Search PubMed⌕ Search

Biomedical subjects

R H Schwinger

Publications and source records attributed to R H Schwinger.

At least 37 records · Page 2Linked to original sources
PubMed2000

Myofilament calcium regulation in human myocardium.

BACKGROUND: We investigated whether decreased myofilament calcium contractile activation may, in part, contribute to heart failure. METHODS AND RESULTS: Calcium concentration required for 50% activation and Hill coefficient for fibers from nonfailing and failing human hearts at pH 7.1 were not different. Maximum calcium-activated force (F(max)) was also not different. However, at pH 6.8 and 6.9, differences were seen in myofilament calcium activation between nonfailing and failing hearts. At lower pH, failing myocardium was shifted left on the calcium axis compared with nonfailing myocardium, which suggested an increase in myofilament calcium responsiveness. Increased inorganic phosphate concentration decreased maximal force development by 56% in nonfailing and 36% in failing myocardium and shifted the calcium-force relationship by 2.01+/-0.22 versus 0.86+/-0.13 micromol/L, respectively (P<0.05). Addition of cAMP resulted in a 0. 56 micromol/L shift toward higher intracellular calcium concentrations in nonfailing myocardium and a 1.04 micromol/L shift in failing myocardium. Protein kinase A in the presence of cAMP resulted in a further rightward shift in nonfailing human myocardium but did not further shift the calcium-force relationship in fibers from failing hearts. cGMP also resulted in a greater decrease in myofilament calcium sensitivity in fibers from failing hearts. CONCLUSIONS: We propose that changes at the level of the thin myofilaments result in differential responses to changes in the intracellular milieu in nonfailing versus failing myocardium.

Actin Cytoskeleton↗
PubMed2000

Isoform expression of the sarcoplasmic reticulum Ca2+ release channel (ryanodine channel) in human myocardium.

The Ca2+ release channel of the sarcoplasmic reticulum (SR) is essential for the release of Ca2+ from intracellular stores and is expressed widely in various excitable cells. It plays a key role particularly in excitation contraction coupling in myocytes in skeletal and cardiac muscle. Three isoforms of the SR Ca2+ release channel have been cloned. Recently coexpression of different isoforms was reported in different animal species and various tissues. In human cardiac tissue, however, isoform expression is not yet established. Therefore the aim of this study was to characterize isoform expression of the SR Ca2+ release channel in the human heart. We examined specific isoform expression of mRNA and proteins of the SR Ca2+ release channel in the four different chambers of the heart and the interventricular septum from explanted human hearts from nonfailing organ donors (n=8). Reverse transcriptase PCR from total cardiac RNA with isoform specific primers and western blots from myocardial homogenates with isoform specific antibodies were performed. Quantification of protein expression was achieved by densitometric scanning and computer analysis and is expressed as densitometric units per microgram of protein. A single band DNA signal was detected by reverse transcriptase PCR for the skeletal isoform 1 and the cardiac isoform 2 and isoform 3 in all regions of the human heart investigated. Specific protein expression was detected in all five myocardial regions of the human heart in western blots for the skeletal isoform I and cardiac isoform 2, and a weaker specific band was also detectable for isoform 3 of the SR Ca2+ release channel. Quantification of protein expression showed significant (P=0.008) lower expression of isoform 1 in the right ventricle (42+/-4 densitometric units/g tissue) and similar expression in all other regions (right atrium 58+/-3; septum 51+/-5, left atrium 54+/-5; left ventricle 51+/-6). Isoform 2 of the SR Ca2+ release channel was also significantly lower (P=0.001) in the right ventricle (33+/-4 densitometric/g tissue) and similar in the other heart chambers (right atrium 42+/-5: septum 41+/-3, left atrium 52+/-6, left ventricle 42+/-3). Differences in isoform 3 of the SR Ca2+ release channel for the various myocardial regions did not reach significant levels (right atrium 45+/-6, right ventricle 38+/-5, septum 49+/-8, left atrium 46+/-7, and in left ventricle 45+/-3 densitometric units/g tissue). In conclusion, all three isoforms of the SR Ca2+ release channel were determined in the human heart at both mRNA and protein levels with different quantitative expression in the different heart chambers. Coexpression of the three different isoforms with different functional properties might increase the complexity of regulation of excitation contraction coupling in the human heart in a chamber specific mode.

Adult↗
PubMed2000

Modulation of cross-bridge interaction by 2,3-butanedione monoxime in human ventricular myocardium.

OBJECTIVES: 2,3-butanedione monoxime (BDM) has been suggested as an additive to cardioplegic solutions, because it may reduce the energy cost associated with force production in heart muscle. METHODS: The present study investigated the effect of BDM (10 mM) on developed tension (DT), Ca(2+)-dependent myosin ATPase activity (MYO) and tension cost (myosin ATPase activity/ tension ratio), characterizing the cross-bridge detachment rate, of skinned fiber preparations (1% Triton X, 20 h, 4 degrees C) of human left ventricular failing myocardium (dilative cardiomyopathy, heart transplants, n=6) at increasing concentrations of Ca2+ (0.01-32 microM). RESULTS: BDM decreased Ca2+ sensitivity of DT [EC50 Ca2+, control: 1.3+/-0.2 microM, + BDM (10 mM): 4.5+/-0.3 microM] and MYO [EC50 Ca2+, control: 0.9+/-0.2 microM, + BDM (10 mM): 3.1+/-0.3 mM]. In addition, BDM reduced maximal DT [control: 26.0+/-1.9 mN/mm2, + BDM (10 mM): 8.1+/-1.1 mN/mm2] and MYO [control: 124+/-21 RM ADP/s, + BDM (10 mM): 62 9 microM ADP/s]. However, the influence of BDM on maximal DT (-69%) was more pronounced than on maximal MYO (-50%). The myosin ATPase activity/tension relation was significantly higher in the presence of BDM. CONCLUSIONS: BDM exerts negative inotropic activity by reducing the number of force-generating cross-bridges, possibly by increasing the cross-bridge detachment rate as well as by reducing force generation per cross-bridge in human myocardium. As BDM reduces force generation more than ATPase activity, BDM may not necessarily reduce energy demand in human myocardium.

Adult↗
PubMed2000

The enhanced contractility in phospholamban deficient mouse hearts is not associated with alterations in (Ca2+)-sensitivity or myosin ATPase-activity of the contractile proteins.

Work performing heart preparations from hypercontractile, phospholamban deficient mouse hearts showed no change in parameters of contraction or relaxation in response to isoproterenol stimulation. Thus, the aim of the present study was to investigate whether or not changes at the level of the contractile apparatus occur in addition to the altered expression of Ca2+-regulating proteins observed in these mouse models, e.g., phospholamban, ryanodine receptors. Triton-X skinned fiber preparations from phospholamban deficient (n = 9) and wild-type (n = 10) mice were used and the Ca2+-activated force as well as the myosin ATPase-activity were simultaneously measured. The tension dependent ATPase-activity was unchanged in phospholamban deficient animals when compared to controls. The SERCA 2a-inhibitor cyclopiazonic acid did not affect myosin ATPase-activity in this system. The Ca2+-sensitivity of Ca2+-activated force and myosin ATPase were unchanged as well. Comparison of the concentrations needed to achieve half maximal activation of the myosin ATPase-activity and force demonstrated that the Ca2+-sensitivity of the myosin ATPase was higher compared to the Ca2+-sensitivity of tension development. This holds true for phospholamban deficient mice (EC50 ATPase: 0.9 +/- 0.2 micromol/l; tension: 1.7 +/- 0.3 micromol/l; p < 0.001) and wild-type controls (1.1 +/- 0.01 micromol/l; 2.2 +/- 0.4 micromol/l; p < 0.01). The myosin ATPase-activity and force were correlated to each other in both, phospholamban deficient mice and controls and did not change at submaximal Ca2+ concentrations. The ATPase/ force-ratio, as a parameter of tension cost, was similar in either phospholamban deficient mice or controls. Thus, the present study provides evidence that at the level of the contractile proteins regulation of Ca2+-activated force and energy demand of force development are not altered in phospholamban deficient mice with enhanced myocardial performance. At the level of the regulation of crossbridge interaction, no adaptive or compensatory mechanisms have been initiated by ablation of phospholamban.

Animals↗
PubMed2000

Diminished posttetanic potentiation in failing human myocardium.

In heart failure a decreased function of SERCA 2 has been demonstrated. The present study aimed at investigating the relation between sarcoplasmic reticulum-Ca2+-load (SR-Ca2+-load) and the activity of the SERCA 2. SR-Ca2+ load was evaluated by measuring posttetanic potentiation (PTP) in human nonfailing (NF, n = 10) and endstage failing myocardium (DCM, n = 11). In addition, the effect of cyclopiazonic acid (CPA), a specific inhibitor of SERCA 2, on PTP was studied in both NF and DCM. In crude membrane preparations from the same hearts the maximal SERCA 2 activity was determined and correlated with the PTP. In failing myocardium the PTP was significantly reduced compared to nonfailing myocardium (13.7+/-0.75 mN/mm2 vs. 17.1+/-1.55 mN/mm2, p<0.05, +/- SEM). When PTP was studied in the presence of increased extracellular Ca2+-concentrations, the difference between NF and DCM was further pronounced. CPA decreased PTP in both nonfailing and failing human tissue. The maximal SERCA 2 activity was significantly reduced in failing myocardium (NF 267+/-18.5 nmol ATP/mg protein x min(-1) vs. DCM 191+/-13.4 nmol ATP/mg protein x min(-1), p<0.05, +/- SEM). Correlation of the PTP and maximal SERCA 2 activity revealed a close correlation between both parameters in NF and DCM. In summary, the presented results suggest that reduced SERCA 2 activity in DCM influences posttetanic force potentiation probably through a reduced SR-Ca2+-load.

Adult↗
PubMed2000

Crataegus special extract WS 1442 increases force of contraction in human myocardium cAMP-independently.

The mode of action of Crataegus extracts in the treatment of heart failure is still under examination. WS 1442, a standardized special extract from Crataegus leaves with flowers, exerts direct positive inotropic effects. This study was designed to investigate the mode of inotropic action of WS 1442 in human myocardium from patients with congestive heart failure (left ventricular myocardium from explanted hearts; NYHA IV, n = 8) as well as in nonfailing controls (right auricular trabeculae from patients with coronary heart disease, n = 8). WS 1442 effectively displaced specifically bound 3H-ouabain but did not influence the activity of adenylate cyclase [control, + Gpp(NH)p (10(-4) microM) 3,500 pmol cyclic adenosine monophosphate (cAMP)/20 min). In isolated left ventricular papillary muscle strips, WS 1442 significantly increased the force of contraction [basal, 1.8+/-0.2 mN; WS 1442 (50 microg/ml), 2.4+/-0.1 mN (130%)] and improved the frequency-dependent force generation (0.5 vs. 2.5 Hz: control, +0.1+/-0.01 mN; WS 1442, +0.9+/-0.3 mN) even in failing human myocardium. In fura-2-loaded muscle strips (right atrial trabeculae), WS 1442 increased both the Ca2+-transient and force generation. These effects also were observed in the lipophilic ethyl acetate-soluble fraction A, enriched in flavone derivatives. In conclusion, these findings suggest a pharmacologic mechanism of WS 1442 similar to the cAMP-independent positive inotropic action of cardiac glycosides. In addition, WS 1442 improves the force-frequency relation in failing human myocardium.

Adenylyl Cyclases↗
PubMed2000

SERCA2a activity correlates with the force-frequency relationship in human myocardium.

The present investigation addresses whether protein expression and function of sarco(endo)plasmic reticulum Ca(2+)-ATPase (SERCA2a) and phospholamban (PLB) correlate in failing and nonfailing human myocardium. SERCA2a activity and protein expression, PLB phosphorylation, and the force-frequency relationship (FFR) have been determined in right atrium (RA) and left ventricle (LV) from nonfailing (NF, n = 12) and terminally failing [dilated cardiomyopathy (DCM), n = 12] human hearts. Only in LV of DCM hearts was SERCA2a activity significantly decreased [maximal turnover rate (V(max)) = 196 +/- 11 and 396 +/- 30 nmol. mg(-1). min(-1) in LV and RA, respectively], whereas protein expression of SERCA2a in the different chambers was unchanged in NF (3.9 +/- 0.3 and 3.2 +/- 0.4 densitometric units in LV and RA, respectively) and DCM hearts (4.8 +/- 0.8 and 3.4 +/- 0.1 densitometric units in LV and RA, respectively). Phosphorylation of PLB was higher in LV than in RA in NF (Ser(16): 180.5 +/- 19.0 vs. 56.8 +/- 6.0 densitometric units; Thr(17): 174.6 +/- 11.2 vs. 37.4 +/- 8.9 densitometric units) and DCM hearts (Ser(16): 132.0 +/- 5.4 vs. 22.4 +/- 3.5 densitometric units; Thr(17): 131.2 +/- 10.9 vs. 9.2 +/- 2.4 densitometric units). SERCA2a function, but not protein expression, correlated well with the functional parameters of the FFR in DCM and NF human hearts. Regulation of SERCA2a function depends on the phosphorylation of PLB at Ser(16) and Thr(17). However, direct SERCA2a regulation might also be affected by an unknown mechanism.

Adult↗
PubMed2000

Different effect of the Ca(2+) sensitizers EMD 57033 and CGP 48506 on cross-bridge cycling in human myocardium.

Ca(2+) sensitizers may be advantageous for treatment in human heart failure by increasing cardiac force without increasing the Ca(2+) transient or energy consumption. To study the mode of action of the Ca(2+) sensitizers EMD 57033 (EMD) and CGP 48506 (CGP), their influence on butanedione monoxime (BDM)-mediated depression of cross-bridge cycling was analyzed in human myocardium (explanted hearts, dilated cardiomyopathy, n = 19). In Triton X (1%)-skinned fiber preparations of left ventricular myocardium from patients suffering from dilated cardiomyopathy, troponin I was extracted by vanadate (10 mM) treatment, resulting in a Ca(2+)-independent contraction. In troponin I-depleted fibers BDM (5-50 mM) was applied in the absence and presence of EMD (10 microM) or CGP (10 microM). To analyze the influence on cross-bridge kinetics, tension cost (ratio of ATPase activity and tension development) was studied. BDM exerted a dose-dependent force inhibition in troponin I-depleted fibers (IC(50) = 7.22 mM), which was antagonized by EMD (IC(50) of BDM + EMD = 19.97 mM) and CGP (IC(50) of BDM + CGP = 15.30 mM). EMD increased Ca(2+) sensitivity of force and maximal force in Triton X-skinned fibers. The Ca(2+)-sensitizing effect of CGP was accompanied by an increased Ca(2+) sensitivity of myosin-ATPase activity, an increased slope of the Ca(2+) force and Ca(2+) ATPase curve, as well as a reduced maximal myosin ATPase activity. CGP and EMD reduced tension cost. In conclusion, EMD and CGP antagonize the BDM-mediated relaxation in troponin I-depleted cardiac muscle fibers. The Ca(2+)-sensitizing effect of CGP seems to be dependent on an improvement of the myofilament cooperativity, whereas EMD seems to operate by increasing the force per cross-bridge.

Adult↗
PubMed1999

Reduced sodium pump alpha1, alpha3, and beta1-isoform protein levels and Na+,K+-ATPase activity but unchanged Na+-Ca2+ exchanger protein levels in human heart failure.

BACKGROUND: Cardiac glycosides initiate an increase in force of contraction by inhibiting the sarcolemmal sodium pump (Na+, K+-ATPase), thereby decreasing Ca2+ extrusion by the Na+-Ca2+ exchanger, which increases the cellular content of Ca2+. In patients with heart failure the sensitivity toward cardiac glycosides is enhanced. METHODS AND RESULTS: Because the inotropic effect of cardiac glycosides may be a function of the sodium pump and Na+-Ca2+ exchanger (NCE) expression levels, the present study aimed to investigate protein expression of both transporters (immunoblot with specific antibodies against the sodium pump catalytic alpha1-, alpha2-, alpha3-, and glycoprotein beta1-isoforms and against NCE) in left ventricle from failing (heart transplantations, New York Heart Association class IV, n=21) compared with nonfailing (donor hearts, NF, n=22) human myocardium. The density of 3H-ouabain-binding sites (Bmax) and the Na+,K+-ATPase activity were also measured. In NYHA class IV, protein levels of Na+,K+-ATPase alpha1- (0.62+/-0.06 of control), alpha3- (0.70+/-0.09), and beta1- (0.61+/-0.04) but not alpha2-isoforms were significantly reduced (P<0.01), whereas levels of NCE (0.92+/-0.13 of control) and calsequestrin (0.98+/-0.06) remained unchanged. Both Na+,K+-ATPase activity (NF: 1.9+/-0.29; NYHA class IV: 1.1+/-0.17 micromol ATP/min per milligram of protein) and the 3H-ouabain binding sites (Bmax NF: 15.9+/-1.9 pmol/mg protein; NYHA class IV: 9.7+/-1.5) were reduced in NYHA class IV and correlated significantly to each other (r2=0. 73; P<0.0001), as did beta1-subunit expression. In left ventricular papillary muscle strips from NYHA class IV compared with nonfailing tissue the Na+-channel modulator BDF 9198 exerted an increase in force of contraction with unchanged effectiveness but enhanced potency. CONCLUSIONS: The enhanced sensitivity of failing human myocardium toward cardiac glycosides may be, at least in part, attributed to a reduced protein expression and activity of the sarcolemmal Na+,K+-ATPase without a change in Na+-Ca2+ exchanger protein expression.

Adolescent↗
PubMed1999

Regional expression and functional characterization of the L-type Ca2+-channel in myocardium from patients with end-stage heart failure and in non-failing human hearts.

The purpose of the present study was to investigate the expression and functional relevance of sarcolemmal L-type Ca2+-channels in failing and non-failing human myocardium. The protein expression of sarcolemmal L-type Ca2+-channels was determined with 3H-(+)-PN 200-110-binding experiments and Western blot analysis using a specific antibody against the alpha1-subunit in membrane preparations of ventricular and atrial myocardium from both failing (n = 15) and non-failing hearts (n = 8). The gene expression of the ion conducting pore of the L-type Ca2+-channel was examined with Northern blot technique in human failing and non-failing RNA. For normalization the RNA expression of calsequestrin was used. In electrically driven ventricular papillary muscle strips and auricular trabeculae, the responses to nifedipine and Ca2+ as parameters of myocardial function were studied. The protein expression as measured by 3H-(+)-PN 200-110-binding (Bmax) and Western Blot analysis with calsequestrin as reference was similar in left ventricular failing and non-failing myocardium. However, both were reduced in atrial compared to ventricular tissue in failing and non-failing hearts. The KD remained unchanged. Calsequestrin levels were unaltered in failing and non-failing hearts. The gene expression of the alpha1-subunit was similar in human failing and non-failing hearts. The L-type Ca2+-channel antagonist nifedipine reduced force of contraction with the same potency and efficiency in ventricular failing and non-failing myocardium. In contrast, the potency of nifedipine was higher in atrial than in ventricular tissue. Consistently, atrial myocardium from patients with dilated cardiomyopathy was more sensitive towards Ca2+ than those of the control group. In conclusion, the altered Ca2+-homeostasis in failing human myocardium may be less due to changes in sarcolemmal L-type Ca2+-channel expression or function than due to an altered intracellular Ca2+-handling.

Adolescent↗
PubMed1999

Reduced Ca(2+)-sensitivity of SERCA 2a in failing human myocardium due to reduced serin-16 phospholamban phosphorylation.

It is still a matter of debate, whether decreased protein expression of SERCA 2a and phospholamban (PLB), or alterations in the phosphorylation state of PLB are responsible for the reduced SERCA 2a function in failing human myocardium. Thus, in membrane preparations from patients with terminal heart failure due to idiopathic dilated cardiomyopathy (NYHA IV. heart transplants) and control hearts (NF), SERCA 2a activity was measured with an NADH coupled assay with as well as without stimulation with protein kinase A (PKA). The protein expression of SERCA 2a, PLB and calsequestrin as well as the phosphorylation status of PLB (Back-phosphorylation technique: Serine-16-PLB specific antibody) were analysed using Western blotting technique and specific antibodies. In NF, the maximal activity (Vmax) and the Ca(2+)-sensitivity of SERCA 2a activity were significantly higher compared to NYHA IV. Protein expression of SERCA 2a, PLB and calsequestrin were unchanged, whereas both, the phosphorylation status of PLB as well as serine-16-PLB-phosphorylation, were significantly reduced in NYHA IV. After stimulation with PKA only the Ca(2+)-sensitivity, but not Vmax increased concentration-dependently. Therefore, in human myocardium, the Ca(2+)-sensitivity but not the Vmax of SERCA 2a is regulated by cAMP-dependent phosphorylation of phospholamban at position serine-16. Threonine-17-PLB-phosphorylation or direct phosphorylation of SERCA 2a may be candidates for regulation of maximal SERCA 2a activity in human myocardium.

Adult↗
PubMed1999

Na+-channel modulating effect of the inotropic compound S(-)BDF 9196 in human myocardium.

S(-)BDF 9196, the active enantiomer of racemic (+/-)BDF 9148, has been shown to increase force of contraction in myocardium from different species including humans. The present study aimed to investigate the mechanism of the positive inotropic action of the active enantiomer S(-)BDF 9196 in human myocardium. In electrically driven human left ventricular papillary muscle strips (dilated cardiomyopathy, NYHA IV, cardiac transplantation, n=9), S(-)BDF 9196 increased force of contraction concentration-dependently. The maximal positive inotropic effect remained unchanged after the addition of carbachol (1 mmol/l, indicating a cAMP-independent mode of action of S(-)BDF 9196. While [3H]ouabain binding in human myocardial membranes was not influenced by S(-)BDF 9196 up to 10 micromol/l, the inward Na(+)-current in isolated human left ventricular myocytes was increased significantly by S(-)BDF 9196 (1 micromol/l, n=5). These results provide evidence that S(-)BDF 9196 increases force of contraction in human myocardium primarily by enhancing Na(+)-influx, while cAMP-dependent or Na(+),K(+)-ATPase blocking effects do not seem to play a role.

Azetidines↗
PubMed1999

The intracellular Ca(2+)-homeostasis influences the frequency-dependent force-generation in man.

The present study investigates the effect of stimulation frequency and external Ca(2+)-concentration on intracellular systolic and diastolic Ca2+ as well as on the force-frequency relationship (FFR, 0.5 to 3.0 Hz, 1.0 mmol/l extracellular Ca2+) in human myocardium using fura-2 AM loaded electrically stimulated right atrial muscle strips (coronary bypass surgery, n = 15, age: 60.0 +/- 1.9 years). The FFR was positive (3.0 vs. 0.5 Hz: 184 +/- 43% of basal value) and linked to an increase in peak systolic (R340/380sys, 119 +/- 7%) as well as diastolic Ca2+ (R340/380ED, delta fura-2 ratio +0.20 +/- 0.02). After elevating the extracellular Ca2+ concentration from 1.0 to 2.4 mmol/l, force of contraction (FOC) increased from 0.5 up to 1.0 Hz (128 +/- 8%) and declined after further augmentation of stimulation frequency (3.0 Hz: 87 +/- 15%). However, this decrease in FOC was accompanied by an increase in diastolic Ca2+ (delta fura-2 ratio +0.45 +/- 0.08), while systolic Ca2+ declined at high stimulation frequencies. In conclusion, the frequency-dependent force generation is accompanied by an increase in both systolic and diastolic Ca2+ levels. Thus, especially at high stimulation frequencies the Ca(2+)-lowering mechanisms may become crucial and may be responsible for the blunted force-frequency relationship in failing human myocardium.

Aged↗
PubMed1999

The force-frequency relationship is dependent on Ca(2+)-influx via L-type- and SR-Ca(2+)-channels in human heart.

UNLABELLED: The present study investigated the influence of Bay K 8644 and nifedipine (Nif) on the force-frequency relationship and on tetanic tension and force of contraction of failing human myocardium (PAP, n = 12). In addition, ryanodine (Rya) was studied on the force-frequency relationship. Bay K 8644 (0.1 microM) increased, but Nif (0.01 microM) reduced isometric force of contraction significantly. However, both, Bay K 8644 (2 Hz vs. 0.5 Hz: CONTROL: -31.6 +/- 7.8%; +Bay K 8644: +103 +/- 30% (% basal); p < 0.005) as well as Nif (2 Hz vs. 0.5 Hz: CONTROL: -8.8 +/- 9.7%; +Nif: +90.9 +/- 31.5% (% basal); p < 0.05), were able to restore a positive FFR in PAP. By measurement of tetanic tension and posttetanic potentiation in the presence of the 1,4-dihydropyridines, we support the hypothesis of the existence and functional relevance of a dihydropyridin-ryanodine receptor junctional complex. In skinned fiber preparations, Bay K 8644 showed no effect on Ca(2+)-sensitivity or caffeine induced Ca(2+)-release. Rya (10 microM) decreased force of contraction in PAP and was effective in restoring a positive FFR (2 Hz vs. 0.5 Hz: CONTROL: -7.3 +/- 5.1%; +Rya: +98.0 +/- 31.9% (% basal); p < 0.05). Thus, the altered FFR and Ca(2+)-homeostasis in failing human myocardium may result from changes in sarcolemmal Ca(2+)-influx and/or from altered SR-Ca(2+)-load.

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