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Biomedical subjects

J B Osnes

Publications and source records attributed to J B Osnes.

At least 19 recordsLinked to original sources
PubMed2001

Differential effects of cocaine on the positive inotropic effect of noradrenaline mediated by alpha1- and beta-adrenoceptors in failing human myocardium.

Electrically driven (1 Hz) ventricular trabeculae from explanted failing human myocardium were indirectly examined for the localization of the alpha1-adrenoceptor population and the beta-adrenoceptor population in relation to sympathetic nerve endings. We examined the influence of neuronal uptake blockade by cocaine upon the horizontal position of the concentration-response curves for the inotropic effects exerted by noradrenaline in the presence and absence of appropriate adrenoceptor antagonists. Cocaine shifted the concentration-response curve for alpha1-adrenoceptor stimulation, but not that for beta-adrenoceptor stimulation, to lower concentrations of noradrenaline in a parallel manner. The concentration-response curve for combined adrenoceptor stimulation was shifted by cocaine to lower concentrations of noradrenaline in a nonparallel manner. In explanted allograft heart, cocaine had no effect upon the position of the concentration-response curve to alpha1-adrenoceptor stimulation. The data indicate that in the explanted native hearts the alpha1-adrenoceptor population is located close to or within the synaptic cleft, while the beta-adrenoceptor population remaining in the failing myocardium is located more distantly to the neuronal release sites.

Adult↗
PubMed2000

Differential recruitment of alpha 1- and beta-adrenoceptors in inotropic control of atrial child myocardium by endogenous noradrenaline.

Noradrenaline release, graded by frequency variation of field stimulation (0.1-2 Hz), in atrial myocardial specimens (n=45) from children (n=21) with congenital heart defects, was used to examine the inotropic responses of graded, receptor-selective, endogenous stimulation. Muscle trabeculae subjected to autonomic blockage by timolol, prazosin and atropine showed a slight positive force-frequency relationship (staircase phenomenon). Blockage by atropine/prazosin (i.e. beta-adrenoceptor stimulation) or atropine/timolol (i.e. alpha1-adrenoceptor stimulation) both resulted in positive inotropic effects. A group of specimens opposed by atropine and primarily subjected to frequency variation, secondly was returned to 1 Hz. Stabilization was followed by sequential reversal by beta-blocker (timolol), alpha 1-adrenoceptor stimulation by exogenous noradrenaline, reversal by alpha 1-blocker (prazosin), and finally supramaximal beta-adrenoceptor stimulation (isoprenaline). The maximal levels of inotropic responses mediated by exogenous alpha 1- and beta-adrenoceptor stimulation was estimated. Analysis of the contraction-relaxation cycles revealed that alpha1- and beta-adrenoceptors were recruited differentially. The alpha1-adrenoceptor mediated, endogenous inotropic effect at 1 Hz was close to the level obtained by exogenous noradrenaline stimulation. In contrast, less than 70% of the beta-adrenoceptor mediated, exogenous inotropic effect was expressed by endogenous noradrenaline at the same stimulating frequency, thus indicating that the alpha1-adrenoceptors may be located closer to the adrenergic nerve terminals than the beta-adrenoceptors. There may be a heterogeneous relationship within the same heart as to the relative distance between the nerve terminals and the adrenoceptors. Spatial localization of adrenergic receptors relative to adrenergic nerve terminals adds another aspect to adrenergic regulation. The alpha1-adrenoceptor pathway may play an important role, especially in low-intensity sympathetic inotropic myocardial control, whereas the beta-adrenoceptor pathway adds important effects to the high-intensity sympathetic regulation. Sympathetic activity may thus tonically stimulate the alpha1-adrenoceptor pathway, without necessarily stimulating the beta-adrenoceptor pathway to the same extent.

Adolescent↗
PubMed2000

Angiotensin II activates a bumetanide sensitive increase in 86RB+ efflux in the rat heart.

We previously reported that alpha-adrenoceptor (AR) stimulation of the isolated perfused rat heart increased the efflux of 42K+ and the K+ analogue 86Rb+. The main part of this increase was bumetanide sensitive, indicating an activation of the Na+/K+/2Cl- cotransporter. The purpose of the present study was to investigate the effects of angiotensin II (1-100 nmol/l) and the protein kinase C (PKC) activator PMA (phorbol-12-myristate-13-acetate, 1-1000 nmol/l) on 86Rb+ efflux from isolated rat hearts and to compare the effects with the effect of the alpha1- AR agonist phenylephrine (30 micromol/l) in the presence of a beta-AR antagonist. Phenylephrine increased the 86Rb+ efflux rate by 47+/-4.1% (n=5, p<0.001). Angiotensin II induced a maximal increase in 86Rb+ efflux rate of 13+/-1.6% (n=12, p<0.0001). The effect of angiotensin II was totally eliminated by bumetanide (50 micromol/l). PMA decreased the 86Rb+ efflux rate by 23+/-7.0 % (n=7, p=0.02) and this effect of PMA was not sensitive to bumetanide. Pre-treatment of the hearts with PMA for 30 min did not influence the response to phenylephrine. In conclusion, angiotensin II stimulation, but not PKC activation by PMA increased the 86Rb+ efflux rate in isolated rat hearts, but the effect was smaller than that of alpha1- AR stimulation. The effect of angiotensin II was completely abolished by bumetanide indicating an activation of the Na+/K+/2Cl- -cotransporter.

Adrenergic alpha-Agonists↗
PubMed1999

Similar localisation of alpha1- and beta-adrenoceptors in rabbit heart in relation to sympathetic nerve endings.

Electrically driven (1 Hz) rabbit papillary muscles were examined ex vivo for the localisation of the alpha1- and beta-adrenoceptor populations relative to the sympathetic nerve endings and to each other. We determined the influence of neuronal uptake blockade by cocaine upon the horizontal position of the dose-response curves for the inotropic and lusitropic effects exerted by noradrenaline in the presence of extra neuronal uptake blockade by hydrocortisone and in the presence and absence of adrenoceptor blockers. Cocaine similarly shifted the dose-response curves for both alpha1- and beta-adrenoceptors mediated effects to 10-30 times lower concentrations of noradrenaline. This potentiation by cocaine indicates that also the alpha1-adrenoceptor population is located close to or within the sympathetic synaptic clefts, as is known for the beta-adrenoceptor population.

Adrenergic alpha-Agonists↗
PubMed1999

Endogenous muscarinic activity attenuates adrenergic inotropic effects in field stimulated atrial myocardium from children with congenital heart defects.

To analyse the possible influence of endogenous muscarinic activity on the inotropic effects of endogenously released noradrenaline in field stimulated myocardial preparations from atria of children with congenital heart defects, we studied the maximal effect of the muscarinic antagonist atropine (1.5 micromol L(-1)). Maximal force of contraction increased by 12.8 +/- 2.0% (SEM), while the maximal rate of development of the force increased by 16.7 +/- 2.7% (SEM). Time to half maximal developed force was 57 +/- 5 s (SEM). Time to peak force, time to relax to the 20% level and relaxation time all decreased significantly after atropine. Compared with endogenous adrenoceptor stimulation alone, the combined effects of partial muscarinic and adrenergic receptor stimulation thus were moderate reductions of the maximal force of contraction and maximal rate of development of the force and increased time to peak force, time to relax to the 20% level and relaxation time. The main effect of the endogenous muscarinic activity probably was to attenuate the effect of the beta-adrenoceptor stimulation. The endogenous muscarinic activity in field stimulated atrial preparations from children is significant, and has to be taken into account in experimental set-ups.

Acetylcholine↗
PubMed1998

Effect of concomitant beta-adrenoceptor stimulation on alpha 1-adrenoceptor-mediated increase of inositol-1,4,5-trisphosphate mass in adult rat cardiomyocytes.

The aim of the present study was to investigate the accumulation of inositol-1,4,5-trisphosphate (IP3) in isolated adult rat ventricular cardiomyocytes after alpha 1- and beta-adrenoceptor stimulation, separate and in combination, in order to elucidate a possible influence of concomitant beta-adrenoceptor stimulation on the alpha 1-adrenoceptor stimulated response. IP3 was measured by a radioligand binding assay based on an (1,4,5)IP3-specific binding protein from bovine adrenal cortex. The basal IP3 content was 4.06 +/- 0.31 pmol/mg protein (N = 56). alpha 1-Adrenoceptor stimulation resulted in a rapid increase in the IP3 level, which reached a plateau, 50-80% above basal level, at 10-30 sec. The plateau lasted at least up to 120 sec., while at 300 sec. there was no significant difference between control values and values after alpha 1-adrenoceptor stimulation. Li+ did not affect either the basal IP3 level, or the magnitude or time course of alpha 1-adrenoceptor-stimulated IP3 accumulation. Combined adrenoceptor stimulation gave a similar response as separate alpha 1-adrenoceptor stimulation, whereas there was no significant change in the IP3 level after beta-adrenoceptor stimulation. No inhibitory influence of simultaneous beta-adrenoceptor stimulation on the alpha 1-adrenoceptor-stimulated increase of IP3 mass was revealed.

Adrenergic alpha-Agonists↗
PubMed1998

Alpha1-adrenergic activation of myocardial Na-K-2Cl cotransport involving mitogen-activated protein kinase.

The translocation mechanisms involved in the alpha1-adrenoceptor-stimulated efflux of the potassium analog 86Rb+ were studied in isolated rat hearts. Phenylephrine (in the presence of a beta-blocker) increased the efflux of 86Rb+ and 42K+, and the Na-K-2Cl (or K-Cl) cotransport inhibitor bumetanide reduced the response by 42 +/- 11%. Furosemide inhibited the response with a lower potency than that of bumetanide. The bumetanide-insensitive efflux was largely sensitive to the K+ channel inhibitor 4-aminopyridine. Inhibitors of the Na+/H+ exchanger or the Na+-K+ pump had no effect on the increased 86Rb+ efflux. The activation of the Na-K-2Cl cotransporter was dependent on the extracellular signal-regulated kinase (ERK) subgroup of the mitogen-activated protein (MAP) kinase family. Phenylephrine stimulation increased ERK activity 3.4-fold. PD-98059, an inhibitor of the ERK cascade, reduced both the increased 86Rb+ efflux and ERK activity. Specific inhibitors of protein kinase C and Ca2+/calmodulin-dependent kinase II had no effect. In conclusion, alpha1-adrenoceptor stimulation increases 86Rb+ efflux from the rat heart via K+ channels and a Na-K-2Cl cotransporter. Activation of the Na-K-2Cl cotransporter is apparently dependent on the MAP kinase pathway.

4-Aminopyridine↗
PubMed1997

Anti-M2 muscarinic receptor antibodies inhibit beta-adrenoceptor-mediated inotropic response in rat myocardium.

The modulation of the inotropic effect by affinity-purified antibodies against a synthetic peptide corresponding to the second extracellular loop of the human muscarinic M2 receptors was studied in adult rat ventricular myocardium. These anti-muscarinic M2 receptor antibodies shifted the dose-response relationship of the beta-adrenoceptor agonist isoproterenol to higher concentrations whereas preimmune rabbit immunoglobulin G (IgG) or antibodies against the N-terminus of the beta 1-adrenoceptor had no effect. This effect of anti-muscarinic M2 receptor antibodies was fully blocked after preincubation with the antigenic peptide. No significant change of maximal inotropic response to isoproterenol was observed in the presence of anti-muscarinic M2 receptor antibodies. The anti-muscarinic M2 receptor antibodies did apparently not hamper the access of the muscarinic receptor agonist carbachol. The muscarinic receptor antagonist atropine attenuated the effect of the anti-muscarinic M2 receptor antibodies. The present study demonstrates for the first time in intact adult ventricular myocardium a specific stimulatory muscarinic activity of antibodies raised against a part of the muscarinic M2 receptor protein.

Adrenergic beta-Agonists↗
PubMed1997

[Serum digitoxin in concomitant use of antiepileptics in routine therapy].

Concomitant use of digitoxin and enzyme-inducing antiepileptics may lower serum levels, and accordingly the effect of digitoxin, unless the higher metabolic clearance is compensated for by higher dosage. Use of digitoxin is almost always guided by serum concentration measurements. Information on a possible enzyme-inducing effect of phenobarbital, phenytoin and carbamazepine is easily accessible. Compilation of serum level measurements for digitoxin showed that serum levels shifted towards lower values during concomitant use of phenytoin or carbamazepine than when digitoxin was used alone. As a consequence, the fraction of patients with serum levels below the therapeutic range was doubled. Concomitant use of phenobarbital did not cause a shift in the levels of digitoxin. In fact, in this group, a larger fraction of the serum level measurements were within the therapeutic range. Thus, the dosage of digitoxin appears to be fully compensated during concomitant use of phenobarbital, but obviously deserves attention during concomitant use of phenytoin or carbamazepine.

Anticonvulsants↗
PubMed1997

Alpha 1-adrenoceptor subtypes involved in increased 86Rb+ influx rate and inositol 1,4,5-trisphosphate mass in adult rat cardiomyocytes.

The aim of the present study was to identify the receptor subtypes involved in the alpha 1-adrenoceptor-mediated increase in 86Rb+ influx rate and in inositol 1,4,5-trisphosphate (IP3) accumulation in isolated ventricular cardiomyocytes from adult rat heart, in order to identify a possible response pattern compatible with a causative relationship. Subtype-selective receptor antagonists used were: 5-methylurapidil (alpha 1A), WB 4101 [2([2,6-dimethoxyphenoxy-ethyl]aminomethyl)-1,4-benzodioxane] (alpha 1A), chloroethylclonidine (alpha 1B) and BMY 7378 [8-[2-[4-(2-methoxyphenyl)-1-piperazinyl]ethyl]-8-azaspiro[4,5]dec ane-7,9-dione] (alpha 1D). The basal 86Rb+ influx rate was 0.22 +/- 0.01 ml/g protein x min. At 15 min, 5 x 10(-5) mol/l noradrenaline in the presence of 3 x 10(-5) mol/l timolol increased the 86Rb+ influx rate by 33 +/- 1%. This response was not affected by either chloroethylclonidine or BMY 7378 at concentrations up to 10(-5) mol/l. 5-Methylurapidil dose dependently inhibited the response to 5 x 10(-5) mol/l noradrenaline with a -logIC50 value of 5.27 +/- 0.12 and 5.61 +/- 0.27 in the presence and absence of 10(-5) mol/l chloroethylclonidine, respectively. WB 4101 in the presence of 10(-5) mol/l chloroethylclonidine dose dependently inhibited the response to 5 x 10(-5) mol/l noradrenaline with a -logIC50 value of 6.10 +/- 0.14. Noradrenaline in the presence of 10(-5) mol/l chloroethylclonidine dose dependently increased the 86Rb+ uptake rate with a -logEC50 value of 6.19 +/- 0.35. The basal IP3 level was 2.15 +/- 0.19 pmol/mg protein. Incubation with 10(-5) mol/l noradrenaline for 2 min increased this by 65 +/- 7% of control levels. 10(-5) mol/l chloroethylclonidine and 10(-4) mol/l 5-methylurapidil reduced the response to 27 +/- 6% and 18 +/- 9% of control level, respectively. BMY 7378 dose dependently inhibited the IP3 response at relatively high concentrations, and it was completely eliminated at 10(-5) mol/l BMY 7378. The combination of chloroethylclonidine and 5-methylurapidil or 3 x 10(-6) mol/l prazosin alone completely abolished the hormone-induced effect. We conclude that whereas the alpha 1-adrenoceptor-stimulated increase in 86Rb+ influx rate is mediated via the alpha 1A-adrenoceptor subtype only, both alpha 1A- and alpha 1B-adrenoceptor subtypes are involved in the increase in IP3 mass. Furthermore, a contribution from the alpha 1D-adrenoceptor in the IP3 response cannot be excluded. Thus there does not appear to be a simple causative relationship between an increase in 86Rb+ influx rate and an increase in IP3.

Adrenergic alpha-1 Receptor Antagonists↗
PubMed1997

Receptor subtypes involved in the alpha1-adrenoceptor mediated increase in 86Rb+ efflux from the rat heart.

The aim of this study was to determine the involvement of the different alpha1-adrenoceptor subtypes in the alpha1-adrenoceptor mediated increase in 86Rb+ efflux from rat hearts. Isolated hearts were perfused in the presence of a beta-adrenoceptor antagonist (1 microM timolol). After loading with 86Rb+, the efflux was measured during alpha1-adrenoceptor stimulation by phenylephrine (30 microM). Phenylephrine increased the 86Rb+ efflux by about 30%. Pretreatment with the preferentially alpha1B-adrenoceptor inhibitor chloroethylclonidine (CEC), reduced the response to phenylephrine by about 50%. The preferential alpha1D-adrenoceptor inhibitor BMY 7378 inhibited the response to phenylephrine by 35%, with a pKI=8.4 (95% C.I. 8.2-8.6). The response was sensitive to the preferential alpha1A-adrenoceptor inhibitors (+)niguldipine, 5-methylurapidil (5-MU) and WB-4101 at relatively high concentrations, and 5-MU inhibited the response with a pKI=7.7 (95% C.I. 7.2-8.0) in CEC pretreated hearts. In conclusion, the phenylephrine stimulated increase in 86Rb+ efflux in the rat heart is not specifically linked to only one of the alpha1-adrenoceptor subtypes, but involves the alpha1B- and the alpha1D-adrenoceptor subtypes, and probably the alpha1A-adrenoceptor subtype as well.

Adrenergic alpha-Antagonists↗
PubMed1997

Comparison between alpha-1 adrenoceptor-mediated and beta adrenoceptor-mediated inotropic components elicited by norepinephrine in failing human ventricular muscle.

The purpose of our study was to investigate the inotropic response to the endogenous agonist norepinephrine mediated through alpha-1 adrenoceptors and to compare this response to that mediated through beta-adrenoceptors in failing human ventricular myocardium. We studied ex vivo the inotropic effect of norepinephrine in isometrically contracting trabecular myocardium from both ventricles of explanted hearts. By studying influence of appropriate adrenoceptor blockers, qualitative characteristics of the inotropic response and sensitivity of the inotropic response to cholinergic stimulation, it was revealed that norepinephrine evoked both alpha-1 and beta adrenoceptor-mediated inotropic effects in failing human ventricle myocardium. Quantitatively the inotropic responses to norepinephrine varied markedly between preparations, but the mean responses elicited through the respective adrenoceptor systems were of comparable magnitude. Concomitant stimulation of alpha-1 and beta adrenoceptors by norepinephrine alone revealed a contribution of an alpha-1 adrenoceptor-mediated component to the final and unopposed inotropic response. Differential sensitivity of the two adrenoceptor systems to norepinephrine depending on etiology of heart failure and possibly also thyroid status was observed. It is concluded that norepinephrine evokes an alpha-1 adrenoceptor-mediated inotropic effect comparable to that evoked through the beta adrenoceptors in failing human ventricular myocardium, and that this alpha-1 adrenoceptor-mediated inotropic effect may be of functional importance.

Adrenergic Antagonists↗
PubMed1997

The Na+/K+ATPase mediates the alpha 1-adrenoceptor stimulated increase in 86Rb(+)-uptake in isolated ventricular cardiomyocytes from adult rat heart.

The aim of the present study was to identify the mechanism(s) responsible for the alpha 1-adrenoceptor stimulated increase in potassium uptake in ventricular cardiomyocytes isolated from adult rat heart. The Na+/K+ATPase blocker ouabain the Na+/K+/2Cl(-)-cotransporter blocker bumetanide, the Na+/H(+)-exchanger blocker HOE 694 and the potassium channel blocker 4-aminopyridine were used as experimental tools. 86Rb+ was used as potassium analogue. The basal 86Rb(+)-uptake rate was 0.25 +/- 0.01 ml/g protein x min. Maximal alpha 1-adrenoceptor stimulation increased the 86Rb(+)-uptake 38 +/- 2%. Ouabain dose dependently eliminated the alpha 1-adrenoceptor stimulated response with a -logIC50-value of 3.64 +/- 0.23. Bumetanide did not affect the stimulated response, and there was no effect of bumetanide on the ouabain sensitive component. HOE 694 and 4-aminopyridine had no effect on the stimulated 86Rb(+)-uptake. Ouabain and HOE 694 also dose dependently inhibited a portion of the basal 86Rb(+)-uptake (about 60% and 20%, respectively), but there was no effect of bumetanide or 4-aminopyridine on the basal 86Rb(+)-uptake. The results show that the Na+/K+ATPase alone mediates the alpah 1-adrenoceptor stimulated increase in potassium uptake in this preparation of ventricular cardiomyocytes isolated from adult rat heart.

4-Aminopyridine↗
PubMed1997

Alpha 1-adrenoceptor mediated activation of Na/K/2Cl cotransport and K+ channels in the rat heart involves different receptor subtypes.

Involvement of receptor subtypes in the alpha 1-adrenoceptor mediated activation of Na/K/2Cl-cotransport and K+ channels was studied in isolated perfused spontaneously beating rat hearts stimulated by phenylephrine (30 mumol/l) in the presence of a beta-adrenoceptor antagonist (1 mumol/l timolol). The effects of alpha 1-adrenoceptor stimulation on K+ translocation mechanisms were studied by measuring the efflux of 86Rb+ (a potassium analogue). The effects of 50 mumol/l bumetanide (Na/K/2Cl-cotransport inhibitor) and 0.1-0.3 mmol/l 4-aminopyridine (inhibitor of K+ channels) were studied in the presence of alpha 1-adrenoceptor subtype selective antagonists. Bumetanide reduced the alpha 1-adrenoceptor mediated increase in 86Rb+ efflux by 53 +/- 16.4% (n = 14, P < 0.001) in hearts pretreated with the preferentially alpha 1B-adrenoceptor antagonist chloroethylclonidine (CEC, 10 mumol/l), and by 35 +/- 7.3% (n = 15, P < 0.001) in the presence of the preferentially alpha 1D-adrenoceptor antagonist BMY 7378 (1 mumol/l). In the presence of the preferentially alpha 1A-adrenoceptor antagonist 5-methylurapidil (10 mumol/l), however, bumetanide had no effect on the response to phenylephrine. 4-Aminopyridine reduced the phenylephrine stimulated 86Rb+ efflux in the presence of 5-methylurapidil, but the effect of the K(+)-channel blocker was eliminated in CEC treated hearts. Thus the effects of the two translocation inhibitors were influenced differently by the two subtype selective antagonists, showing that alpha 1-adrenoceptor stimulation activates a bumetanide sensitive Na/K/2Cl-cotransport mechanism in the rat heart mainly through the alpha 1A-receptor subtype while the 4-aminopyridine sensitive K+ channels, are mainly activated by the alpha 1B-adrenoceptor subtype.

4-Aminopyridine↗
PubMed1996

Alpha(1)- and beta-adrenoceptor-mediated increase in 86Rb(+)-uptake in isolated cardiomyocytes from adult rat heart: evidence for interaction between the two receptor systems.

The aim of the present investigation was to study the effect of alpha(1)- and beta-adrenoceptor stimulation, alone and in combination, on potassium uptake in isolated ventricular cardiomyocytes from adult rat heart, using the potassium analogue 86Rb+. The reliability of 86Rb+ as a potassium analogue was also investigated. Alpha(1)-, beta-, And combined adrenoceptor stimulation was achieved by using noradrenaline in the presence and absence of appropriate adrenoceptor antagonists. The uptake of 86Rb+ was found to increase linearly with time up to 20 min., both during basal and receptor-stimulated conditions. The basal uptake rate was about 0.18 ml/g protein x min. At 15 min. both alpha(1)-, beta- and combined adrenoceptor stimulation dose-dependently increased the 86Rb(+)-uptake with a -logEC50 of 7.05, 6.68 and 6.73, respectively. The maximal increase in these series achieved by 5 x 10(-5) mol/l noradrenaline was 29%, 24% and 41% above basal level, respectively. Comparison of the maximal effects in the same cell preparations, with the observed value for combined adrenoceptor stimulation in each experiment as 100%, gave a relative maximal increase in 86Rb(+)-uptake after separate alpha(1)-adrenoceptor stimulation of 67 +/- 8%, and of 68 +/- 6% after separate beta-adrenoceptor stimulation. The theoretically calculated value for combined adrenoceptor stimulation, if additivity, was 135 +/- 11%, which was significantly higher than the observed value (100%) (P = 0.026). The effect of noradrenaline was not limited by the maximal 86Rb(+)-uptake capacity, as 10(-5) mol/l forskolin increased the 86Rb(+)-uptake more than noradrenaline. Examining the reliability of 86Rb+ as potassium-analogue by combining 42K+ and 86Rb+ in the same experiments, showed that combined adrenoceptor stimulation dose-dependently increased both the 42K(+)- and 86Rb(+)-uptake with the same potency and to the same extent. Thus 86Rb+ is a reliable potassium-analogue for these effects. In conclusion both alpha(1)- and beta-adrenoceptor stimulation dose-dependently increased the cellular 86Rb(+)-uptake to the same extent and with the same potency. The observed maximal 86Rb(+)-uptake after combined adrenoceptor stimulation was significantly higher than the maximal effect after either form of separate receptor stimulation, but significantly lower than expected if the effects were purely additive. The results thus show inhibitory interaction between the two receptor systems.

Adrenergic Antagonists↗
PubMed1996

Concentration-response relationship of alpha 1-adrenoceptor-stimulated increase of 86Rb+ efflux in rat heart.

UNLABELLED: The aim of the present study was to establish a concentration-response relationship for the alpha 1-adrenoceptor mediated increase of 86Rb+ efflux, and to characterize the sensitivity of this response to the selective alpha 1-adrenoceptor antagonist prazosin. Isolated rat hearts were perfused retrogradely at constant flow and at 31 degrees. Timolol (10(-6) mol/l) was used to block beta-adrenoceptors. After a loading period with 86Rb+ and 55 min. washout, the hearts were exposed to phenylephrine in a concentration range from 3 x 10(-8) mol/l to 10(-4) mol/l. Control experiments comparing the effects of alpha 1-adrenoceptor stimulation on 86Rb+ efflux and 42K+ efflux were performed. alpha 1-Adrenoceptor stimulation increased the 86Rb+ efflux with a pD2 = 6.35 +/- 0.20 (mean +/- S.E.M). The maximal response to phenylephrine was 22.5 +/- 2.0% (mean +/- S.E.M.) of the control values. The concentration-response curve was shifted to higher concentration of agonist in the presence of the alpha 1-adrenoceptor antagonist prazosin (3 x 10(10) mol/l). The calculated inhibition constant for prazosin was 6.1 x 10(-11) mol/l. 86Rb+ was found to be a suitable K+ analogue in the study of relative changes in K+ efflux although the basal efflux kinetics were different for the two isotopes. CONCLUSION: Phenylephrine increased the 86+b+ efflux concentration-dependently. A high sensitivity to prazosin confirmed the involvement of the alpha 1-adrenoceptor population.

Adrenergic alpha-Antagonists↗
PubMed1995

Location of alpha 1-adrenoceptors relative to beta-adrenoceptors in rat myocardium.

Electrically driven rat papillary muscles (1 Hz) were examined for the location of their alpha 1-adrenoceptor and beta-adrenoceptor populations relative to each other. We determined the horizontal position of the dose-response curves for the positive inotropic effects exerted by noradrenaline in the absence and presence of the neuronal uptake blocker cocaine and in the absence and presence of the beta-adrenoceptor antagonist timolol and of the alpha 1-adrenoceptor antagonist prazosin. Cocaine slightly shifted the dose-response curves for alpha 1-adrenoceptor stimulation to a lower concentration of agonist. In contrast, the dose-response curve for beta-adrenoceptor stimulation was markedly shifted by cocaine to a lower concentration of agonist. Experiments with corticosterone (an extraneuronal uptake blocker) revealed no differential shift of either of the dose-response curves. Together, these data indicate that the alpha 1-adrenoceptor population is located more distantly from the adrenergic nerve terminals than the beta 1-adrenoceptor population in rat myocardium.

Adrenergic alpha-Agonists↗