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  • 1
    Electronic Resource
    Electronic Resource
    Positive inotropic effects of phenylephrine in the isolated rabbit papillary muscle mediated both by α-and β-adrenoceptors (1974)
    Springer
    Naunyn-Schmiedeberg's archives of pharmacology 284 (1974), S. 133-148 
    Details
    ISSN: 1432-1912
    Keywords: Adrenoceptors ; Phenylephrine ; Phosphodiesterase Inhibitors ; Rabbit Papillary Muscle
    Source: Springer Online Journal Archives 1860-2000
    Topics: Medicine
    Notes: Summary On the isolated papillary muscle of the rabbit experiments were performed in order to study whether β-and/or α-adrenoceptors mediate the positive inotropic effect of phenylephrine and, for comparison, of other sympathomimetic drugs. 1. The positive inotropic effect of phenylephrine in concentrations of up to 3×10−6M was antagonized by the α-adrenolytic drug phentolamine, while that evoked by higher concentrations was inhibited by the β-adrenolytic drug pindolol. The intrinsic activity of phenylephrine amounted to 0.6 compared with that of isoprenaline. 2. Pretreatment with reserpine altered neither the pD2-value for phenylephrine nor its intrinsic activity. 3. The inhibitors of phosphodiesterase, theophylline (10−4M) and papaverine (10−5M) enhanced the effect of higher concentrations of phenylephrine—mediated mainly by stimulation of β-adrenoceptors, whereas that of lower concentrations—mediated by stimulation of α-adrenoceptors—was not affected. Papaverine strongly increased the intrinsic activity of phenylephrine, which then reached that of isoprenaline. 4. The α-adrenoceptor stimulating drugs, methoxamine, naphazoline and oxymetazoline did not cause positive inotropic effects but, on the contrary, negative ones. The positivei notropic effect of noradrenaline was not changed by phentolamine, whereas that of adrenaline in concentrations of up to 10−5 M was inhibited. 5. From these results it is concluded that in the rabbit papillary muscle not only β- but also α-adrenoceptors are of functional importance for the mediation of the positive inotropic effect of some sympathomimetic drugs. The nature of these α-adrenoceptors is apparently distinct from those of other organs since these receptors were stimulated only by phenylephrine and adrenaline but not by noradrenaline, methoxamine, naphazoline and oxymetazoline.
    Type of Medium: Electronic Resource
    URL: http://dx.doi.org/10.1007/BF00501118
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  • 2
    Electronic Resource
    Electronic Resource
    Phorbol ester does not mimic, but antagonizes the alpha-adrenoceptor-mediated positive inotropic effect in the rabbit papillary muscle (1988)
    Springer
    Naunyn-Schmiedeberg's archives of pharmacology 337 (1988), S. 169-176 
    Details
    ISSN: 1432-1912
    Keywords: Phorbol ester ; Protein kinase C ; alphaAdrenoceptors ; beta-Adrenoceptors ; Positive inotropic effects ; Phenylephrine ; [3H]prazosin binding ; [3H]CGP-12177 binding ; Rabbit papillary muscle
    Source: Springer Online Journal Archives 1860-2000
    Topics: Medicine
    Notes: 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.
    Type of Medium: Electronic Resource
    URL: http://dx.doi.org/10.1007/BF00169245
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  • 3
    Electronic Resource
    Electronic Resource
    Stimulation by phenylephrine of adrenergic alpha- and beta-receptors in the isolated perfused rabbit heart (1974)
    Springer
    Naunyn-Schmiedeberg's archives of pharmacology 282 (1974), S. 307-310 
    Details
    ISSN: 1432-1912
    Keywords: Isolated Perfused Rabbit Heart ; Phenylephrine ; dp/dt max ; Heart Rate ; Adrenolytic Drugs
    Source: Springer Online Journal Archives 1860-2000
    Topics: Medicine
    Notes: Summary In the isolated perfused rabbit heart the effect of phenylephrine on the left ventricular dp/dt max and on heart rate was investigated. 1. The positive inotropic effect of phenylephrine 3×10−7 to 3×10−6 M was abolished by the α-adrenolytic drug phentolamine (3×10−6 M), whereas the β-adrenolytic drug pindolol (10−8 M) was ineffective. On the other hand, the positive inotropic effect evoked by higher concentrations (10−5 to 10−4 M) of phenylephrine was blocked by pindolol while phentolamine was without any effect. 2. The positive chronotropic effect of phenylephrine was antagonized by pindolol. Phentolamine was ineffective. 3. The results presented here show that the ventricular myocardium of the rabbit contains both β- and α-adrenoceptors responsible for the mediation of the positive inotropic effect of phenylephrine.
    Type of Medium: Electronic Resource
    URL: http://dx.doi.org/10.1007/BF00501238
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  • 4
    Electronic Resource
    Electronic Resource
    Relationship between the level of cAMP and the contractile force under stimulation of α- and β-adrenoceptors by phenylephrine in the isolated rabbit papillary muscle (1976)
    Springer
    Naunyn-Schmiedeberg's archives of pharmacology 295 (1976), S. 109-115 
    Details
    ISSN: 1432-1912
    Keywords: α-Adenoceptors ; β-Adrenoceptors ; Phenylephrine ; cAMP ; Papaverine ; Rabbit papillary muscle
    Source: Springer Online Journal Archives 1860-2000
    Topics: Medicine
    Notes: 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.
    Type of Medium: Electronic Resource
    URL: http://dx.doi.org/10.1007/BF00499441
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  • 5
    Electronic Resource
    Electronic Resource
    The preferential inhibition of α1- over β-adrenoceptor-mediated positive inotropic effect by organic calcium antagonists in the rabbit papillary muscle (1990)
    Springer
    Naunyn-Schmiedeberg's archives of pharmacology 341 (1990), S. 206-214 
    Details
    ISSN: 1432-1912
    Keywords: Calcium antagonists ; α-Adrenoceptors ; β-Adrenoceptors ; Positive inotropic effect ; Rabbit ventricular myocardium
    Source: Springer Online Journal Archives 1860-2000
    Topics: Medicine
    Notes: Summary Experiments were carried out to elucidate the mechanism that the positive inotropic effect mediated by α1-adrenoceptors is more susceptible to organic calcium antagonists than the β-adrenoceptor-mediated effect. Verapamil and diltiazem displaced the specific binding of [3H]prazosin to the membrane fraction derived from the rabbit ventricular myocardium, verapamil being about 70 times more potent than diltiazem. Nifedipine did not displace the binding. While these compounds suppressed the positive inotropic effect mediated via αl-adrenoceptors in α1- concentration-dependent manner, there was no correlation between the potency of the compounds to displace the [3H]prazosin binding and to inhibit the α-mediated positive inotropic effect. The relative potency of three calcium antagonists to decrease the basal force of contraction and the al-mediated effect (of the same extent as compared to basal force of contraction) was consistent to each other. The positive inotropic effect mediated by β-adrenoceptors was inhibited much less, and was enhanced by low concentrations of organic calcium antagonists. The differential action of calcium antagonists on the α- and β-mediated positive inotropic effect was mimicked by lowering the extracellular calcium concentration to 1/2, 1/4 and 1/8 of that in normal Krebs-Henseleit solution (2.5 mmol/l). These results indicate that the α1-adrenoceptor blocking activity does not play an essential role for the preferential inhibition of α-mediated positive inotropic effect by organic calcium antagonists. Difference in the subcellular mechanism involved in mobilization of intracellular Ca2+ subsequent to α1-and β-adrenoceptor activation may be responsible for the differential inhibitory action of calcium antagonists in the rabbit heart.
    Type of Medium: Electronic Resource
    URL: http://dx.doi.org/10.1007/BF00169732
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  • 6
    Electronic Resource
    Electronic Resource
    Preponderance of β- over α-adrenoceptors in mediating the positive inotropic effect of phenylephrine in the ferret ventricular myocardium (1989)
    Springer
    Naunyn-Schmiedeberg's archives of pharmacology 339 (1989), S. 362-366 
    Details
    ISSN: 1432-1912
    Keywords: α-Adrenoceptors ; β-Adrenoceptors ; Positive isotropic effect ; Phenylephrine ; Ferret ventricular myocardium
    Source: Springer Online Journal Archives 1860-2000
    Topics: Medicine
    Notes: Summary [3H]prazosin bound to the membrane fraction derived from the ferret ventricular muscle with high affinity in a saturable manner (K d = 0.25 nmol/l and B max = 27 fmol/mg protein in the right ventricle). [3H]CGP-12177, a β-adrenoceptor ligand, bound to the membrane fraction with a K d value of 0.29 nmol/l and a B max of 42 fmol/mg protein. In the isolated ferret papillary muscle driven at 1 Hz at 37°C, phenylephrine elicited a concentration-dependent positive intropic effect. The maximal effect of phenylephrine was comparable to that of isoprenaline. Prazosin (0.3 μol/l) shifted the concentration-response curve for phenylephrine slightly but significantly to the right, the maximal response being unaffected. In contrast, bupranolol (0.3 gmol/l) shifted the curve for phenylephrine markedly downwards: the maximal response was depressed significantly to 40% and the curve became less steep. In the presence of prazosin and bupranolol the curve was shifted to the right, being essentially parallel to the control curve. These results indicate that in the ferret ventricular myocardium both α- and β-adrenoceptors mediate the positive inotropic effect of phenylephrine. The extent of contribution of the two classes of adrenoceptor is quite different from that in other mammalian species. In the ferret heart, β-adrenoceptors predominate over α-adrenoceptors in mediating the positive inotropic effect of phenylephrine, although the number of β-adrenoceptors is not especially high when compared with other species.
    Type of Medium: Electronic Resource
    URL: http://dx.doi.org/10.1007/BF00173593
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  • 7
    Electronic Resource
    Electronic Resource
    Pharmacological differentiation of synergistic contribution of L-type Ca2+ channels and Na+/H+ exchange to the positive inotropic effect of phenylephrine, endothelin-3 and angiotensin II in rabbit ventricular myocardium (1996)
    Springer
    Naunyn-Schmiedeberg's archives of pharmacology 355 (1996), S. 87-96 
    Details
    ISSN: 1432-1912
    Keywords: Key words L-type Ca2+ channels ; Na+/H+ exchange ; Phenylephrine ; Endothelin-3 ; Angiotensin II ; Isoprenaline ; Positive inotropic effect ; Rabbit papillary muscle
    Source: Springer Online Journal Archives 1860-2000
    Topics: Medicine
    Notes: Abstract The present study was designed to delineate pharmacologically the role of sarcolemmal L-type Ca2+ channels and Na+/H+ exchange in the positive inotropic effect (PIE) of phenylephrine mediated by alpha-1 adrenoceptors, endothelin (ET) and angiotensin II (Ang II) that stimulate phosphoinositide (PI) hydrolysis in the rabbit ventricular muscle. The PIE of these receptor agonists was compared with the PIE of isoprenaline that accumulates cyclic AMP. For this purpose, we investigated the influence of a Ca2+ antagonist, verapamil, and of an inhibitor of Na+/H+ exchange, 5-(N-ethyl-N-isopropyl) amiloride (EIPA), alone or in combination, on the cumulative concentration-response curve (CRC) for phenylephrine (with 0.3 μM bupranolol), ET-3 and Ang II in isolated right ventricular papillary muscles of the rabbit, which were electrically stimulated at 1 Hz in Krebs-Henseleit solution at 37°C. Verapamil at 0.3 and 1 μM decreased the basal force of contraction to 37.0 ± 4.0% and 13.2 ± 1.1% of the control, respectively, while EIPA even at 10 μM affected the basal force to much less extent and decreased it to 87.0 ± 1.4%. Verapamil (0.3 and 1 μM) and EIPA (1 and 10 μM), when used alone, each significantly attenuated but did not abolish the PIEs induced by phenylephrine, ET-3 and Ang II, while the simultaneous administration of verapamil (1 μM) and EIPA (10 μM) consistently and almost completely inhibited the PIE induced by these receptor agonists. By contrast, the PIE of isoprenaline was retained even in the presence of verapamil and EIPA. These results indicate that both the influx of Ca2+ ions through L-type Ca2+ channels and activation of Na+/H+ exchange contribute synergistically to the PIE that is mediated by alpha-1 adrenergic, ET and Ang II receptor agonists, while these mechanisms are not essential for the beta-adrenoceptor-mediated PIE.
    Type of Medium: Electronic Resource
    URL: http://dx.doi.org/10.1007/PL00004923
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