Qualitative Differences between the Inotropic Responses in Rat Papillary Muscles to α-Adrenoceptor and β-Adrenoceptor Stimulation by both Noradrenaline and Adrenaline

Abstract: Mammalian heart has obviously both α- and β-adrenergic inotropic mechanisms, and stimulation of these two mechanisms by appropriate agonists lead to qualitatively different inotropic responses. This difference can serve to recognize the two adrenergic inotropic effects. In order to explore if the endogenous catecholamines, noradrenaline and adrenaline, could activate both these mechanisms, and if so, to characterize them qualitatively and quantitatively, the mechanical responses in electrically driven rat left ventricular papillary muscles were examined in the absence or presence of appropriate receptor blockade. Isometric tension (T), 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. α-Adrenergic and β-adrenergic inotropic effects were demonstrated both for noradrenaline and adrenaline. Maximal β-adrenoceptor stimulation (agonist in the presence of an α-adrenoceptor blocker) caused a small increase in T_max, intermediate increases in T'_max and T'_min, and a considerable increase in T_min (β-type effect). Maximal α-adrenoceptor stimulation (agonist in the presence of a β-adrenoceptor blocker) increased all parts of the contraction-relaxation cycle by about the same degree (T_minT_minT'_maxT_max α-type effect). While β-adrenoceptor stimulation gave a dose dependent and pronounced increase in the ratio T_min/T_max (relaxation-onset index), α-adrenoceptor stimulation decreased it to subcontrol values. The time course of the response to the α-adrenoceptor stimulation was characterized by a transient decrease in all qualities followed by an increase which reached maximum at 4–5 min. β-Adrenoceptor stimulation gave a monophasic inotropic response which developed in the course of 1–2 min. Both agents alone gave a monophasic response with the characteristics of a β-type effect (i.e. relative maximal increase of T_minT_minT_maxT_max), and a marked increase in the relaxation-onset index (T_min/T_max). Thus the β-adrenergic inotropic component was the dominating one when the amines were used alone. The two different response patterns probably reflect a dual mechanism of action of the endogenous catecholamines: the β-adrenergic component which is dependent upon an increase in cyclic AMP levels and the α-adrenergic component which is independent on cyclic AMP.     

Qualitative Differences between β-Adrenergic and α-Adrenergic Inotropic Effects in Rat Heart Muscle

Abstract If β- and α-adrenergic inotropic effects are cyclic AMP dependent and cyclic AMP independent, respectively, they may be qualitatively different. The inotropic effects of β-receptor stimulation (isoprenaline) and α-receptor stimulation (phenylephrine combined with propranolol) were characterized in isolated perfused rat hearts, rat atria and rat papillary muscles. The β-effect reached its maximum before the α-effect. The α-effect followed a three-phasic time-course indicating both stimulatory and inhibitory components. The aortic pressure wave (perfused heart) indicated a shorter contraction phase after β-stimulation than after α-stimulation. The time to peak tension (atrium, papillary muscle) was relatively shorter after isoprenaline than after α-stimulation, which tended to prolong it. The contraction-relaxation cycles (atrium, papillary muscle) were examined by recording the isometric tension (T), its first (T′) and second (T″) derivatives, α- and β-stimulation both increased T_max, T′_max (maximal rate of tension rise), T′_min, (maximal rate of tension decline) and T″_min (maximal rate of transition from rise to decline of tension). Isoprenaline increased T_min, (papillary muscle) and T″_min (atrium, papillary muscle) relatively more than did α-stimulation, i.e. the relaxing processes were activated relatively more by β-stimulation. The results indicate different mechanisms for the two adrenergic inotropic effects. The relatively larger activation of relaxation by β-stimulation is assumed to be caused by cyclic AMP.     

Both α1- and β-Adrenoceptor Stimulation Determine the Time Course of the Inotropic Effect of Noradrenaline in Rabbit Heart

It has been a matter of controversy whether α₁-adrenoceptor stimulation contributes to the final inotropic and lusitropic responses in mammalian myocardium to noradrenaline during concomitant and unopposed β-adrenoceptor stimulation. In the present paper we report studies that compare time courses of the inotropic and lusitropic responses to separate and combined α- and β-adrenoceptor stimulation, respectively, in electrically driven rabbit papillary muscles by a submaximal concentration of noradrenaline. Separate α₁- or β-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: α₁-adrenoceptor stimulation caused a negative lusitropic effect giving a prolongation of the time to peak tension (TPT), while β-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 α₁- or β-adrenoceptor stimulation thus indicating a contribution from both adrenoceptor populations to the final inotropic response. Combined α₁- and β-adrenoceptor stimulation gave a pronounced positive lusitropic response as might be expected due to the obviously dominating role of the β-adrenergic component. However, the maximal lusitropic effect and the shortening of TPT were both slightly less during combined adrenoceptor stimulation compared to separate β-stimulation thus indicating an influence of the α₁ -adrenoceptor mediated negative lusitropic effect. Quantitatively, the separate α₁ - and the separate β-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.     

Effects of Trifluoperazine on β-Adrenergic Responses of Rat Papillary Muscle: Related to Calmodulin?

Abstract: The β-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 β-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 β-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 β-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 β-agonist can apparently mobilize enough Ca⁺⁺ to activate calmodulin systems important for the final effects on the contraction-relaxation cycle.     

Preliminary analysis of the discriminative stimuli induced by the calcium channel “agonist” BAY K 8644

Rats were trained in a drug discrimination paradigm to press one of two levers for food reward after injection of the racemic dihydropyridine (DHP) Ca²⁺ -channel activator BAY K 8644 (2.5 mg/kg) and to press the other after vehicle injection. The discrimination was reliably attained in an average of 48 sessions. Thereafter, tests with various doses of BAY K 8544 yielded a dose-dependent selection of the BAY K 8644 lever, with an ED₅₀ of 0.74 mg/kg. The (?)-enantiomer of BAY K 8644 generalized dose-dependently (ED₅₀ = 1.04 mg/kg), while the (+)-enantiomer showed no generalization up to 10 mg/kg. Furthermore, nifedipine pretreatment fully antagonized the BAY K 8644 stimulus. These data indicate that BAY K 8644 produces physiological effects that can readily serve as discriminative stimuli in rats. The results also support the mediation of the BAY K 8644 stimulus through agonistic interaction with the calcium channel DHP receptor.     

Lithium Increases the α1-Adrenoceptor Mediated Inotropic Effect in Rat Heart

Abstract: The intracellular mechanisms activated by stimulation of myocardial α₁-adrenoceptors are not known. As in several other tissues, however, activation of α₁-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 α₁-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 α₁-adrenergic stimulation in the presence of lithium, the α₁-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 β-adrenoceptor mediated inotropic response was also studied. At 3.0 mmol/l lithium, the horizontal position of the dose-response curve to β-adrenoceptor stimulation was shifted significantly to the right (to higher agonist concentrations) and the maximal β-adrenoceptor mediated inotropic response was slightly although not significantly reduced. Thus the augmenting effect of lithium upon the α₁-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 α₁-adrenoceptors.     

Lack of Functional Influence by Prenalterol through α1-Adrenoceptors in Rat Myocardium

Abstract: Some of the cardiac properties of the partial β-agonist prenalterol may indicate a contribution from α₁-adrenergic stimulation. We therefore studied whether prenalterol interacted with α₁-adrenoceptors in rat myocardium. Combination with propranolol did not reveal an α₁-adrenergic inotropic effect of prenalterol in papillary muscles. Neither did prenalterol block the α₁-adrenergic response to phenylephrine. In myocardial cells, prenalterol inhibited ³H-prazosin binding to α₁-adrenoceptors only at very high concentrations. Prenalterol thus exhibited no functionally important interactions with α₁-adrenoceptors in myocardium, and its properties cannot be accounted for in terms of contribution from α₁-adrenergic effects.     

Modulation of adenosine 3',5'-monophosphate contents of rat peritoneal macrophages mediated by beta2-adrenergic receptors.

The modulation of cAMP contents of rat peritoneal macrophages by β-adrenergic stimulants and blocking agents were studied. The maximum increase of cAMP contents induced by isoproterenol, epinephrine, norepinephrine and hexoprenaline (a selective β₂-adrenergic stimulant) was about 170 ~ 200 per cent and about 100 per cent by salbutamol (a selective β₂-adrenergic stimulant) above the basal level. The activity of phenylepherine, a α-adrenergic stimulant, was very weak. The concentration giving a half maximum stimulation was as follows: isoproterenol; 6.3 × 10^?8 M, hexoprenaline; 8.9 × 10^?8 M, salbutamol; 3 × 10^?7 M, epinephrine; 5.6 × 10^?7 M, and norepinephrine; 5.6 × 10^?6 M. Taking propranolol as a standard for comparison, antagonists of the isoproterenol induced increase in cAMP in macrophages ranged in their minimum effective concentrations as follows: bufetolol; 1. metoprolol (a selective β₁-adrenergie blocking agent); 1000, practolol (a selective β₁-adrenergic blocking agent); > 1000, while in rat hearts bufetolol; 1, metoprolol and practolol; 100. The increase of cAMP by 10^?5 M epinephrine or 10^?5 M hexoprenaline in rat peritoneal macrophages was blocked by bufetolol at a concentration of 10^?7 M or 10^?6 M, but not by practolol at a concentration of 10^?4 M. Phentolamine, a α-adrenergic blocking agent, showed no antagonistic activity against isoproterenol in rat peritoneal macrophages.These observations suggest that the increases in cAMP in rat peritoneal macrophages by catecholamines are mediated by β₂-adrenergic receptors.     

Adrenergic receptors in turtle ventricle myocardium

The positive inotropic response to the adrenergic agonists isoproterenol (ISO), norepinephrine (NE), epinephrine (EPI), and phenylephrine (PE) was tested in isolated perfused turtle (Pseudemys elegans) ventricles. The effect of the adrenergic agonists was tested in the absence and presence of adrenergic antagonists, propranolol (PROP) and phentolamine (PHENT). ISO (0.03–0.1 μg), NE (0.03–0.1 μg), EPI (0.05–0.5 μg) and PE (1.0–10 μg), in this order of effectiveness, enhanced contractile tension 50–100% over control tension. The positive inotropic response to 0.5 mg CaCl₂ was used as a control. PROP (5 × 10^?6M) blocked the positive inotropic response to ISO, NE, EPI and PE but not the response to CaCl₂. Neither PHENT nor phenoxybenzamine (PBZ) antagonized the positive inotropic response to the adrenergic agonists or CaCl₂. On the basis of the relative effectiveness of the adrenergic agonists and the specific blockade by β-adrenergic antagonists, it is postulated that turtle ventricle under the conditions of these experiments is devoid of α-adrenergic receptors.     

Differences between α-Adrenergic and β-Adrenergic Inotropic Effects in Rat Heart Papillary Muscles

Abstract: α-And β-adrenergic inotropic effects have been shown to be qualitatively different. In order to further characterize these differences we compared the mechanical responses to α- and β-adrenoceptor stimulation, respectively, in electrically driven left ventricular papillary muscles from rat heart. The muscles were stimulated by either isoprenaline (β-adrenoceptor stimulation), phenylephrine in the presence of propranolol (α-adrenoceptor stimulation) or phenylephrine alone (combined α- and β-adrenoceptor stimulation). Isometric tension (T), 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. These recordings disclosed qualitative differences between the α- and β-inotropic response both in dose-response and time course experiments. Maximal β-adrenoceptor stimulation caused a small increase in T_max (18%), intermediate increases in T′_max (45%) and T′_min (68%) and a considerable increase in T″_min (145%) (“β-type” effect). Maximal α-adrenoceptor stimulation increased all qualities by about the same degree (23–24%) (“α-type” effect). While β-adrenoceptor stimulation gave a dose-dependent and pronounced increase in the ratio T″_min/T′_max (relaxation-onset index), α-adrenoceptor stimulation decreased it to subcontrol values and phenylephrine alone gave a small dose-dependent increase at higher doses. The time course of the α-adrenoceptor stimulation was characterized by a transient decrease in all qualities followed by an increase which reached maximum at 4–5 min. β-Adrenoceptor stimulation gave a monophasic response which reached maximum after 1–2 min. Phenylephrine alone gave mainly an “α-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 β-adrenoceptor stimulation activated relaxation compared to contraction by a higher degree than did α-adrenoceptor stimulation. This probably reflects different mechanisms of action. While the α-effect may rely primarily on an increased calcium influx, the β-effect probably is the final result of several subcellular effects of cyclic AMP.     

Mechanical Response of Rat Myocardium to Dibutyryl Cyclic AMP in Relation to Effects of α- and β-Adrenoceptor Stimulators

Abstract: Dibutyryl cyclic AMP, and α- and β-adrenoceptor stimulators are all able to elicit inotropic effects, α- and β-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 α- and β-adrenoceptor stimulation, respectively. Dibutyryl cyclic AMP (in the presence of propranolol) increased developed tension (T_max) 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 (β-adrenoceptor stimulation). The response to dibutyryl cyclic AMP, however, developed much slowlier 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 α-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 α- and β-adrenoceptor stimulation) elicited a substantial cyclic AMP elevation but gave mechanical effects only slightly different from the pure α-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 α-adrenoceptor stimulation involves other mechanisms.     

Positive inotropic effects of the calcium channel activator Bay K 8644 on guinea-pig and human isolated myocardium

Summary 1. The positive inotropic effects of the dihydropyridine calcium activator Bay K 8644 were studied in guinea-pig isolated contracting myocardium and human papillary muscle strips obtained from patients undergoing mitral valve replacement or cardiac transplantation. 2. Bay K 8644 produced a slowly developing, concentration-dependent positive inotropic response in all cardiac tissues studied. In guinea-pig papillary muscle, the increase in force of contraction was half-maximal at 3.9 × 10^–8 mol/l and the maximal inotropic effect was comparable to that obtained with ouabain, dobutamine or calcium. The guinea-pig left atrium (EC₅₀, 2.1 × 10^–7 mol/l) was fivefold less sensitive than the papillary muscle. 3. The maximal inotropic response to dihydroouabain was significantly increased after preincubation with Bay K 8644 (1 × 10^–6 mol/l) in papillary muscles from both guinea-pig and human. In guinea-pig papillary muscles, the maximal inotropic response to dobutamine was not changed by preincubation with Bay K 8644 whereas in human papillary muscle strips, Bay K 8644 increased the inotropic response to dobutamine. 4. Bay K 8644 increased force of contraction (EC₅₀, 4 × 10^–8 mol/l) in human papillary muscle strips from patients undergoing mitral valve replacement. However, the maximal inotropic response to Bay K 8644 was reduced to 32 ± 4.4% that of calcium (15 mmol/l) measured in the same muscle strips. 5. A further reduction in maximal inotropic response to Bay K 8644 to 13 ± 1.2% that of calcium (15 mmol/l) with no change in potency was measured in human papillary muscle strips taken from terminally failing hearts of cardiac transplant recipients. 6. There was a significant correlation between the preoperative left ventricular ejection fraction and the maximal inotropic response to Bay K 8644 in isolated human papillary muscle strips. 7. These results suggest that Bay K 8644 affects excitation-contraction coupling of cardiac muscle so as to increase the maximal inotropic effect of the digitalis glycosides. Further, the inotropic response of human myocardial tissue to calcium channel activator Bay K 8644 may be reduced in states of pathological heart function.The human heart papillary muscles were provided by Prof. E. Kreuzer, Prof. B. Kemkes, Dr. C. Weinhold and their colleagues, Herzchirurgische Klinik der Universität, Klinikum Grosshadern, D-8000 München 70, Federal Republic of Germany Send offprint requests to E. Erdmann     

Positive inotropic effect of bay K 8644: cAMP-independence and lack of inhibitory effect of adenosine

Summary The aim of the present study was to characterize the positive inotropic effect of the Ca²⁺ channel activator Bay K 8644. In isolated guinea-pig papillary muscles we investigated whether adenosine and the R site adenosine receptor agonist (–)-N⁶-phenylisopropyladenosine (PIA) were able to antagonize the positive inotropic effect of Bay K 8644. The effect of Bay K 8644 and adenosine or PIA on myocardial cAMP content was also measured. The influence of adenosine and PIA on the positive inotropic effect of the -adrenoceptor agonist isoprenaline and of the phosphodiesterase inhibitor amrinone was studied for comparison.Adenosine and PIA antagonized the positive inotropic effects of isoprenaline and amrinone in a concentration-dependent manner. In contrast, adenosine or PIA did not affect the positive inotropic effect of Bay K 8644.The positive inotropic effect of Bay K 8644 was not accompanied by a change in the cAMP content of the papillary muscles. Additionally applied adenosine or PIA also failed to affect the cAMP content.It is concluded that an increased myocardial cAMP content is not involved in the positive inotropic effect of Bay K 8644. Moreover, the results support the view that adenosine and PIA only antagonize the positive inotropic effects of drugs known to increase myocardial cAMP content and that an increased myocardial cAMP content is a prerequisite for the manifestation of a negative inotropic effect of the nucleosides in ventricular cardiac muscle.     

Metabolic requirement for the inotropic effects of digitalis and BAY K 8644

The positive inotropic effects of ouabain and of BAY K 8644 are not apparent in rabbit atria suspended in substrate free medium or in a medium containing 5 mM pyruvate. Addition of glucose in graded concentrations (1-11 mM) during continued exposure of the preparations to the inotropic agents yields graded inotropic effects. The possible involvement of the glycolytic pathway to the development of the inotropic effect of ouabain and BAY K 8644 was tested by using inhibitors of glycolysis that act at two different steps. Iodoacetic acid completely blocks the inotropic effect of ouabain in atria at 0.1 mM and papillary muscles at 0.05 mM. The inotropic effect of BAY K 8644 was blocked partially in atria and papillary muscles. Iodoacetic acid did not change the inotropic effects of isoproterenol and Ca2+. Addition of 1 mM fluoride did not affect significantly the inotropic effect of either ouabain or BAY K 8644 in atria but partially blocked the effect of BAY K 8644 in papillary muscles. The response of atria to ouabain was not changed significantly when glyceraldehyde (10 mM) was substituted for glucose. We suggest that glycolytic ATP may be important for the full inotropic effect of ouabain and BAY K 8644.     

Stimulation frequency alters the inotropic response of atrial muscle to BAY K-8644

The inotropic and chronotropic effects of BAY K-8644 were examined in isolated guinea pig atria. The compound increased both rate and contractile force. Sensitivity to the inotropic effect was enhanced by increasing stimulation frequency between 0.5 and 3.3 Hz. The maximum developed tension elicited by the agent was reduced at 3.3 Hz. At BAY K-8644 concentrations up of to 3 X 10(-5) M, no dysrhythmic effects or other toxic signs such as an increase in resting tension were observed. These results are consistent with the suggestion that BAY K-8644 acts as a partial 'calcium agonist'.     

The Actions of Some β-Receptor Agonists and Xanthines on Isolated Muscle Strips from the Human Oesophago-Gastric Junction

Isolated preparations from the circular muscle layer of the human oesophago-gastric junction were mounted in organ baths and isometric tension recorded. During an equilibration period, active resting tension developed suggesting that the preparations were representing the lower oesophageal sphincter. Active tension was abolished by exposing the preparations to Ca⁺⁺-free medium. The two xanthines theophylline and enprofylline almost equipotently relaxed the preparations in a concentration-dependent manner (10^-7-10^-3M). Within therapeutic concentrations, theophylline inhibited active resting tension by 30–60%, while enprofylline lowered tension by less than 20%. Inhibitory actions of adenosine were demonstrated, and this suggests that adenosine antagonism is not the mechanism of action for xanthines in the oesophagus. Non-selective β-receptor stimulation with isoprenaline inhibited active tension by 70% (10^-7M), while β₂-receptor stimulation with terbutaline inhibited tension by 47% (10^-5M). Dobutamine, believed to preferentially stimulate β₁-receptors, inhibited active tension in a concentration-dependent manner (10^-7-10^-4M). Metoprolol (10^-6M), a selective β₁-receptor antagonist, shifted the concentration-response curve for isoprenaline to the right, but left the maximal response unchanged. It is concluded that xanthines and β-receptor agonists have inhibitory actions on circular muscle from the human oesophagogastric junction. The experimental data suggest the presence of β₁- as well as β₂-receptors, both mediating inhibition of active resting tension.     

Competitive Blockade of α-Adrenergic Receptors in Rat Heart by Prazosi

Abstract: Pheiiykphriiie (PE) in presence of propranolol evokes an α-adrenergic inotroyic response in rat heart. The time course of this response is characterizcd by a transient ducrease in maximal developed tension (T_max) subcontrol levels (negative phase of the inotropic response) followed by an increase which reaches maximum after 4–5 min. (positive phase of the inotropic response). Prazosin (PRZ), a selective α₁-receptor blocker. inhibited preferentially the positive phase of the inotropic response and displaced the dose-responsecurve of PE to the right in nanomolar concentrations, indicating a competitive mechanism of inhibition. Phentolamine, a non-selrctive α-blocker. blocked both the negative and the positive phase olthe inotropicresponse toabout the same degree. PRZ appears to be a competitive α-adrenergic antagonist with high affinity in rat heart. Two populations of α-adrenergic receptors may he present: one stirnulatory (α₁) iind one inhibitory     

The behavioral effects of the calcium agonist BAY K 8644 in the mouse: Antagonism by the calcium antagonist nifedipine

Summary Mice injected with the calcium agonist BAY K 8644 (2–4 mg/kg, i. p.) displayed profound behavioral changes including ataxia, decreased motor activity, Straub tail, arched back, limb clonus and tonus, and an increased sensitivity to auditory stimulation. BAY K 8644 significantly impaired rotorod performance in mice with an ED₅₀ of 0.8 mg/kg. The behavioral effects of BAY K 8644 were antagonized by nifedipine, but not by the non-dihydropyridine calcium channel antagonist verapamil or the -adrenoceptor antagonist prazosin. Further, the actions of BAY K 8644 were not mimicked by the -adrenoceptor agonist methoxamine at doses up to 4.5 mg/kg. These observations, coupled with the findings that BAY K 8644 is a potent, competitive inhibitor of [³H]nitrendipine binding to the dihydropyridine binding site in mouse brain (K _i=7.0×10^–9M), suggests that BAY K 8644 may produce its behavioral actions via an interaction with the DHP binding site, which has been linked to the control of calcium flux across membranes in peripheral tissues.     

羟苯氨酮强心作用的生化机理研究

目的：研究羟苯氨酮(oxyphenamone, Oxy)强心作用的生化机理。方法：采用Na⁺,K⁺-ATP酶活性和cAMP-PDE活性、肌浆网Ca²⁺-ATP酶活性和cAMP含量以及心肌肌原纤维Ca²⁺,Mg²⁺-ATP酶活性等测定法,研究Oxy对它们的影响,并与milrinone和MCI-154作比较。 结果：Oxy对Na⁺,K⁺-ATP酶和PDE无抑制作用,也不影响心肌cAMP含量,但能显著增强心肌肌原纤维对Ca²⁺的敏感性,高浓度时轻度抑制心肌肌浆网Ca²⁺-ATP酶活性。结论：Oxy的强心作用方式不同于强心苷、β受体激动剂和PDE抑制剂等强心药,可能为一种新的钙增敏性强心药物。     

Muscarinic and α1-adrenergic mechanisms contribute to the spinal mediation of stimulation-induced antinociception from the pedunculopontine tegmental nucleus in the rat

The effects of intraperitoneal (i.p.) or intrathecal (i.t.) injection of antagonists of acetylcholine, noradrenaline, serotonin, dopamine, opioids and GABA on stimulation-produced antinociception (SPA) from the pedunculopontine tegmental nucleus (PPTg) of rats were studied using the tail-flick test. The electrical stimulation of the PPTg produced a strong and long-lasting increase in tail-flick latency. The intensity and duration of the effect were significantly reduced in rats pretreated with i.p. or i.t. atropine (a non-selective muscarinic cholinergic antagonist), or i.t. phenoxybenzamine or WB 4101 (non-selective and selective α₁-adrenergic antagonists, respectively). Intraperitoneal phenoxybenzamine, i.p. or i.t. methysergide or naloxone (non-selective serotonin and opioid antagonists, respectively), or i.t. idazoxan (a selective α₂-adrenergic antagonist) only reduced the duration of the effect. The duration of SPA from the PPTg was increased by i.t. phaclofen (a GABA_B antagonist). The effect from the nucleus was not altered following i.t. bicuculline (a GABA_A antagonist), or i.p. or i.t. mecamylamine, propranolol or haloperidol (non-selective nicotinic cholinergic, β-adrenergic and dopaminergic antagonists, respectively). Thus, SPA from the PPTg involves the spinal activation of muscarinic and α₁-adrenergic but not nicotinic cholinergic, β-adrenergic and dopaminergic mechanisms. Serotonergic, endogenous opioid and α₂-adrenergic mechanisms are involved in the duration but not in the intensity of the effect.