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J B Osnes

Publications and source records attributed to J B Osnes.

At least 55 records · Page 3Linked to original sources
PubMed1988

Properties of the inotropic response in rat papillary muscles to the dihydropyridine "Ca-channel activator" BAY K 8644.

The aim of the present study was 1) to characterize qualitatively the positive inotropic effect of the Ca-channel activator BAY K 8644 and to compare this response to response-types with known and different relationship to the cyclic AMP (cAMP) system (e.g. responses elicited through alpha- and beta-adrenergic receptor stimulation) and 2) to study the effect of simultaneous muscarinic cholinergic stimulation upon the BAY K 8644 response in order to further evaluate the role of the cAMP system in this response. The responses were evaluated in isolated, electrically paced, isometrically contracting papillary muscles from rat heart. Isometric tension (Tmax), rate of rise and decline of tension (first derivative = T') and rate of transition from tension rise to tension decline (negative part of second derivative = T") were recorded. In the presence of the alpha 1-adrenergic receptor blocker prazosin (10(-7) mol/l) and the beta-adrenergic receptor blocker timolol (10(-6) mol/l), the positive inotropic effect of 1.7 x 10(-6) mol/l BAY K 8644 developed rather slowly with a time to half maximal effect of about 4 minutes. Qualitatively the response was characterized by an almost proportional ("symmetrical") increase in all parts of the contraction-relaxation cycle with a small prolongation of time to peak tension and of the duration of the whole cycle. This response contrasted sharply with the cAMP-dependent response to beta-receptor stimulation (beta-type response with shortening of time to peak tension), but was very similar to the cAMP-independent response to alpha-receptor stimulation (alpha-type response).(ABSTRACT TRUNCATED AT 250 WORDS)

3-Pyridinecarboxylic acid, 1,4-dihydro-2,6-dimethy↗
PubMed1988

Both alpha and beta adrenoceptor-mediated components contribute to final inotropic response to norepinephrine in rat heart.

The classical approach of displacing the dose-response curve by an alpha adrenoceptor blocker has most often failed to demonstrate a contribution of an alpha adrenoceptor-mediated component in the final inotropic response to norepinephrine unless the beta adrenoceptors are extensively blocked. To unmask and quantify the inotropic components in the response to norepinephrine, we took a different approach by studying reversal responses to appropriate adrenoceptor blockers in isolated paced rat papillary muscles maximally stimulated by norepinephrine. The inotropic response to norepinephrine was rapidly reversed by simultaneous addition of the beta adrenoceptor blocker timolol and the alpha adrenoceptor blocker prazosin. When the adrenoceptor blockers were added sequentially, both alpha and beta adrenoceptor-mediated components in the inotropic response to norepinephrine could be demonstrated: one beta adrenoceptor-mediated component (timolol sensitive only) that represented about 75% of the inotropic response and one alpha adrenoceptor-mediated component (prazosin sensitive only) that represented about 25% of the inotropic response. When one adrenoceptor population was eliminated by giving one of the adrenoceptor blockers before norepinephrine, the inotropic response in this situation could be completely reversed by the other adrenoceptor blocker. The expression of both alpha and beta adrenoceptor-mediated components was significantly less during concomitant receptor stimulation than when the respective receptor populations were stimulated separately. Thus, there was apparently a mutual inhibition of one component upon the other. Although the beta adrenoceptor-mediated inotropic component clearly was the dominating one, the present observations will explain the difficulties in demonstrating an alpha adrenoceptor-mediated component during unopposed beta adrenoceptor stimulation in the inotropic response to norepinephrine in earlier studies.

Animals↗
PubMed1987

Enhancement of the alpha-adrenergic inotropic component of noradrenaline by simultaneous stimulation of muscarinic acetylcholine receptors in rat myocardium.

The contribution of an alpha-adrenoceptor-mediated component to the final inotropic response to noradrenaline in the absence and presence of muscarinic acetylcholine receptor stimulation (which exerts a 'functional' antagonism of effects mediated through beta-adrenoceptors but not through alpha-adrenoceptors) was evaluated by recording contraction and relaxation in isolated, paced rat papillary muscles. In the absence of muscarinic acetylcholine receptor stimulation, the alpha 1-selective adrenoceptor blocker prazosin (0.12 microM) did not significantly influence the dose-dependent response to noradrenaline with respect to either contractility or to relaxation. In the presence of concomitant muscarinic acetylcholine receptor stimulation by 10 microM carbachol, prazosin reduced by 32% (alpha = 0.028) the maximal increase in contractility (expressed as (dT/dt)max) evoked by noradrenaline compared to the absence of prazosin. Prazosin also did not influence the effect of noradrenaline upon relaxation under these conditions. Carbachol itself did not significantly reduce the maximal contractile response to noradrenaline. Thus cholinergic stimulation increases both relatively and absolutely the alpha-adrenergic inotropic component of noradrenaline. These observations indicate a ternary regulatory system of myocardial contractility through the autonomic receptors.

Animals↗
PubMed1987

Qualitative characteristics of the mechanical response in rat papillary muscles to increase in extracellular calcium concentration.

The qualitative characteristics of the inotropic response to increase in extracellular calcium (Cao) were studied in isolated, electrically driven, isometrically contracting rat papillary muscles. All experiments were done in the presence of adrenergic receptor blockers. Cao was increased in a cumulative way by exchanging a small fraction of the incubation solution with a corresponding solution with higher calcium concentration (8 mmol l-1). At any Cao level there was an almost proportional increase in parameters describing different parts of the contraction-relaxation cycle as compared with results at the preceding lower Cao level. Time to peak tension was prolonged at high compared with low Cao levels. The response to increased Cao was very similar to the cyclic AMP (cAMP)-independent inotropic response elicited through activation of alpha-adrenergic receptors (alpha-type response, Skomedal et al. 1982) and strikingly different from the cAMP-dependent inotropic response elicited, for example, through activation of beta-adrenergic receptors (beta-type response, Skomedal et al. 1982). As the inotropic response to increased Cao is known to be cAMP-independent (Dönges et al. 1977), the present results demonstrate the interrelationship between the regulatory function(s) and the direct effector function(s) of calcium in the myocardium.

Adrenergic alpha-Agonists↗
PubMed1987

Alpha-adrenergic stimulation contributes to the inotropic effect of noradrenaline.

The alpha- and beta-adrenoceptor mediated inotropic effects of noradrenaline were determined in rat heart papillary muscle. The pure alpha-adrenergic inotropic effect, obtained in the presence of the beta-blocker timolol, was about half the pure beta-adrenergic inotropic effect, obtained in the presence of the alpha-blocker prazosin. The maximal inotropic effect of noradrenaline in the absence of blockers was, however, of the same magnitude as the pure beta-adrenergic effect. The alpha- and beta-adrenergic components of the inotropic response to noradrenaline were determined as those reversed by prazosin and timolol, respectively. They were smaller than the pure effects evoked separately. When beta-stimulation by noradrenaline was attenuated by carbachol, the alpha-adrenergic inotropic component was increased. Thus the alpha-effect is increased when the beta-adrenergic effect is antagonized. The alpha-adrenergic inotropic component of noradrenaline seems to play a variable role depending upon the degree of concomitant beta-receptor stimulation in the heart.

Animals↗
PubMed1985

Demonstration of an alpha adrenoceptor-mediated inotropic effect of norepinephrine in human atria.

It has been claimed by other investigators that norepinephrine does not evoke a significant alpha adrenergic inotropic effect in human atria in contrast to epinephrine and phenylephrine, indicating a limitation of a possible functional role of the cardiac alpha adrenoceptors. We therefore characterized the inotropic effects of norepinephrine in isometrically contracting muscle strips from human atria obtained during open heart surgery. Both contraction and relaxation were studied by measuring developed tension and its first and second derivatives. Both the influence of propranolol and prazosin upon the inotropic responses to norepinephrine and the qualitative characteristics of the responses revealed that norepinephrine evoked both alpha and beta adrenergic inotropic effects. The alpha adrenergic response to norepinephrine was qualitatively different from the beta adrenergic effect and qualitatively similar to the alpha adrenergic effect of norepinephrine observed in other mammalian species. Although the alpha adrenergic effect was marked, the beta adrenergic effect was the dominating one as has also been found in other species. It is concluded that also in human atria norepinephrine evokes inotropic effects through both alpha and beta adrenoceptors.

Heart Atria↗
PubMed1984

Specific binding of [3H]prazosin to myocardial cells isolated from adult rats.

The characteristics of alpha-adrenoceptors in rat myocardium were investigated by specific binding of [3H]prazosin to cells isolated from adult rat heart by perfusion with collagenase and hyaluronidase. The cells were incubated in Krebs-Ringer bicarbonate buffer gassed with 95% O2 and 5% CO2 at 31 degrees with the appropriate concentrations of the different ligands. Non-specific binding was defined by the addition of 10(-5) mole/l. phentolamine. The binding of [3H]prazosin was saturable and reached equilibrium within 15 min. Scatchard analysis showed a straight line giving an apparent dissociation constant, Kd, equal to 155.9 +/- 8.0 pmole/l. and a maximal number of binding sites equal to 76.7 +/- 11.1 fmole/mg protein. Inhibition of specific [3H]prazosin binding by different adrenergic blockers showed the order of potency characteristic of alpha 1-adrenoceptors: prazosin much greater than phentolamine greater than yohimbine much greater than propranolol. Inhibition by adrenergic agonists showed the order of potency: adrenaline greater than noradrenaline = phenylephrine greater than isoprenaline. The same orders of potency were observed in the presence of propranolol. However, propranolol slightly decreased the affinity for noradrenaline and phenylephrine. Hofstee analyses of the inhibition curves showed two binding components for all ordinary alpha-adrenoceptor blockers and agonists including unlabelled prazosin. In contrast, [3H]prazosin showed only one binding component. Both binding components were of the alpha 1-adrenoceptor subtype according to the order of potency of blockers. The different ligands had different affinity ratios for the two binding components giving them different profiles. Trifluoperazine, a phenothiazine compound, also had high affinity for the [3H]prazosin binding sites. This drug, however, apparently detected one class of binding sites only, as interpreted from the Hofstee analysis. Hill analyses of the inhibition data consistently yielded Hill constants, nH, in the range 0.75-0.85 except for [3H]prazosin, where nH = 1.02 and for trifluoperazine, where nH = 1.07. Although the two binding components may serve different functions, it seems impossible at present to relate the negative and the positive inotropic components, respectively, of the alpha-adrenergic inotropic response observed in functional studies only to one or the other binding component.

Animals↗
PubMed1984

Some pharmacological properties of organic nitrates.

The organic nitrates exert the same pharmacological actions. They differ in potency and in pharmacokinetics. They are more potent as dilators of veins than of arteries/arterioles and more potent as dilators of large arteries than of arterioles. This hemodynamic profile decreases heart work mainly by preload reduction but to some extent also by afterload reduction. The coronary flow is relatively improved and a redistribution to the ischemic myocardium takes place. The nitrates may facilitate the dissociation of oxygen from oxyhemoglobin and also may cause a more efficient energy metabolism. The basal mechanisms of action involve-SH groups and consecutively cyclic GMP. Glyceryl trinitrate is denitrated faster by the liver than is isosorbide dinitrate. The first pass metabolism is easily circumvented by sublingual and dermal application. Oral administration requires large dosages. Metabolites may contribute to the pharmacological activity. Plasma concentrations cannot be used to predict clinical effects of the nitrates.

Angina Pectoris↗
PubMed1983

Characterization of mechanical effects and beta-adrenoceptor binding of prenalterol in rat myocardium.

The partial beta-agonist prenalterol has been found to differ from the full agonist isoprenaline in some aspects of its cardiac action. We therefore studied in rat myocardium whether prenalterol elicited the same qualitative changes of the contraction-relaxation cycle as was previously found for isoprenaline. We also measured binding of prenalterol to beta-adrenoceptors. Prenalterol augmented relaxation more than contraction and thus evoked the same qualitative changes of the contraction-relaxation cycle as did isoprenaline. However, the response developed slower than that to isoprenaline, and the effect on relaxation followed a more protracted time course than the effect on contraction. Prenalterol bound non-selectively to beta 1- and beta 2-adrenoceptors in both heart and lung broken cell preparations. pKd for binding to beta-adrenoceptors and pD2 values for functional effects in heart were similar, i.e. prenalterol had to occupy half the amount of beta-adrenoceptors in order to evoke half-maximal functional effects. The non-selective alpha-blocker phentolamine potentiated the effects of prenalterol on contraction, but did not change the equilibrium binding of prenalterol to cardiac beta-adrenoceptors. Phentolamine did not change the potency and efficacy of isoprenaline. Thus, although prenalterol qualitatively evoked the same response as isoprenaline, it also exhibited some properties which differed.

Animals↗
PubMed1983

Lack of functional influence by prenalterol through alpha 1-adrenoceptors in rat myocardium.

Some of the cardiac properties of the partial beta-agonist prenalterol may indicate a contribution from alpha 1-adrenergic stimulation. We therefore studied whether prenalterol interacted with alpha 1-adrenoceptors in rat myocardium. Combination with propranolol did not reveal an alpha 1-adrenergic inotropic effect of prenalterol in papillary muscles. Neither did prenalterol block the alpha 1-adrenergic response to phenylephrine. In myocardial cells, prenalterol inhibited 3H-prazosin binding to alpha 1-adrenoceptors only at very high concentrations. Prenalterol thus exhibited no functionally important interactions with alpha 1-adrenoceptors in myocardium, and its properties cannot be accounted for in terms of contribution from alpha 1-adrenergic effects.

Animals↗
PubMed1983

Effects of trifluoperazine on beta-adrenergic responses of rat papillary muscle: related to calmodulin?

The beta-adrenergic stimulation of cardiac contraction and relaxation is related to an augmented Ca++ oscillation mediated by cAMP. This Ca++ mobilization may secondarily involve calmodulin in a way modulating the mechanical responses. We tested this possibility by studying interferences of trifluoperazine (which is able to block Ca++-calmodulin) with beta-adrenergic responses in rat heart papillary muscles. Trifluoperazine up to 10(-5) mol/l did not change the basal function. 10(-5) mol/l trifluoperazine augmented the contractile response to isoprenaline above 10(-7) mol/l. The inotropic effects of isoprenaline below 10(-7) mol/l and of the partial beta-agonist prenalterol were not influenced by trifluoperazine. 10(-5) mol/l trifluoperazine attenuated the stimulation of initial relaxation by isoprenaline in the entire concentration range. Thus this beta-adrenergic response was more sensitive to trifluoperazine than the contractile response. But trifluoperazine only slightly and non-significantly attenuated the stimulation of initial relaxation by prenalterol. From experiments on broken cell preparations the present results can be explained in terms of calmodulin blockade and thus inhibition of Ca++ efflux across the sarcolemma and of Ca++ uptake by the sarcoplasmic reticulum. Trifluoperazine effects unrelated to calmodulin can hardly account for the results. Thus a full beta-agonist can apparently mobilize enough Ca++ to activate calmodulin systems important for the final effects on the contraction-relaxation cycle.

Adrenergic beta-Agonists↗
PubMed1983

Demonstration of an alpha adrenoceptor-mediated inotropic effect of norepinephrine in rabbit papillary muscle.

Other investigators have claimed that norepinephrine does not evoke a significant alpha adrenergic inotropic effect in rabbit ventricular myocardium in contrast to some other mammalian species, indicating an important functional limitation of the cardiac alpha adrenoceptors. We therefore characterized the inotropic effects of norepinephrine in isometrically contracting rabbit papillary muscles. We studied both contraction and relaxation by measuring developed tension and its first and second derivatives. Both the influence of propranolol and prazosin on concentration-effect curves of norepinephrine and the qualitative characteristics of the responses revealed that norepinephrine evoked both alpha and beta adrenergic inotropic effects. The alpha adrenergic response to norepinephrine was qualitatively markedly different from the beta adrenergic effect and qualitatively similar to the alpha adrenergic effect of phenylephrine which was also characterized for comparison. Although the alpha adrenergic response to norepinephrine was marked, the beta adrenergic effect was the dominating one when norepinephrine was administered alone. Thus, the beta adrenergic effect had to be extensively blocked to reveal the prazosin-sensitive alpha-1 adrenergic response. It is concluded that also in rabbit papillary muscles, norepinephrine evokes inotropic effects through both alpha and beta adrenoceptors.

Animals↗
PubMed1982

Differences between alpha-adrenergic and beta-adrenergic inotropic effects in rat heart papillary muscles.

alpha-And beta-adrenergic inotropic effects have been shown to be qualitatively different. In order to further characterize these difference we compared the mechanical response to alpha- and beta-adrenoceptor stimulation, respectively, in electrically driven left ventricular papillary muscles from rat heart. The muscles were stimulated by either isoprenaline (Beta-adrenoceptor stimulation), phenylephrine in the presence of propranolol (alpha-adrenoceptor stimulation) or phenylephrine alone (combined alpha-and Beta-adrenoceptor stimulation). Isometric tension (T), rate of rise and decline of tension (first derivate=T') and rate of transition from tension rise to tension decline (negative part of second derivative=T') were recorded. These recordings disclosed qualitative differences between the alpha-and Beta-inotropic response both in dose-response and time course experiments. Maximal Beta-adrenoceptor stimulation caused a small increase in Tmax (18%), intermediate increases in T'max (45%) and T'min (68%) and considerable increase in T'min (145%) ("Beta-type" effect). Maximal alpha adrenoceptor stimulation increased all qualities by about the same degree (23-24% ("a-type" effect). While Beta-adrenoceptor stimulation gave a dose-dependent and pronounced increase in the ratio T"min/T'max (relaxation-onset index), alpha adrenoceptor stimulation decreased it to subcontrol values and phenylephrine alone gave a small dose-dependent increase at higher dose. The time course of the alpha-adrenoceptor stimulation was characterized by a transient decrease in all qualities followed by an increase which reached maximum at 4-5 min. Beta-Adrenoceptor stimulation gave a monophasic response which reached maximum after 1-2 min. Phenylephrine alone gave mainly an "a-type" effect although T"min increased significantly more in the absence than in the presence of propranolol and T"min/T'max showed a small increase which developed slowly. Thus Beta-adrenoceptor stimulation activated relaxation compared to contraction by a higher degree than did alpha-adrenoceptor stimulation. This probably reflects different mechanisms of action. While the alpha-effect may rely primarily on an increased calcium influx, the Beta-effect probably is the final result of several subcellular effects of cyclic AMP.

Animals↗
PubMed1981

Mechanical response of rat myocardium to dibutyryl cyclic AMP in relation to effects of alpha-and beta-adrenoceptor stimulators.

Dibutyryl cyclic AMP, and alpha- and beta-adrenoceptor stimulators are all able to elicit inotropic effects. alpha- and beta-Adrenoceptor stimulation are known to change each myocardial contraction-relaxation cycle differently. In order to elucidate the myocardial function of cyclic AMP the effects of dibutyryl cyclic AMP on the contraction-relaxation cycle of isolated rat heart papillary muscle were examined and compared to the effects of alpha-and beta-adrenoceptor stimulation, respectively. Dibutyryl cyclic AMP (in the presence of propranolol) increased developed tension (Tmax) by 18%, rate of tension rise (T'max) by 46%, rate of tension fall (T'min) by 62% and onset-rate of relaxation (T"min) by 136%. These changes in the contraction-relaxation cycle were strikingly similar to those produced by isoprenaline (beta-adrenoceptor stimulation). The response to dibutyryl cyclic AMP, however, developed much more slowly than did the response to isoprenaline. The latter effect was associated with cyclic AMP elevation in a way indicating a trigger function for cyclic AMP. The alpha-adrenoceptor stimulation (by phenylephrine combined with propranolol), however, increased measures both for contraction and for relaxation by about the same degree, and the effects occurred without changes of cyclic AMP contents. Phenylephrine alone (combined alpha-and beta-adrenoceptor stimulation) elicited a substantial cyclic AMP elevation but gave mechanical effects only slightly different from the pure alpha-adrenergic response. Thus cyclic AMP effects did not seem to be fully expressed in this case. As a whole, the results indicate that the effects of both dibutyryl cyclic AMP and of isoprenaline are mediated by the cyclic AMP-system while alpha-adrenoceptor stimulation involves other mechanisms.

Adrenergic alpha-Agonists↗