Morphometric investigations into the mechanism of the compensatory hypertrophy of the rat adrenal zona fasciculata after unilateral adrenalectomy

Summary Compensatory hypertrophy of the remaining gland in unilaterally adrenalectomized rats was investigated by morphometric techniques. It was observed that compensatory adrenal growth occurred in both dexamethasone-treated and hypophysectomized rats, receiving maintenance doses of ACTH. However, it was only half that found in intact animals. These results support the view that activation of the hypothalamo-hypophyseal axis is not the unique mechanism underlying adrenal compensatory hypertrophy in the rat.     

Introduction: History and Problems of Compensatory Adaptation of Renal Functions and of Compensatory Hypertrophy of the Kidney

The history of observations and experimental work on compensatory changes following the loss of renal mass, and the historical reasons for the distinction between the concepts of compensatory adaptation (of renal functions) and of compensatory hypertrophy (of nephrons) are outlined. While the effector mechanisms of both types of compensatory changes are being elucidated at a rapid pace, many questions concerning the primary changes initiating these events, the control mechanisms implied and the interrelationship between functional adaptation and hypertrophy remain unanswered.     

Involvement of a direct neural mechanism in the control of gonadal functions

Much time has been devoted to study of the hypothalamo-hypophyseal-gonadal axis. However, there is now evidence of a complementary control mechanism for the gonads, namely a pituitary-independent, direct neural link that exists between the central nervous system and the gonads. We investigated whether mediobasal temporal lobe structures could control gonadal functions by a purely neural mechanism or whether they acted through the classical hypothalamo-hypophyseal system. Right- or left-sided deafferentation of the temporal lobe was combined with right- or left-sided hemicastration in adult and prepubertal male and female rats. In adult females right-sided deafferentation, regardless of the side of hemiovariectomy significantly reduced the extent of compensatory ovarian hypertrophy. Similar lesions on the left side did not interfere with the usual compensatory ovarian growth. This difference in compensatory hypertrophy between right- and left-sided lesioned rats was observed even in the face of a significant drop in serum LH concentrations in both groups. In pre- and postpubertal females temporal lobe lesion in either side was unable to alter compensatory hypertrophy or serum LH or progesterone concentrations. In adult male rats only left-sided deafferentation combined with left orchidectomy resulted in decreased T production, while in prepubertal male rats, only right-sided brain surgery plus left orchidectomy resulted in a significant decrease in basal testosterone secretion of the remaining testis. These findings indicate that mediobasal temporolimbic structures are involved in the neural control of gonadal functions. It appears that this lateralized mechanism is age- and sex-dependent.     

Structural and functional changes in the mitochondrial apparatus of cortical tubules of the solitary kidney in chronic blockade of cholinergic mediation

In 15, 30 and 90 days the effect of continuous atropine pharmacological blockade of parasympathetic innervation on morphometrical characteristics of epithelial mitochondria in the cortical segments of the canaliculi has been studied in a single kidney of Wistar rats. The maximal degree of the alternative changes has been determined in the proximal canaliculi. In the distal canaliculi epithelium a compensatory increase of the main quantitative parameters in mitochondria has been registered. The plasticity of the mitochondrial apparatus, specific for the collecting tubules under compensatory hypertrophy, is inhibited under conditions of deparasympathization.     

Cyclosporin A inhibits cardiac hypertrophy and enhances cardiac dysfunction during postinfarction failure in rats

Calcineurin has recently been implicated as a mediator in the signaling pathways that transform intracellular calcium signals to the phenotype of myocardial hypertrophy. The present study was conducted to examine the effects of cyclosporin A (CsA), an inhibitor of calcineurin, on myocardial hypertrophy and remodeling during congestive heart failure (CHF) in rats. After ligation of the left coronary artery, rats were randomized to treatment with CsA or vehicle for 14 days. Compared with vehicle, CsA substantially attenuated myocardial hypertrophy in the CHF rats as assessed by alterations in ventricular weight-to-tibial length ratios (P < 0.05). Myocardial gene expression of skeletal alpha-actin was also reduced in the failing left ventricle (LV) after treatment with CsA (P < 0. 05), although the mRNA levels were still substantially elevated relative to those of sham rats. CsA-induced inhibition of compensatory myocardial hypertrophy in the CHF rats led to increased dilatation of the LV cavity and reduced fractional shortening and peak positive and negative first derivatives of LV pressure (P < 0. 05). Plasma renin and endothelin-1 levels were increased in the CHF-CsA rats, providing humoral cues of aggravated cardiac function. Thus this study supports a crucial role of calcineurin-dependent pathways in the mechanisms of compensatory myocardial hypertrophy during CHF. In addition, our data indicate that inhibition of compensatory myocardial hypertrophy exerts detrimental effects on cardiac remodeling and function after myocardial infarction.     

Enhancement of compensatory renal hypertrophy by beta-1-24 corticotropin in the rat]

In the rat, the administration of beta1-24-corticotrophin during 7 days following an uninephrectomy enhances significantly the compensatory hypertrophy of the remaining kidney. There is no increase in renal compensatory hypertrophy when ACTH is injected to previously adrenalectomized rats. This action of ACTH could be related to the diabetes mellitus induced by this hormone or to an increase in sodium reabsorption by the tubular epithelial cells.     

Ultrastructural stereological analysis of the absolute parameters of the cardiomyocytes in myocardial hypertrophy

Arterial hypertension was produced in male Wistar rats by abdominal aorta ligation. By the 35th day of experiment the animals had developed myocardial hypertrophy. The subcellular organization of cardiomyocytes was studied by electron microscopy and stereology (computation of relative and absolute parameters). In myocardial hypertrophy, the absolute volume of myofibrils, sarcoplasmic reticulum and T system in the left ventricle of the heart was increased, whereas the absolute volume of the mitochondria remained unchanged. The general surface area of all organelles was noticeably increased. The myofibrils and sarcoplasmic reticulum experienced greater changes, which may reflect the features of compensatory processes under the experimental conditions described.     

Local Effect of PACAP and VIP on Testicular Function in Immature and Adult Rats

Csaba, Zs., V. Csernus, and I. Gerendai. Local effect of PACAP and VIP on testicular function in immature and adult rats. Peptides 18(10) 1561–1567, 1997.—PACAP, VIP, anti-PACAP and anti-VIP antisera were injected intratesticularly. In 9-day-old hemicastrated rats PACAP or VIP decreased basal testosterone secretion. In 22-day-old hemicastrates VIP but not PACAP reduced compensatory testicular hypertrophy, however, neither PACAP nor VIP altered steroidogenesis. Anti-VIP antiserum to this age group increased testosterone production and enhanced compensatory testicular hypertrophy. In adult hemicastrates neither the peptides nor the antisera influenced steroidogenesis. Neither in immatures nor in adults treatment of both testes with PACAP or VIP had any effect. Data indicate that both PACAP and VIP might exert a local action on testicular steroidogenesis, on compensatory testicular hypertrophy, and these effects are age-dependent.     

Compensatory renal hypertrophy after nephrectomy in newborn rats]

The process of the kidney compensatory hypertrophy in young rats has been studied after nephrectomy on the 2nd day of life. The intact kidney was investigated by morphometrical and electron microscopical methods from the 1st day till the 3rd month after operation. The kidney compensatory hypertrophy in the early postnatal ontogenesis is accompanied by the acceleration of growth and differentiation of renal structures. The hypertrophy involves three successive steps: (1) functional tension of ultrastructures; (2) expressed hyperplasia and hypertrophy of cells; (3) structural-functional specialization. Among the cellular factors of the kidney compensatory growth at this age, the main role is played by the process of cell hyperplasia.     

An increase in hypothalamic sensitivity to the inhibiting effects of estrogens caused by use of L-DOPA, diphenine, epithalamin and phenformin in old rats]

Daily treatment of hemicastrated young rats with 0.57 mug of stilbestrol inhibited compensatory ovarian hypertrophy (COH) by 48% in the 3-month animals and by 3% only in the 18-month animals. Administration of L-DOPA, dilantin, epithalamin or phenoformin with the same dose of estrogen to old rats suppressed the COH by 65-98%. L-DOPA and epithalamin were effective when administered into the 3rd cerebral ventricle. A functional nature of the age changes in the hypothalamic sensitivity to the estrogen action is suggested.     

Excretion of water, sodium, and potassium during the compensatory renal hypertrophy in hypothyroid rats]

Renal compensatory hypertrophy is studied in age matched euthyroid and radiothyroidectomized female rats. 7 days after uninephrectomy, the hypertrophy of the remaining kidney is equally small in both groups. But 60 days after this operation, the hypothyroid animals show only a 12% increase in the wet weight of the remaining kidney whereas the euthyroid controls increase this weight by 21%. The excretion of water, Na and K are determined in the urine excreted in 5 h after a small water load. The results are related to 1 gram of kidney wet weight. These outputs increase in all animals after uninephrectomy. They are significantly higher in the hypothyroid rats than in the euthyroid controls as well before than 60 days after uninephrectomy. The reduction in tubular Na reabsorption found in the hypothyroid rat may account for the impairment of compensatory renal hypertrophy in hypothyroidism.     

Changes in the ovarian structure and fertility of the rat after various ovarian neurectomies

The changes undergone by the ovary 30 days after different unilateral neurectomies were investigated in 45 rats. Fertility modification was observed in a second group of 40 rats that, after the same neurectomies, were placed with a male for a period of 20 days. The only significant change in the ovarian sympathectomized rats was a decrease in the nuclear area of the luteal cells. In the rats with an additional ovariectomy a significant compensatory hypertrophy appeared in the luteal cells. Vagotomy provoked a significant nuclear hypertrophy in the interstitial and luteal cells, as well as in the corpora lutea. In the cases with contralateral ovariectomy this hypertrophy was considerably reduced. Section of the pelvic splanchnic nerve only produced a decrease of the nuclear size in the luteal cells. Subsequent contralateral ovariectomy was followed by an additional atrophy of the luteal cells and corpora lutea. These results indicate that the parasympathetic system, in normal conditions, plays an inhibitory role, while the sympathetic has a light stimulatory effect, principally on the luteal cells. In relation to fertility, 50% of the neurectomized rats, 75% of the control ones and 100% of the neurectomized and contralaterally ovariectomized rats were found pregnant. The average of the embryos implanted in the uterine horn of the neurectomized ovary was significantly smaller than in the control side. On the contrary, in the ovariectomized rats, especially in the case of sympathectomy, the average of the embryos implanted in the uterine horn of the ovariectomized side was significantly higher than in the control animals.     

Counteraction of testosterone-induced suppression of the pituitary-ovarian axis in rats by flutamide.

Daily administration of 100 micrograms of testosterone to unilaterally ovariectomized rats for 18 days caused a significant decrease in compensatory ovarian hypertrophy. The number of corpora lutea was markedly reduced and many cystic follicles were noticeable. Administration of graded doses (0.5, 1 and 3 mg daily) of flutamide over the same period did not cause any significant change in the weight and histology of the ovary in untreated unilaterally ovariectomized animals. However, treatment with the same doses of flutamide prevented the changes observed in the reamining ovary of testosterone-treated animals.     

Compensatory testosterone secretion in unilaterally orchidectomized rats

Blood and testis samples were taken from rats 3 weeks after unilateral (sinistral) orchidectomy or sham operation to study the regulation of circulating testosterone. Although plasma testosterone concentrations did not differ, the concentration of testicular testosterone was twofold greater in orchidectomized rats than in sham operated controls. At autopsy, weights of right testes as well as Leydig cell number of orchidectomized and control rats were similar. These observations indicate that, after unilateral orchidectomy, compensatory hypersecretion is not related to compensatory testicular hypertrophy.     

Myocardial reaction of the right ventricle to lung resection

Right-sided pulmonectomy (resection of 63-65% of the lung parenchyma) in white noninbred rats resulted in development of chronic cor pulmonale, that develops according to the stages: I--from the time of the operation up to the 10th-15th days after the operation--the stage of acute disturbances and mobilization forces of the organism; II--from the 11th-15th up to the 90th day is the stage of a relative steady compensatory hypertrophy of the cardiac right ventricle; III--after the 90th day--the stage of decompensation. The hypertrophy of the right ventricle myocardium transfers into its dilatation. Amount of cardiomyocytes and their nuclei in 1 mg of the right ventricle tissue progressively decreases, quantity of multinuclear cardiomyocytes increases, ploidy of the nuclei changes: number of tetraploid nuclei decreases, octaploid nuclei appear. Lethality among the animals is 56%.     

Physiological adaptation of the heart to pathological overloading

Chronic overloading of the rat heart induces a cascade of adaptational events that compensate for the increase in work. At the myocardial level there are two types of adaptational mechanisms: qualitative, represented by the isomyosin changes leading to an improved efficiency; and quantitative, the hypertrophy. We present new approaches exploring possible adaptational changes at other levels within the myocardial cell. Studies of heart overload were performed either in young rats with experimental aortic stenosis or in humans with chronic compensatory hypertrophy. By means of double immunofluorescence labeling of isolated myocytes with anti-V1 and anti-V3 myosin immunoglobulins, we showed that the shift from high- to low-ATPase isomyosins occurs rapidly after aortic stenosis (2-3 days). Cardiac myocytes were shown to be poor in tubulin but a microtubule pattern was clearly visualized by an immunofluorescence approach. Their role in the onset of adaptational processes after aortic stenosis in not yet clear. On the other hand, we showed that in humans, contrary to small rodents, the adaptational process at the isomyosin level is very small or nonexistent.     

慢性缺氧对大鼠心室功能和ATP酶活性的影响

将大鼠置于不同模拟海拔高度低压舱内4d,观察其左、右心室功能代偿与失代偿的某些生物化学基础。结果表明,5000m中度缺氧4d使左、右心室功能、重量、心肌蛋白含量及Ca~(2 )-ATP酶活性均有不同程度的增高。提示机体在整体、心脏器官及心肌细胞分子各个水平的代偿机制均有加强。8000m重度缺氧4d后,左室重量增加,dp/dt_(max)与蛋白含量均下降,肌原纤维ATP酶活性则保持中度缺氧的代偿水平,提示左心功能似已受到损害。与此同时,右室蛋白含量虽也明显减少,但其ATP酶活性则继续增高,dp/dt_(max)未出现下降,表明右心功能仍具有相当的代偿能力。从而支持我们关于在短期内因供氧严重不足而造成的左室心肌的直接损伤作用大于右室心肌的推论。     

Some hormonal factors (hypophysectomy, castration and testosterone administration) modifying the course of "compensatory" muscle hypertrophy in the rat.

1. Maximum compensatory hypertrophy of the soleus and plantaris muscle in male rats is attained seven days after tenotomy of the gastrocnemius muscle (39% and 9% respectively). When tenotomy of the gastrocnemius was performed seven days ater hypophysectomy, hypertrophy in these two muscles was aproximately half that found in control animals. 2. After 81-day castration of young male rats the weight of the saleus and plantaris was reduced and hypertrophy following tenotomy of the gastrocneumius muscle did not develop. 3. Chronically castrated rats received testosterone two weeks prior to tenotomy of the gastrocnemius and a week during the muscle hypertrophy phase. Hypertrophy of the soleus in castrated rats which had received testosterone seven days after tenotomy of the gastrocnemius was 25% as compared with muscles of castrated animals. The corresponding value in the plantaris muscle was 10%. 4. These results indicate that even calf muscles of the rat, namely the soleus and plantaris muscles, are significantly affected by testosterone under these conditions, although it is not, as yet, clear whether its action is direct or indirect.     

Restorative processes in the parathyroid glands in experimental hypothyroidism

By means of morphological, morphometrical and autoradiographical methods restorative processes in the parathyroid glands in 41 euthyroid and in 41 hypothyroid rats have been studied during 1-24 days after mechanical trauma of the glands or after hemithyroparathyroidectomy. Seven hypothyroid and 7 euthyroid rats serve as a control. Hypothyroidism is produced with daily injection of mercazolil (6 mg/kg) 3 weeks before the operation and during the time of the experiment. In nonoperated hypothyroid rats development of hypertrophy in parathyrocytes is noted. Prolonged injection of mercazolil weakens (posttraumatic regeneration) or completely suppresses (compensatory hypertrophy) mitotic activity of the glandular cells (in comparison with the euthyroid animals). Manifestation of hypertrophy in parathyrocytes of the hypothyroid rats in comparison with the corresponding control is also less, than against the background of euthyreosis.     

Nuclear proteins and DNA in the myocardial myocytes in compensatory cardiac hypertrophy]

Using cytophotometry, the amount of DNA, total nuclear proteins and of histones were studied in the myocardial cells during days 21--36 of experimental compensatory hypertrophy of the heart (in rats). The enlargement of myocardial nuclei during the cardial hyperfunction was accompanied by accumulation of total nuclear protein, in particular, the histone fraction, without distinct changes in DNA. Analysis of correlations between nuclear proteins and DNA in the myocardial cells allows to reveal a delayed accumulation of histones in the big and gigantic nuclei, with a superfluous increase in non-histone nuclear proteins. In middle-sized nuclei, non-histone proteins have little changes against intensive accumulation of histones.