Studies on the Cardiomegaly of the Spontaneously Hypertensive Rat

Farmer, Barbara B.; Harris, Robert A.; Jolly, Walter W.; Vail, William J.

doi:10.1161/01.res.35.1.102

Cited by 24 publications

(11 citation statements)

References 25 publications

(12 reference statements)

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“…This estimate assumes 48 mg of mitochondrial protein/g wet wt. of heart (Farmer et al, 1974), a fresh-weight/ dry-weight ratio of 5 (Opie & Owen, 1975) and that proteins solubilized by ultrasonic treatment account for 22% of total mitochondrial protein (Lin & Davis, 1974). Thus the rate of reduction of pent-4-enoylCoA by the heart mitochondrial extract is about 50-fold less than a minimum estimate of the rate of pent-4-enoate metabolism by the perfused heart.…”

Section: Resultsmentioning

confidence: 99%

Metabolism of pent-4-enoate in rat heart. Reduction of the double bond

Hiltunen¹,

Davis²

1981

Biochemical Journal

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1. Soluble extracts from rat heart and liver mitochondria were used to evaluate the early steps in the conversion of pent-4-enoyl-CoA into tricarboxylic acid-cycle intermediates. Hitherto the unresolved problem was the reduction of the double bond of pent-4-enoate. 2. Soluble extracts from heart mitochondria reduced pent-4-enoyl-CoA and penta-2,4-dienoyl-CoA in the presence of NADPH at rates (nmol/min per mg of protein) of 0.9 + 0.1 and 132 + 8 and from the liver mitochondria at the rates of 1.9 + 0.2 and 52 + 6 respectively. No reduction of acryloyl-CoA was found. 3. We show that primarily the double bond in position 4, not in position 2, of penta-2,4-dienoyl-CoA is reduced. 4. It is concluded that the principal metabolic pathway of penta-4-enoate is reduction of the double bond in position 4 after an initial oxidation to penta-2,4-dienoyl-CoA. The pent-2-enoyl-CoA thus formed can be further metabolized by the usual enzymes of f-oxidation, and by the further metabolism of propionyl-CoA to tricarboxylic acid-cycle intermediates.The hypoglycaemic agent pent-4-enoate inhibits fatty acid oxidation under many different kinds of conditions (e.g. Senior et al., 1968;Brendel et al., 1969;Fukami & Williamson, 1971). Pent-4-enoate itself can be slowly metabolized through #-oxidation, forming acetyl-CoA and acryloyl-CoA as end products (Brendel et al., 1969;, and the inhibition is apparently caused by some inhibitory intermediates during pent-4-enoate metabolism. We have shown, however, that in perfused rat hearts (Hiltunen, 1978) and in isolated heart mitochondria (Hiltunen et al., 1980) pent-4-enoate causes a rapid increase of tricarboxylic acid-cycle intermediates, and that pent-4-enoate itself is the source of these extra carbon skeletons. The mechanism seems to be that the C3 end products formed during the fl-oxidation of pent-4-enoate are metabolized via the propionate pathway into the tricarboxylic acid cycle.Reduction of the double bond is a prerequisite for the metabolism of pent-4-enoate by a mechanism suggested above. How and at which step of pent-4-enoate metabolism this takes place has remained unclear. We now show in experiments done with soluble extracts from heart and liver mitochondria and intermediates of pent-4-enoate metabolism that only the reduction of penta-2,4-dienoyl-CoA to pent-2-enoyl-CoA is rapid enough to account for the rate of pent-4-enoate metabolism found in perfused heart and liver.

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Section: Resultsmentioning

confidence: 99%

Metabolism of pent-4-enoate in rat heart. Reduction of the double bond

Hiltunen¹,

Davis²

1981

Biochemical Journal

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“…Thus, Aoki et al 26 have shown that myofibrillar ATPase activity per weight of protein was normal in 15-to 25-week-old SHR. In addition, Farmer et al 24 reported normal myocardial cytochrome oxidase activity and mitochondrial protein concentration in SHR of comparable age. Thus, total myofibrillar ATPase activity and mitochondrial protein levels are greater in the SHR by virtue of the increased myocardial mass and not as a result of alterations in tissue concentrations.…”

Section: Discussionmentioning

confidence: 96%

“…23 The hypertrophic process in the left ventricle of SHR is pathological, since the ventricular mass increases out of proportion to body size 16 and is associated with a reduction in myocardial deoxyribonucleic acid concentration 23 and an increased muscle fiber diameter. 24 Although ventricular hypertrophy is, in actuality, a physiological adaptation to permit sustained increases in cardiac performance, the functional ability of this pathologically induced hypertrophied myocardium is unresolved at present. Frequently, the models of experimentally induced hypertrophy caused by pressure-load fail to demonstrate a stable stage of ventricular function in which the increased myocardial mass compensates for the imposed hyperfunctional state.…”

Section: Discussionmentioning

confidence: 99%

Pumping ability of the hypertrophying left ventricle of the spontaneously hypertensive rat.

Pfeffer¹,

Pfeffer²,

Fröhlich³

1976

Circulation Research

157

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SUMMARY Cardiac pumping ability was assessed during the natural development of left ventricular hypertrophy by elevating venous pressure by infusing Tyrode's solution intravenously to produce peak cardiac output. This experiment was performed on spontaneously hypertensive rats (SHR) of three age groups (11, 24, and 83 weeks). From 11 to 24 weeks, peak cardiac output of SHR increased in direct proportion to the abnormally increased ventricular mass; Thus peak cardiac output per gram of left ventricle (LV) remained stable. Similar results were obtained for two strains of normotensive rats at each of the same three age groups. Thus, in the normotensive animal peak cardiac output per gram of LV remained stable over a wide range of ages and varying left ventricular weights. However, with progressive elevation of arterial pressure in aging SHR (83 weeks), we observed severe ventricular hypertrophy (100% increases in left ventricular to body weight ratio). In this oldest SHR group, unlike age-matched normotensive rats, there was a marked reduction in the pumping ability per gram of LV. Thus, during the natural development of left ventricular hypertrophy SHR demonstrated both a stable stage of hypertrophy in which the increased left ventricular mass maintained its pumping ability, and a later stage of deterioration in which there was a loss of the normal relationship between ventricular mass and pumping ability.STUDIES ON the mechanical performance of models of pressure-induced ventricular hypertrophy have produced conflicting results. Thus, contractile function in experimental models of both right and left ventricular isometric hyperfunction has been reported as supranormal, 1 ' 3 normal,* and depressed.6 ' 8 These experiments have used the rat, 1 -' dog, 2 -3 and cat. 4 -6 The most common means for producing pressure-induced ventricular hypertrophy has been by the surgical production of outflow tract obstruction or banding, a method which rapidly increases ventricular mass while often depressing contractile performance.Meerson 7 described three stages in the development of ventricular hypertrophy. In the first stage, before myocardial mass increases, contractile function is impaired. Subsequently, during the second stage myocardial mass increases to maintain normal myocardial function; however, in Meerson's third stage there is a progressive deterioration of myocardial function, and eventually cardiac failure is believed to supervene. In contrast, the development of ventricular hypertrophy has been characterized by others as a progressive downhill course leading to overt failure. 8 In support of this latter observation, many experimental models of pressure-induced ventricular hypertrophy failed to demonstrate Meerson's second stage of stable ventricular hyperfunction.Williams and Potter 4 recently have reported that the contractile function of the hypertrophied right ventricle (from cats in which the pulmonary artery was banded) was reduced at six weeks but returned to normal levels after 24 weeks of banding. They sug...

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“…The results confirm the preferential accumulation of mitochondrial protein during the early stages of cardiac hypertrophy in SHR and compensated weight-specific aerobic capacity. 31 Myocardial function, as assessed by contractility of papillary muscles, is normal or enhanced in SHR between 6 and 18 months of age relative to WKY. 32 Presumably, pressure overload produces a greater energy demand on the left ventricle and initially promotes synthesis of mitochondria for increased production of ATP.…”

Section: Discussionmentioning

confidence: 99%

Metabolic, hemodynamic, and cardiac effects of captopril in young, spontaneously hypertensive rats

Swislocki

LaPier

Khuu

et al. 1999

American Journal of Hypertension

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Spontaneously hypertensive rats (SHR)demonstrate elevated blood pressure, cardiac hypertrophy, glucose intolerance, and insulin resistance compared with age-matched WistarKyoto rats (WKY). We investigated concurrent effects of captopril on blood pressure, cardiac mass, myocardial enzyme activities, glucose tolerance, and insulin action in young male SHR. At 10 weeks of age, SHR were randomized into two groups, one receiving distilled water, the other a captopril solution (50 mg/kg body weight/day). We also examined age-matched WKY receiving distilled water. Blood pressure was measured by tail-cuff during the 4-week treatment period and oral glucose tolerance was tested at the end of treatment. Hearts were weighed and ventricular tissue was assayed for activities of 3-hydroxyacylCoA dehydrogenase, citrate synthase, and hexokinase. Growth rates were similar between captopril-treated and control SHR, but less than those of WKY. Captopril reduced blood pressure (134 ؎ ؎ 8 v 177 ؎ ؎ 8 mm Hg, P < < .05) and left ventricular mass (؊ ؊18%, P < < .05) in SHR. Cardiac enzyme activities also changed with captopril treatment, reflecting an increased capacity for ␤-oxidation of fatty acids and reduced potential for glucose phosphorylation in the left ventricle of SHR. Serum concentrations of glucose, insulin, and free fatty acids after a brief fast and in response to oral glucose were not different after captopril treatment, suggesting no improvement in insulin action or glucose tolerance. In summary, treatment of young male SHR with captopril reduces blood pressure and cardiac mass, and promotes a small but significant increase in cardiac capacity for oxidation of fatty acids and reduction of glucose phosphorylation. In contrast, metabolic effects of captopril on oral glucose tolerance and insulin action were not evident. Am J Hypertens 1999; 12:581-589

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Studies on the Cardiomegaly of the Spontaneously Hypertensive Rat

Cited by 24 publications

References 25 publications

Metabolism of pent-4-enoate in rat heart. Reduction of the double bond

Metabolism of pent-4-enoate in rat heart. Reduction of the double bond

Pumping ability of the hypertrophying left ventricle of the spontaneously hypertensive rat.

Metabolic, hemodynamic, and cardiac effects of captopril in young, spontaneously hypertensive rats

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