Biomedical subjects

J Müller-Ehmsen

Publications and source records attributed to J Müller-Ehmsen.

29 records · Page 2Linked to original sources

PubMed1997

Effect of inotropic interventions on contraction and Ca2+ transients in the human heart.

The present study investigated the influences of inotropic intervention on the intracellular Ca2+ transient (intracellular Ca2+ concentration ([Ca2+]i)) and contractile twitch. Isometric twitch and [Ca2+]i (fura 2 ratio method) were measured simultaneously (1 Hz, 37 degrees C) after stimulation with Ca2+ (0.9-3.2 mM), the cardiac glycoside ouabain (Oua; 0.1 microM), the beta1- and beta2-adrenoceptor-agonist isoprenaline (Iso; 1-10 nM), and the Ca2+ sensitizer EMD-57033 (30 microM) by using isolated human nonfailing right auricular trabeculae (n = 19). Inotropic interventions increased force of contraction and peak rate of tension rise (+T) significantly. Only Iso stimulated peak rate of tension decay (-T) higher than +T (P < 0.05), thereby reducing time of contraction (Ttwitch). EMD-57033 increased +T more effectively than -T and prolonged Ttwitch (P < 0.05). Ca2+, Oua, and Iso, but not EMD-57033, increased systolic Ca2+. Diastolic Ca2+ increased after stimulation with Oua or Ca2+, but not in the presence of EMD-57033. Iso shortened the Ca2+ transient and did not influence diastolic Ca2+. In conclusion, positive inotropic agents differently affect force and [Ca2+]i depending on their mode of action. Inotropic interventions influence diastolic Ca2+ and thus may be less advantageous in a situation with altered intracellular Ca2+ homeostasis (e.g., heart failure due to dilated cardiomyopathy).

Adult↗

PubMed1997

Effect of cyclopiazonic acid on the force-frequency relationship in human nonfailing myocardium.

The present study investigated the functional role of the sarcoplasmic reticulum Ca++-ATPase in contraction and relaxation, intracellular Ca++-transients, as well as on the force-frequency relationship in human myocardium. The Ca++-ATPase activity of membrane vesicles isolated from sarcoplasmic reticulum (SR) obtained from nonfailing donor hearts (n = 7) was measured in the presence of cyclopiazonic acid (CPA, 0-30 microM), a highly specific inhibitor of the Ca++-ATPase of the SR (SERCA). The effects of CPA on parameters of contraction and relaxation, force-frequency relationship and [Ca++]i transients (with fura-2) were studied on isolated left ventricular muscle strips from human nonfailing myocardium. CPA concentration-dependently inhibited SERCA activity of isolated SR vesicles. In the presence of CPA (30 microM) the former positive force-frequency relationship in human left ventricular nonfailing myocardium became negative. Especially at high frequencies of stimulation, CPA decreased developed tension, peak rate of tension rise and systolic fura-2-light emission, whereas time to peak tension, time to peak [Ca++]i, time to 95% relaxation, diastolic tension and diastolic Ca++ levels were increased. Peak rate of tension decay and time to half-relaxation and half-decay of [Ca++]i were not altered significantly after treatment with CPA. These findings provide evidence that the SERCA plays a functional role in the frequency-dependent increase in force of contraction in human myocardium. Because an impaired function of the SERCA is predominantly followed by alterations of inotropic and to a lesser degree of lusitropic function, other important factors to lower [Ca++]i and influence relaxation may be present in human myocardium to compensate for the reduced SERCA activity, e.g., Na+-Ca++ exchanger.

Adult↗

PubMed1996

Regional expression of sodium pump subunits isoforms and Na+-Ca++ exchanger in the human heart.

Cardiac glycosides exert a positive inotropic effect by inhibiting sodium pump (Na,K-ATPase) activity, decreasing the driving force for Na+-Ca++ exchange, and increasing cellular content and release of Ca++ during depolarization. Since the inotropic response will be a function of the level of expression of sodium pumps, which are alpha(beta) heterodimers, and of Na+-Ca++ exchangers, this study aimed to determine the regional pattern of expression of these transporters in the heart. Immunoblot assays of homogenate from atria, ventricles, and septa of 14 nonfailing human hearts established expression of Na,K-ATPase alpha1, alpha2, alpha3, beta1, and Na+-Ca++ exchangers in all regions. Na,K-ATPase beta2 expression is negligible, indicating that the human cardiac glycoside receptors are alpha1beta1, alpha2beta1, and alpha3beta1. alpha3, beta1, sodium pump activity, and Na+-Ca++ exchanger levels were 30-50% lower in atria compared to ventricles and/or septum; differences between ventricles and septum were insignificant. Functionally, the EC50 of the sodium channel activator BDF 9148 to increase force of contraction was lower in atria than ventricle muscle strips (0.36 vs. 1.54 microM). These results define the distribution of the cardiac glycoside receptor isoforms in the human heart and they demonstrate that atria have fewer sodium pumps, fewer Na+-Ca++ exchangers, and enhanced sensitivity to inotropic stimulation compared to ventricles.

Adult↗

PubMed1996

Altered inotropism in the failing human myocardium.

Beta-adrenoreceptor-cAMP-dependent inotropic interventions lose their effectiveness depending on the degree of myocardial failure. This blunted effect of beta-adrenoreceptor-dependent stimulation might be due to a downregulation of beta-adrenoreceptors and an increase of inhibitory G-proteins leading to decreased intracellular cAMP-concentrations. However, the maximal positive inotropic effect elicited by elevation of the extracellular [Ca2+] does not differ between failing and nonfailing human myocardium, indicating that terminally failing human myocardium is effective to increase force of contraction to the same degree as nonfailing tissue. Agents which increase force of contraction primarily via increasing the intracellular [Na+], e.g., cardiac glycosides and the Na(+)-channel activator BDF 9148, exert a higher potency in failing myocardium than in nonfailing tissue to increase force of contraction. This could result from an enhanced protein expression of the Na+/Ca(2+)-exchanger observed in diseased human hearts. Alterations in the intracellular Ca(2+)-homeostasis reported in failing myocardium lead to a negative force-frequency-relationship and a prolonged relaxation. As the protein expression of SERCA IIa and phospholamban seems to be similar in NYHAIV and nonfailing tissue, the reduced Ca(2+)- uptake may result from an altered regulation of these proteins, e.g., reduced phosphorylation of phospholamban or the SERCA IIa. After inhibition of the Ca(2+)-ATPase of the sarcoplasmic reticulum with the high specific inhibitor cyclopiazonic acid the former positive force-frequency-relationship became significantly less positive even in the nonfailing tissue and twitch course became similar to diseased hearts. These findings may be indicative for the importance of the Ca(2+)-reuptake mechanism into the sarcoplasmic reticulum in addition to the regulatory control at the site of the contractile apparatus for the regulation of contraction and relaxation in human myocardium.

Adrenergic beta-Agonists↗

PubMed1996

Enhanced sensitivity of the failing human myocardium to cardiac glycosides and Na(+)-channel activators.

Cardiac glycosides and Na+ -channel activators increase intracellular Na+ and thereby enhance the transport rate of the sarcolemmal Na+/Ca2+ exchanger. We tested the hypothesis of whether increased expression of the Na+/Ca2+ exchanger in failing human myocardium is accompanied by enhanced sensitivity of the failing human myocardium toward cardiac glycosides and Na+ -channel activators. We studied the positive inotropic effects of the new Na+ -channel activator BDF and the cardiac glycoside ouabain in human failing (New York Heart Association [NYHA] functional class IV, heart transplants for dilated cardiomyopathy, n = 11) and nonfailing (donor hearts, n = 5) myocardium on electrically driven left ventricular papillary muscle strips (1 Hz, 37 degrees C). The effectiveness of ouabain and BDF to increase force of contraction was similar in human nonfailing and failing myocardium. BDF was more potent to increase force of contraction in failing than in nonfailing tissue (p < 0.05). The time until maximal inotropic effect developed after ouabain was significantly shorter in NYHA IV (mean 150 +/- 16 min) than in nonfailing myocardium (mean 240 +/- 20 min). These results suggest that human failing myocardium exerts and enhanced sensitivity to cardiac glycosides and Na+ -channel activators, possibly because of enhanced expression of the Na+/Ca2+ exchanger or because of an altered intracellular Na+ -homeostasis.

Adolescent↗

PubMed1996

Enantioselective inotropic actions of the Na+-channel activators BDF 9148, BDF 9196 and BDF 9167 in human failing and nonfailing myocardium.

Our study investigated the inotropic effect of the novel Na+-channel activator BDF 9148 and its enantiomeres [S(-)BDF 9169, R(+)BDF 9167] in human failing [New York Heart Association Class (NYHA IV) heart transplants, n = 15] and nonfailing myocardium (NF, donor hearts, n = 5). We studied the effect of BDF 9148 (BDF, 0.03-10 micromol/liter) and of its enantiomeres [S(-) BDF 9196; R(+)BDF 9167] on isometric force of contraction (1 Hz) as well as on the force-frequency-relationship (0.5-3 Hz) in electrically driven (37 degrees C) left ventricular papillary muscle strips, BDF and S-BDF, but not R-BDF, increased force of contraction in a dose-dependent manner in NYHA IV and NF. The effectiveness of BDF, S-BDF and Ca2+ (15 mmol/liter) to increase force of contraction was similar in human nonfailing and failing myocardium. The potency of BDF and S-BDF to increase force of contraction was significantly higher in NYHA IV compared to NF. Carbachol (1 mmol/liter) did not affect the positive inotropic response of the studied compounds. In the presence of 3 micromol/liter BDF or S-BDF force of contraction increased after an increase in stimulation frequency only from 0.5 to 1 Hz in NYHA IV and human nonfailing myocardium. At frequencies above 1 Hz the force-frequency-relationship was negative in human nonfailing myocardium and NYHA IV in the presence of high concentrations of BDF or S-BDF. These results suggest that the racemic Na+-channel activator BDF 9148 and the S(-) BDF-enantiomere, but not the R(+) BDF-enantiomere, are effective to increase force development maximally in NYHA IV and in nonfailing myocardium. Human failing myocardium exerts an enhanced sensitivity toward the Na+-channel activator BDF 9148 and its S(-) enantiomere to increase force of contraction when compared to nonfailing tissue. As Na+-channel activators increase force in a frequency-dependent mode of action the force-frequency-relationship may depend on the intracellular Ca2+- and Na+- homeostasis.

Azetidines↗

PubMed1996

Inotropic and coronary vasodilatory actions of the K-adenosine triphosphate channel modulator nicorandil in human tissue.

The present study aimed to characterize the inotropic and vasodilatory properties of the K-ATP channel opener nicorandil (NIC) in isolated human cardiac tissue. For comparison, the Ca+2 channel blockers diltiazem (DIL) and nifedipine (NIF) have been studied. Concentration-dependent effects of NIC, DIL and NIF on the force of contraction (FOC) and the vascular tone have been studied on left ventricular papillary muscle strips (dilated cardiomyopathy, New York Heart Association Class IV, n = 20; nonfailing, donor hearts, n = 4), on right auricular trabeculae (nonfailing, n = 5) and on precontracted (prostaglandin F2 alpha: 0.3, 0.5 or 1 mumol/l) isolated human coronary artery rings (cardiac transplantation, n = 15). NIC, DIL and NIF concentration-dependently reduced the FOC of the papillary muscle preparations. However, the IC25 for the negative inotropic effect was significantly higher for NIC compared to DIL and NIF. The maximal negative inotropic effects of NIC, DIL and NIF (100 mumol/l) were -48.2 +/- 4.1, -92.9 +/- 0.9 and -93.4 +/- 1.4% of the basal FOC. The negative inotropic actions of NIC were similar in the human failing and the nonfailing ventricular and in the right atrial myocardium. Whereas pretreatment with methylene blue, an inhibitor of guanylyl cyclase, had no effect on the negative inotropic action of NIC, it was almost abolished by glibenclamide, a selective antagonist of the ATP-dependent K channels. NIC, DIL and NIF relaxed the coronary artery rings with 97.1 +/- 0.5, 90.7 +/- 0.9 and 96.4 +/- 0.7% of maximal relaxation (papaverine, 100 mumol/l). The rank order of vasodilatory potency was NIF > NIC > DIL. In conclusion, NIC is as effective as DIL and NIF in relaxing human coronary artery rings. However, NIC showed significantly lower negative inotropic effects when compared with the Ca+2 channel antagonists. The negative inotropic action of NIC is probably due to an interaction with the ATP-dependent K channels. In addition, activation of guanylyl cyclase does not seem to exert any negative inotropic action in the human myocardium.

Adenosine Triphosphate↗

PubMed1994

Influence of halothane on the effect of cAMP-dependent and cAMP-independent positive inotropic agents in human myocardium.

Volatile anaesthetics have a variety of effects on the myocardium, namely a negative inotropic effect and a catecholamine sensitizing effect. The present study was designed to see if the hydrocarbon anaesthetics interact specifically with subcellular targets of the myocardial cell, by examining the effects of halothane in the presence of positive inotropic agents with different mechanisms of action. Experiments were performed in isolated electrically driven left ventricular preparations (1 Hz, 37 degrees C, Ca2+ 1.8 mmol litre-1) from human hearts obtained at cardiac surgery. The concentration-response curves of noradrenaline, milrinone, BayK 8644 and Ca2+ were investigated in the absence and in the presence of halothane. Halothane enhanced the efficacy of noradrenaline and milrinone but not of Ca2+ or BayK 8644. The potency of milrinone was also increased by halothane, whereas the potency of BayK 8644 was decreased and those of noradrenaline and Ca2+ were unchanged. Halothane differentially influences the effects of agents with different positive inotropic mechanisms. This experimental approach can be taken as a functional method to localize the mechanisms of action of the inhalation anaesthetics in human myocardium, namely sensitization of cAMP formation and interaction with L-type Ca2+ channels.

3-Pyridinecarboxylic acid, 1,4-dihydro-2,6-dimethy↗

PubMed1994

Studies of the nucleoside transporter inhibitor, draflazine, in the human myocardium.

1. The aim of the present study was to determine the effect of the nucleoside transporter inhibitor, draflazine, on the force of contraction in human myocardium and the affinity of the compound for the nucleoside transporter. Nucleoside transport inhibitors, like draflazine, are of potential importance for cardiopreservation of donor hearts for heart transplantation. 2. Functional experiments were performed in isolated electrically driven (1 Hz, 1.8 mmol l-1 Ca2+) human atrial trabeculae and ventricular papillary muscle strips. The affinity of draflazine for the myocardial nucleoside transporter was studied in isolated membranes from human ventricular myocardium and human erythrocytes in radioligand binding experiments using [3H]-nitrobenzylthioinosine ([3H]-NBTI). Dipyridamole was studied for comparison. 3. In membranes from human myocardium and erythrocytes, [3H]-NTBI labelled 1.18 pmol mg-1 protein and 23.0 pmol mg-1 protein, respectively, nucleoside transporter molecules with a KD value of 0.8 nmol l-1. Draflazine concentration-dependently inhibited binding of [3H]-NBTI to myocardial and erythrocyte membranes with a K(i)-value of 4.5 nmol l-1. The potency as judged from the K(i) values was ten times greater than that of dipyridamole in both myocardial and erythrocyte membranes. 4. Draflazine, at concentrations up to 100 mumol l-1, did not produce negative inotropic effects in atrial and ventricular myocardium. (-)-N6-phenylisopropyladenosine (R-PIA) and carbachol did not reduce force of contraction in ventricular myocardium, but exerted concentration-dependent direct negative inotropic effects in atrial myocardium. 5. The data provide evidence that draflazine specifically binds to the nucleoside transporter of the human heart and erythrocytes with high affinity. The compound does not produce negative inotropic effects at concentrations as high as 100 micromol 1-1.6. Draflazine could be a useful agent for cardio preservation because it does not produce cardio depressant effects. Thus, it may be possible to perfuse explanted hearts directly with this agent without the hazard of cardiodepression.

Adult↗

PubMed1993

Effect of inotropic stimulation on the negative force-frequency relationship in the failing human heart.

BACKGROUND: In severe human heart failure, an increase in frequency of stimulation is accompanied by a reduced force of contraction in vivo and in vitro. The present study was aimed to investigate whether inotropic stimulation influences the inverse force-frequency relationship in failing human myocardium. METHODS AND RESULTS: The effects of the cAMP-independent positive inotropic agents ouabain (0.01 mumol/L) and BDF 9148 (0.1 mumol/L) as well as the beta-adrenoceptor agonist isoprenaline (0.01 mumol/L and 0.1 mumol/L) on the force-frequency relationship in electrically driven papillary muscle strips from nonfailing (brain death, n = 5) and terminally failing (NYHA class IV, heart transplants, dilated cardiomyopathy, n = 22) human myocardium were studied. For comparison, we examined the effect of elevation of the extracellular Ca2+ concentration (3.2 mmol/L and 6.2 mmol/L). In nonfailing myocardium, force of contraction, peak rate of tension rise, and peak rate of tension decay increased, whereas time to peak tension and time to half relaxation decreased following an increase of stimulation frequency. In NYHA class IV, force of contraction gradually declined followed by changes of other parameters of isometric contraction. Moderate stimulation of contractility by isoprenaline (0.01 mumol/L) partly reversed the negative force-frequency relationship in NYHA class IV and preserved the positive force-frequency relationship in nonfailing myocardium. The addition of ouabain and BDF 9148 together restored completely the force-frequency relationship in NYHA class IV. In contrast, high concentrations of isoprenaline (0.1 mumol/L) and an elevation of the extracellular Ca2+ concentration enhanced the decline in force of contraction in the presence of higher stimulation frequencies. CONCLUSIONS: It is concluded that functionally important changes occur in the intracellular Ca2+ handling, leading to the negative force-frequency relationship in terminally failing human myocardium. Interestingly, the negative force-frequency relationship can be restored by agents producing positive inotropic effects by elevation of the intracellular Na+ concentration. These findings suggest that hitherto unknown changes in the intracellular ionic homeostasis occur in the failing human heart. Even though increasing [Ca2+]i in failing heart cells may be detrimental, increasing [Na+bdi may be beneficial through a mechanism independent of an increase in [Ca2+]i.

Adult↗

PubMedDate not supplied

Effect of epinine on tension of human renal arteries.

BACKGROUND: The present study aimed to characterize the effects of epinine, the active metabolite of ibopamine on tension development in human renal arteries. METHODS AND RESULTS: Experiments were performed on isolated human renal arteries rings obtained during surgery due to kidney tumors (n = 12). Epinine concentration-dependently relaxed isolated precontracted (PGF2 alpha) human renal artery rings (P < 0.05) in the presence of phentolamine, as effectively (epinine -30 +/- 4 mN, dopamine -31 +/- 5 mN) and with the same potency as dopamine (epinine EC50 0.7 mumol/l (0.4-1.2 mumol/l), dopamine 0.5 mumol/l (0.2-1.7 mumol/l). This effect was antagonized by the specific D1-receptor-antagonist SCH 23390. Effective beta-adrenoceptor antagonistic concentrations of propranolol did not affect epinine-induced vasorelaxation. In the absence of alpha- and beta-adrenoceptor-antagonists the potency of epinine to contract renal artery rings was significantly higher compared to dopamine indicating a higher affinity of epinine to alpha-adrenoceptors. CONCLUSION: The present study provides evidence for direct vasodilatory effects of epinine via activation of D1-receptors on human renal arteries.

Adrenergic alpha-Antagonists↗