Myocardial Contractile Force Research Articles

Age-related decline in stress responses of human myocardium may not be explained by changes in mtDNA

Elderly patients undergoing cardiac surgery are more likely to suffer postoperative heart failure than younger patients. This phenomenon is mirrored by an age-related loss of mitochondrial function and by an in vitro loss of myocardial contractile force following a stress. To examine the possibility that loss of mtDNA integrity may be responsible, we quantified representative age-associated mtDNA mutations (mtDNA 4977 and mtDNA A3243G) and mtDNA copy number using quantitative polymerase chain reaction in atrial samples obtained during cardiac surgery. The myocardium underwent organ bath contractility testing before and after either an ischaemic or hypoxic stress. We found that with age, recovery of developed force after either stressor significantly declined ( p < 0.0001). The abundance of mtDNA 4977 correlated weakly with loss of contractility ( R 2 = 0.09, p = 0.047). However, the abundance level was low (average 0.0075% of total mtDNA) and the correlation disappeared when age was included in a multivariate analysis. Neither the abundance of mtDNA A3243G nor mtDNA copy number correlated with reduced recovery of developed force after stress. We conclude that, although mtDNA mutations (as exemplified by mtDNA 4977) accumulate in the ageing heart, they are unlikely to make a major contribution to loss of contractile function.

A preliminary study on the evaluation of relationship between left ventricular torsion and cardiac cycle phase by two-dimensional ultrasound speckle tracking imaging

In normal subjects there is a certain corresponding relationship between the peak rotation angle of the apex and the base with respect to the phase of the cardiac cycle. We hypothesized that the myocardial contractile force and the delay of conduction may affect the correspondence of them. Our study aims to use speckle tracking imaging (STI) technique to analyze the relationship between the left ventricular rotation/torsion (LVrot/ LVtor ) characteristics and cardiac cycle phase, to investigate its clinical feasibility. The echocardiographic images of the short-axis view of the left ventricles (LV) at the apical and basal planes were acquired by STI in 32 healthy controls and 48 heart failure patients (New York Heart Association class I or II). LVtor angle, LVrot angle, the peak value and time of LVtor and LVrot were measured offline using frame-to-frame tracking of gray-scale speckle patterns at the standardized time point, respectively. All the acquired data of the two groups were compared and analyzed. In the healthy controls, there was no significant difference among the isovolumetric contraction time, peak time of clockwise rotation at the apical level and the peak time of clockwise rotation at the basal level segments (P > 0.05). There was no significant difference among systolic time, peak time of counterclockwise rotation at the apical level and peak time of counterclockwise rotation at the basal level segments (P > 0.05). There was no significant difference between systolic time and peak time of LVtor (P > 0.05). Compared with normal group, the peak of LVtor and LVrot angle were decreased at both apical and basal planes in heart failure group (P < 0.05). The peak time of LVtor was delayed in heart failure group (P < 0.05). The peak time of clockwise rotation at the apical level segments was longer than control group (P < 0.05) and continued to the ejection period. In the normal subjects, there is no sequence difference of LVrot between the basal and apical planes. They were correspondent to cardiac cycle. There is a temporal sequence difference of LVrot between basal and apical planes during LV contraction in heart failure group and decreased LVtor/rot have been demonstrated to influence left ventricular function. STI has shown great potential in early detecting the conduction variability in ventricular wall.

The Long-term Effect of Autologous Endothelial Progenitor Cells from Peripheral Blood Implantation on Infarcted Myocardial Contractile Force

This study was designed to evaluate the long-term effect of endothelial progenitor cell (EPC) implantation in acute myocardial infarction in Sprague-Dawley rats after ligation of the left anterior descending coronary artery. Autologous EPCs from peripheral blood were purified and implanted into an acute myocardial infarct site. Specimens and muscle strip were harvested at 3 and 6 weeks, and at 6, 8 and 12 months for contractile force assessment and, by immunohistology, for expression of vascular endothelial growth factor (VEGF), basic fibroblast growth factor (bFGF) and factor VIII. Expression of VEGF and bFGF, and microvessel counts and contractile force in the cell implantation group were significantly higher than in the control group up to 8 months after implantation. Beyond 8 months following implantation, however, no further improvement occurred. The EPCs showed an ability to improve contractile performance in infarcted myocardium by means of angiogenesis and vasculogenesis, and the results seemed to persist long-term.

Fréquence cardiaque et ischémie myocardique expérimentale

Every increase in heart rate represents a poor prognostic factor in cardiology, and multiple arguments have now led to the belief that reducing heart rate is a major therapeutic challenge. A comparison of the pharmacological effects of If current inhibitors such as zatebradine, and more recently ivabradine (Procoralan®) and β-blockers, have demonstrated experimentally that reductions in heart rate and myocardial contractile force contribute equally to the reduction in myocardial oxygen consumption in the normal heart. Conversely, at a similar level of reduction in heart rate, the lack of a concomitant negative inotropic effect with ivabradine affords longer diastolic perfusion times than β-blockers. In other words, a negative inotropic effect is deleterious when an increase in coronary blood flow is required. Hence, if the anti-ischaemic effects afforded by an If current inhibitor and a β-blocker are roughly comparable, the former are clearly of higher benefit than β-blockers in the treatment of myocardial dysfunction accompanying cardiac ischaemia-reperfusion, especially myocardial stunning.

Cardiomiopatia de cães da raça Cocker Spaniel Inglês: aspectos clínicos, eletrocardiográficos, radiográficos e ecocardiográficos

Face aos poucos relatos sobre a cardiomiopatia na raça Cocker Spaniel Inglês na literatura compilada, o presente trabalho visou contribuir para melhor elucidação das lacunas relativas ao seu diagnóstico, e somar conhecimentos para sua caracterização com relação aos aspectos clínicos, eletrocardiográficos, radiográficos e ecocardiográficos. Os estudos foram conduzidos em vinte animais da raça Cocker Spaniel Inglês, portadores da cardiomiopatia dilatada e submetidos à avaliação clínica, eletrocardiográfica, radiográfica, ecocardiográfica, exames laboratoriais e determinação da pressão arterial. O tratamento foi individualizado na dependência da gravidade da insuficiência cardíaca congestiva. Os resultados obtidos confirmaram o longo período assintomático da doença, sendo a insuficiência cardíaca congestiva o evento terminal, em decorrência da perda continuada da força contrátil do miocárdio. A idade média dos animais acometidos foi de sete anos. A sintomatologia foi diretamente relacionada com a diminuição do débito cardíaco. A maioria dos animais apresentou uma evolução clínica favorável da insuficiência cardíaca congestiva; todavia, naqueles com severa cardiectasia ao exame radiográfico, surgimento abrupto de taquiarritmias atriais e redução acentuada da função contrátil ao ecocardiograma, observou-se a ocorrência de uma insuficiência cardíaca congestiva esquerda e também direita, refratárias ao protocolo terapêutico empregado. A eletrocardiografia representou o exame subsidiário de maior diferenciação em relação ao padrão congestivo das raças grandes e gigantes. A maioria dos animais revelou variações do ritmo sinusal, sendo as arritmias supraventriculares observadas nos animais com aumentos importantes das câmaras atriais, constituindo, ainda, aqueles de prognóstico mais reservado. O aumento da amplitude da onda R, a maior duração do complexo QRS e a maior profundidade da onda Q, na derivação II, constituíram um bom indicador para o seu diagnóstico. Uma correlação positiva entre os achados eletrocardiográficos e ecocardiográficos foi observada somente em relação à duração do complexo QRS. A função ventricular apresentou valores médios de 19 %, sendo observados índices inferiores a 12 % em cinco animais, indicativo de severa disfunção contrátil. Não obstante, a longa sobrevida de um destes animais indicou a baixa confiabilidade dos índices de ejeção como fator único na determinação de um prognóstico.

Inhibition of caspase 1 reduces human myocardial ischemic dysfunction via inhibition of IL-18 and IL-1beta.

The proinflammatory cytokine IL-18 was investigated for its role in human myocardial function. An ischemia/reperfusion (I/R) model of suprafused human atrial myocardium was used to assess myocardial contractile force. Addition of IL-18 binding protein (IL-18BP), the constitutive inhibitor of IL-18 activity, to the perifusate during and after I/R resulted in improved contractile function after I/R from 35% of control to 76% with IL-18BP. IL-18BP treatment also preserved intracellular tissue creatine kinase levels (by 420%). Steady-state mRNA levels for IL-18 were elevated after I/R, and the concentration of IL-18 in myocardial homogenates was increased (control, 5.8 pg/mg vs. I/R, 26 pg/mg; P < 0.01). Active IL-18 requires cleavage of its precursor form by the IL-1beta-converting enzyme (caspase 1); inhibition of caspase 1 also attenuated the depression in contractile force after I/R (from 35% of control to 75.8% in treated atrial muscle; P < 0.01). Because caspase 1 also cleaves the precursor IL-1beta, IL-1 receptor blockade was accomplished by using the IL-1 receptor antagonist. IL-1 receptor antagonist added to the perifusate also resulted in a reduction of ischemia-induced contractile dysfunction. These studies demonstrate that endogenous IL-18 and IL-1beta play a significant role in I/R-induced human myocardial injury and that inhibition of caspase 1 reduces the processing of endogenous precursors of IL-18 and IL-1beta and thereby prevents ischemia-induced myocardial dysfunction.

The effect of aspirin and two nitric oxide donors on the infarcted heart in situ

Nitric oxide (NO) donors are heterogeneous substances which release NO, a biologically active compound. NO released by nitric oxide donors has important effects on the circulation by causing vasodilation, diminishing myocardial contractile force, inhibiting platelet aggregation, and counteracting the effects of thromboxane A 2. In the infarcted heart, activation of the inducible form of nitric oxide synthase (iNOS) and the formation of prostacyclin and thromboxane A 2 by cyclooxygenase (COX) were increased. Myocardial infarction also resulted in increased myocardial NO production. Aspirin (acetylsalicylic acid, ASA) at low concentration (35 mg/kg/day) fails to change iNOS production, in contrast to higher dose (150 mg/kg/day) which, as previously shown, inhibits iNOS activity. ASA at all doses also suppresses myocardial prostanoid formation because of inhibition of COX. Recently, two NO donors have been synthesized: NCX 4016 and Diethylenetriamine/NO (DETA/NO). NCX 4016 combines an NO-releasing moiety with a carboxylic residue via an esteric bond. We describe here that NCX 4016 (65 mg/kg/day) increased prostacyclin and thromboxane A 2 production in the infarcted heart muscle, overcoming the inhibitory effects of ASA. As a result of nitric oxide release, oxidation products of NO (NO 2 − and NO 3 −; NOx) in arterial blood rose following administration of NCX 4016. On oral administration, NCX 4016 did not change systemic arterial pressure. The effects of a single NO donor, DETA/NO (1.0 mg/kg/day) on the infarcted heart were also investigated On intravenous administration, the compound increased NO concentration in arterial blood slightly but to a lesser degree than NCX 4016. Like NCX 4016, it raised myocardial production of prostacyclin and thromboxane A 2 in the infarcted heart. However, it caused a severe fall in blood pressure. These findings demonstrate that newly-synthesized NO donors release nitric oxide in situ and increase myocardial production of prostanoids. NCX 4016 has therapeutic potential because it can be orally administered, lacks hypotensive effects, increases blood levels of nitric oxide and myocardial prostacyclin production.

Downregulation of ventricular contractile function during early ischemia is flow but not pressure dependent.

The mechanism responsible for the abrupt fall in myocardial contractile function following coronary artery obstruction is unknown. The "vascular collapse theory" hypothesizes that the fall in coronary perfusion pressure after coronary artery obstruction is responsible for contractile failure during early ischemia. To test the role of vascular collapse in downregulating myocardial contractile force at the onset of ischemia, coronary flow of isolated rat hearts was abruptly decreased by 50, 70, 85, and 100% of baseline, and subsequent changes in coronary perfusion pressure and ventricular function were recorded at 0.5-s intervals. At 1.5 s after flow reductions ranging from 50 to 100%, decreases in contractile function did not differ, although perfusion pressure varied significantly from 45 +/- 1 to 20 +/- 2 mmHg. When function fell to 50% of baseline, perfusion pressures ranged from 35 +/- 0.5 to 2.5 +/- 1 mmHg for flow reductions ranging from 50 to 100%. Identical contractile function at widely differing coronary perfusion pressures is incompatible with the vascular collapse theory.

Adverse effects of regional anaesthesia in children.

True complications of regional block procedures pertain to the performance of the block technique and the local anaesthetic. Such complications include lesions caused by the device used, and many of these complications can be avoided by using specifically designed devices.Complications related to the local anaesthetic solution mainly consist of local and systemic complications. Local toxicity has mainly been reported in adults following spinal administration of 5% lidocaine (lignocaine), a drug that is not usually used in children. Systemic toxicity consists of CNS and cardiovascular complications, methaemoglobinaemia and allergic reactions. Systemic toxicity has special features in children, especially in those <1 year old. Infants have a much higher free serum concentration of local anaesthetics than older children and adults, and are more prone to the deleterious effects of local anaesthetics. Additionally, as regional blocks are usually performed under general anaesthesia in children, signs of CNS toxicity may be concealed. Because of their higher heart rate, newborns and infants are thought to be more prone to the phasic block produced by tertiary amine agents such as bupivacaine than are adults. Serum concentrations at which bupivacaine (and etidocaine) exert cardiac toxicity seem to be similar to those producing CNS toxicity. As there is an increased threshold for CNS toxicity in infants plus an increased (or equal) sensitivity to bupivacaine cardiotoxicity, cardiac signs may not be preceded by any sign of CNS toxicity. Cardiac complications include: (i) arrhythmias with high degree conduction block, major QRS widening, torsade de pointes, and ventricular tachycardia related to re-entry phenomena; and (ii) major vascular collapse favoured by a concomitant decrease in the myocardial contractile force. Other complications of regional block procedures result from poor selection of agent, and inadequate safety precautions and monitoring of the patient, especially during the postoperative period. There are 2 other groups of disorders often reported as complications of regional anaesthetics: (i) effects that were not anticipated by the anaesthetist because of a lack of knowledge of all the consequences of the technique used; and (ii) complications attributed to a concomitant regional block procedure but with no established, sometimes even improbable, causal link with the regional technique. The overall morbidity of regional anaesthesia in children is low. Sound selection of local anaesthetics, insertion routes and block procedures, together with appropriate and careful monitoring, should prevent any major undesirable effects and enable regional anaesthesia to be a well tolerated and effective tool to overcome pain associated with minimal morbidity.

Chronotropic and inotropic effects of terikalant on isolated, blood-perfused atrial and ventricular preparations of dogs.

We investigated the effects of terikalant, which blocks inward rectifier K+ current, on the sinus rate, atrial and ventricular contractile force in the isolated, blood-perfused right atrial and left ventricular preparations of dogs, and the effects of terikalant on the negative cardiac responses to acetylcholine, adenosine or pinacidil (an ATP-sensitive K+ channel opener) and on the positive cardiac responses to norepinephrine. Terikalant (1-100 nmol) decreased sinus rate and briefly and slightly increased atrial contractile force in isolated atria. However, terikalant did not increase ventricular contractile force in isolated ventricles. Neither propranolol nor atropine inhibited the positive inotropic and negative chronotropic responses to terikalant, respectively. Terikalant (10 or 30 nmol) did not significantly affect the negative cardiac responses to acetylcholine, adenosine nor pinacidil and the positive responses to norepinephrine. These results suggest that terikalant decreases sinus rate with a small changes in myocardial contractile force and does not affect the cardiac responses to muscarinic and adenosine receptor agonists, ATP-sensitive K+ channel openers nor beta-adrenoceptor agonists in the dog heart.

Correlation between myocardial contractile force and cytosolic inorganic phosphate during early ischemia.

To test the role of inorganic phosphate (Pi) in downregulation of myocardial contractile force at the onset of ischemia, Pi of rat hearts was determined with 31P nuclear magnetic resonance spectroscopy. Forty cycles of brief hypoperfusion (30% of baseline flow for 33 s) were used to achieve a time resolution of 0.512 s for comparing dynamic changes in Pi and contractile force. Initial control values of left ventricular developed pressure (LVP), heart rate, and oxygen consumption were 136 +/- 11 mmHg, 236 +/- 4 beats/min, and 95 +/- 3 microl O2 x min(-1) x g(-1); these values were unchanged at the end of the experiment. During the first 10 s of hypoperfusion, Pi increased at a rate (percentage of the total observed change) faster than the decrease in LVP; Pi and LVP then changed at the same rate during the remainder of the hypoperfusion. ADP did not change in advance of LVP. Intracellular pH did not change. The results indicate that Pi plays an important role in initiating the downregulation of myocardial contractile force at the onset of ischemia. Perfusion pressure also declined faster than LVP at the onset of ischemia, indicating potential importance of vascular collapse in contractile downregulation during early ischemia.

Effects of pimobendan on exercise tolerance and quality of life in patients with heart failure.

There has been an intensive search for safe and clinically effective inotropic agents for use as adjunctive therapy in patients with advanced heart failure. Pimobendan is a benzimidazole-pyridazinone derivative with calcium-sensitizing properties that increases myocardial contractile force without increasing intracellular calcium. This review summarizes the data from five controlled, randomized prospective trials of pimobendan that demonstrate significant improvements in exercise capacity and quality of life in patients with heart failure. The clinical benefits of pimobendan found in these trials contrast with the adverse experience noted previously with milrinone and enoximone. This may be related to the different mechanism of action of pimobendan or to a study design that permitted examination of a lower dosage. These cumulative data suggest that pimobendan may have a useful adjunctive role in heart failure and that further assessment of its effects on overall mortality is needed.

What kind of cardiovascular alterations could be influenced positively by oral antidiabetic agents?

Since the first publication of the University Group Diabetes Programme in 1970 the possible deleterious cardiovascular effects of certain hypoglycaemic sulphonylurea products has been well known. In contrast, international knowledge of the advantageous cardiovascular effects of certain sulphonylurea compounds became available recently. Glibenclamide decreases the incidence of fatal myocardial infarction and the development of ventricular fibrillation in patients suffering from acute myocardial infarction. It also lowers the incidence of ventricular ectopic beats in digitalized patients compared with patients treated with other investigated sulphonylurea compounds. The survival of patients treated with glibenclamide, insulin or diet alone is longer after the first attack of angina pectoris or after first acute myocardial infarction compared with those on other investigated sulphonylurea therapy. Glibenclamide decreases arrhythmogenesis during acute myocardial infarction in rats and strophanthin cardiotoxicity in rabbits. Arterial blood pressure and myocardial contractile force are not influenced by glibenclamide whereas these parameters are increased by other investigated sulphonylurea compounds. Consequently, deleterious cardiovascular effects of certain hypoglycaemic sulphonylurea drugs may contribute to the high cardiovascular mortality rate in diabetes mellitus, partly due to the effect on membrane channels and partly due to independent cardiac and extracardiac actions. Finally, recent observations suggest that glimepiride has a more advantageous cardiovascular effect than glibenclamide.

Effects of in vivo vanadate administration on calcium exchange and contractile force of rat ventricular myocardium

The aim of this study was to evaluate the effect of a 14-day intragastric administration of Na 3VO 4 (0.03 mmol/kg daily) on calcium metabolism and contractile force of rat myocardium. Left ventricular pressure as well as its first derivative ( dP dt ) were registered with a balloon inserted to this ventricle and the cellular content of exchangeable calcium with the aid of 45Ca 2+. Left ventricular pressure of the hearts exposed to vanadium was 11.8 ± 0.2 kPa and was lower by 23% in comparison with control hearts (without vanadate), and its first derivative was 131.01 ± 2.8 kPa/s (lower by 36.4%). The cellular content of exchangeable calcium in myocardium of rats treated with vanadium was 1.305 ± 0.173 and 2.019 +- 0.231 mmol/kg of wet weight (w.w.) in the stimulated and in the rested (for the last 10 min) ventricles, respectively. Accordingly, in the control group, the Ca content in stimulated hearts was lower by 0.384 mmol/kg w.w., and in the rested ones it was lower by 0.715. This indicates that the myocardial contractile force decreases, in spite of the fact that the content of calcium is considerably higher than that in the control group. These results also show a toxic effect of vanadate on the myocardium, probably due to large intracellular accumulation of calcium and cell damage.

The effects of sevoflurane on contractile and electrophysiologic properties in isolated guinea pig papillary muscles.

We examined, in guinea pig papillary muscles, whether the negative inotropic effect of sevoflurane is due to the depression of the influx of extracellular Ca2+ or to inhibition of the availability of intracellularly stored Ca2+. Sevoflurane decreased action potential duration and contractile force in a concentration-dependent fashion in normally polarized guinea pig papillary muscles. Sevoflurane produced a depression of contractile force with different rates or patterns of stimulation in the rested state and at low stimulation frequencies. In a potentiated state, sevoflurane did not depress contractile forces. Although sevoflurane decreased action potential duration and contractile force in a concentration-dependent fashion in normal Tyrode's solution, in high K+ Tyrode's solution, it caused a depression of contractile force without a shortening of action potential duration. Sevoflurane also depressed contractile force in normal and high K+ Tyrode's solution with ryanodine 1 microM. Our results suggest that in myocardial contractile force the negative inotropic effect of sevoflurane might be caused by depression of transsarcolemmal Ca2+ influx, accompanied by shortening of the action potential duration.

Role of vascular adrenergic mechanisms in the haemodynamic and PGI2 stimulating effects of angiotensin in diabetic dogs.

In aware of the well-known altered vascular responsiveness in the diabetic vasculature, this study aimed to compare the haemodynamic and PGI2 releasing effects of angiotensin in metabolically healthy (12) and alloxan-(560 umol/kg) diabetic (12) dogs as well as to analyze the role of vascular adrenoceptors in this. In vivo the effect of intracoronarially administered angiotensin (63-125-250-500-1000 pmol/kg/min) on coronary blood flow, mean arterial blood pressure, myocardial contractile force and heart rate was investigated without and with pretreatment of 2 umol/kg phentolamine. In vitro PGI2 release by isolated coronary rings was induced by 50 nmol/l angiotensin before and after pretreatment with 5 umol/l phentolamine and measured by radioimmunoassay. Angiotensin enhances dose-dependently both the mean arterial blood pressure and coronary blood flow, while it provokes a considerable (p < 0.05) increase of PGI2 formation by isolated coronary arterial rings. These alterations could be prevented by phentolamine administration both in vivo and in vitro, while this drug did not affect the angiotensin-induced enhancement of diabetic coronary blood flow. On the other hand the increase of blood pressure by angiotensin was found to be more (p < 0.05) expressed in diabetes and it could be further potentiated by phentolamine. PGI2 synthesis by isolated diabetic coronary rings could not be modified either by angiotensin alone or in combination with phentolamine. On the basis of above data, the lack of stimulated vascular PGI2 formation mediated by alpha-adrenergic mechanisms is supposed to causatively contribute to the diminished sensitivity of diabetic coronary arteries to vasodilation.

744-4 Evidence for Downward-Shift of Coronary Pressure-Flow Relationship Following a Brief Period of Ischemia in Dogs

This study was undertaken to test whether a brief period of ischemia affects the coronary pressure-flow relationship during reduction of coronary perfusion pressure (CPP). The left anterior descending coronary artery was cannulated and perfused with blood from the left carotid artery in 40 open-chest dogs. Coronary blood flow (CBF) was measured during intracoronary administrations of papaverine and adenosine. Coronary pressure-flow relationship was assessed during transient reduction of CPP from 100 to 30 mmHg with 10 mmHg intervals. Coronary hyperemic flow due to adenosine and papaverine was attenuated at 30 min of reperfusion following 10 and 15 min of ischemia. In the group of transient 10 min ischemia, both fractional shortening (FS) and CBF returned to the pre-ischemic values at 30 and 60 min of reperfusion, however, marked decreases in CBF (35 ± 5 vs 56 ± 4 ml/100 g/ml at CPP = 60 mmHg, p &lt; 0.01) during graded reductions in CPP were observed. Furthermore, both FS (6 ± 1 vs 14 ± 1% at CPP = 60 mmHg. p &lt; 001) and lactate extraction ratio (–41 ± 15 vs 1 ± 6% at CPP = 60 mmHg, p &lt; 0.05) were decreased. The endocardial vs. epicardial flow ratio was reduced relative to the control condition. The downward-shift of the coronary perfusion pressure-flow relationship and the deterioration of myocardial contractile and metabolic function during reduction of CPP were restored at 60 min of reperfusion. In contrast, in the group of transient 15 min ischemia, although both baseline FS and coronary hyperemic flow due to adenosine and papaverine remained to be at 30 and 60 min of reperfusion, the coronary perfusion pressure-flow relationship was not shifted. Transient brief period of ischemia can reversibly affect the coronary pressure-flow relationship due to the reduced capability of vascular relaxation, however, the downward-shift of coronary pressure-flow relationship can be blunted by the reduced myocardial contractile force against the coronary resistance vessels.

Coronary perfusion related changes in myocardial contractile force and systolic ventricular stiffness

The mechanism by which changes in coronary perfusion alter myocardial oxygen consumption (MVO2; Gregg phenomenon) is controversial. This study examined the effect of coronary perfusion on myocardial contractile force and systolic ventricular stiffness in the intact, ejecting heart. During selective perfusion of the left anterior descending coronary artery, coronary blood flow was changed with or without concurrent changes in coronary perfusion pressure in 19 alpha chloralose anaesthetised dogs. Regional myocardial segment length (end diastolic length; end systolic length) and developed force were measured with piezoelectric crystals and with a miniature force transducer, respectively. MVO2 was calculated from coronary flow and arteriovenous O2 difference. The slope of the force-length curve during ejection period (delta F/delta SL) was used as an index of systolic myocardial stiffness. When coronary perfusion pressure was varied from 60 to 180 mm Hg (protocol 1, n = 11), maximum developed force (Fmax), delta F/delta SL, and MVO2 increased with perfusion pressure while end diastolic length, segmental shortening, and other haemodynamic variables stayed constant. When coronary blood flow was increased at constant perfusion pressure by infusion of either a low dose or a high dose adenosine (protocol 2, n = 8), Fmax, delta F/delta SL, and MVO2 increased while end diastolic length, segmental shortening, and other haemodynamic variables stayed constant. MVO2 and delta F/delta SL increased more steeply with flow in protocol 1. (1) Increased coronary blood flow enhances myocardial contractile force, systolic ventricular stiffness, and MVO2 in the intact, ejecting heart. (2) Coronary blood flow induced changes in myocardial contractile force and systolic ventricular stiffness, but not end diastolic length, are probably responsible for coronary blood flow related changes in MVO2.

Cardiovascular Profile of RWJ 29009, a New Potassium Channel Activator, in Anesthetized and Conscious Dogs

RWJ-29009, (6S)-trans(-)-1-(6,7-dihydro-6-hydroxy-5,5-dimethyl-2-nitro-5 H-thieno[3,2-b]pyran-7-yl)-2-piperidinone, is a structurally novel and extremely potent potassium channel activator that may be useful for treatment of hypertension and ischemic heart disease. We assessed the cardiovascular profile of RWJ 29009 in anesthetized and conscious dogs. RWJ 29009 (0.1-2 micrograms/kg intravenously, i.v.) dose-relatedly increased coronary blood flow (CBF) and decreased arterial pressure in anesthetized dogs. Total peripheral resistance and coronary vascular resistance were concurrently reduced without significant changes in heart rate (HR) or cardiac output (CO). Left ventricular (LV) dP/dtmax and myocardial contractile force were decreased only at the highest dose of 10 micrograms/kg. Cromakalim (3-100 micrograms/kg), although much less potent, had a qualitatively similar profile. Glyburide pretreatment (5 mg/kg i.v.) shifted the dose response of RWJ 29009 for increasing CBF and decreasing arterial pressure to the right. The dose responses of cromakalim were similarly shifted to the right, whereas the effects of nifedipine on CBF and arterial pressure were not affected by glyburide. RWJ 29009 (0.3 and 1 microgram/kg) had no effect on myocardial O2 consumption (MVO2) except for a transient increase immediately after administration of 1 microgram/kg. MVO2 returned to control 15 min after dosing, although CBF remained significantly increased. In conscious dogs, RWJ 29009 (0.3-10 micrograms/kg, i.v. and orally, p.o.) produced dose-related increases in CBF and decreases in arterial pressure similar to those produced in anesthetized dogs, except that HR was increased concurrently. The i.v. and p.o. potency of RWJ 29009 were comparable, indicating high oral bioavailability. Thus, RWJ 29009 is an extremely potent coronary and peripheral vasodilator with a cardiovascular profile similar to that of other potassium channel activators. Like those of other potassium channel activators, its mechanism of action appears to involve activation of ATP-regulated potassium channels.

Positive inotropic action of angiotensin II in the pithed rat

The cardiovascular effects of angiotensin II were examined in aortic blood pressure-controlled and -uncontrolled pithed rats. Angiotensin II induced a dose-dependent increase in diastolic blood pressure, left ventricular pressure (LVP), dP/dt (the first derivative of LVP) and heart rate in pithed rats. The maximal responses for these parameters were similar to those to noradrenaline, except for the rise in diastolic blood pressure, where noradrenaline caused a greater increase than angiotensin II. After treatment with propranolol, the positive chronotropic effect of angiotensin II was abolished. Angiotensin II produced a dose-dependent increase in diastolic blood pressure, which was similar to that of vasopressin, and an increase in dP/dtmax, which proved much greater than that of vasopressin. When aortic blood pressure was controlled and the beta-receptors were blocked by propranolol, angiotensin II caused a dose-dependent increase in dP/dtmax without affecting the left ventricular enddiastolic pressure. The same results were obtained after both beta- and alpha-adrenoceptors were blocked by propranolol and phentolamine. Losartan but not PD123177 caused parallel rightward shifts of the dose-response curve of angiotensin II for dP/dtmax in the aortic blood pressure controlled pithed rat without altering the maximal response. It is concluded that in the pithed rat angiotensin II produced an increase in myocardial contractile force which is not mediated by beta- or alpha-adrenoceptors. The inotropic effect appears to be mediated by angiotensin receptors, of the AT1-subtype.