Positive inotropic effects of methoxamine: evidence for alpha-adrenergic receptors in ventricular myocardium

Rabinowitz, Babeth; Chuck, Leonard; Kligerman, Miriam; Parmley, W.W.

doi:10.1152/ajplegacy.1975.229.3.582

Cited by 75 publications

(22 citation statements)

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“…A dissociation between cyclic AMP levels and cardiac contractile activity has been observed in rat and rabbit heart when phenylephrine (an a-and P-adrenoceptor agonist) was administered together with a ,B-adrenoceptor blocking drug (Osnes & Oye, 1975;Brodde, Motomura, Endoh & Schumann, 1978). A similar cyclic AMPindependent inotropic effect has been described in rabbit and cat papillary muscle for methoxamine (Rabinowitz, Chuck, Kligerman & Parmley, 1975;. In the rabbit papillary muscle the positive inotropic effect of phenylephrine, during blockade of f-adrenoceptors, is depressed by D600 (a 'calcium antagonistic ' compound, Fleckenstein, 1971), suggesting that the effect of ax-adrenoceptor stimulation may be caused mainly by a change of calcium influx through the myocardial cell membrane .…”

Section: Introductionmentioning

confidence: 73%

Α‐sympathomimetic Amines and Calcium‐mediated Action Potentials in Guinea‐pig Ventricular Muscle

Ledda

Mantelli

Mugelli

1980

British J Pharmacology

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1 The ability of amines, having ca-or a-and f-adrenoceptor stimulating activity, to restore excitability and contractility in heart preparations partially depolarized by potassium, was investigated in guinea-pig ventricular muscle in order to elucidate the mechanism of the positive inotropic effect mediated via a-adrenoceptors. 2 In preparations in which fast sodium channels were inactivated by K+-rich medium (22 mM) slow electrical responses as well as contractions were consistently induced by high concentrations of phenylephrine (10-' to 3 x 1O-' M) and synephrine (3 x 10-M).3 The restorative effects of both phenylephrine and synephrine were unaffected by phentolamine (10'-M) but were readily abolished by practolol (10'-M) or sotalol (10-i M). 4 Methoxamine induced a dose-dependent positive inotropic effect in ventricular strips paced at 0.5 Hz in normal Tyrode solution; the maximum increase in contractile tension was obtained with methoxamine 10'-M. However, at the same concentration, the amine did not induce slow electrical responses in potassium-depolarized preparations. 5 It is concluded that the induction of slow responses by phenylephrine and synephrine is due to ,B-adrenoceptor stimulation, and that the increase in cardiac contractility caused by a-adrenoceptor stimulation does not involve an increase in slow inward calcium current.

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Section: Introductionmentioning

confidence: 73%

Α‐sympathomimetic Amines and Calcium‐mediated Action Potentials in Guinea‐pig Ventricular Muscle

Ledda

Mantelli

Mugelli

1980

British J Pharmacology

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“…Furthermore, the positive inotropic actions of noradrenaline and adrenaline in the presence of adequate fl-adrenoceptor blockade were not influenced by aL-adrenoceptor blockade with phentolamine. The observations that the positive inotropic action of dopamine (which was not affected by pindolol because of masking by the a-adrenoceptor-mediated action in the rabbit heart; Endoh et al, 1976) was antagonized in a competitive manner by pindolol in the dog ventricle, and that the other ax-adrenoceptor stimulating agents, methoxamine and clonidine which have an a-adrenoceptor-mediated positive inotropic action in other species (Nakashima et al, 1973;Endoh & Schumann, 1975a;Rabinowitz et al, 1975), had only a negative inotropic effect in the dog support this view. The results obtained with papaverine, a phosphodiesterase inhibitor and with changes in experimental temperature are also consistent with the view that the adrenoceptors mediating the positive inotropic action in the dog ventricle are only of the f-type.…”

Section: Isolated Ventricular Stripsmentioning

confidence: 99%

Characterization of Adrenoceptors Mediating Positive Inotropic Responses in the Ventricular Myocardium of the Dog

Endoh

Shimizu

Yanagisawa

1978

British J Pharmacology

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1 The pharmacological characteristics of adrenoceptors mediating the positive inotropic action in the dog heart were assessed by the use of blood-perfused papillary muscles and isolated strips of ventricular myocardium. 2 On the blood-perfused papillary muscle driven at 2 Hz and in sinus node preparations, phenylephrine induced positive inotropic and chronotropic responses in the same dose range and was much less potent than isoprenaline. The dose-response curve for the chronotropic action of phenylephrine was parallel to that of isoprenaline, whilst the dose-response curve for the inotropic action of phenylephrine was less steep than that of isoprenaline.3 The infusion of pindolol, a P-adrenoceptor blocking agent, at a rate of 1 1±g/min, shifted the isoprenaline dose-response curves to the right, and to the same extent, in both papillary muscle and sinus node preparations. In contrast to isoprenaline, the antagonism of phenylephrine by pindolol was noncompetitive. Phentolamine did not affect the positive inotropic and chronotropic actions of phenylephrine. 4 On isolated ventricular strips a-adrenoceptor blockade by 10-6M phentolamine did not affect dose-response curves to phenylephrine or dopamine. Pindolol shifted the dopamine dose-response curves to the right in a competitive manner and those of phenylephrine in a noncompetitive manner. 5 On ventricular strips from reserpine-pretreated dogs phenylephrine and tyramine dose-response curves were shifted markedly to the right and downwards. Desipramine (10-5M) which enhanced the action of noradrenaline considerably reduced the myocardial responses of phenylephrine.6 Papaverine (10' M) decreased the threshold concentration of phenylephrine required to stimulate the myocardium and shifted phenylephrine dose-response curves to the left. 7 Raising the temperature from 32°C to 37°C shifted phenylephrine dose-response curves to the right; when the temperature was raised from 37°C to 42°C the affinity of the drug was not changed.8 Other a-adrenoceptor stimulants, methoxamine and clonidine, decreased the active tension of ventricular strips. The responses to noradrenaline and adrenaline (in the presence of pindolol; 3 x 10-'M) were not affected by phentolamine (10-6 M).9 The results indicate that adrenoceptors mediating positive inotropic responses in the dog ventricle are of the P-type and that post-synaptic a-adrenoceptors are not involved. Phenylephrine acts mainly by releasing noradrenaline from adrenergic nerve endings and partly by a weak direct action on ,B-adrenoceptors.

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“…DISCUSSION The widely accepted view (28) that both chronotropic and inotropic responses to catecholamines are mediated exclusively through cardiac adrenergic receptors of the ,63-subtype has recently been challenged on two fronts. Persuasive evidence supporting the existence of functional postsynaptic cardiac alpha adrenergic receptors influencing both chronotropy and inotropy has been presented (15,(29)(30)(31); and some investigators have advanced the hypothesis that cardiac receptors of the 832-subtype may play a role in mediating chronotropic, but not'inotropic, responses to catecholamines. For example, Carlsson et al (32) observed in a reserpinized anesthetized cat model that the ratio ofthe drug dose required to produce a 50% maximal chronotropic response to the dose required to produce a 50% maximal inotropic response was 0.93 for the 8,-selective agonist (-) H80/60, 0.5 for the non-subtype selective agonist (-) isoproterenol, and 0.16 for the p32-selective agonist terbutaline.…”

Section: Resultsmentioning

confidence: 99%

“…Previous pharmacologic data confirm this prediction: dobutamine has only minimal effects upon peripheral B32-receptors mediating relaxation of vascular smooth muscle (1)(2)(3)(4), and previous studies of biochemical responses to dobutamine have also suggested that this compound has little agonist activity at ,82-receptors. For example, Pike and Lefkowitz (43) found dobutamine to be a partial agonist for stimulation of adenylate cyclase or of GTPase activity in turkey erythrocyte membranes (i83) with peak stimulatory activity 24 and 19%, respectively, of that observed for (-) isoproterenol, whereas dobutamine had only minimal activity for stimulation of adenylate cyclase (8% of [-] (29)(30)(31), perhaps direct al-agonist activity in the heart could account for dobutamine's distinctive effects. The work of Tuttle and Mills (1) suggested that dobutamine's inotropic effects were only minimally affected by phenoxybenzamine, but the effects of alpha blockade on the heart rate responses to dobutamine have not, to our knowledge, been reported.…”

Section: Resultsmentioning

confidence: 99%

Selectivity of Dobutamine for Adrenergic Receptor Subtypes

Williams¹,

Bishop²

1981

J. Clin. Invest.

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A B S T R A C T The cardiovascular responses elicited by dobutamine are distinctly different from those produced by other adrenergic or dopaminergic agonists. To test the hypothesis that dobutamine could have differential affinities for adrenergic receptor subtypes, and that such subtype selectivity could be related to its relatively unique pharmacologic properties, we assessed the ability of dobutamine to displace adrenergic radioligands from membrane receptors in a number of tissues of previously characterized adrenergic receptor subtype. For beta adrenergic receptors identified by (-) [3H]dihydroalprenolol (DHA), dobutamine had significantly greater affinity for the ,f3 subtype (KD = 2.5 MM in rat heart and 2.6 MM in turkey erythrocyte) than for the (82 subtype (KD = 14.8 AM in frog heart and 25.4 ,uM in rat lung) (P < 0.001). For alpha adrenergic receptors, dobutamine had markedly greater affinity for the a,-subtype identified by [3H]prazosin (KD = 0.09 ,uM in rat heart and 0.14 AM in rabbit uterus) than for the a2-subtype identified by [3H]dihydroergocryptine (DHE) (KD = 9.3 MuM in human platelet) or by [3H]-yohimbine (KD = 5.7 MM in rabbit uterus) (P < 0.001).Like other 3B,-agonists, in the absence of guanine nucleotide, dobutamine competition curves for DHA binding in rat heart demonstrated two classes of binding sites, with one site of significantly higher affinity (KD = 0.5 MM, P = 0.008) than the single class of binding sites (KD = 5.2 MuM) identified in the presence of guanine nucleotide. However, unlike /32-or a2-agonists, dobutamine displacement of DHA binding in rat lung or of DHE binding in human platelets demonstrated only a single class of binding sites, and guanine nucleotide had only minimal effects.

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Positive inotropic effects of methoxamine: evidence for alpha-adrenergic receptors in ventricular myocardium

Cited by 75 publications

References 0 publications

Α‐sympathomimetic Amines and Calcium‐mediated Action Potentials in Guinea‐pig Ventricular Muscle

Α‐sympathomimetic Amines and Calcium‐mediated Action Potentials in Guinea‐pig Ventricular Muscle

Characterization of Adrenoceptors Mediating Positive Inotropic Responses in the Ventricular Myocardium of the Dog

Selectivity of Dobutamine for Adrenergic Receptor Subtypes

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