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Positive Inotropic Effect (positive + inotropic_effect)
Selected AbstractsPositive inotropic effect of coenzyme Q10, omega-3 fatty acids and propionyl-L-carnitine on papillary muscle force-frequency responses of BIO TO-2 cardiomyopathic Syrian hamstersBIOFACTORS, Issue 1-4 2008Romina Vargiu Abstract The inability of heart muscle to generate ventricular pressure to adequately propel blood through the cardiovascular system is a primary defect associated with congestive heart failure (CHF). Force-frequency relationship (FFR) is one of the main cardiac defects associated with congestive heart failure. Thus FFR is a convenient methodological tool for evaluating the severity of muscle contractile dysfunction and the effectiveness of therapeutic agents. Papillary muscle isolated from BIO TO-2 cardiomyopathic Syrian hamsters (CMSHs), show a depressed FFR and represents an animal model of human idiopathic dilated cardiomyopathy. In the present study we investigated the effect of CoQ10, omega-3 fatty acids, propionyl-L-carnitine (PLC) and a combination of these 3 agents (formulation HS12607) on FFR in 8 month old BIO TO-2 CMSHs. Papillary muscles isolated from the anesthetized animals were placed in an incubation bath and attached to an isometric force transducer. A digital computer with an analog/digital interface allowed control of both muscle developed force and electrical stimulus parameters. Force-frequency response was evaluated, at Lmax, with increasing frequencies: 0.06, 0.12, 0.25, 0.5, 1, 2 and 4 Hz. HS12607-treatment produced a positive inotropic effect resulting in a significant enhancement (p < 0.05) of the peak force at the highest frequencies (1,4 Hz). In the range of frequency of 1,4 Hz also CoQ10 and omega-3 significantly(p < 0.05) attenuated the fractional decline in developed force. The significant improvement (p < 0.05) of the timing parameter peak rate of tension rise (+T') and peak rate of tension fall (,T') indicating a faster rate of muscle contraction and relaxation respectively, found in CoQ10, omega-3 and PLC-treated CMSHs, may be due to the positive effects of these substances on sarcoplasmic reticulum functions. These findings suggest that naturally occurring CoQ10, omega-3 and PLC, particularly when administered together in a coformulation, might be a valid adjuvant to conventional therapy in dilated cardiomyopathy especially when considering that they are natural substances, devoid of side effects. [source] Cardiac function during mild hypothermia in pigs: increased inotropy at the expense of diastolic dysfunctionACTA PHYSIOLOGICA, Issue 1 2010H. Post Abstract Aim:, The induction of mild hypothermia (MH; 33 °C) has become the guideline therapy to attenuate hypoxic brain injury after out-of-hospital cardiopulmonary resuscitation. While MH exerts a positive inotropic effect in vitro, MH reduces cardiac output in vivo and is thus discussed critically when severe cardiac dysfunction is present in patients. We thus assessed the effect of MH on the function of the normal heart in an in vivo model closely mimicking the clinical setting. Methods:, Ten anaesthetized, female human-sized pigs were acutely catheterized for measurement of pressure,volume loops (conductance catheter), cardiac output (Swan-Ganz catheter) and for vena cava inferior occlusion. Controlled MH (from 37 to 33 °C) was induced by a vena cava inferior cooling catheter. Results:, With MH, heart rate (HR) and whole body oxygen consumption decreased, while lactate levels remained normal. Cardiac output, left ventricular (LV) volumes, peak systolic and end-diastolic pressure and dP/dtmax did not change significantly. Changes in dP/dtmin and the time constant of isovolumetric relaxation demonstrated impaired active relaxation. In addition, MH prolonged the systolic and shortened the diastolic time interval. Pressure,volume analysis revealed increased end-systolic and end-diastolic stiffness, indicating positive inotropy and reduced end-diastolic distensibility. Positive inotropy was preserved during pacing, while LV end-diastolic pressure increased and diastolic filling was substantially impaired due to delayed LV relaxation. Conclusion:, MH negatively affects diastolic function, which, however, is compensated for by decreased spontaneous HR. Positive inotropy and a decrease in whole body oxygen consumption warrant further studies addressing the potential benefit of MH on the acutely failing heart. [source] Synthesis and calcium channel modulating effects of modified Hantzsch nitrooxyalkyl 1,4-dihydro-2,6-dimethyl-3-nitro-4-(pyridinyl or 2-trifluoromethylphenyl)-5-pyridinecarboxylatesDRUG DEVELOPMENT RESEARCH, Issue 4 2000Ramin Miri Abstract A group of racemic nitrooxyalkyl 1,4-dihydro-2,6-dimethyl-3-nitro-4-(pyridinyl or 2-trifluoromethylphenyl)-5-pyridinecarboxylates 8a,o were synthesized using modified Hantzsch reactions. In vitro calcium channel antagonist activities, determined using a guinea pig ileum longitudinal smooth muscle (GPILSM) assay, showed that compounds 8a,o exhibited weaker calcium antagonist activity (10,5 to 10,7 M range) than the reference drug nifedipine (IC50 = 1.43 × 10,8 M). Compounds 8 possessing a C-4 R1 = 2-pyridyl substituent were always more potent than the approximately equiactive analogs having an R1 = 3-pyridyl, 4-pyridyl or 2-CF3 -C6H4 -substituent, within each subgroup of nitrooxyalkyl compounds [R2 = , (CH2)nONO2 (n = 2, 3, 4) or ,CH(CH2ONO2)2]. Although the length of the R2 = ,(CH2)nONO2 substituent (n = 2,4) was not a determinant of smooth muscle calcium antagonist activity when the C-4 R1 -substituent was 2-pyridyl, when R1 was a 3-pyridyl, 4-pyridyl, or 2-CF3 -C6H4 -substituent, the relative potency order with respect to the R2 = ,(CH2)nONO2 substituent was n = 3 and 4 > n = 2. Replacement of the isopropyl substituent of the ester moiety of the calcium antagonist (±)-2-pyridyl 3a by a ,(CH2)nONO2 (n = 2,4) moiety increased calcium antagonist activity on GPILSM by 8-fold. In contrast, replacement of the isopropyl substituent of the ester moiety of the calcium agonists (±)-3-pyridyl 3b, (±)-4-pyridyl 3c or the methyl substituent of the ester moiety of Bay K8644 by a R2 nitrooxyalkyl substituent resulted in abolition of their calcium agonist effects on GPILSM that is replaced by a smooth muscle calcium antagonist effect. These calcium antagonist data support the concept that incorporation of a nitrooxyalkyl ester substituent constitutes a valuable drug design strategy to enhance Hantzsch 1,4-dihydropyridine calcium antagonist and/or abolish calcium agonist effects on smooth muscle. Replacement of the isopropyl (8b,c), or the methyl (8d) group by a ,CH2CH2ONO2 moiety resulted in retention of the cardiac positive inotropic effect where the relative potency order with respect to the C-4 substituent was 2-CF3 -C6H6 - (8d) > 3-pyridyl (8b) , 4-pyridyl (8c). Model hybrid (calcium channel modulation, ·NO release) compounds, that exhibit dual cardioselective agonist / smooth muscle selective antagonist activities, represent a novel type of 1,4-dihydropyridine CC modulator that offers a potential approach to drug discovery targeted toward the treatment of congestive heart failure and for use as probes to study the structure,function relationship of calcium channels. Drug Dev. Res. 51:225,232, 2000. © 2001 Wiley-Liss, Inc. [source] Treatment of congestive heart failure , current status of use of digitoxinEUROPEAN JOURNAL OF CLINICAL INVESTIGATION, Issue S2 2001G. G. Belz Digitalis glycosides exert a positive inotropic effect, i.e. an increase in myocardial contractility associated with a prolongation of relaxation period, and glycosides lower the heart rate (negative chronotropic), impede stimulus conduction (negative dromotropic) and promote myocardial excitability (positive bathmotropic). They seem to influence the activities of both the vagal and the sympathetic systems. Digitalis glycosides that belong to different substance classes are closely comparable concerning pharmacodynamics but differ substantially in regard to pharmacokinetics. Digoxin and its derivatives are less lipophilic, show lower protein binding and shorter half-life, are mainly eliminated via the kidney and accumulate rather rapidly in cases of insufficient kidney function. Digitoxin is highly lipophilic and extensively bound to plasma proteins, has a longer half-life, is mainly eliminated in the metabolized state via urine and faeces and does not accumulate in kidney dysfunction. As a result of a more stable pharmacokinetic profile, the incidence of toxic side effects seems to be lower with digitoxin than with digoxin. Since the beginning of the 1990s, the antagonists of the RAAS qualified as the standard treatment for congestive heart failure, often in combination with diuretics, vasodilators or ,-antagonists. However, the important role of digitalis glycosides as therapeutic comedication or alternative was never denied, especially in atrial fibrillation with tachycardia. The PROVED and RADIANCE trials proved a detrimental effect of the withdrawal of digoxin therapy on exercise capacity, left-ventricular ejection fraction and clinical symptoms. The DIG trial revealed that digoxin comedication in sinus rhythm patients with congestive heart failure was associated with a lower morbidity (as taken from death or hospitalization because of worsening heart failure) and an unchanged overall mortality , being a unique feature among the available inotropic drugs. Comparable studies for digitoxin have not yet been performed but, because of its higher pharmacological stability, it might well be associated with even more advantages in this regard than digoxin. [source] Effect of digoxin on circadian blood pressure values in patients with congestive heart failureEUROPEAN JOURNAL OF CLINICAL INVESTIGATION, Issue 4 2000Kirch Background The aim of the study was to investigate the effect of chronic digoxin treatment on circadian blood pressure profile in normotensive patients with mild congestive heart failure. Methods In a randomized double-blind, placebo-controlled cross-over protocol, 12 normotensive patients with mild congestive heart failure took digoxin or placebo for a total of 7 days. Automatic 24-h ambulatory blood pressure measurements were carried out at day 7, of either digoxin or placebo. Results Diastolic blood pressure significantly decreased and systolic blood pressure significantly increased during overnight sleep in the digoxin phase compared to placebo. Digoxin had no effect on either systolic or diastolic blood pressure during daytime. Heart rate decreased in the overnight sleeping phase but did not differ significantly between placebo and digoxin phase. Conclusions Digoxin significantly decreases diastolic blood pressure during overnight sleep in patients with congestive heart failure. This effect is likely to be caused by reduction of sympathetic activity or increase of parasympathetic activity. Increase of systolic blood pressure during sleep is probably caused by the positive inotropic effect of the drug. [source] Cocaine- and amphetamine-regulated transcript (CART) peptide as an in vivo regulator of cardiac function in Rana ridibunda frogEXPERIMENTAL PHYSIOLOGY, Issue 6 2007Iliyana V. Ivanova The aim of this study was to investigate the effect of CART peptide on cardiac performance and on the physiological signalling pathways involved using Rana ridibunda frog heart preparations in vivo. The CART peptide, when injected into the venous sinus, significantly and reproducibly increased the force of frog heart contractions by up to 33.0 ± 6.4% during the first 15 min after its application but did not influence the chronotropic activity of the frog heart. The positive inotropic effect was entirely blocked by prazosin, pertussis toxin, Rp -adenosine 3,,5,-cyclic monophosphorothioate, autosauvagine 30 or metyrapone, as well as by extirpation of the pituitary gland, functional elimination of the inter-renal glands and long-lasting starvation, and was not observed on isolated heart preparations. Propranolol and double pithing were without significant effect on this phenomenon. It was concluded that: (i) CART peptide, administered to frogs in vivo, increases the force of heart contractions; (ii) this effect of the peptide is exerted via activation of the hypothalamic,pituitary,inter-renal gland axis through a corticoliberin-sensitive mechanism; (iii) CART augments the pumping function of the heart via a corticosteroid-dependent potentiation of myocardial ,1 -adrenoreceptors signalling; and (iv) prolonged food deprivation abolishes the positive inotropic effect of CART, suggesting the participation of endogenous CART in the physiological adaptation of the circulatory system to limitations of energy consumption. [source] Effects of dofetilide on cardiovascular tissues from normo- and hypertensive ratsJOURNAL OF PHARMACY AND PHARMACOLOGY: AN INTERNATI ONAL JOURNAL OF PHARMACEUTICAL SCIENCE, Issue 5 2002Sheila A. Doggrell The aim was to test whether dofetilide has some potential for use in the treatment of heart failure. Dofetilide at ,3 times 10,5 M had no effect on the quiescent Wistar Kyoto (WKY) rat aorta, mesenteric and intralobar arteries, or the spontaneous contractions of the WKY rat portal vein. Dofetilide at 10,6 to 3 times 10,5 M relaxed the KCl-contracted aorta. Dofetilide at 10,9 -10,7 M augmented the force of contraction of left ventricle strips from 12- and 18-month-old WKY rats at 2 Hz. Spontaneously hypertensive rats (SHRs) at 12 and 17,21 months of age are models of cardiac hypertrophy and failure, respectively. The augmentation of force at 2 Hz with dofetilide was similar on 12-and 18-month-old WKY rats and 12-month-old SHRs but reduced on the 18-month-old SHR left ventricle. At a higher more physiological frequency, 4 Hz, the threshold concentration of dofetilide required to augment the force responses of 21-month-old SHR left ventricles was markedly increased and the maximum augmenting effect was decreased. Dofetilide at 10,7 -10,5 M reduced the rate of the 17-month-old WKY rat right atrium, and had a similar effect on age-matched SHR right atrium. In summary, dofetilide is a positive inotrope and negative chronotrope in the rat. However, as the positive inotropic effect is not observed with clinically relevant concentrations at a physiological rate in heart failure, dofetilide is unlikely to be useful as a positive inotrope in the treatment of heart failure. [source] Severe intoxication after an intentional overdose of amlodipineACTA ANAESTHESIOLOGICA SCANDINAVICA, Issue 8 2003L. Rasmussen Intoxication with 280 mg of amlodipine caused severe hypotension, third-degree heart block and hyperkalaemia in a 36-year-old female patient. The patient was initially treated with fluids, dopamine, calcium chloride, and epinephrine without effect. The patient was then given a bolus injection of insulin and glucose as a temporary mean to treat the hyperkalaemia. We observed a rise in blood pressure (BP) after insulin was given and the BP was subsequently responsive to epinephrine. A possible positive inotropic effect of insulin therapy in patients with calcium channel blocker intoxication is in accordance with previous findings. In conclusion, it is suggested that hyperinsulinaemia-euglycaemia therapy may be considered as a first-line therapy in calcium channel blocker intoxication. [source] Different sensitivity of isoprenaline-induced responses in ventricular muscle to sodium nitroprusside in normotensive and spontaneously hypertensive rats 1AUTONOMIC & AUTACOID PHARMACOLOGY, Issue 2 2000A. M. Manso 1 The aim of the present work was to study the possible modulatory role of nitric oxide (NO) on the positive inotropic effect induced by the ,-adrenoceptor agonist isoprenaline in myocardial contractility, and whether this modulation is altered by hypertension. 2 The study was performed using right ventricular strips from the hearts of 6-month-old male Wistar,Kyoto (WKY) rats and spontaneously hypertensive rats (SHR). The contractile force of electrically-stimulated ventricular strips was measured by a force-displacement transducer. 3 Isoprenaline (from 10 nmol l,1 to 10 ,mol l,1) induced a concentration-dependent increase in cardiac contractility in strips from both rat strains. This positive inotropic effect to isoprenaline was reduced by the NO donor sodium nitroprusside (SNP, 0.1 mmol l,1) in muscles from WKY rats and slightly increased in those from SHR. The SNP-induced increase in strips from SHR was abolished by superoxide dismutase (100 U ml,1). 4 NG-nitro-arginine-methyl ester (L-NAME, 0.1 mmol l,1) and 1H-[1,2,4]oxadiazolo[4,3]quinoxalin-1-one (ODQ, 10 ,mol l,1), respective inhibitors of NO synthase and guanylate cyclase, increased the response to isoprenaline in muscles from WKY rats, whereas it was unaltered in strips from SHR. 5 In strips from WKY rats, the combination of ODQ and SNP produced an increase in the response elicited by isoprenaline, which was similar to that observed with ODQ or L-NAME. 8-Br-cyclicGMP (8-Br-cGMP, 0.1 mmol l,1), a permeable and structural cGMP analogue, decreased the effect induced by isoprenaline only in muscles from WKY rats. 6 These results suggest that the positive inotropic response to isoprenaline in ventricular strips from WKY rats is negatively modulated by NO, and positively by superoxide anions in those from SHR. The lack of a modulatory response to NO in ventricular strips from SHR is probably a result of an alteration of mechanisms in NO-signalling pathway downstream of cGMP formation in SHR hearts. [source] Positive inotropic effect of coenzyme Q10, omega-3 fatty acids and propionyl-L-carnitine on papillary muscle force-frequency responses of BIO TO-2 cardiomyopathic Syrian hamstersBIOFACTORS, Issue 1-4 2008Romina Vargiu Abstract The inability of heart muscle to generate ventricular pressure to adequately propel blood through the cardiovascular system is a primary defect associated with congestive heart failure (CHF). Force-frequency relationship (FFR) is one of the main cardiac defects associated with congestive heart failure. Thus FFR is a convenient methodological tool for evaluating the severity of muscle contractile dysfunction and the effectiveness of therapeutic agents. Papillary muscle isolated from BIO TO-2 cardiomyopathic Syrian hamsters (CMSHs), show a depressed FFR and represents an animal model of human idiopathic dilated cardiomyopathy. In the present study we investigated the effect of CoQ10, omega-3 fatty acids, propionyl-L-carnitine (PLC) and a combination of these 3 agents (formulation HS12607) on FFR in 8 month old BIO TO-2 CMSHs. Papillary muscles isolated from the anesthetized animals were placed in an incubation bath and attached to an isometric force transducer. A digital computer with an analog/digital interface allowed control of both muscle developed force and electrical stimulus parameters. Force-frequency response was evaluated, at Lmax, with increasing frequencies: 0.06, 0.12, 0.25, 0.5, 1, 2 and 4 Hz. HS12607-treatment produced a positive inotropic effect resulting in a significant enhancement (p < 0.05) of the peak force at the highest frequencies (1,4 Hz). In the range of frequency of 1,4 Hz also CoQ10 and omega-3 significantly(p < 0.05) attenuated the fractional decline in developed force. The significant improvement (p < 0.05) of the timing parameter peak rate of tension rise (+T') and peak rate of tension fall (,T') indicating a faster rate of muscle contraction and relaxation respectively, found in CoQ10, omega-3 and PLC-treated CMSHs, may be due to the positive effects of these substances on sarcoplasmic reticulum functions. These findings suggest that naturally occurring CoQ10, omega-3 and PLC, particularly when administered together in a coformulation, might be a valid adjuvant to conventional therapy in dilated cardiomyopathy especially when considering that they are natural substances, devoid of side effects. [source] Cardiac dysfunction during exercise in patients with primary hyperparathyroidismBRITISH JOURNAL OF SURGERY (NOW INCLUDES EUROPEAN JOURNAL OF SURGERY), Issue 9 2000I.-L. Nilsson Background ,Non-traditional' manifestations of primary hyperparathyroidism (HPT) are controversial, and include morbidity, mortality and risk factors for cardiovascular diseases with some prospects of normalization by parathyroidectomy (PTX). This study evaluated previously unexplored data on cardiac function during exercise in HPT. Methods Thirty patients with HPT (mean(s.d.) serum calcium 2·96(0·24) mmol l,1) and 30 normocalcaemic controls (selected randomly from the background population, and matched for age and sex) underwent exercise testing, echocardiography and 24-h ambulatory blood pressure recordings before and a mean of 13 months after PTX. Results HPT was associated with higher systolic blood pressure during exercise (mean(s.d.) 223(28) versus 203(33) mmHg; P = 0·02), which correlated to the left ventricular (LV) mass and serum PTH (P = 0·014, P = 0·004); higher LV mass in men (mean(s.d.) 142(20) versus 113(28) g m,2), which might relate to the hypertrophic effect of PTH; and increased LV isovolumic relaxation times (mean(s.d.) 102(19) versus 91(15) ms; P = 0·018), indicating LV diastolic dysfunction. ST depression during exercise decreased significantly (mean(s.d.) , 1·0(0·9) versus 0·7(0·5) mm; P = 0·028) and LV mass declined in proportion with the time after PTX (P = 0·04 in men). PTX also affected systolic functions, as fractional shortening, atrioventricular plane displacement and systolic index decreased in men (P = 0·05, P = 0·04, P = 0·04). Twenty-four-hour blood pressures were higher in HPT (P = 0·008), when subjects on ,-blockers (seven patients, five controls) were excluded, and were unaltered by PTX. Conclusion LV systolic and diastolic dysfunction occurs in HPT. The diastolic dysfunction seems to diminish with time after PTX, while the positive inotropic effect of calcium in itself may alleviate the systolic dysfunction. © 2000 British Journal of Surgery Society Ltd [source] | |||||||||||||