Expression of sarcoplasmic reticulum (SR) Ca(2+)-ATPase was shown to be reduced in failing human myocardium. The functional relevance of this finding, however, is not known. We investigated the relation between myocardial function and protein levels of SR Ca(2+)-ATPase in nonfailing human myocardium (8 muscle strips from 4 hearts) and in myocardium from end-stage failing hearts with dilated (10 muscle strips from 9 hearts) or ischemic (7 muscle strips from 5 hearts) cardiomyopathy. Myocardial function was evaluated by the force-frequency relation in isometrically contracting muscle strip preparations (37 degrees C, 30 to 180 min-1). In nonfailing myocardium, twitch tension rose with increasing rates of stimulation and was 76% higher at 120 min-1 compared with 30 min-1 (P < .02). In failing myocardium, there was no significant increase in average tension at stimulation rates above 30 min-1. At 120 min-1, twitch tension was decreased by 59% (P < .05) in dilated cardiomyopathy and 76% (P < .05) in ischemic cardiomyopathy compared with nonfailing myocardium. Protein levels of SR Ca(2+)-ATPase, normalized per total protein or per myosin, were reduced by 36% (P < .02) or 32% (P < .05), respectively, in failing compared with nonfailing myocardium. SR Ca(2+)-ATPase protein levels were closely related to SR Ca2+ uptake, measured in homogenates from the same hearts (r = .70, n = 16, and P < .005).(ABSTRACT TRUNCATED AT 250 WORDS)

These data indicate that the altered force-frequency relation of the failing human myocardium results from disturbed excitation-contraction coupling with decreased calcium cycling at higher rates of stimulation.

Levels of SR proteins involved in calcium binding and release are unchanged in failing dilated cardiomyopathy. In contrast, protein levels of calcium ATPase involved in SR calcium uptake are reduced in the failing myocardium. Moreover, SR calcium ATPase is decreased relative to its inhibitory protein, phospholamban.(ABSTRACT TRUNCATED AT 250 WORDS)

In various mammalian species, shapes of action potentials vary within the cardiac wall because of differences in transient outward current (Ito). A prominent I,. exists in human ventricular myocytes, but cells have not been separated according to their original localization. Human ventricular myocytes were isolated from separated subepicardial and subendocardial tissue, and regional variations in 'to were studied. Ito was larger in subepicardial than subendocardial cells. Current density at +60 mV was 7.9±0.7 pA/pF (n=28) in subepicardial cells and 2.3+±0.3 pA/pF (n=16) in subendocardial cells. When cells from explanted failing and nonfailing donor hearts were compared, 'to was not different in subepicardial cells; however, it was larger in subendocardial cells from nonfailing hearts. The potential of half-maximal activation (V0.5) was more positive in subendocardial cells (+25.6+3.5 mV, n=15) than in subepicardial cells (+9.2±1.8 mV, n=28). There was no difference in Vo.s between cells from failing and nonfailing hearts. 'to inactivation was similar in all cell types and independent of membrane depolarization (time constant [r]= =60 milliseconds at 22°C). The potential of half-maximal steady-state inactivation was similar in all cell types. Recovery from inactivation of Io was fast in subepicardial cells at -100 mV (r=24+4 milliseconds, n=6), exceeding control values transiently (overshoot), and slow at -40 mV without overshoot (r=638+91 milliseconds, n=6). In subendocardial cells, I, recovered at -100 mV with a fast phase (r=25 milliseconds) and a slow phase (r=328 milliseconds), and recovery was not complete after 6 seconds at -100 mV. In conclusion, regional differences in Ito between subepicardial and subendocardial cells may have clinical implications with respect to rhythmic disturbance during heart failure. (Circ Res. 1994;75:473-482 thought to contribute to the physiological regulation of excitation and conduction, and their disturbance during heart disease may lead to cardiac arrhythmia.3 Therefore, regional properties of I,o were studied not only in cells from terminally failing hearts but also in cells from healthy donor hearts. These results have been published in part in abstract form.10 Materials and Methods Characterization of PatientsMyocytes were obtained from 10 explanted hearts from patients with heart failure and from four nonfailing donor hearts that could not be transplanted for technical reasons. Details of patient data are listed in Table 1. Cell IsolationTissue samples derived from human left ventricle were transported in cold cardioplegic solution maintained at 4°C and supplemented with 2,3-butanedione monoxime (30 mmol/L) for protection of the tissue against damage from Ca 2+ overload."1 In the laboratory, the sample was placed in Ca2-free oxygen-saturated solution. Epicardial fat and connective tissue were removed from the muscle specimen. To separate subepicardial and subendocardial tissue layers, -3-mm segments from either side of the ventricular wall were used, and the m...

Coronary artery contractile 5-HT1-like receptors resemble cloned 5-HT1D beta receptors and predominate over 5-HT2 receptors in mediating serotonin-evoked contractions. Sumatriptan contracts coronary arteries as a full agonist through 5-HT1-like receptors.