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O E Brodde

Publications and source records attributed to O E Brodde.

At least 19 recordsLinked to original sources
PubMed1995

Selective downregulation of rat cardiac beta 1-adrenoceptors by cyclosporine A: prevention by diltiazem or angiotensin-converting enzyme inhibitors.

OBJECTIVES: This study attempted to determine whether long-term treatment with cyclosporine A in rats affects cardiac beta 1-adrenoceptors and whether this can be prevented by angiotensin-converting enzyme inhibitors or calcium-entry blocking agents. BACKGROUND: In the transplanted human heart the density of beta 1-adrenoceptors decreases with time after transplantation, whereas that of beta 2-adrenoceptors does not. Because heart transplant recipients are treated with cyclosporine A, we studied whether administration of cyclosporine A in rats might cause this beta 1-adrenoceptor downregulation. METHODS: We performed two studies. First, we treated groups of 10 male normotensive Wistar rats orally with 30 mg/kg body weight per day of cyclosporine A, 10 mg/kg per day of enalapril and 60 mg/kg per day of diltiazem, alone or in combination, for 6 weeks each. Second, we treated groups of 15 male normotensive Wistar rats orally with 15 mg/kg per day of cyclosporine A and 10 mg/kg per day of lisinopril, alone or in combination, for 6 weeks each. At the end of each treatment regimen, cardiac beta-adrenoceptor density and subtype distribution were assessed by (-)-[125I]iodocyanopindolol binding. RESULTS: Both doses of cyclosporine A caused a significant decrease in cardiac beta 1-adrenoceptor density without affecting beta 2-adrenoceptor density. Although diltiazem and the angiotensin-converting enzyme inhibitors alone did not affect cardiac beta-adrenoceptors, they prevented the cyclosporine A-induced downregulation of beta 1-adrenoceptors. CONCLUSIONS: In normotensive Wistar rats, cyclosporine A causes a significant decrease in cardiac beta 1-adrenoceptors without affecting beta 2-adrenoceptors. This can be prevented by diltiazem or angiotensin-converting enzyme inhibitors. In heart transplant recipients, who undergo long-term treatment with cyclosporine A, there is a very similar beta 1-adrenoceptor down-regulation with time after transplantation. Thus, administration of cyclosporine A may cause these beta-adrenoceptor subtype alterations.

Animals↗
PubMed1995

Myocardial and pulmonary uptake of S-1'-[18F]fluorocarazolol in intact rats reflects radioligand binding to beta-adrenoceptors.

The biodistribution of S-(-)-4-(2-hydroxy-3-(1'-[18F]fluoroisopropyl)- aminopropoxy)carbazole ([18F]S-fluorocarazolol, a non-selective beta-adrenoceptor antagonist) was studied in rats (60 min after 18F injection when specific binding in peripheral organs was maximal). 18F uptake in brain, erythrocytes, heart and lung appeared to be linked to beta-adrenoceptors. CGP-20712A and ICI-89,406 inhibited 18F uptake in heart (predominantly beta 1-adrenoceptors) more potently than in lungs (predominantly beta 2-adrenoceptors). In contrast, ICI-118,551 and procaterol were more potent in the lungs than in the heart. ICI-118,551 inhibited 18F uptake in cerebellum (predominantly beta 2-adrenoceptors) more potently than in cerebral cortex (predominantly beta 1-adrenoceptors). Stereoselectivity of the in vivo binding was demonstrated since S-(-)-propranolol inhibited uptake in target tissues more effectively than R-(+)-propranolol. Myocardial and cerebral imaging may be hampered by poor heart-to-lung contrast and low signal-to-noise ratios, but [18F]S-fluorocarazolol seems suitable for positron emission tomography (PET) of pulmonary beta-adrenoceptors.

Adrenergic beta-Antagonists↗
PubMed1995

PAF effects on eicosanoid release in neonatal rat cardiomyocytes.

The aim of this study was to find out whether, in neonatal rat cardiomyocytes, platelet-activating factor (PAF) can stimulate eicosanoid formation. For this purpose neonatal cardiomyocytes were incubated for 60 min at 37 degrees C in HANKS buffer with PAF (10-1000 nM), and the eicosanoids thromboxane A2 (TXA2) and prostacyclin (PGI2) were assessed in the supernatant as TXB2 and 6-keto-PGF1 alpha, respectively, by an enzyme immunoassay. PAF caused concentration-dependent release of PGI2; TXA2, however, was significantly released only at the highest concentration of PAF (1000 nM). Acetylsalicylic acid (556 microM) and the PAF antagonist WEB 2086 (10 microM) significantly attenuated PAF-induced eicosanoid formation. We conclude that in neonatal rat cardiomyocytes PAF can induce eicosanoid formation and this effect is brought about by activation of a specific PAF receptor.

Animals↗
PubMed1995

Age-dependent changes in the beta-adrenoceptor-G-protein(s)-adenylyl cyclase system in human right atrium.

With increasing age, cardiac beta-adrenoceptor function decreases. To study possible mechanisms underlying this process, we assessed in right atrial appendages from 52 patients of different ages (group A, < 20 years, mean age 3.7 +/- 1.0 years, n = 20; group B, 20-50 years, mean age, 37.9 +/- 2.3 years, n = 9; group C, > 50 years, mean age 66.1 +/- 1.5 years, n = 23) without apparent heart failure who were undergoing open heart surgery beta-adrenoceptor number and subtype distribution (by (-)-[125I]-iodocyanopindolol [ICYP] binding), adenylyl cyclase activity, and Gs- and Gi-protein alpha-subunits (by quantitative Western blotting). beta-Adrenoceptor number in the three groups was not significantly different; in contrast, basal, 10 microM GTP-, 100 microM isoprenaline (ISO), 10 mM NaF-, 100 microM forskolin-, and 10 mM Mn(2+)-stimulated adenylyl cyclase activity was significantly higher in group A than in group B and was further decreased in group C. Similarly, 100 microM terbutaline-, 100 microM histamine-, and 100 microM 5-HT-stimulated adenylyl cyclase activity significantly decreased from group A to group C. Moreover, all these adenylyl cyclase parameters were significantly negatively correlated with the age of the patients. Although Gs alpha was not altered, Gi alpha in group C was significantly higher than in group A; moreover, there was a weak but significant positive correlation between Gi alpha and the age of the patients. We conclude that an impairment of the activity of the catalytic unit of adenylyl cyclase is involved in the decrease in cardiac beta-adrenoceptor function with age; an increase in Gi alpha might contribute further to the reduced beta-adrenoceptor function.

Adenylyl Cyclases↗
PubMed1995

Relation between myocardial beta-adrenoceptor density and hemodynamic and neurohumoral changes in a rat model of chronic myocardial infarction: effects of ibopamine and captopril.

OBJECTIVES: The purpose of this study was to investigate the changes in beta-adrenoceptor density (Bmax) and distribution in a model of chronic myocardial infarction in rats, and to relate possible changes to hemodynamic and neurohumoral abnormalities. In addition, we examined the effects of 8 weeks treatment with ibopamine and captopril. METHODS: There were 3 experiments: (1) Bmax and plasma catecholamines were examined (n = 46), (2) Bmax was compared in infarcted and non-infarcted tissue (n = 13), and (3) contractile function was evaluated by isolated heart perfusion (n = 40). Of rats in Expts. (1) and (3), 50% had myocardial infarction induced by coronary ligation and 50% were controls. Each group was divided between ibopamine, ibopamine and captopril, or standard (no drug) treatment. RESULTS: Bmax was not decreased in rats with myocardial infarction (10.8 +/- 0.8 fmol/mg protein), compared to normal rats (11.4 +/- 0.6 fmol/mg protein), and the ratio beta 1/beta 2 was also unaffected. In infarcted tissue, Bmax was significantly (P = 0.03) lower than in non-infarcted tissue. Baseline left ventricular pressure, systolic and diastolic dP/dT were all impaired (P < 0.001), and plasma norepinephrine levels were elevated in rats with myocardial infarction (16.03 +/- 230 vs. 1287 +/- 83 pg/ml; P < 0.05), compared to normals. Both ibopamine alone and in combination with captopril reduced the elevated plasma norepinephrine levels in infarcted rats (P < 0.001), but only the combination of the 2 drugs significantly increased Bmax in infarcted rats (14.7 +/- 0.8 fmol/mg protein; P = 0.03 vs. untreated myocardial infarction), while ibopamine alone had no significant effect (13.1 +/- 1.1 fmol/mg protein; p = ns). Also, active drug treatment had no significant effect on the hemodynamic changes. CONCLUSIONS: In this coronary artery ligation model of myocardial infarction in rats, no beta-adrenoceptor down-regulation is observed, despite marked abnormalities in baseline left ventricular function and plasma norepinephrine levels. The combination of ibopamine and captopril significantly increases Bmax in infarcted rats, which is accompanied by a reduction in plasma norepinephrine levels, but not by an improvement in hemodynamic parameters.

Adrenergic beta-Agonists↗
PubMed1995

The beta-adrenoceptor subtype(s) mediating adrenaline- and dobutamine-induced blood pressure and heart rate changes in healthy volunteers.

In order to characterize the beta-adrenoceptor subtype(s) mediating blood pressure and heart rate changes induced by adrenaline and dobutamine, we compared the effects in healthy male volunteers of propranolol (5 mg i.v.) and of the beta 1-adrenoceptor selective antagonist bisoprolol (15 mg p.o.) on adrenaline- and dobutamine-infusion induced changes in systolic (P(syst)) and diastolic blood pressure (P(diast)) and heart rate with those on blood pressure and heart rate (HR) changes induced by "pure" alpha- or beta-adrenoceptor agonists (phenylephrine, selective alpha, terbutaline, selective beta 2, isoprenaline, non-selective beta 1 and beta 2). Both beta-adrenoceptor antagonists did not affect phenylephrine (0.25 -1.0 microgram/kg/min for 10 min) infusion induced P(syst)- and P(diast)-increases and HR-decreases. On the other hand, propranolol completely suppressed terbutaline (25-150 ng/kg/min for 15 min) and isoprenaline (3.5-35 ng/kg/min for 8 min) infusion induced P(syst)- and HR-increases and P(diast)-decreases while bisoprolol significantly attenuated only isoprenaline-effects but had nearly no effect on terbutaline effects. Thus, in these doses bisoprolol antagonized only beta 1-adrenoceptor mediated effects, propranolol both beta 1- and beta 2-adrenoceptor mediated effects, but both antagonists had no alpha-adrenoceptor antagonistic effects. Dobutamine (1.0-6.0 micrograms/kg/min for 15 min) infusion significantly increased P(syst), but did not significantly affect P(diast) and HR; bisoprolol markedly reduced dobutamine-induced P(syst)-increase. In the presence of propranolol, however, dobutamine caused P(syst)- and P(diast)-increases and HR-decreases. Adrenaline (20-120 ng/kg/min for 15 min) infusion increased P(syst) and HR and decreased P(diast). Bisoprolol did not affect P(syst)- and HR-increases, but significantly attenuated P(diast)-decreases.(ABSTRACT TRUNCATED AT 250 WORDS)

Adult↗
PubMed1994

Comparison of alpha 1A- and alpha 1B-adrenoceptor coupling to inositol phosphate formation in rat kidney.

We have compared the coupling mechanisms of rat renal alpha 1A- and alpha 1B-like adrenoceptors to inositol phosphate formation. The experiments were performed in parallel in native renal tissue preparations and in those where alpha 1B-adrenoceptors had been inactivated by treatment with 10 mumol/l chloroethylclonidine for 30 min at 37 degrees C; renal slices were used in most experiments but isolated renal cells were also used in some cases. The Ca2+ chelating agent, EGTA (5 mmol/l), reduced noradrenaline-stimulated inositol phosphate formation in native but enhanced it in chloroethylclonidine-treated renal slices. The inhibitory effect of EGTA was not mimicked by 100 nmol/l nifedipine. Inactivation of 87% of cellular Gi by 16-20 h treatment with 500 ng/ml pertussis toxin did not significantly affect noradrenaline-stimulated inositol phosphate formation in isolated renal cells but abolished the inhibitory effect of chloroethylclonidine. The adenylate cyclase activator, forskolin (20 mumol/l), inhibited noradrenaline-stimulated inositol phosphate formation in native and chloroethylclonidine-treated slices, and the inhibitory effects of chloroethylclonidine treatment and forskolin were additive. We conclude that in rat kidney inositol phosphate formation via alpha 1B-like adrenoceptors may involve the influx of extracellular Ca2+ and a pertussis toxin-sensitive G-protein but is insensitive to inhibition by forskolin. In contrast alpha 1A-like adrenoceptor-mediated inositol phosphate formation does not require the presence of extracellular Ca2+ or of Gi and is sensitive to inhibition by forskolin. In comparison to published data from other model systems we further conclude that the signaling mechanisms of alpha 1-adrenoceptor subtypes may depend on their cellular environment.

Animals↗
PubMed1994

Positive inotropic effects of the beta 2-adrenoceptor agonist terbutaline in the human heart: effects of long-term beta 1-adrenoceptor antagonist treatment.

OBJECTIVES: This study was conducted to determine whether activation of cardiac beta 2-adrenoceptors increases contractility in humans and whether this is affected by long-term beta 1-adrenoceptor antagonist treatment. BACKGROUND: Coexistence of beta 1- and beta 2-adrenoceptors in the human heart is generally accepted. The functional importance of cardiac beta 2-adrenoceptors for increases in contractility in humans, however, has not been completely established. METHODS: We studied 1) the beta-adrenoceptor subtype mediating positive inotropic effects of the beta 2-adrenoceptor agonist terbutaline in vitro (on right atrial and left ventricular preparations from nonfailing human hearts) and increases in contractility (by measurement of systolic time intervals) in vivo in seven healthy male volunteers; and 2) in vivo whether long-term treatment of volunteers with the beta 1-adrenoceptor antagonist bisoprolol affects terbutaline-induced increases in contractility. RESULTS: In vitro terbutaline caused a concentration-dependent increase in atrial and ventricular adenylate cyclase activity and force of contraction. Terbutaline effects were antagonized only by the beta 2-adrenoceptor antagonist ICI 118,551, indicating that they were mediated by beta 2-adrenoceptor stimulation. In vivo intravenous infusions of terbutaline (dose range 25 to 300 ng/kg body weight per min for 15 min) dose dependently increased heart rate and shortened the pre-ejection period and heart rate-corrected electromechanical systole (QS2) time. These effects are mediated predominantly by beta 2-adrenoceptor stimulation because they were only marginally affected by the beta 1-adrenoceptor antagonist bisoprolol (1 x 10 mg orally), either given 2 h before infusion or long term for 3 weeks. CONCLUSIONS: Stimulation of cardiac beta 2-adrenoceptors in humans causes not only in vitro but also in vivo positive inotropic effects. Long-term beta 1-adrenoceptor antagonist treatment does not considerably affect beta 2-adrenoceptor-mediated in vivo increases in contractility. Thus, it may be possible to treat patients with chronic heart failure and long-term beta 1-adrenoceptor antagonist therapy with beta 2-adrenoceptor agonists if immediate inotropic support is needed.

Adenylyl Cyclases↗
PubMed1994

Ontogenesis of sympathetic responsiveness in spontaneously hypertensive rats. II. Renal G proteins in male and female rats.

Previously we have reported an increased renal alpha 1- and beta-adrenergic receptor expression in male spontaneously hypertensive rats that occurred ontogenetically in parallel with blood pressure elevation. However, increased receptor numbers were not accompanied by enhanced stimulation of inositol phosphate and cyclic AMP formation, respectively, indicating relative desensitization. We have now quantified alpha-subunits of the G proteins Gs (Gs short and Gs long), G(i), and Gq by immunoblotting and pertussis toxin-catalyzed ADP-ribosylation in renal membranes from 3-, 6-, 8-, and 28-week-old normotensive and spontaneously hypertensive male Wistar-Kyoto rats; additionally, 28-week-old female normotensive and spontaneously hypertensive rats were studied. During ontogenesis of male normotensive rats, Gs short increased, Gs long remained unchanged, and G(i) alpha and Gq alpha decreased. In adult normotensive rats no sex differences were detected for Gs short, Gs long, and G(i) alpha. When male rats from the normotensive and spontaneously hypertensive strains were compared, all G protein alpha-subunits were similar in the prehypertensive phase (3 weeks). In established hypertension (28 weeks), Gs long and Gq alpha were reduced, whereas Gs short and G(i) alpha remained unchanged. Gs long was also reduced during the development of hypertension (6 and 8 weeks), whereas Gs short and G(i) alpha were not consistently altered in this phase. The reduction in Gs long seen in male adult hypertensive rats was not detectable in female hypertensive rats.(ABSTRACT TRUNCATED AT 250 WORDS)

Animals↗
PubMed1994

Endothelin ETA-receptors couple to inositol phosphate formation and inhibition of adenylate cyclase in human right atrium.

To study signal transduction pathways of endothelin (ET) in human heart, we assessed, in isolated human right atria, the effects of ET-1 and ET-3 on inositol phosphate (IP) formation and on the adenylate cyclase/cyclic AMP system. In right atrial slices, ET-1 (10(-10)-10(-6)M) concentration-dependently increased [3H]IP accumulation and decreased 10-microM isoprenaline-induced or 1-microM forskolin-induced increases in cyclic AMP content. ET-3 was approximately 100 times less potent. The cyclic AMP-decreasing effect of ET-1 (10(-11)-10(-6)M) could also be demonstrated directly in adenylate cyclase assays in right atrial membranes; again, ET-3 was approximately 100 times less potent. We conclude that in human right atrium, ETA receptors couple to two different signal-transduction pathways: IP formation and inhibition of adenylate cyclase.

Adenylyl Cyclase Inhibitors↗
PubMed1993

Alpha 1A and alpha 1B-adrenoceptors enhance inositol phosphate generation in rat renal cortex.

We have studied the role of alpha 1A- and alpha 1B-adrenoceptors in noradrenaline- and methoxamine-stimulated inositol phosphate accumulation in rat renal cortical slices. [3H]Prazosin binding studies with and without inactivation of alpha 1B-adrenoceptors by chloroethylclonidine treatment suggested that noradrenaline lacks relevant selectivity for alpha 1-adrenoceptor subtypes. Both agonists stimulated [3H]inositol phosphate accumulation with similar maximal effects. The alpha 1A-selective antagonists 5-methyl-urapidil and (+)-niguldipine inhibited inositol phosphate formation by both agonists with shallow biphasic curves but the high affinity component was only 15%-31% and 38%-41%, respectively. The irreversible alpha 1B-selective antagonist chloroethylclonidine inhibited inositol phosphate generation by both agonists by 54%-57%. In contrast to our previous data in rat cerebral cortical slices, we conclude that in rat renal cortex both alpha 1A- and alpha 1B-adrenoceptors are involved in noradrenaline- and methoxamine-stimulated inositol phosphate generation.

Adrenergic alpha-Antagonists↗
PubMed1993

Alpha 1-adrenoceptor subtype affinities of drugs for the treatment of prostatic hypertrophy. Evidence for heterogeneity of chloroethylclonidine-resistant rat renal alpha 1-adrenoceptor.

We have used radioligand binding and inositol phosphate accumulation studies to determine the affinity at mixed alpha 1A- and alpha 1B-adrenoceptors (rat cerebral cortex and kidney), alpha 1A-adrenoceptors (rat cerebral cortex and kidney following inactivation of alpha 1B-adrenoceptors by chloroethylclonidine treatment) and alpha 1B-adrenoceptors (rat spleen) for drugs currently under investigation for the treatment of benign prostatic hypertrophy, alfuzosin, naftopidil and (-)- and (+)-tamsulosin. Alfuzosin and naftopidil had similar affinities in all model systems (approximately 10 nM and 130 nM, respectively) and lacked relevant selectivity for alpha 1-adrenoceptor subtypes. Their potency to inhibit noradrenaline-stimulated inositol phosphate formation in cerebral cortex matched their affinities as determined in the binding studies. Tamsulosin had higher affinity at alpha 1A- than at alpha 1B-adrenoceptors, and was slightly more potent than alfuzosin and naftopidil at alpha 1B- and considerably more potent at alpha 1A-adrenoceptors. However, the interaction of the tamsulosin isomers with chloroethylclonidine-insensitive (alpha 1A-like) adrenoceptors was complex. A detailed analysis of the tamsulosin data and those obtained with other drugs, most notably noradrenaline and oxymetazoline, suggested that chloroethylclonidine-insensitive alpha 1-adrenoceptors may be heterogeneous and that this heterogeneity may differ between cerebral cortex and kidney of the rat.

Alkylating Agents↗
PubMed1993

Lack of desensitization of alpha- and beta-adrenoceptor function during chronic treatment of healthy volunteers with ibopamine, an orally active dopamine receptor agonist.

In 18 healthy volunteers, in a double-blind placebo-controlled study, we investigated of whether 14 days treatment with a therapeutic dose of ibopamine (3 x 100 mg/day p.o.), respectively its active metabolite epinine, would desensitize lymphocyte beta 2- or platelet alpha 2-adrenoceptors, or alpha 1- and beta-adrenoceptor mediated (phenylephrine- and isoprenaline infusions, respectively), changes in systolic and diastolic blood pressure and heart rate. Ibopamine-treatment, which resulted in peak plasma epinine concentrations of 4-5 nmol.l-1, neither affected resting heart rate or blood pressure, nor any of the alpha- or beta-adrenoceptor parameters measured. Since in man in general long-term administration of alpha- and beta-adrenoceptor agonists desensitizes alpha- and beta-adrenoceptors, the lack of any alpha- and beta-adrenoceptor desensitizing effect of ibopamine suggests that, in the dose employed (3 x 100 mg per day), ibopamine does not exert alpha- or beta-adrenoceptor agonistic effect in humans.

Adult↗
PubMed1993

Beta-adrenoceptors in cardiac disease.

The human heart contains both beta 1 and beta 2-adrenoceptors; both mediate positive inotropic and chronotropic effects. In chronic heart failure, beta-adrenoceptor number is reduced, presumably, by down-regulation by endogenous noradrenaline which is elevated due to increased sympathetic activity. Since the human heart contains only a few spare receptors for beta-adrenoceptor-mediated positive inotropic effects and the amount of spare receptors declines in chronic heart failure, it is not surprising that the reduced beta-adrenoceptor number is accompanied by decreased contractile responses to beta-adrenoceptor agonists (including endogenous catecholamines), and the extent of decrease in maximal inotropic response is more pronounced as the disease becomes more advanced. Moreover, in chronic heart failure myocardial G(i)-protein, which inhibits cAMP formation, is increased, which might further contribute to the reduction in beta-adrenoceptor-mediated effects. It appears that, at present, the best therapy for severe heart failure is a successful heart transplant, since in the transplanted heart beta-adrenoceptor number and function seems to be normalized. Moreover, the data currently available do not suggest any development of super- or subsensitivity of postsynaptic cardiac beta-adrenoceptors in the transplanted human heart.

Adrenergic beta-Agonists↗
PubMed1993

Effects of ketotifen on human lymphocytes in vitro and in vivo.

The effects of the antiasthmatic drug ketotifen (CAS 34580-13-7) on human mononuclear leukocytes were studied in vitro and in vivo. In vitro ketotifen concentration-dependently inhibited mitogen-stimulated lymphocyte proliferation. High ketotifen concentrations also inhibited T-lymphocyte mitogen- and adenosine triphosphate stimulated increases in intracellular Ca2+ in lymphocytes and the U937 human monocyte precursor cell line, respectively; this involved inhibition of both Ca2+ influx and intracellular mobilization. In in vivo experiments, treatment of healthy volunteers with 1 mg ketotifen b.i.d. for 7 d did not alter the number or subset composition of circulating lymphocytes. Moreover, the mitogen-stimulated in vitro proliferation of lymphocytes obtained before and after ketotifen treatment in vivo was similar. It is concluded that high ketotifen concentrations can inhibit the activation of resting lymphocytes in vitro but standard ketotifen treatment does not notably affect the number of function of circulating lymphocytes in vivo.

Adenosine Triphosphate↗
PubMed1992

Uptake of radioligands by rat heart and lung in vivo: CGP 12177 does and CGP 26505 does not reflect binding to beta-adrenoceptors.

The biodistribution of (-)-4-(3-t-butylamino-2-hydroxypropoxy)-[5,7-3H-benzimidazol-2-one (CGP12177, a non-selective beta-adrenoceptor antagonist) and 1-[2-(3-carbamoyl-4-hydroxy)-(5-3H-phenoxy)]-2-propanol methanesulfonate, (CGP26505, a beta 1-adrenoceptor antagonist) was studied in rats pretreated with various alpha- and beta-adrenoceptor blocking drugs (5 min before 3H injection, in dosages at which the drugs demonstrated the expected selectivity). Cardiac and pulmonary radioactivity were measured after 10 min, when specific binding was maximal. Uptake of [3H]CGP12177 was linked to binding to beta-adrenoceptors since it was not affected by prazosin or yohimbine, and was equally well inhibited by propranolol, unlabelled CGP12177 and isoprenaline. Moreover, atenolol and CGP20712A inhibited [3H]CGP12177 uptake in heart (predominantly beta 1-adrenoceptors) more potently than ICI 118,551, while in lungs (predominantly beta 2-adrenoceptors) ICI 118,551 was more potent than atenolol or CGP20712A. In contrast, [3H]CGP26505 uptake in the target organs was equally effectively inhibited by propranolol and ICI 118,551, and significantly lowered by alpha-adrenoceptor antagonists. We conclude that [11C]CGP12177, but not [11C]CGP2605 will be suitable for positron emission tomography imaging of beta-adrenoceptors in animals.

Adrenergic alpha-Antagonists↗
PubMed1992

Dissociation between phytohaemagglutinin-stimulated generation of inositol phosphates and Ca2+ increase in human mononuclear leucocytes.

We have tested whether phytohaemagglutinin (PHA)-stimulated generation of inositol phosphates (IP) and increases in intracellular Ca2+ can be dissociated in human mononuclear leucocytes. Lowering the incubation temperature from 37 degrees to 25 degrees C decreased PHA-stimulated IP generation by more than 80%, but only marginally affected PHA-stimulated Ca2+ increases. In the absence of extracellular Ca2+, PHA did not stimulate IP generation or Ca2+ increases, although PHA binding to its acceptor sites was not impaired. Increasing extracellular Ca2+ up to 0.15 mM enhanced PHA-stimulated PHA generation but this increase was attenuated by further increasing extracellular Ca2+ to 2.6 mM. Increasing extracellular Ca2+ to 0.3 mM also enhanced PHA-stimulated Ca2+ increases, and further increasing extracellular Ca2+ did not affect it. Co-treatment with 100 microM-prostaglandin E2 completely abolished PHA-stimulated IP generation, but inhibited Ca2+ increases by only 20-30%. These results could be explained by IP-generation-independent Ca2+ increases or by non-linear coupling of IP generation to Ca2+ increases. Since the PHA concentrations required to increase Ca2+ were greater than those required for IP generation, the latter hypothesis can be excluded. Furthermore, the Ca2+ ionophore ionomycin increased intracellular Ca2+ and weakly stimulated IP generation, but with very similar concentration-response relationships. Our data suggest that PHA-stimulated IP generation and Ca2+ increases in human mononuclear leucocytes mainly occur independently of one another rather than sequentially.

Calcium↗