Spontaneously hypertensive rats (SHR) of advanced age exhibit depressed myocardial contractile function and ventricular fibrosis, as stable compensated hypertrophy progresses to heart failure. Transition to heart failure in SHR aged 18-24 months was characterized by impaired left ventricular (LV) function, ventricular dilatation, and reduced ejection fraction without an increase in LV mass. Studies of papillary muscles from SHR with failing hearts (SHR-F), SHR without failure (SHR-NF), and age-matched Wistar Kyoto (WKY) rats allowed examination of changes in the mechanical properties of myocardium during the transition to heart failure. Papillary muscles of SHR-F exhibited increased fibrosis, impaired contraction, and decreased myocyte fractional area. These findings in papillary muscles were correlated with a higher concentration of hydroxyproline and increased histological evidence of fibrosis in the LV free wall. While a depression in active tension accompanied these structural alterations in papillary muscles, it was not evident when active tension was normalized to myocyte fractional area. Together, these data suggest that individual myocyte function may be preserved but that myocyte loss and replacement by extracellular matrix contribute substantially to the decrement in active tension. An absent or negative inotropic response to isoproterenol is observed in SHR-F and SHR-NF papillary muscles and may result in part from age-related alterations in beta-adrenergic receptor dynamics and a shift from alpha- to beta-myosin heavy chain (MHC) protein. During the transition to failure, ventricles of SHR exhibit a marked increase in collagen and fibronectin mRNA levels, suggesting that an increase in the expression of specific extracellular matrix genes may contribute to fibrosis, tissue stiffness, and impaired function. Transforming growth factor-beta 1 (TGF-beta 1) mRNA levels also increase in SHR-F, consistent with the concept that TGF-beta 1 plays a key regulatory role in remodelling of the extracellular matrix gene during the transition to failure. The renin-angiotensin-aldosterone system is also implicated in the transition to failure: SHR treated with the angiotensin converting enzyme inhibitor captopril starting at 12 months of age did not develop heart failure during the 18-24 month observation period. Captopril treatment that was initiated after rats were identified with evidence of failure led to a reappearance of alpha-MHC mRNA but did not improve papillary muscle function. Research opportunities include investigation of apoptosis as a mechanism of cell loss, delineation of the regulatory roles of TGF-beta 1 and the renin-angiotensin-aldosterone system in matrix accumulation, and studies of proteinase cascades that regulate matrix remodelling.
Oxygen-derived free radicals (OFR) have been implicated as mediators of tissue injury in various disease states. Their participation in myocardial injury due to ischemia-reperfusion has also been suggested. To characterize the mechanical dysfunction associated with OFR-induced injury, we studied alterations in isometric contractions of rat papillary muscle at 28 degrees C. A purine-xanthine oxidase system was used to generate OFR. Neither purine nor xanthine oxidase alone had significant effects on rest or active tension, duration of the contraction, or peak rates of tension development or decline. In contrast, their combination resulted in a reduction of active tension to 38% of base-line values without alteration in rest tension. This reduction was largely due to a decline in the peak rate of tension development. When catalase or superoxide dismutase was introduced into the bath prior to the generation of OFR, catalase but not superoxide dismutase offered essentially complete functional protection. These results substantiate that impaired myocardial function can result from exposure to OFR. In this case the active radicals appear to be either peroxides or hydroxyl and not superoxide. These observations provide a basis for understanding the functional protection afforded ischemic myocardium by OFR scavenging enzymes.
An inverse linear relationship between normalized tension development (T/mm2) and muscle cross-sectional area (range 0.32-1.68 mm2) is seen in fully oxygenated rat papillary and columnar carnease muscles studied while contracting isometrically at the apex of the length-tension curve. The data demonstrate progressively poorer performance with thicker preparations, presumatic blockade) is added to fully oxygenated muscle preparations, no significant change in performance is seen even with the thickest preparations, suggesting that no portion of mechanical activity is supported by anaerobic glycolysis. With progressive lowering of the muscle bath PO2, the relative contributions of aerobic and glycolytic activity to mechanical performance are demonstrated. Viewed from the Hill model of oxygen and lactic acid distribution in a cylindrical section of muscle, the data that suggest the presence of a hypoxic core appear contrary to the evidence that indicates the absence of tension supported by glycolytic activity. A possible solution to this apparent contradiction is presented. The findings of these experiments emphasize limitations of isolated muscle studies and help define the relationship between oxygenation and mechanical activity of cardiac muscle.
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