inotropic effects ; Phenylephrine ; [3H]prazosin binding ; [3H]CGP-12177 binding ; Rabbit papillary muscle
    Quelle: Springer Online Journal Archives 1860-2000
    Thema: Medizin
    Notizen: Summary The phorbol ester 12-O-tetradecanoyl phorbol-13-acetate (TPA) was used to examine the hypothesis that phosphoinositide turnover is involved in the regulation of myocardial contractility mediated by stimulation of alpha-adrenoceptors in the mammalian cardiac muscle. Exposure of the isolated rabbit papillary muscle electrically driven at a rate of 1 Hz at a temperature of 37°C to TPA in concentrations of 10–1000 nmol/l for 30 min did not affect the basal force of contraction. The concentration-response curve for the positive inotropic effect of (−)-phenylephrine mediated by stimulation of alpha-adrenoceptors in the presence of (±)-bupranolol (100 nmol/1) was shifted to the right and downward by TPA in concentrations of 30–1000 nmol/l, while the effect of (−)-phenylephrine mediated by stimulation of beta-adrenoceptors in the presence of prazosin (100 nmol/l) was not decreased, but slightly enhanced by exposure of the muscle to relatively low concentrations of TPA (10–100 nmol/l). Incubation of the membrane fraction isolated from the rabbit ventricular muscle with TPA in vitro under the same condition as employed in the physiological experiments decreased the specific binding of [3H]prazosin but not that of [3H]CGP-12177, while the non-tumor promoting phorbol ester, αPDD, was ineffective. These results indicate that activation of protein kinase C by TPA does not mimic the positive inotropic effect of catecholamines mediated by activation of myocardial alpha-adrenoceptors. on the other hand, the specific interaction of alpha-adrenoceptor-mediated processes with TPA in the rabbit papillary muscle is in line with the view that the facilitation of phosphoinositide turnover and subsequent activation of protein kinase C may play a certain role in the coupling of alpha-adrenoceptor occupation by agonists to the process leading to the positive inotropic action.
    Materialart: Digitale Medien
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  • 6
    ISSN: 1432-1912
    Schlagwort(e): Adenosine ; Phenylisopropyladenosine ; Adenosine receptors ; Negative inotropic effect ; G proteins ; Ferret ventricular myocardium
    Quelle: Springer Online Journal Archives 1860-2000
    Thema: Medizin
    Notizen: Summary An adenosine A1 receptor agonist R-N6-phenylisopropyladenosine (R-PIA) elicited a pronounced negative inotropic effect with the EC50 value of 0.69 μmol/1 in the presence of a β-adrenoceptor blocking agent bupranolol (0.3 μmol/1) in the isolated ferret papillary muscle. The negative inotropic effect of R-PIA was not associated with changes in cyclic AMP level. Adenosine and other A1 receptor agonists also elicited a negative inotropic effect. DPCPX (1,3-dipropyl-8-cyclopentyl xanthine) antagonized the negative inotropic effect of R-PIA in a competitive manner (pA2 value = 8.4). The inhibitory action of R-PIA was markedly attenuated in the ventricular muscle preparation isolated from ferrets pretreated with pertussis toxin that caused ADP-ribosylation of 39 kDa proteins in the membrane fraction. In the membrane fraction derived from the ferret ventricle, [3H]-DPCPX bound to a single binding site in a saturable and reversible manner with high affinity (Kd value = 1.21±0.41 nmol/l; B max = 12.8±3.02 fmol/mg protein; n = 7). The binding characteristics of [3H]-DPCPX in the rat ventricle (Kd value = 1.51 ±0.09 nmol/l; B max = 12.7±1.47 fmol/mg protein; n = 5) were similar to those in the ferret. On the other hand, the content of Go, a major pertussis toxin-sensitive G protein in the ferret heart, was much higher in the ferret than in the rat ventricle. The present results indicate that adenosine receptors may play an important role in the inhibitory regulation of ventricular contractility in the ferret in contrast to other mammalian species. The signal transduction process subsequent to agonist binding to A1 receptors including the pertussis toxin-sensitive G protein and ion channels may be responsible for the unique inhibitory action of adenosine in this species.
    Materialart: Digitale Medien
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  • 7
    ISSN: 1432-1912
    Schlagwort(e): α-and β-Adrenoceptors ; Methoxamine ; Isoprenaline ; cAMP ; Papaverine ; Rabbit Papillary Muscle
    Quelle: Springer Online Journal Archives 1860-2000
    Thema: Medizin
    Notizen: Summary In the isolated papillary muscle of the rabbit the time course of the effects of selective β-and α-adrenoceptor stimulation by isoprenaline and methoxamine, respectively, on the contractile force and on the level of 3′,5′-cyclic AMP (cAMP) was determined. 1. Isoprenaline (3×10−7 M) increased significantly the content of cAMP at 15 sec and elevated it to the maximal level-about twice the control value-at 30 sec after its administration, while the developed tension of the papillary muscle was also increased significantly at 15 sec and reached gradually its maximum at 90 sec. 2. Compared with isoprenaline methoxamine (10−4 M) increased the developed tension very slowly: the maximal response was reached after 20 min. The level of cAMP, on the other hand, was changed neither before nor during the induction of the positive inotropic effect of methoxamine. 3. The phosphodiesterase inhibitor papaverine (10−5 M) inhibited the PDE activity of the papillary muscle by about 40% after an incubation of 1 hr, and increased the level of cAMP significantly. The effects of isoprenaline on the contractile force and on the level of cAMP were considerably enhanced by papaverine: the content of cAMP was increased by isoprenaline (3×10−7 M) to about 3 times the control value and also its positive inotropic effect was significantly greater than in controls without papaverine. On the other hand, the positive inotropic effect of methoxamine (10−4 M) was not affected by papaverine (10−5 M). Further-more, in the papillary muscle treated with papaverine the level of cAMP was significantly reduced by methoxamine: the papaverine-induced increase of cAMP was abolished by methoxamine. 4. The present results are compatible with the hypothesis that cAMP is involved as a mediator in the positive inotropic effect induced by β-adrenoceptor stimulation, and indicate further that the stimulation of α-adrenoceptors evokes its positive inotropic effect through a mechanism other than that elicited by β-adrenoceptor stimulation, i.e., independent of cAMP.
    Materialart: Digitale Medien
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  • 8
    Digitale Medien
    Digitale Medien
    Springer
    Naunyn-Schmiedeberg's archives of pharmacology 351 (1995), S. 610-617 
    ISSN: 1432-1912
    Schlagwort(e): Ferret ; Ventricular myocytes ; Acetylcholine ; Adenosine ; Muscarinic K+ ; channel ; G protein
    Quelle: Springer Online Journal Archives 1860-2000
    Thema: Medizin
    Notizen: Abstract The properties of the K+ channel activated by acetylcholine (ACh) and adenosine (Ado) were examined in single ferret ventricular myocytes using patch-clamp techniques. In the whole-cell configuration, ACh and Ado induced an inwardly rectifying K+ current and shortened the action potential duration. The effect of ACh was blocked by atropine, while the Ado effect was interrupted by 8-cyclopenty1,1,2-dipropyl xanthine, a specific Ado A1 receptor antagonist. In cell-attached recordings, ACh and Ado added to the pipette solution activated a single population of inwardly rectifying K+ channels, distinct from the i K1 channel. The channel had a slope conductance of ∼ 40 pS in symmetrical 150 mM K+ solutions and a mean open time of 0.8 ms. Excision of the patch into the inside-out patch configuration in guanosine triphosphate (GTP)-free solution abolished the channel activity. The channel was reversibly reactivated by adding GTP to the intracellular side of the patch. GTPγS activated the channel irreversibly. When the inside-out patch was treated with the A protomer of pertussis toxin (PTX), intracellular GTP no longer activated the K+ channel. The results show that ferret ventricular myocytes possess a K+ channel activated by both muscarinic and Ado A1 receptors. Its electrophysiological properties and the gating by a PTX-sensitive G protein in a membrane-delimited fashion are identical with those of the muscarinic K+ channels in nodal and atrial tissues of other species. In conclusion, the G protein-gated muscarinic K+ channel is expressed in ferret ventricular myocardium and may underlie the direct negative inotropism of ACh and Ado in this tissue.
    Materialart: Digitale Medien
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