Higher Concentrations Of Phenylephrine Research Articles

Relationship between the level of cAMP and the contractile force under stimulation of ?- and ?-adrenoceptors by phenylephrine in the isolated rabbit papillary muscle

The time course of changes of the level of 3',5'-cyclic AMP (cAMP) and of the tension developed under stimulation of alpha- and beta-adrenoceptors by phenylephrine was investigated in the isolated rabbit papillary muscle. Furthermore the dose-response relationships for increases of cAMP and of developed tension elicited by phenylephrine were determined. 1. A submaximally effective concentration of phenylephrine (10(-5) M) increased significantly the level of cAMP of the papillary muscle at 15 and 30 s by 45 and 36% respectively; the level of cAMP returned to the control value at 60 s after the administration. The developed tension increased significantly not before 45 s and reached its maximal level at 180 s. 2. When alpha-adrenoceptors were blocked by phentolamine (10(-6) M), the positive inotropic effect of phenylephrine was decreased significantly but the increase of cAMP induced by phenylephrine was not reduced. In the presence of phentolamine the increase of cAMP induced by phenylephrine lasted longer than in the control experiments. 3. The effects of phenylephrine (10(-5) M) both on the level of cAMP and the developed tension mediated via stimulation of beta-adrenoceptors in the presence of phentolamine were enhanced by the phosphodiesterase inhibitor papaverine throughout the course of responses. 4. Phenylephrine produced an increase in developed tension as well as in cAMP. The corresponding dose-response curves run parallel to each other but differed by about 1.5 log units whereby the developed tension was evoked by lower concentrations. Phentolamine (10(-6) M) shifted the curve for the positive inotropic action by about 1.5 log units but did not affect that for increase in cAMP. Therefore, in the presence of the alpha-adrenolytic drug phentolamine the difference between both curves became smaller so that both curves were superimposed. Papaverine (10(-5) M) shifted the whole curve for cAMP upwards and enhanced the maximal contractile response to phenylephrine mediated by stimulation of beta-adrenoceptors. 5. The present results indicate that the positive inotropic action of phenylephrine in lower concentrations (less than 10(-5) M) induced by stimulation of alpha-adrenoceptors is independent of the level of cAMP. The positive inotropic action of the higher concentrations of phenylephrine induced via stimulation of beta-adrenoceptors was preceded by an accumulation of cAMP; the inhibition of the cAMP phosphodiesterase activity by papaverine enhanced the actions of phenylephrine both on the level of cAMP and on the contractile force.

Studies on the alpha-andrenergic activation of hepatic glucose output. II. Investigation of the roles of adenosine 3':5'-monophosphate and adenosine 3':5'-monophosphate-dependent protein kinase in the actions of phenylephrine in isolated hepatocytes.

The effects of the alpha-adrenergic agonist phenylephrine on the levels of adenosine 3':5'-monophosphate (cAMP) and the activity of the cAMP-dependent protein kinase in isolated rat liver parenchymal cells were studied. Cyclic AMP was very slightly (5 to 13%) increased in cells incubated with phenylephrine at a concentration (10(-5) M) which was maximally effective on glycogenolysis and gluconeogenesis. However, the increase was significant only at 5 min. Cyclic AMP levels with 10(-5) M phenylephrine measured at this time were reduced by the beta-adrenergic antagonist propranolol, but were unaffected by the alpha-blocker phenoxybenzamine, indicating that the elevation was due to weak beta activity of the agonist. When doses of glucagon, epinephrine, and phenylephrine which produced the same stimulation of glycogenolysis or gluconeogenesis were added to the same batches of cells, there were marked rises in cAMP with glucagon, minimal increases with epinephrine, and little or no changes with phenylephrine, indicating that the two catecholamine stimulated these processes largely by mechanisms not involving cAMP accumulation. DEAE-cellulose chromatography of homogenates of liver cells revealed two major peaks of cAMP-dependent protein kinase activity. These eluted at similar salt concentrations as the type I and II isozymes from rat heart. Optimal conditions for preservation of hormone effects on the activity of the enzyme in the cells were determined. High concentrations of phenylephrine (10(-5) M and 10(-4) M) produced a small increase (10 tp 16%) in the activity ratio (-cAMP/+cAMP) of the enzyme. This was abolished by propranolol, but not by phenoxybenzamine, indicating that it was due to weak beta activity of the agonist. The increase in the activity ratio of the kinase with 10(-5) M phenylephrine was much smaller than that produced by a glycogenolytically equivalent dose of glucagon. The changes in protein kinase induced by phenylephrine and the blockers and by glucagon were thus consistent with those in cAMP. Theophylline and 1-methyl-3-isobutylxanthine, which inhibit cAMP phosphodiesterase, potentiated the effects of phenylephrine on glycogenolysis and gluconeogenesis. The potentiations were blocked by phenoxybenzamine, but not by propranolol. Methylisobutylxanthine increased the levels of cAMP and enhanced the activation of protein kinase in cells incubated with phenylephrine. These effects were diminished or abolished by propanolol, but were unaffected by phenoxybenzamine. It is concluded from these data that alpha-adrenergic activation of glycogenolysis and gluconeogenesis in isolated rat liver parenchymal cells occurs by mechanisms not involving an increase in total cellular cAMP or activation of the cAMP-dependent protein kinase. The results also show that phosphodiesterase inhibitors potentiate alpha-adrenergic actions in hepatocytes mainly by a mechanism(s) not involving a rise in cAMP.

Evidences for alpha excitatory action of catecholamines on the electrical activity of the guinea-pig stomach.

Effects of catecholamines and their inhibitors on the electrical activity of the smooth muscle of the guinea-pig stomach were studied by using pressure electrodes. The spontaneous electrical activity of antrum and corpus preparations consisted of slow waves with or without superimposed spikes. In quiescent fundus preparations, the spike activity and slow waves were generated by TEA. Catecholamines (noradrenaline, isoprenaline and adrenaline) suppressed or blocked the spike discharges and the generation of slow waves. However, the spike activity was enhanced at a higher concentration of phenylephrine in the antrumand fundus preparations. Inhibitory responses of the smooth muscles from whole regions to adrenaline, noradrenaline or isoprenaline were antagonized by propranolol or DCI but not by phentolamine or phenoxybenzamine. Therefore, inhibitory actions of these amines appear to involve beta-adrenoceptors. After treatment with tetrodotoxin, noradrenaline and isoprenaline blocked the spike activity and the generation of slow waves. Phenylephrine or adrenaline potentiated the spike activity in the presence of tetrodotoxin. After treatment with DCI or propranolol, phenylephrine potentiated the spike activity of the antrum and fundus preparations. These excitatory effects were antagonized by phentolamine or phenoxybenzamine. It is concluded that excitatory actions of these amines are mediated by alpha-adrenoceptors rather than via a nervous pathway.

Beta-adrenolytic, antiarrhythmic and local anaesthetic effects of phenylephrine.

The β-sympathomimetic effect of phenylephrine was investigated on the electrically driven atrium, as well as on the tracheal chain of the guinea pig. 1. Phenylephrine (PE) was found to be less effective than isoprenaline (IPN) with regard to its positive inotropic effect on the guinea-pig atrium and to its relaxing action on the tracheal chain. The intrinsic activity for PE amounted to 0.75 on the tracheal chain and to 0.45 on the atrium, when compared with IPN. 2. From these low intrinsic activities, PE was assumed to be a partial β-agonist, exerting a competitive dualism in action to IPN. This dualism could be confirmed by dose-response curves for PE in the presence of IPN and vice versa: PE behaved as a β-agonist as well as a β-antagonist. 3. The intrinsic activity of PE steadily decreased with prolongation of the incubation period. After 1 h PE had almost lost its intrinsic activity. Under these conditions the dose-response curves for IPN on the tracheal chain, as well as on atrium, were shifted to the right in a parallel manner, i.e. PE behaved as a competitive β-antagonist. 4. High concentrations of PE (10−3 M) protected the electrically driven guineapig atrium against arrhythmias induced by k-strophanthoside. The onset of both the first extrasystoles and of heart standstill, which occurred after infusion of k-strophanthoside, were delayed after preincubation with PE. 5. Phentolamine was without any influence on these antiarrhythmic properties of PE. Therefore, it could be excluded that the antiarrhythmic effect of phenylephrine is due to a stimulation of myocardial α-adrenoceptors. 6. The local anaesthetic activity of phenylephrine, as tested on the rabbit cornea, was 4 times higher than that of propranolol. 7. The effective concentrations for the β-adrenolytic, antiarrhythmic, and local anaesthetic activities of PE were clearly different. We concluded, therefore, that the different actions produced by phenylephrine were not associated with each other.

Interactions of phenylephrine and theophylline in contractility and excitability of isolated rabbit left atria.

Abstract Rabbit left atria were driven electrically at frequencies from 6 to 240/min or higher. The contractile tension-frequency curve was significantly moved upward by phenylephrine (10-6 and 10-5 M). The positive inotropic effect was not influenced by propranolol but was markedly attenuated by phentolamine. Theophylline in a concentration (10-4 M) sufficient to potentiate the effect of isoproterenol did not alter the positive inotropic effect of phenylephrine. Cardiac excitability studied in preparations driven at high frequencies was reduced by phenylephrine, the effect being inhibited by phentolamine and potentiated by propranolol. The excitability was enhanced by isoproterenol. Theophylline potentiated the effect of isoproterenol but inhibited the effect of phenylephrine in a high concentration (10-5 M). It may be concluded that an enhancement of the contractile force by stimulation of myocardial alpha-receptors is not due to increased formation of cyclic AMP. Theophylline does not appear to change the effect of alpha-receptor stimulation on cardiac excitability but rather to unmask the effect of beta-receptor stimulation when high concentrations of phenylephrine are applied.

Interactions of Phenylephrine and Theophylline in Contractility and Excitability of Isolated Rabbit Left Atria

Rabbit left atria were driven electrically at frequencies from 6 to 240/min or higher. The contractile tension-frequency curve was significantly moved upward by phenylephrine (10-6 and 10-5 M). The positive inotropic effect was not influenced by propranolol but was markedly attenuated by phentolamine. Theophylline in a concentration (10-4 M) sufficient to potentiate the effect of isoproterenol did not alter the positive inotropic effect of phenylephrine. Cardiac excitability studied in preparations driven at high frequencies was reduced by phenylephrine, the effect being inhibited by phentolamine and potentiated by propranolol. The excitability was enhanced by isoproterenol. Theophylline potentiated the effect of isoproterenol but inhibited the effect of phenylephrine in a high concentration (10-5 M). It may be concluded that an enhancement of the contractile force by stimulation of myocardial alpha-receptors is not due to increased formation of cyclic AMP. Theophylline does not appear to change the effect of alpha-receptor stimulation on cardiac excitability but rather to unmask the effect of beta-receptor stimulation when high concentrations of phenylephrine are applied.