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The relationship between the covalent binding, uptake, and toxicity produced by pentachlorobutadienyl-L-cysteine (PCBC) was examined in rabbit renal proximal tubules (RPT), renal basolateral membrane vesicles, and isolated renal cortical mitochondria. Renal proximal tubules rapidly metabolized PCBC to a reactive intermediate that bound to tubular protein. Approximately 70-90% of PCBC found in the cell at any given time was bound to protein. PCBC initially uncoupled oxidative phosphorylation, followed by a 45% reduction of state 3 respiration and a 90% decrease in cellular adenosine triphosphate (ATP) levels. These events preceded cell death. Isolated mitochondria also metabolized PCBC to a reactive intermediate that bound to mitochondrial protein and initiated mitochondrial toxicity. These results show that PCBC-induced mitochondrial dysfunction occurred as a result of mitochondrial bioactivation and that the mitochondrion is the critical subcellular target in PCBC toxicity. Aminooxyacetic acid (AOAA), an inhibitor of cysteine conjugate beta-lyase, reduced the covalent binding of PCBC-equivalents to tubular protein by approximately 90% and decreased but did not prevent the toxic effects produced by PCBC on RPT respiration and cellular ATP levels. AOAA delayed but had no effect on the overall extent of cell death produced by PCBC. The protective effect of AOAA was independent of any effects on PCBC uptake. These results show that AOAA decreased but did not prevent the metabolism of PCBC by cysteine conjugate beta-lyase. The partial inhibition of PCBC metabolism, and hence, PCBC-induced cell death by AOAA, may be related to limited concentrations of AOAA within the tubule cell or mitochondria.

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This study delineates the various operational modes catalyzed by the organic anion exchanger present in the canine renal brush-border membrane. The experiments examined the carrier-mediated effects of various organic and inorganic anions on the transport of either p-[3H]aminohippuric acid ([3H]PAH) or 36Cl-. [3H]PAH countertransport was significantly stimulated by PAH, urate, Cl-, Br-, HCO3-, and by a pH gradient. This pH stimulation remained in the absence of HCO3- (i.e., under N2), implying PAH-OH- exchange. Furosemide, bumetanide, penicillin, and probenecid inhibited countertransport of [3H]PAH. Likewise, the above anions produced cis inhibition of [3H]PAH transport. The cis and trans effects of SO4(-2) and formate were minimal. 36Cl- countertransport was stimulated by PAH, Cl-, Br-, HCO3-, formate, and by a pH gradient that was effective even in the absence of HCO3- (i.e., under N2), implying Cl- -OH- exchange. Cl- -OH- and Cl- -Cl- exchange was inhibited by PAH. In each instance, the trans-stimulation of 36Cl- efflux was insensitive to maneuvers that created an inside-positive membrane potential, demonstrating electroneutral mediated exchange. We conclude that the organic anion transporter can operate in three distinct exchange modes: organic-organic, organic-inorganic, and inorganic-inorganic.

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Study of 16 normal and 33 flail mitral valves provides evidence of the active participation of chordae tendineae in mitral valve opening. The normal valves have straight chordae at all phases of opening. During isovolumic relaxation and progressive opening phases, the smooth configuration of the mid-anterior mitral leaflet is broken by a sharp outward "tenting." This tenting is localized at chordal insertions, reflecting significant tension at these points. Flail mitral valves allow comparison of opening motion between mitral segments with normal chordal attachment and flail segments without chordal support. Posterior flail leaflets demonstrate delay in initiation of opening motion relative to the normal anterior leaflet. The most dramatic examples of this delay reveal a maximal opening excursion of the anterior leaflet before the flail posterior leaflet initiates opening motion. The untethered free margins of opening flail anterior leaflets produce the appearance of the flail segment trailing the body of the anterior leaflet with a sharp break in leaflet contour between the supported and unsupported segments. These configurational expressions of mitral valve opening are inconsistent with a passive hemogenic mechanism. They support an active myogenic process mediated through direct traction on the valve by the chordae tendineae.

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Because of the potential benefits froma noninvasive technique in assessing cardiac output, we compared cardiac output estimates from left ventricular echocardiograms with results obtained simultaneously by a standard technique, dye dilution in 10 healthy normal volunteers. During rest, cardiac outputs by echocardiographic and dye dilution techniques were reproducible and not significantly different. Increases in cardiac output produced by intravenous infusion of isoproterenol (15 ng/kg/min for 4 min) were accurately estimated by echocardiography in subjects whose stroke volume increased less than 40%, but were significantly underestimated when stroke volume increased more than 40%. Decreased cardiac output produced by intravenous propranolol (0.2 mg/kg) was comparable by both methods. Although echocardiography accurately estimated mean cardiac output for the group it over- or underestimated cardiac output in individual subjects. We propose that echocardiography can reliably estimate cardiac output in groups at rest and when stroke volume changes less than 40%.

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The effect of chronic adjunctive vasodilator therapy was assessed in 14 symptomatic patients with idiopathic cardiomyopathy. Thirteen of the 14 patients improved by one or more in the New York Heart Association functional class, one remained unchanged. Three became asymptomatic (class I). Noninvasive and invasive (hemodynamic) parameters before and after vasodilators were assessed. The echocardiographic findings of septal and posterior wall thickness of 1.2 cm or greater were the best predictors of good response in our patients who subsequently became asymptomatic.

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Clinical and echocardiographic studies were done in a patient with a secondary right ventricular tumor. Stationary cardiac tumors produce differential diagnostic problems not associated with mobile cardiac tumors. In spite of limitations of specificity, positive diagnostic features do exist. This report emphasizes the usefulness as well as technical difficulties in assessing the presence of a secondary right ventricular tumor echocardiographically.

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Multiple, short runs of repetitive ventricular premature beats are present in 5 adolescents. These premature beats are continually present, uniform, long and variably coupled and occasionally fuse with sinus beats. This pattern is constant over several years and is associated with generally healthy individuals and otherwise normal hearts. Four of the subjects are completely asymptomatic without syncope or palpitations. The 5th case was asymptomatic for 2 yr until she died suddenly during sleep. Autopsy revealed a pathology of the specialized conduction system in the region of the AV junction. The distinctive pattern and characteristics of this arrhythmia suggest a congenital etiology and a mechanism different from other forms of ventricular ectopia. The single incident of sudden death indicates that this disorder is not benign.

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