Positive chronotropic and inotropic effects of glucagon on the canine isolated atrium.

Effects of glucagon on SA node pacemaker activity and atrial contractility were investigated in isolated canine atrium preparations which were perfused with blood led from a support dog and suspended in a bath. Glucagon at a dose from 0.1 to 10 mug was injected into the sinus node artery, which caused a marked positive chronotropic but a less inotropic effect. The positive inotropic response was simulated by atrial acceleration produced by atrial pacing. Glucagon effects were not influenced by treatment with an adrenergic beta-blocking agent, alprenolol to SQ 11725, which blocked effects of norepinephrine. It was concluded that glucagon is more effective on pacemaker activity than on atrial contractile force, and glucagon effects may not be mediated by an adrenergic beta-mechanism.     

Pharmacological analysis of the cardiac actions of xamoterol, a beta adrenoceptor antagonist with partial agonistic activity, in guinea pig heart: evidence for involvement of adenylate cyclase system in its cardiac stimulant actions

The pharmacological effects of xamoterol, a beta adrenoceptor antagonist with partial agonistic activity, were examined in guinea pig cardiac preparations and compared with those of isoproterenol to assess possible mechanisms of its cardiac stimulant actions. Xamoterol produced a positive inotropic effect in the papillary muscles and a positive chronotropic effect in the spontaneously beating right atria in a concentration-dependent manner. The maximum inotropic and chronotropic effects of xamoterol were about 33 and 35% of those of isoproterenol, respectively. Although xamoterol failed to produce a consistent increase in contractile force in the left atria, the positive inotropic effect of the agent was observed clearly in preparations obtained from reserpine-pretreated animals. The positive inotropic and chronotropic effects of xamoterol were antagonized by atenolol, but not by ICI 118,551. On the other hand, xamoterol antagonized competitively the positive inotropic and chronotropic responses to isoproterenol. In papillary muscles the increases in contractile force induced by xamoterol and isoproterenol were depressed markedly in the presence of carbachol or adenosine. In all of left atria, right atria and papillary muscles obtained from reserpine-pretreated animals, xamoterol caused a significant elevation in cyclic AMP levels, while inhibiting the isoproterenol-induced increase in cyclic AMP levels. Computer-assisted analysis of concentration-response curves for the inhibition by xamoterol of the binding of [125I]iodocyanopindolol in the membranes from guinea pig ventricles showed the existence of the 5'-guanylylimidodiphosphate sensitive, highly affinity site of beta adrenoceptors for xamoterol, suggesting that xamoterol may induce the formation of a ternary complex with the beta adrenoceptor and a stimulatory guanine nucleotide regulatory protein.(ABSTRACT TRUNCATED AT 250 WORDS)     

Changes in mechanical events and adenosine 3',5'-monophosphate levels induced by enantiomers of isoproterenol in isolated rat atria and uteri.

Beta adrenergic receptors of rat atria and uteri were examined with the use of enantiomers of isoproterenol as agonists and mechanical responses and adenosine 3',5'-monophosphate (cyclic AMP) levels as measured effects. Assuming that stereoselectivity reflects the unique asymmetry of receptors, potency differences between the enantiomers are expected to provide a sensitive indication of ligand binding. All effects in each tissue were investigated under similar experimental conditions. Both isomers produced the same maximum effect on all measured responses. Enantiomeric potency differences (in log units) for positive chronotropic and inotropic responses and increases in cyclic AMP levels in atria were 3.31, 3.51 and 3.48, respectively. In uteri, the values for reduction of spontaneous contractile amplitude and increases in cyclic AMP were 2.90 and 2.79 log units, respectively. Even though these absolute values varied slightly with the experimental conditions, they were consistently smaller in uteri than in atria. In both tissues, dose-response curves for production of mechanical effects were greater than 2 log units to the left of those for increases in cyclic AMP levels. Regardless of the interpretation of this phenomenon, the results show the following. 1) The stereoselectivity for isoproterenol-induced effects is different between the two tissues at both levels of response. Therefore, it is suggested that this reflects dissimilar beta adrenergic receptor types in rat atrium vs. rat uterus. 2) The stereochemical selectivity for isoproterenol-induced mechanical effects and increases in cyclic AMP is the same in rat atrium and in rat uterus. Therefore, the data support the postulate that cyclic AMP is formed from interaction of isoproterenol with a receptor that is similar to the one activated to produce a mechanical effect.     

Pharmacological analysis of dopamine action on the isolated dog atrium.

The isolated right atrium of the dog was perfused with arterial blood introduced from a carotid artery of a support dog. The selective injection of dopamine, tyramine and norepinephrine into the cannulated sinus node artery induced dose-relatedly positive chronotropic and inotropic effects. However, for an equal increase in sinus rate, dopamine caused less increase in tension development than norepinephrine. Tyramine caused least increase in contractility. Effects induced by dopamine were not blocked by treatment with tetrodotoxin which blocked those induced by nicotine. Desmethylimipramine treatment significantly suppressed dopamine-induced effects and completely blocked tyramine-induced ones but rather enhanced norepinephrine-induced ones. Alprenolol inhibited effects of dopamine, tyramine and norepinephrine. From these results, it is concluded that positive chronotropic and inotropic effects of dopamine are partly due to tyramine-like effect which causes the release of norepinephrine from sympathetic storage sites.     

Differential effects of sulmazole (AR-L 115 BS) on contractile force and cyclic AMP levels in canine ventricular muscle: comparison with MDL 17,043

MDL 17,043 [1,3-dihydro-4-methyl-5-[4-(methylthio)-benzoyl]-2H-imidazol-2-one] and AR-L 115 BS [sulmazole, 2-[(2-methoxy-4-methylsulfinyl)phenyl]-1H-imidazo[4,5-b] pyridine] produced substantial positive inotropic effects in a concentration-dependent manner (10(-5) to 10(-3) M) in the isolated canine ventricular trabeculae in the presence of pindolol (3 X 10(-8) M). Both agents exhibited equal potency and intrinsic activity in this preparation. The time to peak tension, relaxation time and total duration of contraction were shortened by MDL 17,043 in a concentration-dependent manner up to the highest concentrations tested (10(-3) M). In contrast, AR-L 115 BS shortened these times in concentrations of 3 X 10(-4) M and lower, but prolonged them in higher concentrations. The positive inotropic effects of MDL 17,043 and AR-L 115 BS were associated with increases in the cyclic AMP levels of the muscles. The time course of the increase in cyclic AMP levels differed for the two drugs. The elevation in cyclic AMP and the positive inotropic effect produced by MDL 17,043 followed a similar time course. By contrast, the rise in the cyclic AMP level became significant only after the positive inotropic effect produced by AR-L 115 BS had reached a steady level. Carbachol, a muscarinic agonist, converted the positive inotropic effect of 10(-3) M MDL 17,043 into a negative inotropic effect, but did not alter the positive inotropic effect of 10(-3) M AR-L 115 BS.(ABSTRACT TRUNCATED AT 250 WORDS)     

The influence of ketamine on inotropic and chronotropic responsiveness of heart muscle.

The influence of ketamine on the inotropic and chronotropic responsiveness of heart muscle was examined in spontaneously beating right atrial preparations and in electrically driven left atrial preparations of guinea pigs. Ketamine (2.63 X 10(-5) to 4.2 X 10(-4) M) decreased heart rate of right atria and decreased contractile tension and its maximum rate of increase in both right and left atrial preparations (right atria greater than left atria). Ketamine did not prevent the heart rate increase produced by norepinephrine (NE; 1 X 10(-8) to 1 X 10(-4) M) in right atria; however, the maximum heart rate was consistently lower in ketamine-treated than in control muscles even after exposure to NE. Although contractile tension was decreased by ketamine, the maximum inotropic response to NE was consistently greater in ketamine-treated atria than in control atria. An inhibitor of the slow Ca++ current in heart muscle, D600, depressed the contractile effects of NE but did not prevent the positive inotropic interaction of ketamine and NE. Ketamine similarly enhanced the inotropic responses to norepinephrine (1 X 10(-6) M), epinephrine (1 X 10(-6) M), isoproterenol (1 X 10(-7) M) and dibutyryl cyclic adenosine 3':5'-monophosphate (AMP; 4 X 10(-3) M) in left atria electrically paced at a constant frequency of contraction of 1 Hz; however, ketamine inhibited the positive inotropic response to increased frequency of stimulation (0.1-3.0 Hz) and to ouabain (3 X 10(-7) M). These findings demonstrate that ketamine can exert a selective positive inotropic influence in heart muscle independent of heart rate or direct or reflexogenic autonomic nervous system changes, and suggest that this activity could in some way be associated with an alteration of the intracellular disposition of cyclic AMP.     

Effect of PGD2 on cardiac contractility: a negative inotropism secondary to coronary vasoconstriction conceals a primary positive inotropic action

The purpose of this study was to characterize by pharmacological means the inotropic action of prostaglandin D2 (PGD2) in the guinea-pig heart. In the whole heart perfused at constant pressure, PGD2 (0.01-10 micrograms) reduced coronary flow rate and decreased left ventricular contractile force in a dose-dependent manner. When the coronary vasoconstricting effect of PGD2 was antagonized by the PG antagonist sodium p-benzyl-4[1-oxo-2-(4-chlorobenzyl)-3-phenyl propyl]phenyl phosphonate (N-0164), by the cyclooxygenase inhibitor indomethacin or by the thromboxane synthetase inhibitor sodium (E)-3-[4-(1-imidazolyl-methyl)phenyl]-2-propanoate (OKY 046), the negative inotropic response to PGD2 was attenuated or completely abolished and a positive inotropic effect was unmasked. In the isolated left atrium or right ventricular papillary muscle preparations, PGD2 induced only a positive inotropic response. The atrial response to PGD2 was unaffected by N-0164, indomethacin or propranolol but was markedly decreased by carbachol or adenosine. Conversely, the response of the papillary muscle to PGD2 was potentiated by papaverine. Thus, these data indicate that PGD2 has a primary positive inotropic effect, which may involve cyclic AMP metabolism. On the other hand, because PGD2 is also a potent coronary vasoconstrictor, the secondary negative inotropic effect of PGD2 predominates.     

Adenosine selectively attenuates H2- and beta-mediated cardiac responses to histamine and norepinephrine: an unmasking of H1- and alpha-mediated responses

Adenosine is known to attenuate the positive inotropic and chronotropic effects of norepinephrine and histamine by reducing cyclic AMP accumulation. We assessed whether adenosine, while inhibiting the cardiac responses mediated by beta and H2 receptors, leaves unmodified the responses mediated by alpha and H1 receptors. In isolated cardiac preparations from the guinea pig, adenosine antagonized the positive inotropic effect of histamine more than that of norepinephrine. This most likely occurred because, by attenuating H2 and beta responses, adenosine unmasked the H1-negative and alpha-1-positive components of the inotropic effects of histamine and norepinephrine. Consistent with this hypothesis, the pure H2 agonist impromidine appeared to be antagonized by adenosine less than histamine, and norepinephrine less than isoproterenol. In addition, adenosine antagonized the positive inotropic effect of norepinephrine in the presence of the alpha-1 blocker prazosin, whereas it did not affect the inotropic effect of phenylephrine. In the papillary muscle depolarized by 22 mM K+, adenosine antagonized the restoration of contractile responses induced by histamine or norepinephrine. This action of adenosine was reversed by the phosphodiesterase inhibitor papaverine and by the adenylate cyclase activator forskolin, suggesting that adenosine attenuates beta and H2 responses by suppressing the cyclic AMP-dependent facilitation of Ca++ influx promoted by the two amines. Our data indicate that adenosine selectively attenuates H2 and beta but not alpha and H1 responses. Thus, when catecholamines, histamine and adenosine are released together, as in myocardial ischemia, in addition to their individual effects, negative inotropism, decreased impulse conduction velocity and coronary constriction (i.e., H1- and alpha-mediated responses) may result from the adenosine-histamine-norepinephrine interaction.     

Enkephalins increase cyclic adenosine monophosphate content, calcium uptake, and contractile state in cultured chick embryo heart cells.

Peripheral vascular effects of opioid peptides are well known, but direct myocardial effects have not been established. We studied the inotropic response of spontaneously beating cultured chick embryo ventricular cells to the enkephalin analogue [D-Ala2]-enkephalin. Amplitude of cell motion increased in a concentration-dependent manner with 0.53 microM [D-Ala2]-enkephalin producing half-maximal response. The mechanism of this positive inotropic effect was investigated by examining alterations in 45Ca influx, cyclic AMP accumulation and adenylate cyclase activity in response to [D-Ala2]-enkephalin. At maximally inotropic concentrations, the 45Ca influx rate increased 39%, adenylate cyclase was stimulated by 30%, and cyclic AMP content rose more than twofold. Thus, in contrast to neural tissue, receptors for enkephalin in cultured heart cells are coupled to adenylate cyclase in a stimulatory manner. Occupancy of these receptors produces an increase in cyclic AMP levels and exerts a positive inotropic effect via a verapamil-sensitive enhancement of Ca influx.     

Effect of dibutyryl cyclic adenosine 3′,5′-monophosphate, theophylline, and other nucleotides upon calcium and phosphate metabolism

The effect of dibutyryl cyclic adenosine 3',5'-monophosphate upon calcium and phosphate metabolism in thyroparathyroidectomized rats was undertaken in an effort to clarify the possible role of adenosine 3',5'-monophosphate (3',5' AMP) in parathyroid hormone action. The infusion of dibutyryl cyclic 3',5' AMP at a rate of 3 mg/hr into thyroparathyroidectomized rats leads to changes in calcium, phosphate, and hydroxyproline excretion, and calcium and phosphate concentrations in plasma that are qualitatively similar to those induced by parathyroid hormone given at a rate of 5 mug/hr. The effect of dibutyryl cyclic 3',5' AMP upon calcium and hydroxyproline mobilization from bone is blocked by thyrocalcitonin administration in the same way that thyrocalcitonin blocks PTH effects. Other closely related nucleotides do not act in the same way.These data indicate that dibutyryl cyclic 3',5' AMP produces effects similar to parathyroid hormone in thyroparathyroidectomized rats, and support the notion that 3',5' AMP is an intermediate in the mechanism of PTH action. However, the changes in magnesium and potassium excretion are different after dibutyryl cyclic 3',5' AMP infusion from those seen after PTH infusion. Also, theophylline was found to potentiate the action of smaller doses of dibutyryl 3',5' AMP, but not that of PTH.     

The relative efficiency of beta adrenoceptor coupling to myocardial inotropy and diastolic relaxation: organ-selective treatment for diastolic dysfunction.

The relative effects of drugs which elevate cytosolic cyclic AMP on inotropy and diastolic relaxation (lusitropy) of guinea pig atria were quantified in vitro. There was a temporal difference between these responses in that inotropy reached peak response considerably faster than lusitropy. Also, although the relaxation response was sustained to an elevated steady state, the inotropic responses to beta adrenoceptor agonists were transient and returned to base line over 90 min. However, the inotropic responses to forskolin and dibutyryl cyclic AMP (cAMP) were sustained. For all of the drugs tested, the lusitropic response was at least 4 times more sensitive than the inotropic response (i.e., the concentration response curve for relaxation was shifted to the left of the curve for inotropy). In the case of beta adrenoceptor agonists, these differences were greater, presumably because of the fading inotropic response over 90 min. It was found that although high efficacy beta adrenoceptor agonists such as isoproterenol (and the direct activator of adenylate cyclase forskolin) produced both inotropy and lusitropy, lower efficacy agonists produced predominant lusitropy. The low efficacy agonist prenalterol produced insignificant inotropy but 60% maximal lusitropy. These data were modeled mathematically by a "differential coupling model" which assumed that a uniform cytosolic level of elevated cAMP activated two biochemical processes of differing sensitivity. Thus, the lusitropic response (phosphorylation of phospholamban) was coupled more efficiently to the cAMP response than the inotropic response (phosphorylation of calcium channels). A second model ("differential messenger concentration model") which calculated the effects of a compartmentalization of cAMP concentration within the cardiac cell by restricted diffusion and/or selective degradation by phosphodiesterases also was used.(ABSTRACT TRUNCATED AT 250 WORDS)     

Effects of an aldose reductase inhibitor, ONO-2235, insulin and their combination on the altered responsiveness to the nerve stimulation and agonists of the isolated atria of diabetic rats

To determine the effects of an aldose reductase inhibitor (ARI) on diabetes-induced cardiac autonomic nerves disturbance, we examined the effects of ONO-2235, an ARI, as well as insulin on the responsiveness to the nerve stimulation and agonists of the isolated atria of the streptozotocin-induced diabetic rats. Insulin, 4 U/animal/day, was administered s.c. for 4 weeks before the experiment and ARI (ONO-2235), 40 mg/kg/day, was administered p.o. 3 weeks before the experiment. The transmural nerve stimulation (TNS) of sympathetic nerves and parasympathetic nerve was performed in the presence of atropine and metoprolol plus prazocin, respectively. The positive chronotropic and the inotropic responses of the atria to sympathetic TNS and to norepinephrine decreased in the rats diabetic for 8 and 12 weeks. In the rats diabetic for 8 weeks, the insulin treatment restored completely both the positive chronotropic and the inotropic responses to sympathetic TNS, whereas the ARI treatment partially improved the positive chronotropic response and did not improve the positive inotropic response. In the rats diabetic for 12 weeks, the insulin treatment partially improved the positive chronotropic and the inotropic responses to sympathetic TNS, whereas the ARI treatment only slightly improved the positive chronotropic response and did not improve the positive inotropic response to TNS. The combination treatment with insulin and ARI restored completely both the positive chronotropic and the inotropic responses in the rats diabetic for 12 weeks. In rats diabetic for both 8 and 12 weeks, the decreased positive chronotropic and the inotropic responses to norepinephrine recovered completely with the insulin treatment, but did not with the ARI treatment.(ABSTRACT TRUNCATED AT 250 WORDS)     

Differential effects of 8-bromo-cyclic GMP on the basal contractile force and beta-adrenoceptor-mediated positive inotropic action in the canine atrium

8-Bromo-cyclic GMP caused a negative inotropic action on the canine atrial muscle, whilst it did not affect the positive inotropic action of phenylephrine mediated via beta-adrenoceptors. These findings are in line with the hypothesis that the muscarinic receptor stimulation may exert functional changes in the heart via two different intracellular biochemical processes: one involving cyclic AMP and the other involving cyclic GMP. 8-Bromo-cyclic GMP mimics the latter but not the former mechanism in canine atria.     

Vascular and cardiac effects of a new dihydropyridine derivative, YC-170: a comparison with Bay K 8644

The pharmacological effects of YC-170, a new dihydropyridine derivative, were studied in the rabbit aortic strips and guinea pig cardiac preparations and compared with those of Bay K 8644. In the rabbit aortic strips, YC-170 produced contraction in normal physiological saline solution ([K+]0 = 5.9 mM) in a concentration-dependent manner. Increasing the [K+]0 of the medium to 15 mM enhanced the contractile response. The maximum contraction produced by YC-170 at [K+]0 of 15 mM was comparable to that by Bay K 8644. However, YC-170 induced relaxation when the strip was contracted by 60 mM K+. In guinea pig left atrium, YC-170 produced a positive inotropic effect in a concentration-dependent manner, but its extent was far less than that of Bay K 8644. Like Bay K 8644, however, YC-170 increased the time to peak tension and relaxation time of the isometric tension, and prolonged the action potential duration. YC-170 failed to produce a positive inotropic action in the papillary muscle in which Bay K 8644 was a potent positive inotropic agent. In spontaneously beating right atria, YC-170 caused a negative chronotropic effect, whereas Bay K 8644 a positive one. The positive inotropic and vasoconstrictor effects of YC-170 were antagonized competitively by a Ca++ antagonist nicardipine. When the left atria were depolarized with high-K+ medium, the positive inotropic effect of YC-170 was attenuated progressively with increasing [K+]0 and at 13.2 mM K+ a negative inotropic effect was induced by YC-170.(ABSTRACT TRUNCATED AT 250 WORDS)     

Positive inotropic effect of histamine on guinea pig left atrium: H1-receptor-induced stimulation of phosphoinositide turnover

The purpose of this study was to investigate the mechanism of histamine's H1-receptor-mediated positive inotropic effect, a response which is not associated with an increase in cyclic AMP levels. We found that the concentration-response curve for the positive inotropic effect of histamine on cavian left atrium was similar to that of the alpha-1 agonist phenylephrine, in terms of slope and maximum response. Additionally, both agents slightly prolonged time-to-peak tension and relaxation times. In contrast, the concentration-response relationship for the beta-agonist isoproterenol, whose positive inotropic effect is mediated by an increase in cyclic AMP, had a steeper slope and a much greater maximum. Furthermore, isoproterenol abbreviated time-to-peak tension and relaxation times. As reported previously for alpha-1 agonists, the development of the contractile response to a submaximal histamine concentration (10 microM) coincided with a rapid increase in left atrial tissue levels of inositol triphosphate. The concentration-response curves for histamine effects on contractility and phosphoinositide (PI) turnover were both unaffected by the H2-antagonist tiotidine, but were shifted markedly to the right by the H1-antagonist pyrilamine. High-performance liquid chromatography techniques were applied to resolve the various inositol mono-, di- and tri-phosphate isomers and to assess the possible production of higher phosphates (IP4, IP5 and IP6) in control and histamine-treated (10 microM) atria. Under both conditions IP products were qualitatively similar, but quantitatively greater after treatment with histamine; these products included inositol(1)phosphate, inositol(4)phosphate,inositol(1,4)diphosphate and inositol(1,4,5)triphosphate. No evidence of higher phosphate production was obtained.(ABSTRACT TRUNCATED AT 250 WORDS)     

Cardiac responses and binding sites for endothelin in normal and cardiomyopathic hamsters.

The effects of endothelin-1 in the spontaneously beating atrium and the field-stimulated right ventricular strip preparation and the binding of [125I]endothelin-1 to membrane preparations from the atrium, ventricle, lung parenchyma, kidney and brain were compared using the 90-day-old dystrophic hamster strain CHF 147 (a strain displaying marked cardiomyopathologies at this age) and its age/genetically matched normal control, CHF 148. In the atrium, endothelin-1 produced dose-dependent positive inotropic and positive chronotropic effects in both CHF 148 and CHF 147 over the dose range of 10(-8) M to 3 x 10(-7) M. However, although no significant difference between CHF 148 and CHF 147 was observed for the positive chronotropic effects of endothelin-1, it produced a small, but significantly less positive inotropic effect in CHF 147 compared to CHF 148 at endothelin-1 concentrations of 2 x 10(-8) M and 3 x 10(-8) M. Field-stimulated right ventricular strips from CHF 148 contracted with a greater force compared to those from CHF 147. Endothelin-1 produced a dose-dependent decrease in the developed tension of the field-stimulated ventricular strip preparation, the extent of which did not differ between CHF 148 and CHF 147. [125I]Endothelin-1 bound with high affinity and in an apparently irreversible manner to membranes from both CHF 148 and CHF 147 atrium, ventricle, lung parenchyma, kidney and brain. No significant differences were noted between CHF 148 and CHF 147 for [125I]endothelin-1 binding to membranes prepared from the various tissues.(ABSTRACT TRUNCATED AT 250 WORDS)     

Parasympatholytic effects of vecuronium are mediated by nicotinic and muscarinic receptors in hearts of anesthetized dogs.

We investigated the blocking effects of vecuronium and pancuronium on the negative chronotropic and dromotropic responses to stimulation of the parasympathetic nerves in the anesthetized, open-chest dog. We stimulated the intracardiac parasympathetic nerves to the SA nodal region (SAP stimulation) or to the atrioventricular nodal region (AVP stimulation). SAP stimulation or AVP stimulation selectively decreased heart rate or increased atrioventricular conduction time, respectively. Vecuronium and pancuronium inhibited the chronotropic response to SAP stimulation and the dromotropic response to AVP stimulation in a dose-dependent manner. The ID50 of each drug for the dromotropic response was less than that for the chronotropic response. The blocking effect of vecuronium on the negative cardiac responses to parasympathetic stimulation was about 10-fold less potent than that of pancuronium. These results suggest that the blocking effects of vecuronium and pancuronium on the negative chronotropic and dromotropic responses to parasympathetic stimulation differ from those of atropine in the heart. In the isolated right atrium perfused with blood from the support dog, vecuronium, injected into the external jugular vein of the support dog, dose-dependently inhibited the negative chronotropic and inotropic responses to carbachol or SAP stimulation and the negative followed by positive chronotropic and inotropic responses to nicotine. The ID50 values for carbachol, nicotine and SAP stimulation were not significantly different. These results suggest that parasympatholytic effects of vecuronium are mediated by not only muscarinic receptors but also neuronal nicotinic receptors in hearts of anesthetized dogs.     

Adenosine promotes histamine H1-mediated negative chronotropic and inotropic effects on human atrial myocardium

Because histamine and adenosine are coreleased from the ischemic heart, we investigated the effects of their interaction on human myocardium. Surgical specimens of human right atrium (i.e., pectinate muscles) responded to histamine with increases in spontaneous rate and contractile force. Adenosine, and the A1-selective adenosine agonist N6-cyclopentyladenosine (CPA), reduced the spontaneous rate and suppressed the positive chronotropic and inotropic effects of histamine. CPA was more potent than adenosine in slowing the spontaneous rate and in suppressing histamine's positive chronotropic effect, suggesting that the responses to CPA and adenosine are A1-mediated. CPA was also more potent than adenosine in attenuating histamine's positive inotropic effect on human ventricular papillary muscle. The adenosine-induced suppression of histamine's effects on pectinate muscles was mimicked by carbachol, which like adenosine is known to attenuate H2-mediated histamine-induced adenylate cyclase activation. The H1-selective histamine antagonist pyrilamine potentiated histamine's chronotropic and inotropic responses, and inhibited the attenuation of these responses by adenosine or carbachol. In contrast, pyrilamine failed to modify the adenosine-induced attenuation of the cardiac stimulatory effects of dimaprit, an H2-selective histamine agonist. Our data suggest that adenosine-induced suppression of histamine's positive chronotropic and inotropic effects on human myocardium results both from an A1-mediated attenuation of H2-stimulatory effects and from the uncovering of H1 negative chronotropic and inotropic effects. Thus, the results of the histamine-adenosine interaction may exceed the "retaliatory" purpose of adenosine release and uncover H1-mediated myocardial depression.     

Direct Inhibitory Effect of Hypercalcemia on Renal Actions of Parathyroid Hormone

The effects of calcium on the renal actions of parathyroid hormone (PTH) were studied in vivo and in vitro. In parathyroidectomized rats, variable levels of blood calcium concentration were induced by intravenous infusion of calcium. The renal responses to the injected PTH, i.e. phosphate and cyclic AMP excretion, were compared in these animals. After PTH injection, the increases of both phosphate and cyclic AMP excretion were less in the calcium-infused animals than in the control group without calcium infusion. There was an inverse correlation between the renal responses to PTH and plasma calcium concentration of 4.2-13.5 mg/100 ml. But calcium had no effect on phosphate excretion induced by infusion of dibutyryl cyclic AMP. In the in vitro experiments, the increase of cyclic AMP concentration in response to PTH was less in renal cortical slices taken from the calcium-infused animals than in ones from the control group without calcium infusion. Calcium also inhibited the activation of renal cortical adenylate cyclase in response to PTH, but calcium had no effect on phosphodiesterase. The data indicate that calcium directly inhibits renal actions of PTH both in vivo and in vitro. Such inhibitory mechanism is probably at or before the step of PTH-dependent cyclic AMP generation in the kidney.     

Does the positive inotropic action of a novel cardiotonic agent, MCI-154, involve mechanisms other than cyclic AMP?

MCI-154 is a new positive inotropic agent with vasodilating property. Experiments were carried out in the canine isolated right ventricular muscle in order to elucidate whether or not cyclic AMP is involved in the positive inotropic effect (PIE) of MCI-154. MCI-154 (10(-7) to 10(-4) M) produced a concentration-dependent PIE amounting to 75% of the maximal effect of isoproterenol. MCI-154 did not affect the time to peak tension and had a tendency to shorten the relaxation time and total duration of contraction. Pindolol, reserpine-pretreatment or tetrodotoxin did not modify the PIE of MCI-154. MCI-154 increased the cyclic AMP levels only at 3 X 10(-4) M, whereas CI-914, of which chemical structure is similar to that of MCI-154, elevated definitely the cyclic AMP at the lower concentrations (10(-5) to 10(-4) M). Carbachol at a concentration known to decrease markedly the PIE of amrinone, milrinone and papaverine, did not affect the PIE of MCI-154. MCI-154 inhibited the activity of a crude phosphodiesterase (PDE) from the canine ventricular muscle and it enhanced the PIE of isoproterenol, which implied the involvement of cyclic AMP. However, the maximal inhibition of PDE by MCI-154 remained less than 18%. Amrinone, milrinone and papaverine inhibited more potently the PDE activity than MCI-154. These results suggest that the elevation of cyclic AMP levels is only partially involved in the PIE of MCI-154 in the canine right ventricular muscle, and that MCI-154 may have novel mechanisms of action different from those of amrinone, milrinone and CI-914 that are largely cyclic AMP-dependent.