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)     

Mechanism of inotropic action of xestoquinone, a novel cardiotonic agent isolated from a sea sponge.

Xestoquinone (XQN) isolated from the sea sponge Xestospongia sapra produced dose-dependent cardiotonic effects on guinea pig left and right atria. A direct action of XQN (1-30 microM) on the contractile machinery of cardiac myofilaments was demonstrated in chemically skinned fiber preparations from guinea pig papillary muscles. In atrial preparations, the XQN-induced inotropic effect was markedly inhibited by verapamil or nifedipine, but was not affected by practolol, chlorpheniramine, cimetidine, tetrodotoxin or reserpine. The Ca++ dependence curve for the contractile response of the atria was substantially shifted to the left by XQN (10 microM), and this XQN-induced shift was reversed by verapamil. The time-to-peak tension and relaxation times of the atrial contractions were shortened by XQN, and the action potential duration was markedly prolonged. Whole-cell patch clamp recordings in left atrial strips confirmed that XQN (30 microM) increased the slow inward current. However, there was a temporal dissociation between altered tension development and prolongation of the action potential duration. Cyclic AMP phosphodiesterase activity was inhibited and tissue cyclic AMP content of guinea pig left atria was increased by XQN (0.3-10 microM) in a concentration-dependent manner, but increases in cyclic AMP content did not occur in parallel with increases in contractile response. These observations suggest that an enhancement of intracellular cyclic AMP content and Ca++ influx across the cell membrane contribute to the late phase of XQN-caused cardiotonic responses, whereas the early phase may largely be elicited through direct activation of contractile elements. XQN may provide a novel leading compound for valuable cardiotonic agents.     

Effects of the cyclic GMP lowering agent LY83583 on the interaction of carbachol with forskolin in rabbit isolated cardiac preparations

Cyclic GMP (cGMP) has been proposed to be involved in mediating negative inotropic responses to muscarinic agonists in the presence of cyclic AMP (cAMP)-generating agents in the heart. In order to investigate this hypothesis, the effects of the novel cGMP lowering agent, LY83583, on carbachol-induced increases in cGMP levels and decreases in tension were measured in rabbit isolated left atria and right ventricular papillary muscles, in the presence and absence of the adenylate cyclase activator, forskolin. In vehicle-treated preparations, negative inotropic responses to 3 microM carbachol in the presence of 3 microM forskolin were accompanied by significant increases in cGMP levels. Carbachol had no significant effect on forskolin-induced increases in cAMP levels. LY83583 (10 microM) reduced basal tension and basal cGMP levels, and completely abolished carbachol-induced increases in cGMP both in left atria and in papillary muscles. The LY83583 significantly reduced the magnitude of the negative inotropic responses of papillary muscles to carbachol in the presence of forskolin, but had no effect on these responses in left atria. Although a causal relationship has not been established, these data suggest that cGMP may be involved in negative inotropic responses to muscarinic stimulation in the presence of cAMP-generating agonists in ventricular muscle, but not in atria.     

Cardiotonic action of [8]-gingerol, an activator of the Ca++-pumping adenosine triphosphatase of sarcoplasmic reticulum, in guinea pig atrial muscle

[8]-Gingerol (gingerol), a component of ginger, produced a concentration-dependent positive inotropic effect on guinea pig isolated left atria at concentrations of 1 X 10(-6) to 3 X 10(-5) M. Gingerol also exhibited positive inotropic and chronotropic effects on guinea pig right atria. The gingerol-induced inotropic effect was abolished by ryanodine, but was little affected by propranolol, chlorpheniramine, cimetidine, tetrodotoxin, diltiazem or reserpine. The time to peak tension and relaxation time within a single contraction were shortened by gingerol (1 X 10(-5) M) as well as isoproterenol, whereas they were prolonged by BAY K 8644. In guinea pig isolated atrial cells, gingerol (3 X 10(-6) M) caused an increase in the degree and the rate of longitudinal contractions. In guinea pig left atria, gingerol (1 X 10(-6) to 3 X 10(-5) M) gave little influence on the action potential, although it increased the contractile force of the atria. The whole-cell patch-clamp experiments showed that the slow inward current was little affected by gingerol (1 X 10(-6) to 3 X 10(-5) M) in voltage-clamped guinea pig cardiac myocytes. The measurement of extravesicular Ca++ concentration using a Ca++ electrode indicated that gingerol (3 X 10(-6) to 3 X 10(-5) M) accelerated the Ca++ uptake of fragmented sarcoplasmic reticulum (SR) prepared from canine cardiac muscle in a concentration-dependent manner.(ABSTRACT TRUNCATED AT 250 WORDS)     

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.     

Pharmacological characterization of a new Ca(2+) sensitizer

The benzimidazole molecule was modified to synthesize a Ca(2+) sensitizer devoid of additional effects associated with Ca(2+) overload. Newly synthesized compounds, termed 1, 2, 3, 4, and 5, were evaluated in spontaneously beating and electrically driven atria from reserpine-treated guinea pigs. Compound 3 resulted as the most effective positive inotropic agent, and experiments were performed to study its mechanism of action. In spontaneously beating atria, the inotropic effect of 3 was concentration-dependent (3.0 microM-0.3 mM). Compound 3 was more potent and more active than the structurally related Ca(2+) sensitizers sulmazole and caffeine, but unlike them it did not increase the heart rate. In electrically driven atria, the inotropic activity of 3 was well preserved and it was not inhibited by propranolol, prazosin, ranitidine, pyrilamine, carbachol, adenosine deaminase, or ruthenium red. At high concentrations (0.1-1.0 mM) 3 inhibited phosphodiesterase-III, whereas it did not affect Na(+)/K(+)-ATPase, sarcolemmal Ca(2+)-ATPase, Na(+)/Ca(2+) exchange carrier, or sarcoplasmic reticulum Ca(2+) pump activities of guinea pig heart. In skinned fibers obtained from guinea pig papillary muscle and skeletal soleus muscle, compound 3 (0.1 mM, 1 mM) shifted the pCa/tension relation curve to the left, with no effect on maximal tension and no signs of toxicity. Compound 3 did not influence the basal or raised tone of guinea pig isolated aorta rings, whose cells do not contain the contractile protein troponin. The present results indicate that the inotropic effect of compound 3 seems to be primarily sustained by sensitization of the contractile proteins to Ca(2+).     

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.     

Negative and positive inotropic responses to muscarinic agonists in guinea pig and rat atria in vitro

In the guinea pig atria, carbachol, acetylcholine and bethanechol elicited negative inotropic and positive inotropic effects. In the rat atria, a negative inotropic response occurred, but the positive inotropic response was small. The positive and negative inotropic responses to carbachol and bethanechol (but not acetylcholine) were unaffected by pretreating the animals with reserpine and were antagonised by pirenzepine with pKB values of 6.7. Pretreatment with pertussis toxin abolished the negative inotropic responses, but was without effect on the positive inotropic responses in the guinea pig. Pretreatment of rats with pertussis toxin abolished the negative inotropic response and enhanced the positive inotropic response. The positive inotropic response was attenuated by pretreatment with dietary lithium for 2 weeks, whereas no effect was observed on the negative inotropic response. Negative and positive inotropic responses to muscarinic agonists in these species are mediated directly through an M2 muscarinic receptor. The ability of dietary lithium to selectively inhibit the positive inotropic response may provide evidence for the involvement of inositol phospholipid hydrolysis in this effect.     

Non-cyclic AMP-dependent, positive inotropic cyclodepsipeptides with negative chronotropy.

The effects of natural cyclodepsipeptides (CDPs) on isolated rat cardiac tissue preparations were examined in vitro. Destruxin A, destruxin B (DB), roseotoxin B (RB), and roseocardin (RC), a novel CDP, each caused a concentration-dependent increase in the contraction force of the right atrium and the papillary and trabecular muscles of the right ventricle at 0.6 to 600 microM. RB, destruxin A, and DB did not affect the half-decay time of relaxation of the papillary muscles, but RC slightly prolonged it, although to a much lesser extent than BA 41899, a calcium sensitizer. This inotropic effect is accompanied by a prolongation of the automatic atrial contraction intervals. The RB-induced increase in the contraction force of papillary muscle was not affected by phentolamine, propranolol, pyrilamine, or cimetidine. RB- and RC-induced increases in the contraction force of papillary muscles were not affected by 3-isobutyl-1-methylxanthine or carbachol. Neither peptide changed the cyclic AMP levels in trabecular muscles. Neither RB nor RC affected the activity of Na(+),K(+)-ATPase from rat kidney. Neither RB, RC, nor DB affected the resting membrane potential or the apparent input resistance of papillary muscles. These results suggest that these CDPs produce both non-cyclic AMP-dependent positive inotropic and negative chronotropic effects.     

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)     

Cardiac effects of adenosine and adenosine analogs in guinea-pig atrial and ventricular preparations: evidence against a role of cyclic AMP and cyclic GMP

The effects of adenosine, the Ri site adenosine receptor agonist (-)-N6-phenylisopropyladenosine (PIA), the Ra site agonist 5'-N-ethylcarboxamideadenosine (NECA) and the P site agonist 2',5'-dideoxyadenosine (DIDA) on force of contraction, cyclic AMP (cAMP) and cyclic GMP (cGMP) content and on transmembrane action potential were studied in isolated electrically driven left auricles and papillary muscles from guinea pigs. Furthermore, the effects on adenylate cyclase activity in a particulate membrane preparation were investigated. In the auricles, adenosine, PIA and NECA had negative inotropic effects which were accompanied by a shortening of the action potential. Theophylline antagonized these effects which are likely mediated by R site adenosine receptors. DIDA was ineffective. Except for a small positive inotropic effect of adenosine the analogs were ineffective in the papillary muscles. None of the mechanical effects was accompanied by a change in cAMP and cGMP content in the intact preparations. In the broken cell preparation PIA and NECA had no effect on adenylate cyclase activity. Adenosine and DIDA inhibited the enzyme. The latter effects can be classified as P site-mediated effects. In conclusion, distinct mechanical, i.e., negative inotropic effects of adenosine and its analogs in the heart are observed in auricular preparations only. These effects are unlikely to be related to the cAMP and/or cGMP system. Instead, they are probably due to a direct shortening of the action potential which, in turn, is conceivably due to an increase in K+ outward current and a secondary decrease in Ca++ inward current. This effect is apparently mediated by cardiac R site adenosine receptors which are not detectably coupled to adenylate cyclase.     

Frequency modulation of the inotropic action of isoproterenol in mouse heart

In mouse right ventricular strips, field-stimulated to contract isometrically in an oxygenated bicarbonate-buffered physiological salt solution at 22--24 degrees C, the EC50 for the inotropic action of isoproterenol decreased from 37 nM in muscles stimulated at 0.2 Hz to 5 nM in muscles stimulated at 3.3 Hz. At higher rates of contraction, there was also an increased sensitivity to the inotropic actions of norepinephrine and epinephrine but not to those of Ca++ and N6,O2'-dibutyryl cyclic AMP. Increasing the Ca++ concentration further decreased the EC50 for isoproterenol at 3.3 Hz but had no effect on the EC50 at 0.2 Hz. The leftward shift of the contractile response curve at 3.3 Hz was inhibited by verapamil (0.6 microM) and Mn++ (0.25 mM). The stimulation of cyclic AMP accumulation was approximately 6-fold more sensitive to isoproterenol at 3.3 than at 0.2 Hz, but isoproterenol increased contractile force at concentrations two orders of magnitude lower than those that significantly increased cyclic AMP accumulation. Inhibition of cyclic AMP phosphodiesterase activity further increased the sensitivity to the inotropic actions of isoproterenol but did not attenuate the frequency difference. The results indicate that isoproterenol-stimulated Ca++ influx through the slow channel plays an important role in the mechanism of the increased sensitivity to the inotropic action of isoproterenol found at higher frequencies of contraction. Although cyclic AMP accumulation was also frequency dependent, its role in the inotropic action of isoproterenol in mouse heart is not clear.     

Effects of diacetyl monoxime on cardiac excitation-contraction coupling

Diacetyl monoxime (DAM) is a negative inotropic agent. To identify the mechanism of its actions, electrical and mechanical studies with various cardiac tissues were carried out. DAM (0.2-20 mM) inhibited the contractile force in both normal and 22 mM KCl-depolarized (in presence of 10(-6) M isoproterenol) guinea-pig papillary muscles in a concentration-dependent manner. In general, there was a lack of major effects of DAM on sarcolemmal electrical properties. The fast action potentials were somewhat depressed and the slow action potentials were slightly enhanced. In chemically skinned pig ventricular muscles, the myofibrillar contraction induced in 6.25 pCa was inhibited by DAM in a similar concentration range. DAM also produced an apparent decrease in sensitivity toward Ca++ in this preparation. Myofibrillar adenosine triphosphatase assay showed similar results as in the skinned muscles. All DAM effects were reversible upon washout and could be partially antagonized by raising [Ca++]. Taken together, the negative inotropic effect of DAM cannot be ascribed to an inhibitory effect on the slow inward current, as suggested previously. An inhibitory effect at the myofibril level is a distinct possibility. Additional effects of DAM on the sarcoplasmic reticulum cannot be ruled out.     

Roles for Ca++ and cyclic AMP in mediating the cardiotonic actions of isomazole (LY175326)

The contractile state of cat papillary muscles was increased by isomazole in a concentration-dependent manner; inotropic effects of the drug were not altered by either prazosin, propranolol or cimetidine. Isomazole inhibited the peak III isozyme of dog heart phosphodiesterase with an IC50 of 100 microM; effects on isozymes I and II were less pronounced. In cat papillary muscles, carbachol (10(-5) M) shifted the relationship between contractility and concentration of isomazole to the right. These data suggest cyclic AMP (cAMP) is involved in the actions of isomazole. In order to assess the relative effects of isomazole on intracellular cAMP and Ca++, cAMP-dependent protein kinase and glycogen phosphorylase, respectively, were used as reporters of these two second messengers. The source of enzymes was either cultured cardiomyocytes or right ventricular biopsies obtained from anesthetized dogs. In the latter case, biopsies were obtained after i.v. administration of isomazole; the pure beta agonist, isoproterenol, was included for comparative purposes. A submaximal inotropic dose of isomazole (0.1 mg/kg i.v.) in dogs resulted in a pronounced increase in contractility that was associated with a 3-fold increase in phosphorylase activity (0.15 +/- 0.01 to 0.46 +/- 0.06, -5'-AMP: +5'-AMP, P less than .05); the activation state of protein kinase was not altered. By contrast, a comparably effective inotropic dose of isoproterenol (0.1 microgram/kg) caused less than a 2-fold increase in phosphorylase activity (0.15 +/- 0.01 to 0.26 +/- 0.02, -5'-AMP: +5'-AMP, P less than .05) and this was associated with a significant increase in the protein kinase activity ratio (0.36 +/- 0.01 to 0.51 +/- 0.04, -cAMP: +cAMP, P less than .05).(ABSTRACT TRUNCATED AT 250 WORDS)     

Activation of the third complement component (C3) and C3a generation in cardiac anaphylaxis: histamine release and associated inotropic and chronotropic effects

Activation of the complement system with generation of C3a and C5a anaphylatoxins occurs during immediate hypersensitivity reactions; furthermore, the administration of C3a and/or C5a into isolated hearts causes a dysfunction that closely resembles cardiac anaphylaxis. To determine whether complement is activated and anaphylatoxins are generated in the course of immediate hypersensitivity reactions of the heart, we have challenged presensitized isolated guinea pig atria and papillary muscles with the specific antigen in the presence of a source of complement. We have found that the anaphylactic reaction of these cardiac preparations is characterized by complement activation and C3a generation, as well as by histamine release and positive inotropic and chronotropic effects. The amounts of C3a generated and histamine released directly correlated with the extent of C3 consumption. Furthermore, when C3a and C5a inactivation by serum carboxypeptidase N was prevented by DL-2-mercapto-methyl-3-guanidino-ethylthiopropanoic acid, anaphylactic histamine release was enhanced, and chronotropic and inotropic responses were potentiated and prolonged. Notably, the administration of C3a to nonsensitized guinea pig atria and papillary muscles caused positive chronotropic and inotropic effects, which were associated with histamine release and were antagonized by the H2 receptor blocker cimetidine, thereby mimicking the effects of anaphylaxis. Our findings indicate that complement activation and anaphylatoxin generation are typical of cardiac anaphylaxis and suggest that anaphylatoxins function as mediator-modulators of immediate hypersensitivity reactions of the heart.     

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.     

Inhibition by 5-hydroxytryptamine of the beta adrenoceptor-mediated positive inotropic responses to catecholamines in rabbit papillary muscles: direct interaction with beta adrenoceptors.

The effects of 5-hydroxytryptamine (5-HT) on the positive inotropic responses to catecholamines were investigated in isolated rabbit papillary muscles. 5-HT produced a concentration-dependent positive inotropic effect, an effect which was antagonized by prazosin, but not by propranolol. The positive inotropic effect of 5-HT diminished greatly in muscles from rabbits pretreated with 6-hydroxydopamine. Thus, it is likely that 5-HT causes a release of norepinephrine and increases force of contraction indirectly through alpha-1 adrenoceptors. In the presence of prazosin, 5-HT exerted a concentration-dependent inhibition of the positive inotropic response to isoproterenol. The positive inotropic responses to tyramine and a beta-1 adrenoceptor agonist T-1583 were also inhibited by the addition of 5-HT. The inhibitory effect of 5-HT on the beta adrenoceptor-mediated responses was unaffected by methysergide, ketanserin, ICS 205-930 or atropine. Pretreatment with pertussis toxin did not block the inhibitory effect of 5-HT on the inotropic response to isoproterenol, while abolishing the cholinergic interaction against the isoproterenol response. In contrast to its antagonizing effect on the inotropic response to isoproterenol, 5-HT produced an additive effect on the positive inotropic response to norepinephrine. However, when neuronal amine uptake was blocked by cocaine, the positive intropic response to norepinephrine was suppressed by the addition of 5-HT. 5-HT inhibited (-)-[125I]iodocyanopindolol binding to the membranes from rabbit ventricles with a monophasic displacement curve.(ABSTRACT TRUNCATED AT 250 WORDS)     

Involvement of endogenous opioid peptides and nitric oxide in the blunted chronotropic and inotropic responses to beta-adrenergic stimulation in cirrhotic rats

It is well known that chronotropic and inotropic responses to beta-adrenergic stimulation are impaired in cirrhosis, but the exact reason is not clear. Considering the inhibitory effect of endogenous opioid peptides and nitric oxide (NO) on beta-adrenergic pathway, we examined their roles in hyporesponsiveness of isolated atria and papillary muscles to isoproterenol stimulation in cirrhotic rats. Cirrhosis was induced by chronic bile duct ligation. Four weeks after ligation or sham operation, the responses of the isolated atria and papillary muscles to isoproterenol stimulation were evaluated in the absence and presence of naltrexone HCl (10(-6) m), N(omega)-nitro-L-arginine methyl ester (L-NAME, 10(-4) m), and naltrexone plus L-NAME in the organ bath. Considering the role of inducible NOS (iNOS) in hemodynamic abnormalities of cirrhotic rats, the chronotropic and inotropic responses of cirrhotic rats to isoproterenol stimulation were also assessed in the presence of aminoguanidine (a selective inhibitor of iNOS, 3 x 10(-4) m). Sham operation had no significant effect on basal atrial beating rate, contractile force, and maximal time derivatives for the development and the dissipation of papillary muscle tension. The basal atrial beating rate of cirrhotic rats did not show any significant difference compared with the sham-operated ones; however, the basal contractile parameters were significantly decreased in cirrhosis. Although the maximum effects of isoproterenol on chronotropic and inotropic responses were significantly reduced in cirrhotic rats, there was no difference in half-maximal effective concentrations of isoproterenol in these concentration-response curves. The basal abnormalities and the attenuated chronotropic and inotropic responses to isoproterenol were completely corrected by the administration of naltrexone, L-NAME and aminoguanidine. Concurrent administration of naltrexone and L-NAME also restored to normal the basal abnormalities and the blunted responses to isoproterenol in cirrhotic rats, and did not show any antagonistic effect. Based on these findings, both the endogenous opioid peptides and NO may be involved in the attenuated chronotropic and inotropic responses to beta-adrenergic stimulation in cirrhosis. It seems that the iNOS activity results in NO-induced hyporesponsiveness to beta-adrenergic stimulation in cirrhosis.     

Inotropic, electrophysiological and biochemical responses to histamine in rabbit papillary muscles: evidence for coexistence of H1- and H2-receptors

This study was performed to determine the subtypes of histamine receptors that are involved in the electrophysiological, inotropic and biochemical responses to histamine in isolated rabbit papillary muscles. Histamine increased force of contraction and shortened action potential duration (APD) in a concentration-dependent manner. The former was antagonized by chlorpheniramine, a H1-antagonist, whereas the latter was blocked by cimetidine, a H2-antagonist. However, even when H1-receptors were blocked entirely by chlorpheniramine, histamine still produced a positive inotropic effect, an effect which was antagonized by cimetidine. On the other hand, when H2-receptors were eliminated by cimetidine, histamine caused a H1-receptor mediated APD prolongation. Carbachol attenuated the decrease in APD but not the increase in force of contraction caused by histamine. Cyclic AMP and cyclic GMP levels both were elevated significantly by histamine. The increase in cyclic AMP level induced by histamine was abolished by cimetidine, but not altered by chlorpheniramine, whereas the converse was true for the increase in cyclic GMP level. Additionally, histamine produced a significant stimulation of phosphoinositide hydrolysis as measured by [3H]inositol monophosphate accumulation, although its extent was far less than that produced by carbachol. The phosphoinositide response to histamine was blocked by chlorpheniramine. These data suggest that H1- and H2-receptors coexist in rabbit ventricles. Stimulation of H1- and H2-receptors with histamine independently sets off the biochemical responses linked specifically to the respective subtypes of histamine receptors. On the other hand, the inotropic and electrophysiological responses to histamine are governed predominantly by H1- and H2-receptors, respectively, and this results in an apparent restriction of the expression of the responses mediated by another subtype.     

Regional differences in the responses of guinea-pig cardiac tissue to carbachol and their potentiation by hypothermia

The responses of guinea-pig isolated cardiac tissues to carbachol were examined. Tension responses of paced left atria and right ventricular papillary muscles, rate responses of spontaneously beating right atria and working hearts and contractility (+dP/dt) of paced and unpaced working hearts were obtained at 38 degrees C. Carbachol induced negative inotropic and chronotropic responses of atria, abolishing tension and rate at the maxima. The spontaneously beating heart also exhibited negative chronotropy. The papillary muscles displayed partial inhibition of tension but, in tissues from reserpine-pretreated animals, negative inotropy was absent. Similarly, no reduction of contractility of paced working hearts was obtained. It was concluded that muscarinic receptors mediating a direct inhibition of ventricular muscle are virtually absent and that the small response obtained in untreated tissue may be due either to inhibition of endogenous catecholamine release via presynaptic receptors or to antagonism of released norepinephrine. Lowering the temperature to 30 or 25 degrees C affected resting tension, rate and contractility and the magnitude of carbachol responses. The concentration-response curves, when plotted as a percentage of the maximum, were displaced to the left by cooling of the atria and papillary muscles. The papillary muscles now exhibited a response after reserpine pretreatment. In working hearts, the concentration-response curves for the fall in spontaneous rate were also shifted to the left, but this was not significant, probably because the temperature could be reduced to only 30 degrees C, below which contractions ceased. Cooling of guinea-pig isolated cardiac preparations therefore induced supersensitivity to the muscarinic effects of carbachol.