The purpose of this study was to determine whether cardiac hypertrophy in response to hemodynamic overloading is a primary result of the increased load or is instead a secondary result of such other factors as concurrent sympathetic activation. To make this distinction, four experiments were done; the major experimental result, cardiac hypertrophy, was assessed in terms of ventricular mass and cardiocyte cross-sectional area. In the first experiment, the cat right ventricle was loaded differentially by pressure overloading the ventricle, while unloading a constituent papillary muscle; this model was used to ask whether any endogenous or exogenous substance caused uniform hypertrophy, or whether locally appropriate load responses caused ventricular hypertrophy with papillary muscle atrophy. The latter result obtained, both when each aspect of differential loading was simultaneous and when a previously hypertrophied papillary muscle was unloaded in a pressure overloaded right ventricle. In the second experiment, epicardial denervation and then pressure overloading was used to assess the role of local neurogenic catecholamines in the genesis of hypertrophy. The degree of hypertrophy caused by these procedures was the same as that caused by pressure overloading alone. In the third and fourth experiments, fi-adrenoceptor or a-adrenoceptor blockade was produced before and maintained during pressure overloading. The hypertrophic response did not differ in either case from that caused by pressure overloading without adrenoceptor blockade. These experiments demonstrate the following: first, cardiac hypertrophy is a local response to increased load, so that any factor serving as a mediator of this response must be either locally generated or selectively active only in those cardiocytes in which stress and/or strain are increased; second, catecholamines are not that mediator, in that adrenergic activation is neither necessary for nor importantly modifies the cardiac hypertrophic response to an increased hemodynamic load.

Pressure overload of cat right ventricle causes progressive abnormalities of in vitro contractile function at a time when in vivo contractile function is normal. In marked contrast, the same degree and duration of volume overload of cat right ventricle results in neither in vitro nor in vivo contractile dysfunction. The purpose of the present quantitative structural study was to determine whether there were any histological alterations in pressure-overloaded myocardium that might be causally related to the contractile dysfunction found only in this model. Four experimental groups of eight cats each were studied: a group with pulmonary arterial banding to create a pressure overload, sham-operated controls for this group, a group with atrial septal defects to create a volume overload, and sham-operated controls for this group. Seven to ten weeks after each operative procedure, right ventricular pressure was elevated only in the pressure-overloaded group, pulmonary-to-systemic blood flow ratio was increased only in the volume-overloaded group, and right ventricle-to-body weight ratio was significantly and comparably increased in both the pressure- and the volume-overloaded groups. There was a single striking histological distinction between myocardium hypertrophying in response to pressure as opposed to volume overload: the volume density of cardiocytes in papillary muscles from pressure-overloaded right ventricles was decreased significantly with a proportional increase in connective tissue. Given the critical importance of these two myocardial components to both systolic and diastolic cardiac function, these data provide a potential structural basis for at least some of the functional abnormalities observed in pressure but not in volume overload hypertrophy of the cat right ventricle.

The amino acid sequence of Phaseolus aureus L. (mung-bean) cytochrome c has been determined. The molecule consists of a single polypeptide chain of 111 amino acid residues and is homologous with other mitochondrial cytochromes c. Comparison with the amino acid sequence of wheat-germ cytochrome c (Stevens, Glazer & Smith, 1967) shows 14 differences. On alignment with mammalian cytochromes c, mung-bean cytochrome c has an N-acetylated ;tail' of eight amino acid residues similar to that found in wheat-germ cytochrome c. Of the 22 positions in wheat-germ cytochrome c that contain amino acid residues unique to these positions, 20 were found to contain the same ones in mung-bean cytochrome c. The in-N-trimethyl-lysine residues reported for wheat-germ cytochrome c (Delange, Glazer & Smith, 1969) in positions 72 and 86 were also found in these positions in mung-bean cytochrome c. The sequence was determined from 3mumol, by using chymotryptic and tryptic peptides which were analysed by the ;dansyl'-Edman method (Gray & Hartley, 1963a), with confirmation by amino acid analysis.

Summary Cytochrome c sequences from nineteen plants have been used, in conjunction with those of animal and fungal origin already published, to calculate the times of origin of the animal, fungal and plant kingdoms and also of some higher plant groups. The results show that the Angio‐sperms originated at least several geological periods before the Cretaceous, which is the earliest period in the geological record in which authentic angiosperm fossils have been found.

The structural effects of diabetes and subsequent insulin treatment upon the contractile and supporting elements of the rat myocardium were examined at progressive stages of both untreated and treated disease. Diabetes was induced by intravenous injection of alloxan, and tissue was examined after 6, 12, and 26 weeks. Insulin treatment began after 12 weeks of diabetes and tissue from these animals was examined after the same intervals. Within the cardiocytes, diabetes produced a focal yet progressive loss of myofibrils, transverse tubules, and sarcoplasmic reticulum, and separation of the fasciae adherens was evident at the intercalated disk. Mitochondrial damage was not evident. These cytoplasmic alterations were accompanied by intercellular and perivascular deposition of connective tissue, thickening of the endothelial cytoplasm with pinocytotic hyperactivity, and characteristic basal laminar changes. When insulin treatment began after 12 weeks of diabetes, most, but not all, of these changes were reversed, and this reversal was essentially complete within 6-12 weeks. Even with longer periods of insulin treatment, cardiocytes still exhibited scattered areas of myofibril loss and extracellular matrix was retained. In contrast, diabetic changes in the intercalated disk and capillaries, including their basal laminae, were completely and rapidly reversed. It is hypothesized that the structural manifestations of diabetic cardiomyopathy consist of two major components; the first is a short-term, physiologic adaptation to metabolic alterations, while the other represents degenerative changes for which the myocardium has only a limited capacity for repair.

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The effects of severe, chronic diabetes mellitus and of immediate or delayed insulin replacement on the different components of the myocardium and cardiocytes were quantified and correlated. A significant decrease in cardiocyte cross-sectional area occurred during the first 12 weeks of diabetes and then stabilized. This was accompanied by decreases in the relative volume densities (RVDs) of myofibrils and mitochondria, resulting in absolute loss of more than 40% of each of these cellular components after 26 weeks of diabetes. Interstitial and perivascular deposition of extracellular matrix produced a tripling of its RVD in the myocardium over 26 weeks of diabetes at the expense of both cardiocytes and capillaries. Capillary density and diameter also exhibited progressive decreases of more than 20% over 26 weeks of diabetes. Insulin treatment which maintained euglycemia and restored normal growth prevented this structural pathology when begun three days after induction of diabetes. When delayed for 12 weeks, insulin reversed the changes in cardiocyte and capillary RVD, and in capillary diameter within 6 weeks, ultrastructural changes within 12 weeks, and cardiocyte cross-sectional area after 26 weeks. However, even after 26 weeks of treatment, the extracellular matrix remained more than twice that observed in nondiabetic animals, with a consequent decrease in the number of capillaries per unit volume of tissue. This study demonstrates that diabetes produces a progressive, marked disorganization of the myocardium which can be prevented, but only selectively reversed, by insulin treatment. These structural changes are relevant to the functional changes which occur in diabetic cardiomyopathy.