Biomedical subjects

J B Osnes

Publications and source records attributed to J B Osnes.

At least 37 records · Page 2Linked to original sources

PubMed1995

[Beta 3-receptors: incidence and properties, possible clinical significance].

Beta 3-adrenoceptors is a term used for atypical beta-adrenoceptors which do not fit into either the beta 1- or beta 2-receptor as classified by pharmacological methods. The receptor has been cloned and is thus also genetically defined. Beta 3-adrenoceptors appear to be widely distributed. Until now their importance has been based on studies using agonists with high potency, but yet not selective for beta 3-adrenoceptors. The distribution and functional importance in humans are unclear, and will probably not be clarified before selective antagonists and labelled ligand are developed. Agonists for the beta 3-adrenoceptors may be of clinical value in the treatment of obesity, non-insulin dependent diabetes mellitus, gastrointestinal disorders like irritable colon, inflammatory lung diseases and depression.

Adrenergic beta-Agonists↗

PubMed1995

Endogenous norepinephrine stimulates both alpha 1- and beta-adrenoceptors in myocardium from children with congenital heart defects.

Atrial tissue removed from the cannulation site prior to cardioplegia (n = 15), and ventricular tissue therapeutically excised from the outflow tract of the right ventricle, (RVOT) (n = 2) were examined with respect to adrenoceptor mediated inotropic effect in children with congenital heart defects (CHD). We used sequential reversal by adrenoceptor antagonists of the tyramine enhanced response to endogenous norepinephrine to quantify the role of the beta- and the alpha 1-adrenoceptors, respectively, in the intropic response. Atrial myocardium had an alpha 1-adrenoceptor mediated component of 14% (median) (range 0-44%) and a beta-adrenoceptor mediated component of 86% (median) (range 56-100%). The patients with the highest alpha 1-adrenoceptor mediated inotropic components, had right ventricular pressure loads in the systemic range. In one specimen from RVOT, the ventricular alpha 1-adrenoceptor component was estimated to be 22% of the total inotropic response, compared to 26% in the corresponding right atrium. In a ventricular specimen from another patient, we could not demonstrate any alpha 1-adrenoceptor mediated inotropic component in contrast to 13% in the right atrium. This patient, however, had infusion of the alpha-adrenoceptor antagonist phentolamine after the excision of atrial tissue, but before the excision of muscular tissue from RVOT. In myocardium of children with CHD we found evidence that endogenous norepinephrine stimulated alpha 1-adrenoceptors in addition to beta-adrenoceptors. The relative contributions from the two adrenoceptors to the inotropic response varied considerably, and may be related to the pressure load of the right ventricle. These observations may be relevant with respect both to pathophysiology and to choice of drug therapy.

Child↗

PubMed1995

Improved isolation of cardiomyocytes by trypsination in addition to collagenase treatment.

The present study was undertaken to develop an improved and stabilized method for isolating cardiomyocytes from perfused rat heart. Different lots of the commercial collagenases used for isolating cardiomyocytes give variable results both with respect to the total cell yield and the percentage of elongated cells obtained. When trypsin was present both before and during collagenase treatment of the tissue, the performance of the collagenases was improved and stabilized, and a high and stable cell yield (7.5 x 10(6) cells per heart), and a high percentage of elongated cells (about 70%) was regularly obtained. The cells possessed alpha 1-adrenergic binding sites with binding properties (Bmax = 43.5 fmol/mg protein and Kd = 125.5 pmol/l) in agreement with values previously reported. The cells were able to respond functionally, as the cellular uptake of 86Rb+ increased by 18% after alpha 1-adrenoceptor stimulation with phenylephrine. These criteria indicate that the cells were well preserved during the isolation procedure.

Animals↗

PubMed1994

Intracellular pH measured by 31P-NMR in isolated rat heart during alpha-1-adrenoceptor stimulation.

Changes of intracellular pH (pHi) after alpha-1-adrenoceptor stimulation (5 x 10(-5) mol/l phenylephrine in the presence of 10(-6) mol/l timolol) were studied in isolated perfused rat hearts by 31P-NMR spectroscopy in order to use the whole organ without disruption. The contractility was monitored simultaneously in all hearts. Alpha-1-adrenoceptor stimulation gave an alkalinization by 0.02 +/- 0.01 pH-units (mean +/- S.E.M.) after 5 min and by 0.03 +/- 0.01 pH-units (mean +/- S.E.M.) after 15 min. Thus, an intracellular alkalinization after myocardial alpha-1-adrenoceptor stimulation was observed during close to physiological conditions. The elevation of pHi may contribute to maintain the inotropic effect after alpha-1-adrenoceptor stimulation.

Animals↗

PubMed1994

Functional characterization of an ex vivo preparation of atrial myocardium from children with congenital heart defects: sensitivity to tyramine and adrenoceptor antagonists.

Small pieces of atrial tissue removed from the cannulation site before cardioplegia were used to develop a method for studying adrenergic regulation of the myocardial contractile force in children operated on for congenital heart defects (CHD). We measured the development of the isometric force of contraction dT/dtmax (T'max). Reduction in basal contractility induced by the beta-adrenoceptor antagonist timolol indicated that the myocardium was about half-maximally stimulated by endogenous norepinephrine (NE), probably released from nerve endings by the electrical stimulation. The inotropic effect of endogenous NE could be further increased by tyramine (EC50 approximately 5 microM). A maximal concentration of tyramine increased T'max by a median of 62.5% above the basal level. Sequential blockade of the beta- and alpha 1-adrenoceptors after tyramine stimulation by timolol and prazosin, respectively, indicated that a near-maximal response to combined adrenoceptor stimulation by endogenous NE was mediated by both beta-adrenoceptors (median 77%) and alpha 1-adrenoceptors (median 23%). The basal level of endogenous NE may conceal inotropic effects by exogenous alpha-agonists added to this type of preparation. This preparation is suitable for studying adrenergic regulation by reversing the effects of endogenous NE.

Adolescent↗

PubMed1994

Increased intracellular potassium and water contents in rat heart after alpha-1-adrenoceptor stimulation.

Potassium accumulation in rat heart after alpha-1-adrenoceptor stimulation has previously been reported from indirect measurements. Here we present data on intracellular potassium content measured directly in the heart. Isolated rat hearts perfused in a non-recirculating system were exposed to alpha-1-adrenoceptor stimulation (5 x 10(-5) mol/l phenylephrine in the presence of 10(-6) mol/l timolol). 14C-Sucrose was used to estimate the extracellular space. From heart homogenates intracellular potassium, magnesium and cellular water contents were determined and the ion concentrations calculated accordingly. The intracellular magnesium content remained unchanged during all experimental conditions. alpha-1-Adrenoceptor stimulation evoked an increase in potassium content by 9% (4, 14; 95% confidence interval (CI), P = 0.0006). Due to an observed increase in intracellular water by 17% (9, 26; 95% CI, P = 0.0006), the potassium concentration apparently decreased by 8% (0.3, 15; 95% CI, P = 0.04). During partial inhibition of the Na+/K(+)-ATPase by 10(-5) mol/l ouabain, there was an increase in potassium content by 5% (1, 9; 95% CI, P = 0.008). There was, however, no significant increase in intracellular water in this situation. Calculated intracellular potassium concentration showed accordingly a slight increase. The effects upon potassium and water both in the absence and presence of ouabain were eliminated by the alpha-1-adrenoceptor blocker prazosin (10(-6) mol/l). alpha-1-Adrenoceptor stimulation apparently increased cellular dry weight by 10% (2, 18; 95% CI, P = 0.02). Changes in translocation of potassium and water must be considered as part of the alpha-1-adrenergic heart effects.

Animals↗

PubMed1994

Alpha 1-adrenoceptor stimulation increases 86Rb+ influx in perfused rat heart.

Stimulation of myocardial alpha 1-adrenoceptors has been shown to mediate various changes in potassium fluxes across the sarcolemma. We studied the early effect of alpha 1-adrenoceptor stimulation [5 x 10(-5) M phenylephrine (PE) with 10(-6) M timolol] on potassium influx by measuring uptake of 86Rb+ into isolated rat heart perfused in a nonrecirculating system. The hearts were exposed to alpha 1-adrenoceptor stimulation with or without the Na+/K(+)-ATPase inhibitor ouabain (10(-5) M) during the influx period of 86Rb+ and during the subsequent washout period. 86Rb+ content in the perfusate fractions during the washout period and in heart at the end of experiments were measured. From these data, 86Rb+ content in heart after 2.5, 5.5, and 9.5 min was calculated. alpha 1-adrenoceptor stimulation increased 86Rb+ uptake by 20-40% during the observation period. The influence of ouabain did not indicate clear-cut involvement of Na+/K(+)-ATPase in this effect. The alpha 1-adrenoceptor antagonist prazosin (10(-6) M) prevented the effects of PE. Therefore, increase in potassium influx is mediated by alpha 1-adrenoceptors.

Animals↗

PubMed1993

[Lipid-lowering medication--indications and possible hazards. Report from a hearing].

Drug treatment of hyperlipidaemia should be founded on scientific evidence. A hearing was arranged to arrive at practical measures based on reported clinical trials. Several studies during recent years have shown regression of coronary atheromatosis, and some people would say the effect is striking. Studies using clinical endpoints, like morbidity and mortality, have not yielded equally convincing results, but it should be noted that the results of studies with more than 10% reduction in total serum cholesterol levels are not yet available. So far, the trials have been too small to judge effects on total mortality. It is uncertain whether the treatment actually has untoward effects on the incidence of violent deaths and neoplasms. An upper limit for drug treatment of about 8 mmol/l was proposed during the hearing. The limit can be lowered to 7 if established coronary disease is present. For women without coronary disease the limit should be higher than that for men. All in all, this implies an increase in the total number of individuals treated compared with present practice. It was agreed that at present, high risk individuals are undertreated. The new levels have been set partly on the basis of economic considerations.

Arteriosclerosis↗

PubMed1993

[Therapeutic drug monitoring with the help of serum concentration measurements. How are the analytic results distributed in a population?].

Therapeutic drug monitoring includes measurement of serum concentrations of drugs when this is possible and appropriate. A therapeutic range is defined for populations where the serum levels represent an optimal relationship between clinical effects and side effects for most of the individuals in the population. Compared with the rest of the population, some individuals are atypical, both with respect to response to and elimination of drugs. Therapeutic drug monitoring makes individualization of dosages in these individuals easier, but often requires extra effort. Compilation of serum level measurements for different drugs for a period of six months showed that the tailoring of digitoxin, carbamazepine, lithium and phenobarbital is as close to optimal as can be expected for a population. For amitriptyline, digoxin and theophylline, a considerable increase in clinical effect within a population of users could probably be achieved by bringing more individual serum levels from the subtherapeutic into the therapeutic range. Nor does the therapeutic potential of phenytoin, nortriptyline and valproate seem to be fully utilized.

Blood Chemical Analysis↗

PubMed1992

[Treatment of hypertension in the elderly--diuretics/atenolol?].

The recently published MRC-trial on treatment of hypertension in older adults showed generally beneficial effects. Significantly lower rates of coronary events and cardiovascular events/deaths were found in the diuretic group than in the atenolol group. Special circumstances and weak points in the study it self do not seem to have caused artificial differences between the two treatment groups. Thus the comparison seems to be justified and the demonstrated differences are regarded as real. This study fits into the pattern of other trials. The diuretic regimen with a potassium-magnesium-saving component may have been of importance. Whether the trial reflects a general beta-blocker effect in older adults with hypertension or a more specific atenolol effect is not clarified.

Age Factors↗

PubMed1992

[What can be achieved by treatment with antihypertensive agents? Report from a hearing].

Today it is considered a primary goal to reduce morbidity and mortality from stroke. It will probably also be possible to reduce other pressure-related illnesses, such as heart failure and renal failure. Coronary morbidity is influenced to some extent only, and involves risk of over-treatment. There is most probably a J-shaped relationship between achieved reduction of pressure and mortality. Treatment with drugs is considered when diastolic pressures exceed 90 mm Hg, provided that the patient has been observed when treated in other ways than by drugs for several months. If no other risk factors are present, 5-10 mm Hg higher diastolic blood pressure levels can be accepted. However, all patients with diastolic pressure above 100 mm Hg should be treated. In patients with coronary disease it is advisable not to lower diastolic blood pressure below 85 mm Hg. One should hesitate to give antihypertensive drugs to individuals with high pressures at the doctor's and normal pressures at home. They should preferably receive intense non-drug treatment aimed at reducing total cardiovascular risk.

Antihypertensive Agents↗

PubMed1992

Accumulation of potassium and calcium in rat myocardium exposed to alpha-1-adrenoceptor stimulation.

Net fluxes of potassium, calcium, sodium and chloride were examined in isolated perfused rat hearts during alpha-1-adrenoceptor stimulation. The ion measurements were performed in the non-recirculating perfusate. Hearts were exposed to alpha-1-adrenoceptor stimulation (phenylephrine 5 x 10(-5) mol/l in the presence of the beta-blocker timolol 10(-6) mol/l). During alpha-1-adrenoceptor stimulation perfusate potassium fell relatively rapidly by about 0.10 mmol/l after approximately 100 sec. followed by a slower rise. About 180 sec. after onset of alpha-1-adrenoceptor stimulation, the potassium level was about 0.06 mmol/l below the control concentration level. This reduction was eliminated by the alpha-1-adrenoceptor blocker prazosin (10(-7) mol/l). The effects on net calcium fluxes were measured at two different calcium concentrations. For both concentrations we found a small but statistically significant reduction of the calcium concentration in the perfusate after alpha-1-adrenoceptor stimulation. Neither sodium nor chloride perfusate concentrations showed statistical significant changes compared to control values. The present observations revealed the existence of alpha-1-adrenoceptor regulated mechanisms related to a net uptake of both potassium and calcium in rat heart.

Animals↗

PubMed1991

Lithium increases the alpha 1-adrenoceptor mediated inotropic effect in rat heart.

The intracellular mechanisms activated by stimulation of myocardial alpha 1-adrenoceptors are not known. As in several other tissues, however, activation of alpha 1-adrenoceptors in heart has been related to breakdown of phosphoinositides resulting in production of putative intracellular messengers: different inositol phosphates and diacylglycerol. Lithium has been shown to inhibit enzymes hydrolyzing inositol phosphates. In the present paper we report studies on the effect of lithium upon the alpha 1-adrenoceptor mediated inotropic response elicited in electrically driven rat papillary muscles. While there was no shift of the horizontal positioning of the dose-response curve to alpha 1-adrenergic stimulation in the presence of lithium, the alpha 1-adrenoceptor mediated inotropic effect was increased in a concentration dependent manner (0.25 to 3.0 mmol/l lithium). For comparison, the effect of lithium upon the beta-adrenoceptor mediated inotropic response was also studied. At 3.0 mmol/l lithium, the horizontal position of the dose-response curve to beta-adrenoceptor stimulation was shifted significantly to the right (to higher agonist concentrations) and the maximal beta-adrenoceptor mediated inotropic response was slightly although not significantly reduced. Thus the augmenting effect of lithium upon the alpha 1-adrenoceptor mediated response was specific for this receptor type. Although the effect of lithium may be complex, the data are compatible with the hypothesis that the inositol phosphates may be of functional importance during stimulation of myocardial alpha 1-adrenoceptors.

Animals↗

PubMed1990

[Drug therapy of acute coronary syndrome. Summary of a hearing arranged by the Norwegian Cardiologic Society and the Institute of pharmacotherapy].

Acute coronary syndrome is defined as unstable angina or acute myocardial infarction. A discussion on drug treatment of these conditions was arranged by the Norwegian Society of Cardiology and the Department of Pharmacotherapeutics, University of Oslo, soon after preliminary results of the GISSI II study were available. Relatively simple rules were agreed for the use of analgetics, nitrates and fibrinolytic agents. The last are used only after established myocardial injury. Consensus was also reached on the restricted use of calcium antagonists, inotropic agents and diuretics. There was disagreement concerning the dosage of heparin and the exact use of betablockers, aspirin, warfarin, ACE-inhibitors, magnesium and antiarrhythmics.

Adrenergic beta-Antagonists↗

PubMed1990

Both alpha 1- and beta-adrenoceptor stimulation determine the time course of the inotropic effect of noradrenaline in rabbit heart.

It has been a matter of controversy whether alpha 1-adrenoceptor stimulation contributes to the final inotropic and lusitropic responses in mammalian myocardium to noradrenaline during concomitant and unopposed beta-adrenoceptor stimulation. In the present paper we report studies that compare time courses of the inotropic and lusitropic responses to separate and combined alpha 1- and beta-adrenoceptor stimulation, respectively, in electrically driven rabbit papillary muscles by a submaximal concentration of noradrenaline. Separate alpha 1- or beta-adrenoceptor stimulation (presence of appropriate receptor blocker) showed the characteristic slow and fast development, respectively, of the inotropic responses. Qualitatively, the respective characteristic changes were also observed: alpha 1-adrenoceptor stimulation caused a negative lusitropic effect giving a prolongation of the time to peak tension (TPT), while beta-adrenoceptor stimulation caused a pronounced positive lusitropic effect giving a shortening of TPT. The time course of the inotropic response to combined adrenoceptor stimulation had characteristics that deviated from the respective time courses to separate alpha 1- or beta-adrenoceptor stimulation thus indicating a contribution from both adrenoceptor populations to the final inotropic response. Combined alpha 1- and beta-adrenoceptor stimulation gave a pronounced positive lusitropic response as might be expected due to the obviously dominating role of the beta-adrenergic component. However, the maximal lusitropic effect and the shortening of TPT were both slightly less during combined adrenoceptor stimulation compared to separate beta-stimulation thus indicating an influence of the alpha 1-adrenoceptor mediated negative lusitropic effect. Quantitatively, the separate alpha 1- and the separate beta-adrenoceptor mediated inotropic effects were not additive. In accordance with other recent studies, this indicated an inhibitory interaction between the two adrenergic receptor populations in myocardium.

Animals↗

PubMed1990

Prazosin-sensitive component of the inotropic response to norepinephrine in rabbit heart.

Earlier experiments have usually failed to demonstrate a competitively displaceable alpha adrenoceptor blocker-sensitive component in the dose-dependent inotropic response to norepinephrine in mammalian hearts. We reinvestigated if it was possible to reveal this phenomenon by carefully choosing a concentration of the alpha adrenoceptor blocker prazosin that would give a significant displacement while it still was possible to completely surmount the blockade by reasonable concentrations of norepinephrine. Both inotropic and lusitropic dose-dependent responses to norepinephrine in rabbit heart papillary muscles were recorded. In the presence of 3 X 10(-9) M prazosin there was a significant rightward shift of a component corresponding to about 20% of the total inotropic response to norepinephrine. The prazosin-sensitive component was shifted significantly more to the left by 3 X 10(-5) M cocaine than the nonsensitive component. The maximal inotropic response to norepinephrine was increased at lower prazosin-concentrations (3 X 10(-9) M), whereas at 10(-7) M prazosin the maximal response was unchanged compared to the absence of prazosin. The maximal lusitropic response to norepinephrine was increased monophasically and dose-dependently by prazosin. Thus, by carefully considering the relative potencies of the agonist and the antagonist it was possible to demonstrate an alpha adrenoceptor blocker sensitive component in the inotropic response to norepinephrine in rabbit heart. The effect of cocaine upon the prazosin-sensitive component would indicate that the alpha adrenoceptor population in rabbit myocardium is located more closely to the sympathetic nerve endings than the beta adrenoceptor population.(ABSTRACT TRUNCATED AT 250 WORDS)

Animals↗

PubMed1989

Adrenoceptors in myocardial regulation: concomitant contribution from both alpha- and beta-adrenoceptor stimulation to the inotropic response.

The studies presented deal with the alpha 1-adrenoceptor mediated inotropic effects of noradrenaline obtained by exclusive ("pure") alpha 1-adrenoceptor stimulation or by concomitant stimulation of alpha 1- and beta-adrenoceptors in myocardium. The pure beta-adrenergic effects of noradrenaline were also quantified. Interactions between the two receptor systems were studied. The pure alpha 1- and beta-adrenergic effects of noradrenaline, respectively, were achieved separately in the presence of high concentrations of appropriate receptor blockers. The experiments were performed on isolated ventricular myocardium from rat, rabbit, and man. The pure alpha 1-adrenergic inotropic effects were about 35-50% of control (basal) and half the pure beta-adrenergic effects both in rat and rabbit myocardium. Ventricular myocardium from man exhibited an alpha 1-adrenergic inotropic effect of the same magnitude (50% of control [basal]) as did rabbit papillary muscle. Determination of the alpha 1-adrenergic inotropic component during concomitant beta-adrenoceptor stimulation was associated with difficulties. Several experimental approaches on rat and rabbit myocardium are presented and discussed. Some types of experimental approaches obviously underestimate the alpha 1-adrenergic component. The methods regarded as reliable revealed an alpha 1-adrenergic inotropic effect of about 20-30% during combined adrenoceptor stimulation by noradrenaline. Concomitant beta-stimulation reduced the alpha 1-adrenergic effect by about 50%, while alpha 1-stimulation attenuated the beta-effect to a lesser degree (about 20-25%). A model is presented on a mutual attenuation of the functional expression of the two receptor systems.(ABSTRACT TRUNCATED AT 250 WORDS)

Animals↗

PubMed1988

Increase of cyclic AMP in subcellular fractions of rat heart muscle after beta-adrenergic stimulation: prenalterol and isoprenaline caused different distribution of bound cyclic AMP.

Although prenalterol is a partial beta-agonist, it has been reported to produce only a marginal, non-significant increase of cAMP in rat hearts. We studied the effect of prenalterol and isoprenaline on free and bound cAMP content in subcellular fractions of perfused rat hearts to see whether prenalterol increased cAMP and whether there were differences in the subcellular distribution of the cAMP contents after stimulation with the drugs. The in situ binding characteristics of cAMP to the protein kinases at different degree of beta-adrenergic stimulation were elucidated. Prenalterol increased significantly both total cAMP content in homogenate, bound cAMP in a 100,000 g particulate fraction and bound, free and total cAMP contents in the resulting supernatant. While prenalterol increased bound cAMP in the particulate fraction and in the supernatant proportionally, isoprenaline caused a relatively greater increase of bound cAMP in the supernatant. At equieffective concentrations regarding inotropic and lusitropic effects, prenalterol and isoprenaline increased bound cAMP in the particulate fraction to the same degree, while the increase in the other fractions was greater after isoprenaline. Thus, the cAMP bound in the particulate fraction seemed to determine the inotropic state of the cell after beta-adrenergic stimulation, supporting a compartmentation of cAMP in myocardium. In controls 31 to 34% of the total binding capacity for cAMP in the particulate fraction was occupied, increasing to 77% after maximal beta-stimulation. The binding capacity in the supernatant was only 15 to 18% saturated in the basal situation and about half saturated after maximal beta-stimulation. cAMP bound in the particulate fraction is of special interest when cAMP and functional effects are studied.

Animals↗