Marked Positive Inotropic Effect Research Articles

Receptor Subtypes Mediating the Inotropic Effects and Ca2+ Signaling Induced by Endothelin-1 Through Crosstalk With Norepinephrine in Canine Ventricular Myocardium

In canine ventricular myocardium, endothelin-1 (ET-1) alone induced only a weak transient negative inotropic effect (NIE). However, ET-1 induced a marked sustained positive inotropic effect (PIE) subsequent to a transient NIE in the presence of norepinephrine (NE) at low concentrations (0.1 – 1 nM) and elicited a pronounced sustained NIE in the presence of NE at high concentrations (around 100 nM). Thus, the extent of β-adrenoceptor stimulation induced by NE played a crucial role in determining the characteristics of the inotropic effects of ET-1. The characteristics of ET receptor subtypes involved in contractile regulation and Ca2+ signaling induced by ET-1 were determined. The ET-1-induced transient NIE and decrease in Ca2+ transients were abolished by the selective ETA-receptor antagonist FR319317, but not by the selective ETB-receptor antagonist BQ-788. The sustained PIE and the increase in Ca2+ transients induced by ET-1 were abolished by FR319317, but not inhibited by BQ-788. In contrast, the sustained NIE of ET-1 was abolished by the non-selective ET antagonist TAK-044, markedly attenuated by FR319317, and partially inhibited by BQ-788. ET-1 alone elicited a PIE in the presence of BQ-788, which indicates that the activation of ETB-receptors counteracts the development of the PIE of ET-1. The current findings indicate that both ETA and ETB receptors are involved in the regulation of Ca2+ signaling and contractility in canine ventricular myocardium.

New milrinone analogues: in vitro study of structure-activity relationships for positive inotropic effect, antagonism towards endogenous adenosine, and inhibition of cardiac type III phosphodiesterase

Two mechanisms are responsible for the positive inotropic effect of the cardiotonic drug milrinone, i.e., inhibition of type III cAMP phosphodiesterase (PDE III), and displacement of endogenous adenosine from A(1) inhibitory receptor. Since PDE III inhibition may increase the likelihood of cardiac arrhythmias by increasing cAMP content, our attention focused on the synthesis of new compounds with more pronounced characteristics as adenosine antagonists. In this work, four new milrinone analogues were studied, in comparison with the parent drug, for their effects on the contractility of guinea pig isolated atrial preparations, their ability to antagonize endogenous adenosine at the level of A(1) receptor, and to inhibit the activity of PDE III partially purified from guinea pig heart. The new compounds present various chemical substitutions with respect to the parent drug: in compounds SF397 (methyl 5-cyano-2-methyl-6-oxo-1,6-dihydropyridine-3-carboxylate) and SF399 (benzyl 5-cyano-2-methyl-6-oxo-1,6-dihydropyridine-3-carboxylate), the 4-pyridil moiety of milrinone was replaced with a methoxycarbonyl and a benzyloxycarbonyl group, respectively; the same structural modifications were also associated with the replacement of the cyano-group in 5-position with an acetyl group in compounds SF416 (methyl 5-acetyl-2-methyl-6-oxo-1,6-dihydropyridine-3-carboxylate) and SF419 (benzyl 5-acetyl-2-methyl-6-oxo-1,6-dihydropyridine-3-carboxylate). All the new compounds had a marked positive inotropic effect, most of them also being more active and more potent than milrinone. When their affinity for A(1) receptor was assessed as the displacement of [(3)H] 8-cyclopentyl-1,3-dipropylxanthine ([(3)H]DPCPX) from cardiac membranes, SF397 and SF399 showed affinity (K(i) of about 600 nM) similar to that of milrinone (K(i) 550 nM). By contrast, SF416 and SF419 had very low (K(i) of about 10000 nM) or scarce (K(i) of about 2000 nM) anti-adenosine component, respectively. All the new compounds inhibited PDE III activity, their K(i) values proceeding in the following order: milrinone (3.80 microM) <SF397 (7.00 microM) <SF399 (8.80 microM) <SF416 (35.00 microM) SF419< (155.00 microM). To better characterize the mechanisms responsible for the positive inotropic response of the new compounds, we also investigated the effects of new analogues on some systems (ATP-dependent Ca(2+) uptake, Ca(2+)ATPase, Na(+)/K(+)ATPase, Na(+)/Ca(2+) exchange carrier) or a receptor (beta-adrenoceptor) mainly involved in the control of cardiac contractility. None of the tested compounds inhibited enzyme or transport systems; however, SF397, SF399 and SF416, although to different extents, had a direct beta-adrenergic action. Indications about structure-activity relationships are tentatively discussed, in order to obtain useful information for the design of new analogues with better pharmacological profiles.

Effect of sigma ligand haloperidol in guinea pig heart preparations

The effects of sigma ligand haloperidol in the multicellular guinea pig heart preparations were examined. Adult male guinea pigs were used. Left atrium and papillary muscle from right ventricle were examined. The stimulated twiches in horizontal bath were recorded isometrically. Sigma ligand haloperidol (10nM) was administered for 30 minutes. Its effect on the amplitude of contraction and on the mechanical restitution was evaluated. Marked positive inotropic effect (increase in the twitch amplitude ranging from 50 to 90 % for atria and 5 to 45% for ventricles, with maximal effect in the 5th minute of ligand administration for both preparations) has been observed. The mechanical restitution pattern under the effect of sigma receptor ligand is not altered. Thus, the positive inotropic effect of haloperidol was confirmed in guinea pig heart preparations. According to its effect on the mechanical restitution can be assumed that it is mediated via increased cytoplasmatic calcium concentration.

Antiinflammatory effects of colforsin daropate hydrochloride, a novel water-soluble forskolin derivative

Background. To evaluate the effects of colforsin daropate hydrochloride (colforsin), a water-soluble forskolin derivative, on hemodynamics and systemic inflammatory response after cardiopulmonary bypass, we conducted a prospective randomized study.Methods. Twenty-nine patients undergoing coronary artery bypass grafting were randomized to receive either colforsin treatment (colforsin; n = 14) or no colforsin treatment (control; n = 15). Administration of colforsin (0.5 μg · kg−1 · min−1) was started after induction of anesthesia and was continued for 6 hours. Perioperative cytokine and cyclic adenosine monophosphate levels, hemodynamics, and respiratory function were measured serially.Results. Marked positive inotropic and vasodilatory effects were observed in patients receiving colforsin. Interleukin 1β, interleukin 6, and interleukin 8 levels after cardiopulmonary bypass were significantly (p < 0.05) lower in the colforsin group. Plasma levels of cyclic adenosine monophosphate increased significantly (p < 0.05) in the colforsin group, and the levels correlated inversely (r = −0.56, p = 0.002) with the respiratory index after cardiopulmonary bypass.Conclusions. Intraoperative administration of colforsin daropate hydrochloride had potent inotropic and vasodilatory activity and attenuated cytokine production and respiratory dysfunction after cardiopulmonary bypass. The results indicate that the technique can be a novel therapeutic strategy for the systemic inflammatory response associated with cardiopulmonary bypass.

ANTIINFLAMMATORY EFFECT OF COLFORSIN DAROPATE HYDROCHLORIDE AFTER CARDIOPULMONARY BYPASS

Purpose of study. To evaluate the effects of colforsin daropate hydrochloride (colforsin), a novel water-soluble forskolin derivative, on hemodynamics and systemic inflammatory response after cardiopulmonary bypass (CPB), we conducted a prospective randomized study. Methods used. Twenty-nine patients undergoing coronary artery bypass grafting were randomized to receive either colforsin treatment (colforsin; n=14) or no colforsin treatment (control; n=15). Administration of colforsin (0.5μg•kg−1•min−1) was started after induction of anesthesia and was continued for 6 hours. Perioperative cytokine and cAMP levels, hemodynamics, and respiratory function were measured serially. Results. Marked positive inotropic and vasodilatory effects were observed in patients receiving colforsin. IL-1β, IL-6 and IL-8 levels after CPB were significantly (p<0.05) lower in the colforsin group. Plasma levels of cAMP increased significantly (p<0.05) in the colforsin group and the levels correlated inversely with the respiratory index (r=-0.56, p=0.002) and correlated inversely with the peak IL-6 levels (r=-0.57, p=0.001) after CPB. Conclusions. Intraoperative administration of colforsin daropate hydrochloride had potent inodilator activity, and attenuated cytokine production and respiratory dysfunction after CPB. The results indicate that the technique can be a novel therapeutic strategy for the systemic inflammatory response associated with CPB.

Alpha 1-adrenoceptor-mediated negative inotropy of adrenaline in rat myocardium.

1. The effect of alpha- and beta-adrenoceptor stimulation on isotonic contraction was investigated on right ventricular papillary muscles of the rat, stimulated at a rate of 0.5 Hz. 2. Adrenaline (0.5 microM) induced a slight but significant negative inotropic effect: shortening decreased from 0.137 +/- 0.058 to 0.122 +/- 0.059 muscle lengths (mean +/- S.D.; -11%, P < 0.0001) and maximum shortening velocity from 2.9 +/- 1.2 to 2.7 +/- 1.3 muscle lengths s-1 (-7%, P < 0.025). 3. The negative inotropic effect of adrenaline was enhanced after blocking the beta-adrenoceptors with 50 microM atenolol. On the other hand, exposure to adrenaline after blocking the alpha-adrenoceptors with 50 microM phentolamine resulted in an increase in shortening as well as in maximum shortening velocity. 4. Stimulation of the beta-adrenoceptors with 0.5 microM isoprenaline caused marked positive inotropic effects, whereas stimulation of the alpha 1-adrenoceptors with 0.5 microM phenylephrine regularly resulted in a long-lasting decrease in shortening and maximum shortening velocity. 5. 1,2-Dioctanoyl-sn-glycerol (1,2-DOG) and adrenaline induced an activation of protein kinase C (PKC) with translocation of this enzyme from the cytosol to the sarcolemma. 6. Activation of PKC with 10 microM 1,2-DOG and 0.5 microM adrenaline was accompanied by a decrease in shortening and maximum shortening velocity. Inhibition of PKC with 0.1 microM staurosporine abolished the negative inotropic effect of adrenaline. 7. From these results we conclude that a low dose of adrenaline stimulates not only beta-but also alpha-adrenoceptors and that the observed negative inotropic effect of adrenaline is mediated by alpha 1-adrenoceptors, linked to the diacylglycerol-PKC signal transduction pathway.

Histamine H 3 -Receptor–Mediated Inhibition of Calcitonin Gene-Related Peptide Release From Cardiac C Fibers

Antidromic stimulation of cardiac sensory C fibers releases calcitonin gene-related peptide (CGRP), which increases heart rate, contractility, and coronary flow. C-fiber endings are closely associated with mast cells, and CGRP may release mast-cell histamine. Because prejunctional histamine H3-receptors inhibit transmitter release from autonomic nerves, we tested the hypothesis that H3-receptors modulate CGRP release in the heart. CGRP released by bradykinin in the electrically paced guinea pig left atrium and by capsaicin in the spontaneously beating isolated heart caused marked positive inotropic and chronotropic effects, respectively. Capsaicin significantly enhanced the overflow of CGRP (fivefold) and histamine (twofold) into the coronary effluent. All of these effects were prevented by prior chemical destruction of C fibers in vivo. The H3-receptor agonist imetit attenuated the inotropic response to bradykinin by 50%. Imetit also decreased the capsaicin-induced tachycardia and the increase in CGRP overflow by 50%. Imetit, however, did not modify the response to exogenous CGRP. The effects of imetit were blocked by the H3-receptor antagonist thioperamide. Notably, thioperamide by itself potentiated the capsaicin-evoked increases in heart rate and CGRP overflow (by 25% and 50%, respectively). Thus, our findings identify a negative-feedback loop, whereby CGRP releases histamine from cardiac mast cells and histamine in turn inhibits CGRP releases by activating H3-receptors on C-fiber terminals. Because CGRP release is augmented in pathophysiological conditions, such as septic shock, heart failure, and acute myocardial infarction, modulation of CGRP release may be clinically relevant.

Differential effects of the optical isomers of EMD 53998 on contraction and cytoplasmic Ca2+ in isolated ferret cardiac muscle.

EMD 53998 (a thiadiazinone) is a novel inotropic substance that increases the Ca2+ sensitivity of the myofilaments in skinned cardiac fibers and has been found to have similar effects in intact cardiac muscle. However, the compound also possesses the ability to inhibit phosphodiesterase III, indicating that its actions in intact cardiac muscle are likely to be complex. The present study was carried out to investigate the possibility that the optical isomers of EMD 53998--(+)EMD 57033 and (-)EMD 57439--which have recently been shown to possess a separation of sensitization and phosphodiesterase inhibition in subcellular preparations, might also demonstrate this separation of activities in intact cardiac muscle. The experiments were performed on isolated ferret papillary muscles, which were contracting isometrically. In some preparations, the photoprotein aequorin was injected into superficial cells to measure intracellular Ca2+ as well as force. (+)EMD 57033 caused a substantial positive inotropic effect that was associated with prolongation of the twitch, reduction in the amplitude of the Ca2+ transient, and abbreviation of the Ca2+ transient. This is the profile expected of a Ca(2+)-sensitizing compound. Conversely, (-)EMD 57439 caused a less marked positive inotropic effect that was associated with an abbreviation of the twitch, an increase in the amplitude of the Ca2+ transient, and an abbreviation of the Ca2+ transient. This is the profile expected of an agent producing its inotropic effect by increasing cAMP (e.g., phosphodiesterase inhibition). The results indicate that the optical isomers of EMD 53998 possess a remarkable separation of Ca(2+)-sensitizing and phosphodiesterase-inhibiting activities in intact cardiac muscle. These actions were additive and could account for the effects observed with EMD 53998. (+)EMD 57033 appears to be the first inotropic agent that acts predominantly by increasing myofilament calcium sensitivity.

Synthesis of a new type of ‘bent’ heterocyclic benzimidazolo-pyridazinones

The synthesis of some new heterocyclic benzimidazolo-pyridazinones starting from 2,1,3-benzothiadiazole-4-carboxaldehyde 2 is described. Biological evaluation of all new compounds proved them to be inhibitors of phosphodiesterase III with no marked positive inotropic effects.

Okadaic acid, a protein phosphatase inhibitor, increases the calcium transients in isolated ferret ventricular muscle.

Okadaic acid is a protein phosphatase inhibitor which has been found to produce a marked positive inotropic effect in isolated cardiac muscle. Using aequorin-injected ferret papillary muscles, we demonstrate that the increase in tension seen with okadaic acid is accompanied by a simultaneous increase in the amplitude of the calcium transients. By comparison with the effects of changing the extracellular calcium concentration, it is shown that the increase in calcium transient amplitude can account for the inotropic effect of okadaic acid.

Decreased sensitivity of contraction to changes of intracellular pH in papillary muscle from diabetic rat hearts.

1. The relationship between intracellular pH (pHi) and contractile activity was investigated in papillary muscles isolated from right ventricle of normal and streptozotocin (STZ)-induced diabetic rats. pHi changes induced by 20 mM-NH4Cl were recorded with H(+)-sensitive microelectrodes. 2. An increase in pHi of approximately 0.20 pH units on exposure to NH4Cl led to an increase of the maximum developed tension, which was 707.8 +/- 57.5% (mean +/- S.E. of mean, n = 10) of control in normal muscles and 271 +/- 16.3% (n = 10) in diabetic muscles. On the other hand, acidosis induced by NH4Cl withdrawal was associated with a fall in developed tension to 48.2 +/- 6.7% of control in diabetic muscles, as compared to 79.2 +/- 8% in normal muscles. 3. The decrease in tension associated with acidosis was rapidly followed (in approximately 2 min) by a transient redevelopment of force, which peaked at 80.2 +/- 8.6% of control in the diabetic muscles as compared to 153.5 +/- 11.7% in normal papillary muscles. The peak of this secondary positive inotropy coincided in both groups of muscles with the maximum decrease of pHi, i.e. -0.40 +/- 0.02 and -0.28 +/- 0.04 pH units in diabetic and normal muscles, respectively. 4. Caffeine (10 mM), which had a marked positive inotropic effect in both groups of muscles, abolished the transient recovery of tension occurring after NH4Cl withdrawal. Ryanodine (2 microM) which had a marked negative inotropic effect on both normal and diabetic papillary muscles, also suppressed the transient recovery of tension. 5. The presence of amiloride (1 mM) during acidosis induced by NH4Cl withdrawal abolished the observed differences in developed tension, in particular the transient recovery of tension, between normal and diabetic muscles, as it abolished the differences in the amplitude of pHi decrease and in the time course of pHi recovery. 6. The presence of 2',4'-dichlorobenzamil amiloride (40 microM) significantly and similarly delayed and reduced the amplitude of transient recovery of tension in both normal and diabetic papillary muscles. 7. We conclude that STZ-induced diabetes induces a decrease in pHi sensitivity of contractile force. This may be the consequence of a change in sarcoplasmic reticulum (SR) composition and function, and may also indirectly result from changes in Na(+)-H+ exchange activity, particularly during intracellular acidosis.

Increasing Extracellular Calcium Concentration Does Not Prevent Hypotensive Effects of Verapamil in Neonatal Swine

Effects of CaCl2 on cardiac function and regional circulatory responses to verapamil (V) infusion were studied in pentobarbital-anesthetized 2-week-old swine. V 100 micrograms/kg (n = 15) or 300 micrograms/kg (n = 15), given as a 2-min intravenous infusion, was repeated after 30 min. Only V was given to 15 of these. The other 15 were given CaCl2 (15 mg/kg) over 2 min, pre-V (protocol A), and over 4 min, 2 min pre-V and during V (protocol B). Positive chronotropic and negative inotropic responses to V were attenuated by CaCl2; hypotensive effects were unaltered. Renal, but not mesenteric and femoral, vasodilation was augmented by CaCl2, CaCl2 alone produced marked positive inotropic and renal vasodilatory effects which contributed to maintenance of the hypotensive effect of V.

Hexahydrochinolinone mit calciummodulatorischem Effekt ‐ Synthese und pharmakologische Wirkung

The hexahydroquinolinones 4a-I were prepared by Knoevenagel-reaction of cyclohexandione (1) and the aromatic aldehydes 2a-I and subsequent cyclising Michael-addition with methyl beta-aminocrotonate 3. The new compounds are characterized by IR-, 1H-NMR-and mass spectroscopy. At the electrically stimulated left guinea pig-atrium structures of type 4 show marked positive inotropic effects, whereas BaCl2-induced contractions of the guinea pig-ileum are supressed dose-dependently with activity rates comparable to those of nifedipine. Furthermore, relaxation of KCl-stimulated aorta-musculature is observed.

Effects of 2-methyl-1,4-naphthoquinone (menadione) on myocardial contractility and cardiac sarcoplasmic reticulum Ca-ATPase

(1) In electrically driven guinea-pig left atria, menadione (2-methyl-1,4-naphthoquinone) (1 to 20 mumol/l) and menadione sodium bisulfite (30 to 200 mumol/l) produced marked positive inotropic effects. Endogenously released catecholamines and histamine contributed to 80-85% of the effect, the residual 15-20% appearing as a direct effect. (2) In electrically driven guinea-pig ventricular strips, low micromolar concentrations of menadione (0.05 to 0.3 mumol/l) exerted a catecholamine-mediated small positive inotropic effect. (3) In both myocardial preparations, the increase in force of contraction was followed by a non-reversible rise of resting force. In its effects on cardiac contractility menadione resembled the thiol group blocking agent p-chloromercuribenzoate and H2O2. Pretreatment of atria with glutathione prevented the increase in resting force, while dithiothreitol only slightly delayed it. By contrast, the pretreatment with the NAD(P)H-quinone reductase (DT-diaphorase) inhibitor, dicumarol, markedly increased the rate of appearance of the toxic effect of menadione. (4) Among enzymatic and transport systems involved in the onset and control of cardiac contractility, sarcoplasmic reticulum Ca-ATPase was significantly inhibited by menadione after a long contact time. The inhibition was concentration-dependent and persistent, and was antagonized by addition of glutathione. (5) On the basis of these results, the increase in resting force caused by menadione appears to be related to an impairment of the thiol groups of proteins (Ca-ATPase), presumably caused by the drug per se.

Inter-species variations in myocardial responsiveness to cardiac glycosides: Possible relations to the thyroid status

Mammalian species differ in their myocardial responsiveness to cardiac glycosides; whereas glycosides induce a marked positive inotropic effect in species such as dog, rabbit and guinea-pig, the rat myocardium is virtually insensitive. We investigated the physiological basis for this phenomenon by testing the hypothesis that the inter-species variations in the response of the myocardium to cardiac glycosides result, at least in part, from species-related differences in the “thyroid status”. In the present study we focused on the toxic effects of the glycosides, and studied ouabain-induced delayed afterdepolarizations (DAD): (1) in guinea-pigs, rats and mice, which encompass a wide range of thyroid statuses, as indicated by their O 2 consumption and thyroid hormone levels: (2) in guinea-pigs and rats in which the thyroid status was decreased by propylthiouracil treatment or increased by thyroxine administration (in the former species only). DAD were readily induced in guinea-pigs after 40 to 60 min superfusion with 10 −6 m ouabain and 5.4 m m Ca 2+. In rats, DAD were induced only when the Ca 2+ concentration was raised to 8.1 m m, but were absent in mice even after 2 h of superfusion with ouabain and 8.1 m m Ca 2+. In guinea-pigs and rats (at cycle length = 500 ms), DAD amplitude was ( x ± s.e.) : 2.8 ± 0.7 mV and 1.1 ± 0.4 mV, respectively. The slope of the DAD ascending limb ( dV dt ) in guinea-pigs was 47.6 ± 8.6 mV/s and in rats was 8.1 ± 3.4 mV/s. In both species DAD characteristics were altered by the thyroid status. In eu-, hyper- and hypothyroid guinea-pigs, DAD amplitude and dV dt (cycle length = 500 ms) were as follows: 2.8 ± 0.7 mV and 47.6 ± 8.6 mV/s; 1.2 ± 0.4 ∗ mV and 12.6 ± 3.9 ∗ mV/s; 7.5 ± 0.6 ∗ mV and 204.0 ± 18.4 ∗ mV/s, respectively ( ∗, P < 0.005, compared to euthyroid guinea-pigs). The occurrence of triggered beats was also dependent on the thyroid status. They occur more frequently in hypothyroidism and less frequently in hyperthyroidism. Hypothyroidism in rats augmented ouabain toxicity as reflected by an increase in DAD amplitude and dV dt by 109% and 105%, respectively ( P < 0.05, as compared to euthyroid rats). In conclusion, we suggest that species-related differences in the thyroid status may contribute to the inter-species (as well as for the intra-species) variations in the myocardial responsiveness to cardiac glycosides.

Functional alpha-adrenoceptors in human atrial preparations in the presence of beta-receptor blockade.

Inotropic effects via cardiac alpha-adrenoceptors were studied in electrically driven auricular strips (1 Hz, 37 degrees C) from patients treated with beta-blockers for months prior to open heart surgery. Marked alpha-mediated positive inotropic effects were demonstrated with adrenaline (A), noradrenaline (NA) and phenylephrine (PHE) in the presence of beta-blocker and with blockers of the muscarinic receptor and of the neuronal and extraneuronal uptake mechanisms for the catecholamines. In the presence of approximately 10(-6) M propranolol the maximal effects as well as the potencies (pD2-values) for A and NA were not significantly different while higher than for PHE. The alpha 1-blocker, prazosin (10(-6) M), markedly reduced the pD2-values but not the intrinsic activities (alpha-values) for A, NA and PHE in the beta-blocked preparations. Methoxamine, however, induced negative inotropic responses at normal and low frequencies (1, 0.5 and 0.1 Hz) of stimulation, suggestive of non-specific, cardiodepressant effects. Other agonists with alpha-effects in other types of tissue (oxymethazoline, xylomethazoline and clonidine) were without effects on the force and velocity of contraction in the auricular strips under the present experimental conditions. The results show alpha 1-type of adrenoceptor-induced inotropic effects for A, NA and PHE during beta-blockade in human auricular strips, indicating that cardiac alpha 1-receptors may have clinical importance by increasing the inotropy of the human myocardium treated with beta-blocking agents.

Can strontium replace calcium as an activator of internal calcium release in cardiac muscles?: Study on a dual action of A23187

The positive inotropic effect of A23187 has previously been indicated to be attributed to both the enhancement of the slow Ca inward current and the facilitation of Ca release from internal stores. The electromechanical effects of replacing external Ca by Sr on this dual action of A23187 were examined on guinea-pig papillary muscles driven at 0.2 Hz. Replacing most of external Ca by Sr (Sr 2.5 mM plus Ca 0.2 mM) (Sr-medium) increased the developed tension. This procedure simultaneously prolonged the time to peak developed tension (tPT) and the action potential duration at all repolarization phases (APD 10, APD 30 and ADP 80). In such preparations, A23187 (10(-6) M) caused a marked positive inotropic effect (938 +/- 180% of control) accompanied by a prolongation of APD at an early repolarization phase (APD 10), but did not affect tPT. Thereafter, returning superfusate to normal Ca medium (Ca 1.2 mM) in the presence of A23187 also caused a positive inotropic effect, but markedly shortened tPT. The electrical and mechanical responses to A23187 in Sr-medium were completely blocked by nifedipine (2 X 10(-6) M), Ca-channel-blocker, while the positive inotropic effect in normal Ca medium was not blocked by nifedipine. Ryanodine, an inhibitor of internal Ca release, did not affect the positive inotropic effect of A23187 in Sr-medium. These results suggest that in Sr-medium, an internal Ca pool of the myocardium, most likely sarcoplasmic reticulum, does not play a role in the activation of contraction.

Electromechanical effects of A23187 on Guinea-pig ventricular muscle: A dual action of A23187

The effects of A23187 on electromechanical activity of guinea-pig papillary muscles were examined by microelectrode techniques. A23187 (10(-6) M) caused a marked positive inotropic effect (868% of control) on preparations driven at 0.2 Hz. This inotropic effect was accompanied by a significant prolongation of the action potential duration at an early repolarization phase (APD 10), but not at a late repolarization phase (APD 30 and APD 80). Other parameters of action potential were unaffected. In the presence of nifedipine (10(-6) M), Ca2+ channel blocker, A23187 still increased the contractile force (495% of control) but had no effect on APD 10. On the other hand, APD 30 and APD 80 were significantly shortened. In the presence of ryanodine (2 X 10(-6) M), an inhibitor of internal Ca2+ release, A23187 was also able to cause the positive inotropic effect (389% of control). This inotropic effect was accompanied by a prolonged APD 10. These electrical and mechanical effects of A23187 were completely blocked by the combined treatment with nifedipine and ryanodine, suggesting that A23187 has a dual action. In papillary muscles depolarized by 26 mM [K+]0, A23187 augmented the slow action potential. In voltage clamp experiments using a single sucrose-gap method, A23187 caused a marked increase in the slow inward current and the outward current. The effects of A23187 were not antagonized by a beta-adrenoceptor and a histamine (H2) receptor antagonists.(ABSTRACT TRUNCATED AT 250 WORDS)

Excitation-contraction coupling in myocardium of nonhibernating and hibernating chipmunks: effects of isoprenaline, a high calcium medium, and ryanodine.

The electromechanical responses to isoprenaline and a high calcium medium on cardiac muscles from nonhibernating and hibernating chipmunks were studied in the presence and the absence of ryanodine. In nonhibernating animal preparations, isoprenaline (5 X 10(-8) M) caused a marked positive inotropic effect with an increase in the amplitude of the action potential plateau and augmented the slow action potential in muscle depolarized with 26 mM K+. In hibernating animal preparations, isoprenaline failed to cause a positive inotropic effect in spite of an increase in the amplitude of action potential plateau and slow action potentials. Similar inotropic effects were caused in the two preparations when extracellular calcium was raised to 6 mM, but action potential plateau and slow action potentials of the two preparations were less affected by this procedure; only in nonhibernating animal preparations was the amplitude of the slow action potential slightly increased. Ryanodine (2 X 10(-6) M) partially inhibited the contraction but augmented the action potential plateau and slow action potentials in nonhibernating animal preparations, while in hibernating animal preparations, it eliminated the contraction and severely inhibited the action potential plateau and slow action potentials. The electrical effects of isoprenaline on the two preparations and of a high calcium medium on nonhibernating animal preparations were more pronounced in the presence of ryanodine than in the absence of it. However, the electrical activity on hibernating animal preparations was unaffected by a high calcium medium in either the presence or absence of ryanodine.(ABSTRACT TRUNCATED AT 250 WORDS)

Different effectiveness of glucagon on the pacemaker activity and contractility in intact dog hearts and in isolated perfused right atria.

In an isolated right atrial preparation, which was cross-perfused with heparinized arterial blood from a support dog, we investigated the effects of glucagon on heart rate and systemic arterial blood pressure of the support dog and on atrial rate and contractile force of the isolated perfused atrium when glucagon was injected into the external jugular vein of the support dog or into the sinus node artery of the isolated atrial preparation. Glucagon (0.3 to 3 micrograms/Kg i.v.) to the support dog dose-dependently induced a prominent increase in heart rate and a small increase in systemic arterial blood pressure. In the isolated, perfused atrium, marked positive chronotropic and slight, but significant, positive inotropic effects were evoked dose-dependently 1.5 min after intravenous injection of glucagon. These positive effects were not altered significantly by propranolol (1 mg/Kg i.v.). Direct injection of glucagon into the sinus node artery of isolated atria also induced marked positive chronotropic and small positive inotropic effects dose-dependently. CF/HR ratios, inotropic effect per chronotropic effect in isolated atria, of glucagon injected intravenously or intraarterially were less than 0.7 and they were much less than those of norepinephrine (more than 3.6). These results confirm that glucagon injected intravenously or regionally produces a prominent positive chronotropic effect and a small positive inotropic effect and suggest that glucagon may be less effective as a cardiotonic agent.