Dissociation of Cardiac Inotropic and Adenylate Cyclase Activating Adrenoceptors (original) (raw)
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Naunyn-schmiedebergs Archives of Pharmacology, 1982
The positive inotropic effects of catecholamines were studied on samples of ventricular myocardium taken from patients undergoing open heart surgery. The adenylyl cyclase and binding of 3H-(−)-bupranolol were examined in membrane particles prepared from similarly obtained samples. The equilibrium dissociation constant (K D ) for (−)-bupranolol was estimated in 4 ways: blockade of the positive inotropic effects of catecholamines, blockade of the stimulation of the adenylyl cyclase by catecholamines, saturation binding of 3H-(−)-bupranolol, inhibition of the binding of 3H-(−)-bupranolol by its unlabeled stereoisomers. The estimates of K D fall in the range 0.5–1.4 nmol/l. The stereo-selectivity ratio (K D (+)-isomer/K D (−)-isomer) is 73. Both values for bupranolol are very similar in cat and man. The inotropic potency of (−)-noradrenaline is nearly 2 orders of magnitude higher in cat heart tissues than in tissues from human hearts. The difference in inotropic potencies between species is only partially accounted for by the five-fold lower potency of (−)-noradrenaline for the human heart adenylyl cyclase as compared to the cat enzyme.
Naunyn-schmiedebergs Archives of Pharmacology, 2004
The function of β-adrenoceptors was investigated in ventricular myocardium obtained from patients undergoing open heart surgery. Dopamine increased contractile force up to 1/2 and 1/4 of the maximum increase caused by (−)-noradrenaline or (−)-adrenaline in right and left ventricular preparations, respectively. β-adrenoceptors were labelled with 3H-(−)-bupranolol. For 3/4 of the receptors (β1) the affinity of (−)-noradrenaline was 20 times higher than for the remaining 1/4 (β2). (−)-Adrenaline and dopamine appeared to be nonselective for β1 and β2. Dopamine was able to stimulate the adenylate cyclase only up to 1/3 of the maximum stimulation caused by (−)noradrenaline and (−)-adrenaline. Increases in contractile force by (−)-noradrenaline were closely associated with small increases of cyclase activity through β1-adrenoceptors, consistent with a common link. The experiments on human myocardium were compared with similar experiments on feline myocardium. Feline ventricle exhibited a 20- to 30-fold higher sensitivity to catecholamines as activators of contractile force than did human ventricle. However, the binding affinities for catecholamines were similar in cat and man. A 3 h exposure of human and feline ventricular myocardium to (−)-isoprenaline caused desensitization by uncoupling β-adrenoceptors from the adenylate cyclase. Desensitization reduced the maximum contractile response to (−)-isoprenaline in human but not in feline ventricle. The more efficient activation of contractile force by (−)-noradrenaline in cat, compared to man, appears to be related to a 2-fold higher density of β1-adrenoceptors, a 6-fold higher production of cyclic AMP per β1-adrenoceptor and possibly to a more effective use of cyclic AMP for contraction.
Naunyn Schmiedeberg S Archives of Pharmacology, 1989
The function of/~-adrenoceptors was investigated in ventricular myocardium obtained from patients undergoing open heart surgery. 1. Dopamine increased contractile force up to 1/2 and 1/4 of the maximum increase caused by (-)-noradrenaline or (-)-adrenaline in right and left ventricular preparations, respectively. 2. j?-Adrenoceptors were labelled with 3H-(-)-bupranolol. For 3/4 of the receptors (/~1) the affinity of (-)-noradrenaline was 20 times higher than for the remaining 1/4 (/~2). (-)-Adrenaline and dopamine appeared to be nonselective for/~1 and/~2-3. Dopamine was able to stimulate the adenylate cyclase only up to 1/3 of the maximum stimulation caused by (-)noradrenaline and (-)-adrenaline. 4. Increases in contractile force by (-)-noradrenaline were closely associated with small increases of cyclase activity through/~l-adrenoceptors, consistent with a common link. 5. The experiments on human myocardium were compared with similar experiments on feline myocardium. Feline ventricle exhibited a 20-to 30-fold higher sensitivity to catecholamines as activators of contractile force than did human ventricle. However, the binding affinities for catecholamines were similar in cat and man. 6. A 3 h exposure of human and feline ventricular myocardium to (-)-isoprenaline caused desensitization by uncoupling /~-adrenoceptors from the adenylate cyclase. Desensitization reduced the maximum contractile response to (-)-isoprenaline in human but not in feline ventricle. 7. The more efficient activation of contractile force by (-)-noradrenaline in cat, compared to man, appears to be related to a 2-fold higher density of/~l-adrenoceptors, a 6fold higher production of cyclic AMP per/~a-adrenoceptor and possibly to a more effective use of cyclic AMP for contraction.
Temperature effects on theβ2-adrenoceptors of the trout atrium
1981
1. The contractile activity of the isolated atrium of the rainbow trout was studied as a function of temperature. In the absence of adrenaline a rise in temperature from 2 ~ to 17 ~ increased the contractile force and frequency, and the total tension generated during one minute was doubled. On the other hand, the effects of adrenaline on the contractile activity were most pronounced at 2 ~ indicating that sympathetic activation may be especially important in adjusting the heart to maximal performance at the lower range of environmental temperature. 2. The atrial adrenoceptor mediating inotropic and chronotropic effects of adrenaline was characterized as a /~2-adrenoceptor at temperatures between 2 and 14 ~ in agreement with earlier findings for this species at 8 ~ This conclusion was based on the effects of catecholamines and a series of selective receptor agonists and blocking agents. 3. The present results provide further evidence for an ' adrenaline'-receptor of the 132-type in the atrium of the rainbow trout being the 'innervated' and 'humoral' adrenoceptor at all temperatures within the physiological range for this species. 5 ~ It remains to be seen whether adrenaline in the trout plays a similarly important role as in the frog in adjusting the myocardium to maximal performance at low temperature. A temperature-induced transformation of the cardiac adrenoceptor from a /3-at high to an c~-type at low temperature, as postulated by Nickerson and Kunos (1977), could not be confirmed for the 132receptor of the frog myocardium (Benfey 1977 ; Stene-Larsen and Helle 1978b). It is thus of interest to establish whether there are temperature-dependent changes in the responses to adrenaline in the trout atrium which may reflect 1) a transformation of the adrenoceptor type or 2) a modulation of the affinity and intrinsic activity for the neurotransmitter, analogous to that observed in the frog atria (Stene-Larsen and Helle 1979). These questions have been elucidated in the present study which deals with the effects of temperature on the adrenoceptor pattern in the isolated atrium of the rainbow trout, with special emphasis on the role of adrenaline in potentiating atrial performance over a wide range of temperatures.
Temperature effects on the inotropic and chronotropic responses to adrenaline in the frog heart
Journal of Comparative Physiology B-biochemical Systemic and Environmental Physiology, 1979
The contractile force and frequency of the spontaneously beating auricles ofRana tempeoraria were recorded as a function of temperature. Tracings of the tension development, its integrated and derived functions showed that the isolated auricles of warmadapted “winter” frogs responded to temperature with changes in inotropy but not in the tension generated in one minute.
Qualitative Differences between β-Adrenergic and α-Adrenergic Inotropic Effects in Rat Heart Muscle
Acta Pharmacologica et Toxicologica, 1978
If pand a-adrenergic inotropic effects are cyclic AMP dependent and cyclic AMP independent, respectively, they may be qualitatively different. The inotropic effects of p-receptor stimulation (isoprenaline) and a-receptor stimulation (phenylephrine combined with propranolol) were characterized in isolated perfused rat hearts, rat atria and rat papillary muscles. The 0-effect reached its maximum before the a-effect. The a-effect followed a three-phasic time-course indicating both stimulatory and inhibitory components. The aortic pressure wave (perfused heart) indicated a shorter contraction phase after p-stimulation than after a-stimulation. The time to peak tension (atrium, papillary muscle) was relatively shorter after isoprenaline than after a-stimulation, which tended to prolong it. The contraction-relaxation cycles (atrium, papillary muscle) were examined by recording the isometric tension (T), its first (T) and second (T") derivatives. aand p-stimulation both increased Tmx, Tkax (maximal rate of tension rise), TAin (maximal rate of tension decline) and TAin (maximal rate of transition from rise to decline of tension). Isoprenaline increased Tkin (papillary muscle) and TZin (atrium, papillary muscle) relatively more than did a-stimulation, i.e. the relaxing processes were activated relatively more by p-stimulation. The results indicate different mechanisms for the two adrenergic inotropic effects. The relatively larger activation of relaxation by p-stimulation is assumed to be caused by cyclic AMP.
British Journal of Pharmacology, 1989
The effect of drugs on the adenosine 3':5'-cyclic monophosphate (cyclic AMP) content of desmethylimipramine (DMI)-treated bullfrog paravertebral sympathetic ganglia was studied by radioimmunoassay. The adrenaline-induced hyperpolarization (Adh) in this tissue was recorded by means of the sucrose-gap technique. 2 In the presence of propranolol (1 pM) and DMI (0.5 pM), adrenaline (1 AM) significantly reduced the concentration of cyclic AMP in forskolin-treated ganglia. This effect was prevented by pertussis toxin (5 jig ml 1). 3 The relative potency for drugs which increased ganglionic cyclic AMP content was: 50pM forskolin > 5 mM fluoride > 2 mm fluoride > 2 mm isobutylmethylxanthine (IBMX) > 5 mm caffeine. In contrast, their relative potency for inhibition of the Adh was: 2 mm IBMX > 5mM fluoride > 5 mm caffeine > 2 mm fluoride > 50 gM forskolin. The Adh was unaffected by pertussis toxin (5pgml-1). 4 Although the Adh was slightly reduced by the extracellular application of 8-bromo (8-Br) cyclic AMP, the majority of the data suggest that the transduction mechanism underlying the Adh is independent of the intracellular cyclic AMP concentration and provide an example of an a2-adrenoceptor-mediated response that occurs independently of inhibition of adenylate cyclase.
Physiological and Biochemical Zoology, 2003
The purpose of this study was to investigate how the endogenous catecholamine adrenaline protects sarcolemmal Ca 2ϩ flux through the L-type Ca 2ϩ channel (I Ca ) during acute exposure to cold in the fish heart. We examined the response of I Ca to adrenergic stimulation at three temperatures (7Њ, 14Њ, and 21ЊC) in atrial myocytes isolated from rainbow trout acclimated to 14ЊC. We found that I Ca amplitude varied directly with test temperature and was increased by adrenergic stimulation (AD; 5 nM and 1 mM) at all temperatures. However, I Ca was significantly more sensitive to adrenergic stimulation at the coldest test temperature. In fact, at 7ЊC in the absence of AD, I Ca was extremely low. The addition of 1 mM AD increased peak I Ca 7.2-fold at 7ЊC, 2.6-fold at 14ЊC, and 1.6-fold at 21ЊC and ameliorated the temperature-dependent difference in Ca 2ϩ influx across the cell membrane. We suggest that this increased adrenergic sensitivity is a critical compensatory mechanism that allows the rainbow trout heart to maintain contractility during acute exposure to cold temperatures. In particular, the tonic level of adrenergic stimulation provided by circulating plasma catecholamines (i.e., in the nM concentration range) may be crucial for effective excitation-contraction coupling in the cold cardiomyocyte.
British Journal of Pharmacology, 2003
We studied the biochemical and contractile responses of isolated human myocardial tissue expressing native receptor variants of the 389G4R b 1-adrenoceptor polymorphism. 2 Right atrial appendage was obtained from homozygous RR patients (n=37) and homozygous GG patients (n=17) undergoing elective cardiac surgery. The positive inotropic eect of noradrenaline in these tissues, mediated through b 1-adrenoceptors, was studied using electrically stimulated (1 Hz) atrial strips, as well as the eects of noradrenaline on cyclic AMP levels and cyclic AMP-dependent protein kinase. 3 Tissue from RR homozygotes (n=14) showed signi®cantly increased inotropic potency to noradrenaline (7log EC 50 , M=6.92+0.12) compared to GG homozygotes (n=8, 7log EC 50 , M=6.36+0.11, P50.005). This dierence was not dependent on tissue basal force. 4 Tissue cyclic AMP levels (pmol mg 71) were also greater in RR homozygotes (basal 34.8+3.7 n=12, 300 nM noradrenaline 41.4+7.6 n=9, 30 mM noradrenaline 45.2+3.2 n=22, 0.2 mM isoprenaline 48.3+4.2 n=16) compared to GG homozygotes (basal 30.7+4.4 n=5, 300 nM noradrenaline 32.6+6.92 n=5, 30 mM noradrenaline 38.1+3.1 n=8, 0.2 mM isoprenaline 42.6+5.2 n=6, P=0.007). There were no dierences between the variants in terms of cyclic AMP-dependent protein kinase activity. 5 These data provide the ®rst evidence that enhanced G-protein coupling of the R389 b 1adrenoceptor variant reported in rodent ®broblast expression systems is also present in native human receptors. The functional consequence of this is to signi®cantly alter the inotropic potency of b 1-adrenoceptor activation depending on its genotype at the 389 position.