Inotropic Effect Of Phenylephrine Research Articles

Noradrenaline-induced desensitization in cultured heart cells as a model for the defects of the adenylate cyclase system in severe heart failure

Cultivation of rat heart muscle cells for up to 5 days in the presence of 10(-6) mol/l (-)noradrenaline leads to a desensitization of the cells to inotropic stimulation and cAMP formation at different levels of the cAMP-system: The decrease in the responsiveness to the beta-adrenoceptor agonist isoprenaline quantitatively parallels the down-regulation of beta 1-adrenoceptors. The impairment of the positive inotropic effect of the phosphodiesterase-inhibitor IBMX is associated with a diminished basal cAMP-formation but an unchanged phosphodiesterase-activity in noradrenaline-treated cells. This decrease in basal cAMP-accumulation as well as the attenuation of the forskolin-stimulated cAMP-formation indicate that a defect in the adenylate cyclase system beyond the receptor must be involved in noradrenaline-induced desensitization. In contrast to the diminished effectiveness of cAMP-increasing agents the positive inotropic effect of ouabain and the alpha-adrenoceptor-mediated positive inotropic effect of phenylephrine are unaltered in noradrenaline-treated cells. It is concluded from these results that in addition to the down-regulation of beta 1-adrenoceptors a defect on the post-receptor level of adenylate cyclase occurs in noradrenaline-induced desensitization not affecting mechanisms beyond the catalytic subunit of adenylate cyclase. As these findings are very similar to those observed in isolated preparations from severely failing human hearts, the presumption is confirmed that noradrenaline-induced desensitization might constitute an important etiological factor in the subsensitivity of failing human hearts to inotropic stimulation.

Mechanism of the negative inotropic effects of alpha 1-adrenoceptor agonists on mouse myocardium.

This study was done to identify the mechanism of the alpha1-adrenoceptor (AR) mediated negative inotropic effects of phenylephrine (PE) on adult mouse myocardium. As reported by others, we also found that the nonselective alpha1AR agonist PE produced a negative inotropic effect on ventricular strips from adult mice that was inhibited by the alpha1AAR antagonist 5-methylurapidil (5MU) but not by the alpha1BAR antagonist chloroethylclonidine (CEC) or the alpha1DAR antagonist BMY 7378. The selective alpha1AAR agonist A61603 also produced a negative inotropic effect, which was antagonized by 5MU. Phorbol 12,13-dibutyrate (activator of all PKC isoforms) mimicked the negative inotropic responses to PE and A61603. The negative inotropic effects of PE were inhibited by bisindolylmaleimide (inhibitor of all PKC isoforms) but not by Gö 6976 (inhibitor of Ca2+-dependent PKC). Rottlerin, an inhibitor of Ca2+-independent PKCdelta, antagonized the negative inotropic effects of PE and A61603. PE and A61603 increased the translocation of PKCdelta, which was prevented by rottlerin. These data suggest that the alpha1AR-mediated negative inotropy on adult mouse myocardium is signaled by Ca2+-independent PKCdelta.

Role of Ca(2+)-independent PKC in alpha 1-adrenoceptor-mediated inotropic responses of neonatal rat hearts.

We investigated the role of protein kinase C (PKC) in alpha 1-adrenoceptor (alpha 1-AR)-mediated positive inotropic responses of neonatal rat myocardium. Bisindolylmaleimide (BIM), an inhibitor of all PKC isoforms, reduced the positive inotropic responses to phenylephrine and methoxamine but not to isoproterenol. The positive inotropic effect of phenylephrine was not attenuated by Gö-6976, a selective inhibitor of Ca(2+)-dependent isoforms; it was potentiated by the 1,2-diacylglycerol kinase inhibitor R-59949. Phorbol 12,13-dibutyrate, an activator of both Ca(2+)-dependent and-independent PKC isoforms, as well as thymeleatoxin, a selective activator of Ca(2+)-dependent PKC isoforms, inhibited myocardial contractions, which were prevented by BIM and Gö-6976. BIM inhibited the phenylephrine-induced increase in particulate PKC activity but not the increase in phosphatidylinositide turnover. Phenylephrine induced translocation of only Ca(2+)-independent PKC-epsilon and -delta. These results suggest that activation of Ca(2+)-independent PKC isoforms by alpha 1-AR agonists plays a key role in alpha 1-AR-mediated positive inotropic effect on neonatal myocardium.

Electrical and mechanical effects of a novel antihypertensive quinazoline derivative, 3-[[4-(2-methoxyphenyl) piperazin-1-ly]methyl]-5-(methylthio)-2,3-dihydroimidazo [1,2-c]quinazoline, on guinea pig ventricular muscles.

Electrical and mechanical effects of 3-[[4-(2-methoxyphenyl)piperazin-1-ly]methyl]-5-(methylthio)-2,3-+ ++dihydroimidazo[1,2-c]quinazoline (DL-017), a new synthesized antihypertensive agent, were studied in guinea-pig ventricular papillary muscles. In muscle fibers driven at 1 Hz, DL-017 decreased the twitch force in a concentration-dependent manner and significantly increased the action-potential duration and decreased intracellular Na+ activity (ai(Na)) and maximal rate of upstroke of action-potential (Vmax) when concentrations were greater than 1 microM. Phenylephrine in the presence of 1 microM propranolol produced a concentration-dependent positive inotropy. DL-017 (0.01 microM) antagonized the positive inotropic effect of phenylephrine and shifted the concentration-response curve to the right. In K+-depolarized muscle fibers, 0.1 microM DL-017 significantly decreased the contractile force without changing the slow action potential. In low-[K+]o and high-[Ca2+]o solutions, a train of stimuli triggered a spontaneous rhythm that could be abolished by 3 microM DL-017. Our results suggest that DL-017 not only exhibits an alpha1-antagonistic effect but also induces negative inotropy by a decrease in myofibrillar calcium sensitivity and inhibits Na+ channels at higher concentrations, contributing to the drug's negative inotropic and type-I antiarrhythmic effects.

Alpha 1D-adrenoceptors do not contribute to inotropic responses of neonatal rat myocardium.

This study investigated the role of alpha 1D-adrenoceptors (ARs) in the inotropic responses of neonatal (7-day-old) rat myocardium by using the relatively selective antagonist BMY 7378. The positive inotropic effects of phenylephrine on right ventricular strips of neonatal rats were not inhibited by BMY 7378 up to a concentration of 300 nM but potently antagonized by the alpha 1AAR antagonist 5-methylurapidil (5-MU) (pKB, 8.73 +/- 0.12; n = 6). BMY 7378 was approximately 1,000-fold less potent (pKi, 6.63 +/- 0.7; n = 5) in inhibiting the binding of [3H]prazosin to right ventricular membrane preparations of neonatal rats than was 5-MU (pKi, 9.04 +/- 0.54; n = 5). Neonatal rat cerebral cortex and adult rat aorta were used as additional controls. BMY 7378 was a weak inhibitor of [3H]prazosin binding to neonatal cortex (pKi, 6.8 +/- 0.04; n = 3) but highly potent in inhibiting the binding to adult rat aortic membrane preparations (pKi for high-affinity binding, 9.70 +/- 0.30; n = 4); BMY 7378 potently antagonized the effects of phenyleprine on adult rat aortic strips (pKB, 9.05 +/- 0.11; n = 5). It is concluded that alpha 1DARs do not play a significant role in alpha 1AR-mediated inotropic responses of neonatal rat myocardium.

Pharmacological differentiation of synergistic contribution of L-type Ca2+ channels and Na+/H+ exchange to the positive inotropic effect of phenylephrine, endothelin-3 and angiotensin II in rabbit ventricular myocardium.

The present study was designed to delineate pharmacologically the role of sarcolemmal L-type Ca2+ channels and Na+/H+ exchange in the positive inotropic effect (PIE) of phenylephrine mediated by alpha-1 adrenoceptors, endothelin (ET) and angiotensin II (Ang II) that stimulate phosphoinositide (PI) hydrolysis in the rabbit ventricular muscle. The PIE of these receptor agonists was compared with the PIE of isoprenaline that accumulates cyclic AMP. For this purpose, we investigated the influence of a Ca2+ antagonist, verapamil, and of an inhibitor of Na+/H+ exchange, 5-(N-ethyl-N-isopropyl) amiloride (EIPA), alone or in combination, on the cumulative concentration-response curve (CRC) for phenylephrine (with 0.3 microM bupranolol). ET-3 and Ang II in isolated right ventricular papillary muscles of the rabbit, which were electrically stimulated at 1 Hz in Krebs-Henseleit solution at 37 degrees C. Verapamil at 0.3 and 1 microM decreased the basal force of contraction to 37.0 +/- 4.0% and 13.2 +/- 1.1% of the control, respectively, while EIPA event at 10 microM affected the basal force to much less extent and decreased it to 87.0 +/- 1.4%. Verapamil (0.3 and 1 microM) and EIPA (1 and 10 microM), when used alone, each significantly attenuated but did not abolish the PIEs induced by phenylephrine, ET-3 and Ang II, while the simultaneous administration of verapamil (1 microM) and EIPA (10 microM) consistently and almost completely inhibited the PIE induced by these receptor agonists. By contrast, the PIE of isoprenaline was retained even in the presence of verapamil and EIPA. These results indicate that both the influx of Ca2+ ions through L-type Ca2+ channels and activation of Na+/ H+ exchange contribute synergistically to the PIE that is mediated by alpha-1 adrenergic, ET and Ang II receptor agonists, while these mechanisms are not essential for the beta-adrenoceptor-mediated PIE.

Alpha 1-adrenoceptor subtypes mediating inotropic and electrophysiological effects in mammalian myocardium.

Stimulation of alpha 1-adrenoceptors produces a positive inotropic effect in rat and rabbit ventricular myocardium via different mechanisms, the prolongation of action potential duration (APD) exclusively in the former and an increase in myofibrillar Ca2+ sensitivity in large part in the latter. This study was designed to determine whether the two inotropic mechanisms are mediated by different alpha 1-adrenoceptor subtypes. In rat papillary muscles, the positive inotropic effect and APD prolongation induced by phenylephrine (in the presence of propranolol) were inhibited by WB-4101, but not affected by chlorethylclonidine (CEC). WB-4101, but not CEC, blocked the phenylephrine-induced inhibition of the transient outward current (Ito) in rat ventricular cells. On the other hand, WB-4101 and CEC each antagonized the positive inotropic effect of phenylephrine in rabbit papillary muscles. However, the phenylephrine-induced APD prolongation observed in rabbit papillary muscles was blocked only by WB-4101. These results indicate that the WB-4101 sensitive alpha 1-adrenoceptor subtype mediates the positive inotropism that is correlated with the APD prolongation resulting from Ito reduction, whereas the CEC-sensitive subtype mediates the positive inotropism that is probably associated with increased myofibrillar Ca2+ sensitivity. Radioligand binding studies with [3H] prazosin showed a similar ratio of alpha 1A-to alpha 1B-adrenoceptor subtypes in rat and rabbit ventricular myocardium, implying that the different degree of contribution of each action mechanism to the overall inotropic effect in the two species cannot be explained by distribution of the alpha 1-adrenoceptor subtypes.

On the mechanism of action of phenylephrine in rat atrial heart muscle

Both in rat left atrial heart and in aortic smooth muscle preparations, phenylephrine (PE) caused a concentration-dependent increase in force of contraction (FC) in the presence of atenolol (10 mumol/l), which was antagonized by phentolamine, prazosin and WB 4101 in a competitive manner. The pA2 values of the antagonists in the cardiac tissue were 10-20fold lower than those in the rat thoracic aorta. In the spontaneously beating right atrium, PE exerted a positive chronotropic action, which was not significantly antagonized by phentolamine or prazosin. It is therefore assumed that the effects of phenylephrine in the left atrium and in the aorta are mediated by different subtypes of alpha 1-adrenoceptors, whereas the effects in the sino-atrial node are probably unrelated to alpha 1-adrenoceptors. To further elucidate the mechanisms of the positive inotropic effect of PE, action potential configuration and 45Ca2+ fluxes were monitored in the rat left atrium. The increase in FC by PE was associated with an increase in action potential duration (APD) and a reduction in resting membrane potential (RP). In the presence of (-)-devapamil (D888), the effects of PE on APD and RP persisted, whereas the increase in FC was antagonized in a non-competitive manner. Forskolin (300 nmol/l) enhanced the positive inotropic effect of PE. PE exerted a significant increase in 45CA2+ uptake in beating preparations, which was abolished in the presence of (-)D888 (1 mumol/l). In addition to the PE-induced increase in 45Ca2+ uptake, a decrease in 45Ca2+ efflux was observed.(ABSTRACT TRUNCATED AT 250 WORDS)

Differential electrophysiologic and inotropic effects of phenylephrine in atrial and ventricular heart muscle preparations from rats

Stimulation of alpha 1-adrenoceptors evokes a different pattern of inotropic responses in atrial and ventricular heart muscle preparations from rats. The inotropic effects are accompanied by different changes in membrane potential. In an attempt to clarify the question whether or to which extent these events are causally related, the effects of phenylephrine on force of contraction, transmembrane potential, Ca2+ current (ICa) and K+ currents were comparatively studied in either tissue. In atrial preparations, phenylephrine 10 mumol/l caused an increase in force of contraction, a marked prolongation of the action potential duration and a depolarization of the membrane at rest. In the ventricle, however, the addition of phenylephrine 10 mumol/l produced first a decline in force of contraction associated with a hyperpolarization of the membrane and a reduction in the action potential duration. These changes were followed by an increase in force of contraction and a slight prolongation of the action potential, whereas the resting membrane potential remained increased. The hyperpolarization was eliminated in the presence of ouabain 100 mumol/l. In enzymatically isolated atrial and ventricular myocytes, the whole-cell voltage clamp technique was used to study membrane currents on exposure to phenylephrine. Phenylephrine 30 mumol/l did not affect the magnitude of ICa in either cell type. Transient and steady state K+ outward currents, however, were significantly diminished to a similar extent in atrial and in ventricular myocytes. It is concluded that the positive inotropic effect of alpha 1-adrenoceptor stimulation in the rat atrium is related to an increase in action potential duration and a decrease in resting membrane potential due to a decrease in K+ currents.(ABSTRACT TRUNCATED AT 250 WORDS)

Potent inhibitory action of chlorethylclonidine on the positive inotropic effect and phosphoinositide hydrolysis mediated via myocardial alpha1-adrenoceptors in the rabbit ventricular myocardium

The influence of the alpha 1b-adrenoceptor-selective antagonist chlorethylclonidine on the alpha 1-adrenergic positive inotropic effect and the phosphoinositide hydrolysis induced by phenylephrine was investigated in the rabbit ventricular myocardium. Pretreatment of membrane fractions derived from the rabbit ventricular muscle with 10(-5) mol/l chlorethylclonidine decreased the specific binding of [3H]prazosin (at a saturating concentration of 10(-9) mol/l) from the control value of 11.27 +/- 0.48 to 4.18 +/- 1.87 fmol/mg protein. The inhibition by adrenaline of the binding of [3H]prazosin (slope factor and affinity) was not affected by chlorethylclonidine. The positive inotropic effect of phenylephrine (in the presence of 3 x 10(-7) mol/l bupranolol) was inhibited by chlorethylclonidine in a concentration-dependent manner (10(-7)-10(-5) mol/l) and abolished by 10(-5) mol/l chlorethylclonidine. The concentration of chlorethylclonidine to inhibit the phenylephrine-induced maximum response to 50% was 2.4 x 10(-6) mol/l. The accumulation of [3H]inositol monophosphate and [3H]inositol trisphosphate induced by 10(-5) mol/l phenylephrine was inhibited by chlorethylclonidine in the same concentration range. These findings indicate that the myocardial alpha 1-adrenoceptors mediating a positive inotropic effect in the rabbit ventricular myocardium may belong to the chlorethylclonidine-sensitive alpha 1b-subtype, and that the subcellular mechanism of action involve phosphoinositide hydrolysis.

Protein kinase C is not involved in alpha 1-adrenoceptor-mediated positive inotropic effect

This study was performed to determine whether activation of protein kinase C is responsible for the positive inotropic effect of alpha 1-adrenoceptor stimulation in rat papillary muscle. In the presence of 1 microM propranolol, phenylephrine (10 microM) produced triphasic inotropic response that was accompanied by prolongation of action potential duration (APD) and hyperpolarization of membrane potential. Phorbol 12,13-dibutyrate (PDBu, 0.1 microM) abolished the negative inotropic effect of phenylephrine and apparently resulted in enhancement of the positive inotropic effect. PDBu also attenuated the phenylephrine-induced hyperpolarization without affecting the APD prolongation. However, such changes were not observed with 12-O-tetradecanoylphorbol-13-acetate (TPA, 0.1 microM). Neither PDBu nor TPA increased the force of contraction or prolonged APD similar to phenylephrine. The protein kinase C inhibitor 1-(5-isoquinolinylsulfonyl)-2-methyl-piperazine (H 7, 10 microM) did not suppress the changes induced by PDBu, and more importantly H 7 did not affect the inotropic and electrophysiological effects of phenylephrine. Both TPA and PDBu significantly inhibited the phenylephrine-induced phosphoinositide hydrolysis as measured by [3H]inositol monophosphate, and these inhibitory effects were eliminated in the presence of H 7. Our results provide an argument against a role of protein kinase C activation in the alpha 1-adrenoceptor-mediated inotropic and electrophysiological effects.

Inotropic effect of phenylephrine and myocardial alpha-adrenergic receptor in newborn and adult animals

Developmental changes in the myocardial alpha-receptor density were studied using rabbit, rat and dog hearts. In all species studied, alpha-receptor density in the newborn was greater than in the adult. The inotropic effect of phenylephrine was measured using the isolated arterially perfused heart preparation of rabbit and rat. The heart was stimulated electrically at 40/min. In the presence of propranolol, phenylephrine caused a significant positive inotropic effect which was significantly less in the newborn than in the adult. Since alpha-adrenergic stimulation activates protein kinase C, the inotropic effect of protein kinase C activation was studied in the rabbit and rat using phorbol myristate acetate (PMA). PMA caused a negative inotropic effect and the decrease in contractile function in the newborn was greater than in the adult. These data suggest that myocardial alpha-receptor density decreases and the positive inotropic effect of alpha-agonist increases with development. The reasons for this discrepancy remain unclear but there may be developmental differences in the signal transduction processes of alpha-stimulation. The greater negative inotropy of protein kinase C activation in the premature heart may be one of the mechanisms of the reduced inotropy of alpha-agonist in this age group.

Preponderance of ?- over ?-adrenoceptors in mediating the positive inotropic effect of phenylephrine in the ferret ventricular myocardium

[3H]prazosin bound to the membrane fraction derived from the ferret ventricular muscle with high affinity in a saturable manner (Kd = 0.25 nmol/l and Bmax = 27 fmol/mg protein in the right ventricle). [3H]CGP-12177, a beta-adrenoceptor ligand, bound to the membrane fraction with a Kd value of 0.29 nmol/l and a Bmax of 42 fmol/mg protein. In the isolated ferret papillary muscle driven at 1 Hz at 37 degrees C, phenylephrine elicited a concentration-dependent positive inotropic effect. The maximal effect of phenylephrine was comparable to that of isoprenaline. Prazosin (0.3 mumol/l) shifted the concentration-response curve for phenylephrine slightly but significantly to the right, the maximal response being unaffected. In contrast, bupranolol (0.3 mumol/l) shifted the curve for phenylephrine markedly downwards: the maximal response was depressed significantly to 40% and the curve became less steep. In the presence of prazosin and bupranolol the curve was shifted to the right, being essentially parallel to the control curve. These results indicate that in the ferret ventricular myocardium both alpha- and beta-adrenoceptors mediate the positive inotropic effect of phenylephrine. The extent of contribution of the two classes of adrenoceptor is quite different from that in other mammalian species. In the ferret heart, beta-adrenoceptors predominate over alpha-adrenoceptors in mediating the positive inotropic effect of phenylephrine, although the number of beta-adrenoceptors is not especially high when compared with other species.

P-234 - Inotropic effect of phenylephrine may be mediated through phosphoinositide breakdown in rat ventricular muscle

P-234 - Inotropic effect of phenylephrine may be mediated through phosphoinositide breakdown in rat ventricular muscle

Defibrotide, an Antithrombotic Substance That Preserves Postsynaptic α- and β-Adrenergic Function in Post Acute Infarcted Rabbit Hearts

Defibrotide, a simple strand polydeoxyribonucleotide of mammalian origin with a molecular weight of 20,000 daltons, given intravenously to the rabbit before and after production of left ventricular infarction, prevents the alteration of the contractile response to postsynaptic adrenergic stimulation tested in isolated perfused heart preparations 3 days after coronary artery occlusion. According to the dose-response curves for isoproterenol and tyramine, left ventricular dP/dtmax was significantly depressed in infarcted hearts, whereas the dose-response curve for the inotropic effect of phenylephrine was markedly enhanced. These alterations were prevented by pretreatment of the rabbits with defibrotide (32 mg/kg/h i.v. for 6 h). In fact the potency ratios, calculated from the dose-response curves related to dP/dtmax of isoproterenol, tyramine, and phenylephrine in infarcted and control hearts excised from defibrotide treated and shamoperated rabbits, are nearly 1. The observed alterations in myocardial contractility in infarcted hearts seem to be specific for postsynaptic alpha and beta-adrenoceptors since the dose-response curve of left ventricular dP/dtmax for histamine is not different from control. The results obtained with defibrotide reflect the ability of this substance to protect the myocardial tissue from ischemic damage: this is also supported by the capacity of defibrotide (8 mg/kg/h i.v. for 6.5 h) to prevent the reduction of CPK-activity in the infarcted ventricle. Finally, we suggest that the observed beneficial effect of defibrotide in rabbit heart may also be explained by the antithrombotic effect of this substance, which is based on its profibrinolytic activity and PGI2-release.

Influences of age on the positive inotropic effect mediated by alpha- and beta-adrenoceptors in rat ventricular strips.

The positive inotropic effect of phenylephrine (in the presence of atenolol) and isoprenaline was studied in isolated right ventricular strips obtained from Wistar rats aged 2 weeks, 3 months, and 26 months. The positive inotropic effects induced by phenylephrine and isoprenaline were higher in the 2-week-old than in the 3- or 26-month-old rats. The typical 'alpha-type' or 'beta-type' responses were induced by phenylephrine (plus atenolol) or isoprenaline, in all the age groups. The EC50 values for the alpha-mediated positive inotropic effect decreased with age, while the EC50 value for the positive inotropic effect of isoprenaline increased in the senescent heart. These results suggest an enhanced alpha-adrenergic sensitivity in the senescent heart.

Implications of altered inotropic effects of phenylephrine in pressure-overloaded cat ventricular muscle.

The positive inotropic action of phenylephrine in cardiac muscle is mediated by alpha- and beta-adrenoceptors. Data suggest the responsiveness of myocardium to inotropic agents is altered in cardiac disease. We evaluated the actions of phenylephrine on isometric contraction and K+-induced contracture in isolated cat right ventricular muscle from normal hearts and hearts with partial pulmonary artery ligation-induced pressure overload of 5-11 days in duration. Peak contractile force (Po) and rate of force development (dP/dt) were lower (p less than or equal to 0.005) in pressure-overloaded (0.59 +/- 0.2 g/mm2 and 4.6 +/- 1.7 g/s/mm2, respectively) than in normal (1.33 +/- 0.2 g/mm2 and 10.5 +/- 1.6 g/s/mm2, respectively) muscle. Phenylephrine (10(-6), 5 X 10(-6), and 10(-5) M) significantly (p less than or equal to 0.01) increased Po and dP/dt in normal but not in pressure-overloaded muscle. Phenylephrine (5 X 10(-6) M) reduced peak K+-induced contracture force (Pc) similarly in normal (-30 +/- 8%) and pressure-overloaded (-36 +/- 11%) muscles. beta-Adrenergic blockade (nadolol, 10(-4) M) reduced, but did not abolish, the "relaxant" action of the drug on Pc in both muscle groups. The lack of a positive inotropic effect of phenylephrine in pressure-overloaded muscle suggests a derangement in both alpha- and beta-adrenoceptor function in this model of cardiac disease.

Alpha-Adrenoceptors mediating the positive inotropic effect of phenylephrine in the right ventricular muscle of the monkey (Macaca fuscata).

The property of adrenoceptors mediating the positive inotropic effect (PIE) in the ventricular muscle of the Japanese monkey (Macaca fuscata) was investigated by the use of phenylephrine (PE) and adrenoceptor antagonists. The intrinsic activity (0.6) and the pD2-value (5.41) for PE were comparable to those in other mammalian species. The beta-adrenoceptor antagonist, pindolol (3 x 10(-8) mol/l) shifted only the upper part of the concentration-response curve (CRC) for PE to the right; the pD2-value for PE was not significantly affected by pindolol. On the other hand, phentolamine (10(-6) mol/l) shifted the lower part of the CRC for PE more than the upper part. In the presence of both pindolol and phentolamine the curve was shifted to the right in a parallel manner. The time required for twitch relaxation was negatively correlated to the degree of PIE of PE in the presence of phentolamine but not pindolol. These results indicate that both beta- and alpha-adrenoceptors mediate the positive inotropic action in the ventricular muscle of the Japanese monkey and that in contrast to the action via beta-adrenoceptors the action via alpha-adrenoceptors is not accompanied by the "relaxant effect".

Irreversible alpha adrenoceptor blocking effects and reversible muscarinic blocking and nicotinic blocking effects of tetramine disulfides on the heart.

Inotropic effects of phenylephrine, carbachol, and butyrylcholine were used in the rabbit left atrium to evaluate respectively alpha adrenoceptor blocking, muscarinic blocking, and nicotinic blocking effects of tetramine disulfides ((RNH(CH2)nNH(CH2)2S-)2 x 4HX). The alpha adrenoceptor blocking potencies of newly synthesized derivatives R = 3',4'-(OH)2-benzyl, n = 5-9, were similar to those of compounds R = 2'-OCH2-benzyl, n = 5-7. Muscarinic blocking and nicotinic blocking potencies of tetramine disulfides were correlated with alpha adrenoceptor blocking potency. Compounds R = 3',4'-(OH)2-benzyl had relatively low muscarinic blocking potencies and compounds R = 2'-OCH3-benzyl had relatively low nicotinic blocking potencies.

MECHANISM OF CHRONOTROPIC AND INOTROPIC EFFECTS OF PHENYLEPHRINE

The effects of phenylephrine and mcthoxamine were studied on pacemaker activity in the sinoatrial node and on atrial and ventricular contractility in isolated, blood-perfused atrial and ventricular preparations of dogs. Each drug was administered directly into the cannulated sinus node artery of an isolated atrium or the anterior descending branch of the isolated left ventricle over a period of 4 sec. Two response patterns to phenylephrine were observed in atrial preparations: monophasic positive chronotropic and inotropic effects: double peaked effects, positive effects were temporarily interrupted by negative effects. Phenylephrine induced positive effects were blocked by an adrenergic beta-blocker, alprenolol or carteolol, but not by desipramine or phentolamine. Phenylephrine-induced negative effects were inhibited by atropine, tetrodotoxin or phentolamine. In ventricular preparations, phenylephrine usually induced a monophasic positive inotropic effect which was completely blocked by a beta-blocker but not by phentolamine. On the other hand, mcthoxamine usually induced negative chronotropic and inotropic effects in both preparations, and these negative effects were not blocked by atropine, tetrodotoxin and phentolamine. These results suggest that phenylephrine produces a cholinergic excitation which may occur through an adrenergic alpha-mechanism in parasympathetic nerve terminals, in addition to its adrenergic beta-stimulating effect.