Concentration-dependent Positive Inotropic Effect Research Articles

Mechanistic insight into the functional and toxic effects of Strophanthidin in the failing human myocardium

Cardiac glycosides are characterized by a narrow therapeutic range with Ca2+-overload and arrhythmias occurring at higher concentrations. Data on cardiac glycosides in isolated failing human myocardium are scarce and the frequency-dependent actions and toxicity of Strophanthidin have not yet been characterized. To determine inotropic responses and toxicity of Strophanthidin in failing human myocardium. Experiments were performed in trabeculae from 64 end-stage failing hearts. Developed force, and intracellular [Ca2+]i and [Na+]i were recorded with Strophanthidin (0.01 to 1 micromol/L; 37 degrees C, 1 Hz) and compared to interventions with distinct mechanisms of action (elevated [Ca2+]o, Isoproterenol, and EMD57033). The effects of Strophanthidin on force-frequency behaviour were also assessed. Strophanthidin exerted concentration-dependent positive inotropic effects. These were paralleled by increases in intracellular [Na+] as well as increasing [Ca2+]i-transients and SR-Ca2+-load. At high concentrations (>0.5 micromol/L), Strophanthidin caused afterglimmers and aftercontractions, with declining developed force despite further increasing [Ca2+]i-transients. The force-frequency-relationship and diastolic function at higher pacing rates was worsened by Strophanthidin in a concentration-dependent manner. Strophanthidin toxicity was dependent on concentration, calcium load, beating rate and beta-adrenergic receptor activation. Our data support the view that low doses, heart rate control and additional beta-adrenergic receptor blockade are essential in the use of cardiac glycosides in heart failure.

A Comparison of Three Phosphodiesterase Type III Inhibitors on Mechanical and Metabolic Function in Guinea Pig Isolated Hearts

Little is known about of the comparative cardiac lusitropic and coronary vasoactive effects of type III phosphodiesterase inhibitors independent of their systemic circulatory effects. We hypothesized that phosphodiesterase inhibitors have dissimilar concentration-dependent effects on cardiac function and metabolism and that their coronary vasodilatory effects are solely dependent on flow autoregulation secondary to positive inotropic effects. Our aim was to compare the dose-response electrophysiologic, mechanical, vasodilatory, and metabolic properties of three clinically available phosphodiesterase inhibitors in isolated Langendorff perfused guinea pig hearts. We found that, over a range from 10(-7) to 10(-4) M, amrinone, enoximone, and milrinone each produced maximal concentration-dependent positive chronotropic (12%, 18%, 26%), inotropic (16%, 26%, 26%), and lusitropic (14%, 21%, 19%) effects. At clinical concentrations, all phosphodiesterase inhibitors increased heart rate, but only milrinone significantly enhanced contractility and relaxation (11%). Each phosphodiesterase inhibitor similarly increased contractility at its highest concentration; this was accompanied by an increase in oxygen consumption, which was matched by comparable increases in coronary flow and oxygen delivery. Coronary flow reserve was preserved at the highest concentration of each drug, indicating that an increased metabolic rate was responsible for the increase in coronary flow by each drug at each concentration. Over the concentrations examined, we conclude that each of the phosphodiesterase inhibitors does not directly promote coronary vasodilation and that milrinone has the most prominent effects on contractility and relaxation at clinically relevant concentrations.

Diazepam Enhances Inotropic Responses to Dopamine in Rat Ventricular Myocardium

Diazepam inhibits phosphodiesterase type 4 and enhances the effect of some 3',5'-cyclic adenosine monophosphate (cAMP)-dependent positive inotropic drugs. We sought to determine whether diazepam and the selective phosphodiesterase type 4 inhibitor rolipram enhances the contractile response and cAMP levels induced by dopamine in rat myocardium. Dopamine (3-100 microM) produced concentration-dependent positive inotropic effects (-log EC50 = 5.21 +/- 0.2, n = 5), which were augmented in the presence of 10 microM diazepam (-log EC50 = 5.40 +/- 0.08, n = 6, P < 0.05) or 1 microM rolipram (-log EC50 = 5.41 +/- 0.1, n = 6, P < 0.05). The effect of diazepam was not mimicked by 100 microM gamma-aminobutyric acid nor it was antagonized by a 5 microM concentration of the blockers of central and peripheral type benzodiazepine receptors, flumazenil and PK 11195. cAMP levels (pmol/g) produced by dopamine (744.4 +/- 111.8, n = 5) in this tissue were enhanced by the presence of diazepam (1073 +/- 97.7, n = 6, P < 0.05) or rolipram (1034.0 +/- 245.2, n = 5, P < 0.05). Therefore, diazepam, like rolipram, augments the inotropic and biochemical effects of dopamine in rat myocardium. This effect is not mediated by benzodiazepine receptors but is probably the consequence of the phosphodiesterase type 4 inhibitory activity of diazepam.

The phosphodiesterase 3 inhibitor cilostamide enhances inotropic responses to glucagon but not to dobutamine in rat ventricular myocardium

The effects of phosphodiesterase (PDE) inhibitors (1–3) on tissue cAMP concentrations and the inotropic responses to dobutamine and glucagon were investigated in electrically driven right ventricular strips of the rat heart. Dobutamine (0.3–100 μM) produced a concentration-dependent positive inotropic effect which was not affected by 50 nM (±)-1-(2,3-(dihydro-7-methyl-1 H-inden-4-yl)oxy)-3-((1-methylethyl)amino)-2-butanol hydrochloride (ICI 118551), a β 2-receptor antagonist, but was virtually abolished by 0.3 μM (±)-2-hydroxy-5-(2-((2-hydroxy-3-(4-(1-methyl-4-(trifluoromethyl)-1 H-imidazol-2-l)phenoxy)propyl)amino)ethoxy)-benzamide methanesulfonate (CGP 20712A), a β 1-receptor antagonist. Glucagon (0.01–1 μM) also enhanced the contractility of the preparation in a concentration-dependent way. Selective inhibitors of PDE 1 8-methoxymethyl-3-isobutyl-1-methylxantine (MIMX, 1 μM), PDE 2 erythro-9-[2-hydroxy-3-nonyl]adenine (EHNA, 1 μM) and PDE 3 cilostamide (0.1 μM) did not affect basal contractility. Cilostamide increased the positive inotropic effects of glucagon but not those of dobutamine. MIMX and EHNA did not alter the effects of either dobutamine or glucagon. Dobutamine (3 μM), but not glucagon (0.1 μM), increased tissue levels of cAMP. 1 μM of MIMX or EHNA were devoid of effects and failed to alter the effects of dobutamine and glucagon on cAMP. Cilostamide (0.1 μM) did not increase the effects of dobutamine but caused glucagon to enhance cAMP. The pharmacological and biochemical data presented in this study can be explained quantitatively by a cell compartment model in which PDE 3 appears to be colocalized with the contractile machinery responsible for the effects of glucagon but not those of dobutamine. Neither PDE 1 nor PDE 2 appears to regulate the inotropic effects of dobutamine and glucagon in rat ventricular myocardium.

Insulin-like growth factor-1 exerts Ca2+-dependent positive inotropic effects in failing human myocardium.

Myocardial generation of insulin-like growth factor-1 (IGF-1) is altered in hypertrophy and heart failure, but there are no reports on acute functional effects of IGF-1 in human cardiac muscle. We examined inotropic responses and signal transduction mechanisms of IGF-1 in human myocardium. Experiments were performed in isolated trabeculae or cardiomyocytes from 46 end-stage failing hearts. The effect of IGF-1 (0.001 to 0.2 micromol/L) on isometric twitch force (37 degrees C, 1 Hz), intracellular Ca2+ transients (aequorin method), sarcoplasmic reticulum (SR) Ca2+ content (rapid cooling contractures), L-type Ca2+ current (whole-cell voltage clamp), and cAMP concentrations was assessed. In addition, the effects of blocking IGF-1 receptors, phosphoinositide 3-kinase (PI3-kinase), protein kinase C (PKC), or transsarcolemmal Ca2+ entry were tested. IGF-1 exerted concentration-dependent positive inotropic effects (twitch force increased to maximally 133+/-4% of baseline values at 0.1 micromol/L; P<0.05). The IGF-1 receptor antibody alphaIR3 or the PI3-kinase inhibitor wortmannin prevented the functional effects. The inotropic response was paralleled by increases in Ca2+ transients and SR Ca2+ content. IGF-1 (0.1 micromol/L) increased L-type Ca2+ current amplitude by 24+/-7% (P<0.05). Blockade of SR function did not affect the inotropic response to IGF-1. In contrast, L-type Ca2+ channel blockade with diltiazem partially prevented ( approximately 50%) the inotropic response to IGF-1. Inhibition of PKC (GF109203X), Na+-H+ exchange (HOE642), or reverse-mode Na+-Ca2+ exchange (KB-R7943) reduced the response to IGF-1 by approximately 60% to 70%. IGF-1 exerts Ca2+-dependent positive inotropic effects through activation of IGF-1 receptors and a PI3-kinase-dependent pathway in failing human myocardium. The increased [Ca2+]i with IGF-1 originates from both enhanced L-type Ca2+ currents and enhanced Na+-H+ exchange-dependent reverse-mode Na+-Ca2+ exchange. These nongenomic functional effects of IGF-1 may be of clinical relevance.

Pharmacological Characterization of Effects of UK-1745, a Novel Cardiotonic Agent withβ-Adrenoceptor-blocking Action, in Aequorin-loaded Canine Right Ventricular Muscle

UK-1745, a derivative of furoindolinone, is a novel cardiotonic agent that was designed to have bothβ-adrenoceptor-blocking and cardiotonic activity. The aim of this study was to clarify the mode of action of UK-1745 in the canine and rabbit myocardium. UK-1745 elicited a weak but definite concentration-dependent positive inotropic effect in association with a decrease in the total duration of contraction: in particular, a decrease in the relaxation time in isolated canine right ventricular trabeculae. The maximum positive inotropic effect of UK-1745 was achieved at 3×10−5m and amounted to approximately 15% of the maximum response to isoproterenol. The EC50for the positive inotropic effect of UK-1745 was 3.3×10−6m . Carbachol, a muscarinic receptor agonist, at 3×10−6m completely inhibited the positive inotropic effect of UK-1745. UK-1745 shifted the concentration-response curve for isoproterenol to the right with pA2value of 5.70. By contrast, UK-1745 at 3×10−7to 3×10−5m shifted the concentration-response curve for forskolin to the left. In aequorin-loaded ventricular trabeculae, UK-1745 induced a positive inotropic effect that was accompanied by an increase in Ca2+transients. It did not affect the relationship between the amplitude of Ca2+transients and peak force as compared with that associated with elevation of the extracellular concentration of Ca2+ions ([Ca2+]o). The level of cyclic AMP in tissue was not significantly increased at 3×10−5m UK-1745. The present results indicate that UK-1745 exerts a positive inotropic effect mainly via a cyclic AMP-dependent mechanism but, in addition, it hasβ-adrenoceptor-blocking activity over the same range of concentrations. A drug with such a pharmacological profile might have the potential advantage of avoiding Ca2+overload and superfluous oxygen consumption, which may contribute to the unfavorable effects of novel cardiotonic agents that act purely by inhibition of phosphodiesterase III.

Effects of Levosimendan on Myocardial Contractility and Ca2+Transients in Aequorin-loaded Right-ventricular Papillary Muscles and Indo-1-loaded Single Ventricular Cardiomyocytes of the Rabbit

Effects of levosimendan on myocardial contractility and Ca2+transients were assessed in the ventricular myocardium of the rabbit. Levosimendan at and above 0.1μmhad a concentration-dependent positive inotropic effect (PIE) on isolated papillary muscles that had been loaded with aquorin. The maximum inotropic response to levosimendan at 3μmwas approximately 20% of the maximum response to isoproterenol (ISOmax), whereas the maximum increase in the amplitude of Ca2+transients was approximately 11% of ISOmax. For a given PIE, levosimendan increased the amplitude of Ca2+transients much less than an elevation of [Ca2+]o. Levosimendan did not prolong the relaxation time. Similar results were obtained in single ventricular cardiomyocytes that had been loaded with indo-1. In the presence of the muscarinic receptor agonist carbachol, both the PIE and the increase in the Ca2+transient induced by levosimendan were markedly attenuated. During wash-out of both carbachol and levosimendan, the contractile force increased conspicuously with little change in the amplitude of Ca2+transients, an indication that the increase in myofibrillar sensitivity to Ca2+ions elicited by levosimendan was susceptible to carbachol. Levosimendan at and above 0.03μmshifted the concentration–response curve for isoproterenol to the left. Levosimendan had a positive chronotropic effect at 0.01μmand higher in the isolated right atrium of the rabbit. These findings indicate that, in addition to the increase by levosimendan of the sensitivity of contractile proteins to Ca2+ions, the accumulation of cyclic AMP due to the phosphodiesterase-inhibitory action of levosimendan might contribute to the PIE of this drug.

Effect of the Na+-channel modulator BDF 9148 on Ca2+-sensitivity and force of contraction of hypertrophic myocardium from transgene rats harboring the mouse Renin gene (TG(mREN2)27).

The present study aimed to investigate the inotropic effect of the Na+-channel modulator BDF 9148 in hypertrophic myocardium compared to control tissue. Thus, TG(mREN2)27 rats (TGR), a model with hypertension induced cardiac hypertrophy, was compared with age matched Sprague-Dawley rats (SPDR). The effect of BDF 9148 (0.01-10 microM) on force of contraction (1 Hz, 37 degrees C), the force-frequency relationship (0.5-7 Hz) and the frequency-dependent diastolic tension (0.5-7 Hz) was studied on left ventricular papillary muscles from SPDR and TGR. Chemically skinned muscle fibers of the same hearts were used to examine the influence of BDF 9148 on the Ca2+-sensitivity of the contractile proteins. For control the Ca2+-sensitizer EMD 57033 was examined. In addition the Na+/K+-ATPase activity was measured in both, SPDR and TGR. BDF 9148 showed a concentration dependent positive inotropic effect in SPDR and TGR cardiac preparations. Comparing SPDR and TGR, a higher effectiveness of BDF 9148 on TGR was found, while the potency was unchanged. With increasing stimulation rates a significant higher decrease in force of contraction in TGR compared to SPDR was observed. In addition, a significant higher increase in diastolic tension was found in TGR. After exposure to 1 microM BDF 9148 the decrease in force of contraction was significantly reduced in both SPDR and TGR, while only in TGR the increase in diastolic tension was reduced. BDF 9148 had no effect on the Ca2+-sensitivity or maximal developed tension of skinned fiber preparations from SPDR or TGR. In contrast, the Ca2+-sensitizer EMD 57033 increased the Ca2+-sensitivity. The activity of the Na+/K+-ATPase was significantly reduced in TGR compared to controls. The Na+-channel modulator BDF 9148 was more effective in hypertrophic compared to control myocardium in increasing force of contraction, enhancing frequency-dependent force generation and reducing diastolic tension. These effects were not mediated via interaction with the contractile apparatus. The enhanced effectiveness of Na+-channel modulation in hypertrophic myocardium could result from alterations of the Na+ homeostasis, i. e. a reduced Na+/K+-ATPase activity.

Stereoselectivity of actions of the calcium sensitizer [+]-EMD 60263 and its enantiomer [-]-EMD 60264.

The thiadiazinone derivative [+]-EMD 60263 ((+)-5-(l-(alpha-ethylimino-3,4-dimethoxybenzyl)-1,2,3,4-tetrah ydroquinoline -6-yl)-6-methyl-3,6-dihydro-2H-1,3,4 -thiadiazine-2-on) is a Ca(2+)-sensitizing agent with only minor phosphodiesterase inhibitory activity. Our aim was to characterize the inotropic and electrophysiological effects of [+]-EMD 60263 and its enantiomer [-]-EMD 60264 in several cardiac muscle preparations. The Ca(2+)-sensitizing activity resided in the [+]-enantiomer only. [+]-EMD 60263 (3 microM) shifted the EC50 of Ca2+ for contractile activation of skinned fibers of pig heart from 2.41 microM to 0.73 microM, whereas [-]-EMD 60264 (30 microM) was ineffective. In Langendorff-perfused guinea pig hearts, [+]-EMD 60263 and [-]-EMD 60264 induced concentration-dependent positive and negative inotropic effects, respectively; both enantiomers reduced spontaneous heart rate but did not influence perfusion pressure. The maximum increase in force of human atrial trabeculae was 35% of pre-drug control with [+]-EMD 60263 in comparison to 113% with forskolin. In guinea-pig papillary muscles, [+]-EMD 60263 and [-]-EMD 60264 had opposite inotropic responses, however, both agents similarly prolonged action potential duration. Both enantiomers concentration-dependently blocked the rapidly activating component IKr of the delayed rectifier in guinea-pig myocytes. The block saturated at potentials positive to +30 mV, closely resembling the effects of the antiarrhythmic agent E-4031 which had been originally used to define IKr.

Flunarizine but not theophylline modulates inotropic responses of the isolated rat heart to diazepam

Diazepam (2 · 10 −5–6 · 10 −4 M) induced a concentration-dependent positive inotropic effect on the perfused rat heart which was preceded by a transient concentration-dependent negative inotropic response. The influence of the Ca 2+-entry blocking drug, flunarizine, and the adenosine receptor blocking drug, theophylline on these inotropic responses was studied. Flunarizine in concentrations of 10 −9–10 −6 M antagonized the positive inotropic response to diazepam significantly; the negative inotropic response was reduced as well. At the lower concentrations of diazepam the negative inotropic response was completely abolished in the presence of flunarizine. The actions of the Ca 2+-entry blocker were related to the concentrations used. Theophylline in concentrations up to 5 · 10 −5 M did not interfere with either inotropic response to diazepam. The results suggest that Ca 2+ currents in the myocardium are involved with the response of the isolated heart to diazepam. It is concluded that the finding that the negative inotropic effect of diazepam was almost abolished by flunarizine suggests that the site of this response must be associated with Ca 2+-current mechanisms.

(±)-Tamsulosin, an α1A-adrenoceptor antagonist, inhibits the positive inotropic effect but not the accumulation of inositol phosphates in rabbit heart

The influence of (±)-tamsulosin, a selective α 1A-adrenoceptor antagonist, on the positive inotropic effect and the accumulation of inositol phosphates that are induced via α 1-adrenoceptors was studied in comparison with that of another α 1A-adrenoceptor ligand oxymetazoline in the rabbit ventricular myocardium. Phenylephrine elicited a concentration-dependent positive inotropic effect via α 1-adrenoceptors in the presence of either (±)-bupranolol or S(−)-timolol. The mode of antagonism induced by (±)-tamsulosin on the effect of phenylephrine was dependent on the concentration applied: (±)-tamsulosin at 1 and 3 nM acted in a competitive manner, the slope of the regression line of the Schild plot being unity and the p A 2 value being 9.12; at 10 nM, it shifted further the concentration-response curve to the right without affecting the maximal response but the slope became less than unity. At 100 nM and higher, it suppressed the maximal response to phenylephrine. (±)-Tamsulosin effectively antagonized the positive inotropic effect of phenylephrine even after inactivation of α 1B-adrenoceptors by treatment with chlorethylclonidine, which is an indication that the (±)-tamsulosin-sensitive subtype belongs to a class resistant to chlorethylclonidine. (±)-Tamsulosin, over the range of concentrations at which it antagonized the positive inotropic effect mediated by α 1-adrenoceptors, did not affect the accumulation of [ 3H]inositol phosphates that was induced by 10 μM phenylephrine. Oxymetazoline antagonized the positive inotropic effect of phenylephrine in a competitive manner without affecting the accumulation of inositol monophosphate induced by phenylephrine. These results indicate that the positive inotropic effect, mediated via (±)-tamsulosin- and oxymetazoline-sensitive subtype of α 1-adrenoceptors, is exerted by a subcellular mechanism that is independent of the accumulation of inositol phosphates.

Myocardial Contractile Response to Nitric Oxide and cGMP

Cardiac endothelium releases a number of factors that may modulate performance of underlying cardiac muscle. Nitric oxide (NO), which accounts for the biological activity of the vascular endothelium-derived relaxing factor and relaxes vascular smooth muscle by elevating intracellular cGMP, may be involved in this cardiac modulation. We examined the myocardial contractile effects of the NO-releasing nitrovasodilators sodium nitroprusside (SNP), 3-morpholino-sydnonimine (SIN-1), and S-nitroso-N-acetyl-penicillamine (SNAP); of a cGMP analogue, 8-bromo-cGMP; and of the cGMP-phosphodiesterase inhibitor zaprinast in isolated cat papillary muscle. Modulation of these effects by endocardial endothelium (EE) and by cholinergic and adrenergic stimulation was also investigated. Concentration-response curves with addition of NO-releasing nitrovasodilators (SNP, SIN-1, SNAP) and 8-bromo-cGMP resulted in a biphasic inotropic response. Although administration of low concentrations induced a positive inotropic effect, higher concentrations induced a negative inotropic effect. Both NO-induced positive and negative inotropic effects were attenuated by methylene blue, suggesting a role for cGMP. The response to high concentrations of 8-bromo-cGMP was shifted to the right in muscles with damaged EE, whereas cholinergic stimulation shifted the curve leftward. Zaprinast caused a monophasic concentration-dependent positive inotropic effect; damaging the EE shifted the terminal portion of the curve upward. Concomitant cholinergic or adrenergic stimulation modified the response to zaprinast into a negative inotropic response. NO and cGMP induced a concentration-dependent biphasic contractile response. The myocardial contractile effects of NO and cGMP were modulated by the status of EE and by concomitant cholinergic or adrenergic stimulation.

Pharmacological characteristics of endothelin receptors in the rabbit ventricular myocardium: the nonselective endothelin receptor antagonist PD 145065 antagonizes the positive inotropic effect of endothelin-3 but not of endothelin-1.

Endothelin-3 (ET-3) elicited a concentration-dependent positive inotropic effect on rabbit papillary muscle, the maximal response being approximately 65% of the maximal response to isoproterenol. ET-1 induced a positive inotropic effect over the concentration range below 10(-9) M, at which ET-3 did not produce a positive inotropic effect, but the maximal response to ET-1 was equivalent to or slightly lower than that of ET-3. The nonselective ET receptor antagonist PD 145065 effectively antagonized the positive inotropic effect of ET-3 in a concentration-dependent manner and abolished it at 10(-5) M. PD 145065 decreased the positive inotropic effect induced by ET1 at lower concentrations (< 10(-9) M) but it did not affect the main portion of the concentration-response curve for the positive inotropic effect, i.e., the effect induced by high concentrations (> 10(-9) M) of ET-1. PD 145065 antagonized also the positive inotropic effect of sarafotoxin S6c. PD 145065 inhibited the specific binding of [125I]ET-1 and of [125I]ET-3 with a high- and a low-affinity site for competition. ETB selective ligands, RES-701-1 and sarafotoxin S6c, displaced [125Iuc]ET-3 with high affinity but they scarcely affected the [125I]ET-1 binding. These findings indicate that different subtypes of the ET receptor are responsible for the induction of the positive inotropic effect of ET-3 and ET-1. ET receptors involved in the production of the positive inotropic effect in the rabbit ventricular myocardium have pharmacological characteristics that are different from those of conventional ET receptors originally classified based on the pharmacological findings in noncardiac tissues. The positive inotropic effect of ET-3 in the rabbit ventricular muscle may be mediated predominantly by ETA1 receptors that are susceptible to PD 145065 as well as BQ-123 and FR139317, and partially mediated by ETB receptors that are inhibitable with RES-701-1. ETA2 receptors that are resistant to ETA selective as well as nonselective antagonists may mainly be responsible for the positive inotropic effect of ET-1 in the rabbit ventricular muscle.

Effects of angiotensin II and angiotensin-converting enzyme inhibitors on human myocardium

Human myocardial angiotensin II receptors and the angiotensin AT 1 and AT 2 receptor subtypes were characterised using the partial angiotensin II receptor agonist [ 125I][Sar 1,IIe 8]angiotensin II and the selective antagonists losartan (2-n-butyl-4-chloro-5-hydroxymethyl-1-[2′((1 H-tetrazol-5-yl)biphenyl-4-yI)-methyl]imidazole) and PD 123177 (1-[(4-amino-3-methylphenyl)methyl]-5-(diphenyl-acetyl)-4,5,6,7-tetrahydro-1 H-imidazol[4,5- c]pyridine-6-car☐ylic acid). The density of angiotensin II receptors was higher in atrial than in ventricular myocardium. Angiotensin AT 2 receptors were predominant in atria and ventricles (80–85% of total angiotensin II receptors). Only in isolated, electrically driven atrial trabeculae but not in ventricular preparations, angiotensin II did produce a concentration-dependent positive inotropic effect, which was antagonized exclusively by the angiotensin AT 1 receptor antagonist losartan and which amounted to about 20% of the positive inotropic effect of mihinone and isoprenaline. The application of the angiotensin-converting enzyme inhibitors captopril, enalaprilat and ramiprilat had no inotropic effect in either tissue. It is concluded that angiotensin AT 1 receptors exclusively mediate direct positive inotropic effects in atrial myocardium. Since angiotensin-converting enzyme inhibitors do not produce any inotropic effect, tonic regulation of basal force of contraction by angiotensin II does not occur.

Carotid blood flow distribution, haemodynamics and inotropic responses following calcitonin gene-related peptide in the pig

The sensory neuropeptide, calcitonin gene-related peptide (α-CGRP), has been implicated in the pathogenesis of migraine headache. The present study aimed to evaluate the effects of intracarotid infusions of human α-CGRP (10, 30 and 100 pmol/kg · min; n = 8), as compared to that of saline (4 times; n = 8) on haemodynamics and blood flow distribution within the carotid circulation of the anaesthetized pig, using the radioactive microsphere method. Furthermore, the effects of antimigraine drugs, dihydroergotamine (100 μg/kg i.v; n = 4) or sumatriptan (300 μg/kg i.v.; n = 4), on these parameters were studied in the presence of the infusion of the highest concentration of human α-CGRP. Additionally, putative positive inotropic responses to human α-CGRP (10 −9–10 −7 M) were investigated in porcine isolated atrial and ventricular trabeculae. Human α-CGRP increased carotid artery blood flow and conductance dose-dependently, together with an enhancement in vascular pulsations. These effects were associated with a fall in systemic blood pressure with concomitant increases in heart rate and cardiac output. The increase in carotid blood flow was reflected by an increase in total capillary blood flow, predominantly to extracerebral tissues including the dura, whereas blood flow through arteriovenous anastomoses remained stable. Both dihydroerogtamine and sumatriptan reduced carotid blood flow and its capillary fraction without affecting systemic vascular conductance. In tissues, these drugs reversed blood flow increases due to human α-CGRP in most extracerebral tissues, but failed to reduce dural blood flow. In porcine isolated atrial and ventricular trabeculae, noradrenaline (10 −8–10 −5 M) increased force of contraction in a concentration-dependent manner. In contrast, human α-CGRP (10 −9–10 −7 M) failed to increase force of contraction in atrial trabeculae ( n = 6) and exerted only a moderate concentration-dependent positive inotropic effect in ventricular trabeculae (∼ 25% of the response to 10 −5 M noradrenaline, n = 10). These data indicate that human α-CGRP caused arteriolar dilatation together with a fall in blood pressure in the pig. The tachycardia may be reflex-mediated, but the peptide also exerts a moderate positive inotropic action on ventricular trabeculae. The fall in systemic arterial blood pressure and the marked increase in capillary blood flow most likely prevented the opening of arteriovenous anastomoses. Furthermore, the antimigraine drugs, dihydroergotamine and sumatriptan, were able to reverse blood flow changes induced by human α-CGRP in the porcine carotid circulation.

Diazepam potentiates the positive inotropic effect of isoprenaline in rat ventricle strips: role of cyclic AMP

The responses of the electrically driven right ventricle strip of the rat heart to isoprenaline and other cyclic AMP-related inotropic agents were recorded in the absence and in the presence of diazepam. Isoprenaline, in concentrations ranging from 10 nM to 1 μM, significantly increased, in a concentration-dependent manner, the contractile force in this preparation. Diazepam (10 μM) produced a leftward shift in the isoprenaline concentration-response curve and significantly reduced its EC 50. Higher concentrations of diazepam (100 μM) produced no further shift, but reduced the maximum of the concentration-response curve of isoprenaline. Forskolin (0.5–10 μM), which directly stimulates adenyl cyclase, also produced a concentration-dependent increase in cardiac contractility. Diazepam (10 μM) displaced to the left the concentration-response curve for forskolin and reduced its EC 50. The cyclic AMP analogous dibutyryl cyclic AMP (0.1–1 mM) produced concentration-dependent positive inotropic effects which were not significantly modified in the presence of diazepam (10 μM). Diazepam (10 μM) significantly enhanced the cyclic AMP production induced by isoprenaline (0.1 μM) and forskolin (10 μM) by about 136% and 35% respectively. These results indicate that diazepam potentiates the positive inotropic effect induced by β-adrenoceptor agonists, probably by increasing cyclic AMP production induced by these agents.

Positive inotropic effect of nitric oxide in myocardium

Cardiac endothelium modulates underlying cardiac muscle performance probably by releasing certain regulatory factors. Nitric oxide (NO), which accounts for the biological activity of the vascular endothelium-derived relaxing factor and relaxes vascular smooth muscle by elevating intracellular cyclic GMP (cGMP), may be involved in this cardiac modulation. Many recent studies have examined inotropic effects of NO utilizing NO donors and NO-synthase inhibitors, both in vitro and in vivo, with apparently contradictory results. We examined the myocardial effects of NO-releasing nitrovasodilators (sodium nitroprusside (SNP), SIN-1 and S-nitrosoacetyl penicillamine (SNAP)), a cGMP analogue, 8-bromo-cGMP, and the cGMP phosphodiesterase inhibitor zaprinast, in isolated cat papillary muscle. A novel concentration-dependent positive inotropic effect of SNP and SIN-1 in muscles with damaged endocardial endothelium (EE) was observed which contrasted to their negative inotropic effect in muscles with intact EE. Both NO-induced positive and negative inotropic effects were attenuated by methylene blue, suggesting a role for cGMP. Concentration response curves with addition of SNAP and 8-bromo-cGMP resulted in a biphasic inotropic response. While administration of low concentrations of SNAP and 8-bromo cGMP induced a positive inotropic effect, higher concentrations induced a negative inotropic effect. Administration of zaprinast caused a monophasic concentration-dependent positive inotropic effect. We conclude that basal release of NO and consequent modest (physiological?) elevation in cGMP may preserve myocardial function, while large (pathological?) increases would depress myocardial function.

Induction by endogenous noradrenaline of an α1‐adrenoceptor‐mediated positive inotropic effect in rabbit papillary muscles

1. The possible involvement of alpha 1-adrenoceptors in the inotropic and electrophysiological responses to endogenous noradrenaline released by tyramine was examined in rabbit papillary muscles. 2. A concentration-dependent positive inotropic effect was produced by tyramine. This effect of tyramine was not observed in muscles from rabbits pretreated with reserpine. 3. The positive inotropic effect of tyramine was greatly inhibited by propranolol, but not altered by prazosin. However, when beta-adrenoceptors were blocked by pretreatment with propranolol, tyramine still produced a positive inotropic effect, an effect which was antagonized by prazosin. 4. Tyramine caused a decrease in action potential duration (APD) and an increase in action potential amplitude in a concentration-dependent manner. Isoprenaline also produced the same electrophysiological effects. These electrophysiological effects of both agents were inhibited by propranolol. 5. When beta-adrenoceptors were blocked by propranolol, the observed prazosin-sensitive positive inotropic effect of tyramine was not accompanied by any change in APD. In contrast, APD was markedly prolonged by alpha 1-adrenoceptor stimulation with phenylephrine in the presence of propranolol, in association with the positive inotropic effect. 6. It is concluded that in rabbit papillary muscles, endogenous noradrenaline causes a positive inotropic effect predominantly mediated by beta-adrenoceptors, but can still evoke a positive inotropic effect through alpha 1-adrenoceptors when beta-adrenoceptor stimulation is eliminated. This suggests that the alpha 1-adrenoceptor-mediated positive intropic mechanism(s) may be masked by simultaneous activation of beta-adrenoceptors. In addition, this study indicates that APD prolongation is not involved in the alpha 1-adrenoceptor-mediated inotropic responses to endogenous noradrenaline.

High Selectivity for Inhibition of Phosphodiesterase III and Positive Inotropic Effects of MCI-154 in Guinea Pig Myocardium

MCI-154 (0.3-100 microM) exerted a concentration-dependent positive inotropic effect in isolated guinea pig papillary muscles (EC50 0.8 microM). The efficacy of MCI-154 (253% of predrug value) was 1.7-fold higher than that of saterinone but comparable to that of milrinone. Carbachol markedly reduced the increase in force of contraction (FOC) of MCI-154. In intact contracting papillary muscles, the positive inotropic effect was accompanied by an increase in cyclic AMP content to 0.78 +/- 0.09 pmol/mg wet weight (n = 10), corresponding to 150% of the basal value (0.51 +/- 0.05 pmol/mg wet weight, n = 21) in the presence of submaximal cyclic AMP phosphodiesterase (PDE) isoenzyme III inhibiting concentrations of MCI-154 (30 microM). MCI-154 (1-1,000 microM) concentration-dependently inhibited the activity of PDE III from homogenates of guinea pig myocardium. The IC50 was 3.8 microM. PDE I, II, and IV were not significantly affected up to 100 microM (PDE I and IV) and up to 1,000 microM (PDE II). In comparison, milrinone and saterinone were PDE III/IV-selective PDE inhibitors. Rolipram inhibited PDE IV only. IBMX and theophylline were nonselective PDE inhibitors. MCI-154 had only a marginal positive chronotropic effect. The frequency of spontaneously beating right auricles from guinea pig heart was increased by 8.7% at most (n = 5). MCI-154 increased Ca2+ sensitivity in chemically skinned porcine ventricular muscle fibers.(ABSTRACT TRUNCATED AT 250 WORDS)

Effects of histamine on intracellular Na+ activity and twitch tension in guinea pig papillary muscles.

Effects of histamine on the twitch tension, intracellular Na+ activity (aiNa), and action potential were simultaneously and continuously measured in the isolated cardiac papillary muscle of guinea pigs. In the driven fiber at 60 beats/ min, histamine induced a concentration-dependent positive inotropic effect, and apparently increased the amplitude of the action potential and shortened the duration at 3 microM, and significantly decreased aiNa by 6.7% from the control value of 4.5 +/- 0.1 mM (n = 6, p < 0.05) at 0.3 microM. Cimetidine at 10 microM did not produce any significant effect but partially antagonized the action of histamine. The respective concentrations of 1 and 3 microM histamine significantly decreased aiNa by 5.4 and 14.3% from the control 5.6 +/- 0.1 mM (n = 6, p < 0.05) in the presence of 10 microM cimetidine. Chlorpheniramine at 10 microM significantly reduced the twitch tension and aiNa, and prolonged the action potential duration. Histamine at 1 microM increased the twitch tension and decreased aiNa from 4.5 +/- 0.1 to 4.1 +/- 0.1 mM (n = 5, p < 0.05) in the presence of 10 microM chlorpheniramine. The combined application of 10 microM cimetidine and 10 microM chlorpheniramine reduced the twitch tension and abolished most effects of histamine. In high potassium solution (16.2 mM), 1 microM histamine significantly decreased aiNa by 12.9% from the control of 3.1 +/- 0.2 mM (n = 5, p < 0.05). The treatment of 0.5 or 1 microM ouabain increased the tension development and aiNa, and abolished the decrease in aiNa produced by the effect of histamine. The results suggest that histamine can directly stimulate Na-K pump in sarcolemma through means of the activation of both H1- and H2-receptors.