In the isolated papillary muscle of the rabbit the time course of the effects of selective beta- and alpha-adrenoceptor stimulation by isoprenaline and methoxamine, respectively, on the contractile force and on the level of 3',5'-cyclic AMP (cAMP) was determined. 1. Isoprenaline (3 times 10(-7) M) increased significantly the content of cAMP at 15 sec and elevated it to the maximal level-about twice the control value-at 30 sec after its administration, while the developed tension of the papillary muscle was also increased significantly at 15 sec and reached gradually its maximum at 90 sec. 2. Compared with isoprenaline methoxamine (10(-4) M) increased the developed tension very slowly: the maximal response was reached after 20 min. The level of cAMP, on the other hand, was changed neither before nor during the induction of the positive inotropic effect of methoxamine. 3. The phosphodiesterase inhibitor papaverine (10(-5) M) inhibited the PDE activity of the papillary muscle by about 40% after an incubation of 1 hr, and increased the level of cAMP significantly. The effects of isoprenaline on the contractile forced and on the level of cAMP were considerably enhanced by papaverine: the content of cAMP was increased by isoprenaline (3 times 10(-7) M) to about 3 times the control value and also its positive inotropic effect was significantly greater than in controls without papaverine. On the other hand, the positive inotropic effect of methoxamine (10(-4) M) was not affected by papaverine (10(-5) M). Furthermore, in the papillary muscle treated with papaverine the level of cAMP was significantly reduced by methoxamine: the papaverine-induced increase of cAMP was abolished by methoxamine. 4. The present results are compatible with the hypothesis that cAMP is involved as a mediator in the positive inotropic effect induced by beta-adrenoceptor stimulation, and indicate further that the stimulation of alpha-adrenoceptors evokes its positive inotropic effec through a mechanism other than that elicited by beta-adrenoceptor stimulation, i.e., independent of cAMP.
The influence of removing the endothelial cells on the alpha-receptor-mediated contractile response in segments of rat aorta was investigated using agonists with a range of affinity for alpha 1- and alpha 2-receptors. The preferential alpha 1-agonists were methoxamine, cirazoline, ST 587, and Sgd 101/75 and the preferential alpha 2-agonists were B-HT 920, clonidine, and guanfacine. When the endothelium was intact, the intrinsic activity (compared to noradrenaline) varied widely (0.0-0.7) for both groups of agonists. After removal of the endothelium the intrinsic activity was increased in each case to that of noradrenaline, or close to it. Furthermore, an increase in potency was obtained for each agonist, although to different degrees. No correlation, however, was found between the selectivity of the agonists and the degree of enhancement caused by the removal of the endothelium, in terms of either the intrinsic activity or the potency. Moreover, the use of the selective alpha 2-receptor antagonist rauwolscine on intact tissues did not mimic the effect of removing the endothelium. Therefore, the alpha-receptors of the endothelium could not be classified as either of the alpha 1- or alpha 2-subtype.
In isolated, electrically driven right auricular strips of the human heart the inotropic effect of phenylephrine was studied. 1. First, the influence of the driving rate on the tension developed (i.e., the frequency-force relationship) was determined by stimulation of the preparations at 0.1, 0.5, 1, 2 and 3 HZ. The force of contraction was lowest at a stimulation rate of 0.1 HZ (36.9 g/g dry weight). The maximally developed force of contraction observed at frequencies of 0.5, 1 and 2 HZ amounted to about 200 g/g dry weight. The values did not significantly differ from each other. 2. The negative log of the EC50 (-log EC50) for the positive inotropic effect of phenylephrine determined at a frequency of 0.5 and 1.0 HZ amounted to 5.28 +/- 0.08 and 5.34 +/- 0.11, respectively. The alpha-adrenolytic drug phentolamine (3 x 10(-6) M) diminished significantly the -log EC50 to 5.01 +/- 0.04 and 4.89 +/- 0.10, respectively. 3. At a frequency of 1 HZ a shift of the concentration-response curve to the right was observed after treatment with the beta-adrenolytic drug pindolol (3 x 10(-8) M); the -log EC50 of phenylephrine decreased significantly to 4.08 +/- 0.07. 4. From these results it is concluded that alpha-adrenoceptors are present in human atria; they mediate positive inotropic effects and are stimulated by phenylephrine.
Under the conditions of different stimulation frequencies the inotropic effects of the alpha-adrenoceptor stimulationg agents, methoxamine, naphazoling and oxymetazoline were studied on the isolated rabbit papillary muscle. 1. On the papillary muscle stimulated at 0.5 Hz methoxamine in concentrations from 10(-5)M caused a significant and dose-dependent positive inotropic effect. At 10(-3)M methoxamine decreased the developed tension. With increasing frequency of stimulation (0.5--1--1.5Hz), the positive inotropic effect became smaller, while the negative inotropic one was more pronounced. The time course of the disappearance of the negative inotropic effect of methoxamine by washout differed from that of the positive inotropic effect: the negative component disappeared within 30 min, whereas the positive one lasted for about 100 min. The positive inotropic effect of noradrenaline (10(-6)M), in contrast ot that of methoxamine, was not influenced by the frequency under the same conditions of stimulation. Also naphazoline (10(-5)M) caused a significant positive inotropic effect on the papillary muscle stimulated at 0.5 Hz, while oxymetazoline induced exclusively a negative inotropic effect. 2. The positive inotropic effect of metoxamine (10(-4)M) as well as of naphazoline (10(-5)M) evoked at a frequency of 0.5 Hz was abolished by phentolamine (10(-6)M). Methoxamine (10(-4)M) induced a significant negative inotropic effect in the presence of phentolamine. Phentolamine antagonized the positive inotropic effect of methoxamine in a non-competitive manner: the pD2-value was 7.76. 3. In the presence of methoxamine (10(-4)M) the developed tension in the lower range (0.05--1 Hz) of the frequency-force relationship was enhanced, while that in the higher range (greater that 1.5 Hz) was decreased. The enhancement was abolished by phentolamine (10(-6)M). 4. Papaverine (2x10(-5)M) did not affect the positive inotropic effect of methoxamine. 5. The present results show that methoxamine and naphazoline induced a positive inotropic effect via alpha-adrenoceptor in the ventricular myocardium of the rabbit. These effects were caused only at low, but not at high frequencies of stimulation.
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