Cross‐Sex Testosterone Therapy Modifies the Renal Morphology and Function in Female Rats and Might Underlie Increased Systolic Pressure

Mechanisms driving adaptive developmental responses to chronic high-altitude (HA) exposure are incompletely known. We developed a novel rat model mimicking the human condition of cardiopulmonary adaptation to HA starting at conception and spanning the in utero and postnatal timeframe. We assessed lung growth and cardiopulmonary structure and function and performed transcriptome analyses to identify mechanisms facilitating developmental adaptations to chronic hypoxia. To generate the model, breeding pairs of Sprague-Dawley rats were exposed to hypobaric hypoxia (equivalent to 9,000 ft elevation). Mating, pregnancy, and delivery occurred in hypoxic conditions. Six weeks postpartum, structural and functional data were collected in the offspring. RNA-Seq was performed on right ventricle (RV) and lung tissue. Age-matched breeding pairs and offspring under room air (RA) conditions served as controls. Hypoxic rats exhibited significantly lower body weights and higher hematocrit levels, alveolar volumes, pulmonary diffusion capacities, RV mass, and RV systolic pressure, as well as increased pulmonary artery remodeling. RNA-Seq analyses revealed multiple differentially expressed genes in lungs and RVs from hypoxic rats. Although there was considerable similarity between hypoxic lungs and RVs compared with RA controls, several upstream regulators unique to lung or RV were identified. We noted a pattern of immune downregulation and regulation patterns of immune and hormonal mediators similar to the genome from patients with pulmonary arterial hypertension. In summary, we developed a novel murine model of chronic hypoxia exposure that demonstrates functional and structural phenotypes similar to human adaptation. We identified transcriptomic alterations that suggest potential mechanisms for adaptation to chronic HA.

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Role of sex hormones in development of chronic mountain sickness in rats

Journal of Applied Physiology ◽

10.1152/jappl.1994.77.1.427 ◽

1994 ◽

Vol 77 (1) ◽

pp. 427-433 ◽

Cited By ~ 28

Author(s):

L. C. Ou ◽

G. L. Sardella ◽

J. C. Leiter ◽

T. Brinck-Johnsen ◽

R. P. Smith

Keyword(s):

Gender Differences ◽

Pulmonary Hypertension ◽

High Altitude ◽

Sex Hormones ◽

Systolic Pressure ◽

Female Rats ◽

Hypoxic Exposure ◽

Chronic Mountain Sickness ◽

Mountain Sickness

After chronic exposure to hypoxia, Hilltop Sprague-Dawley rats developed excessive polycythemia and severe pulmonary hypertension and right ventricular (RV) hypertrophy, signs consistent with human chronic mountain sickness; however, there were gender differences in the magnitude of the polycythemia and susceptibility to the fatal consequence of chronic mountain sickness. Orchiectomy and ovariectomy were performed to evaluate the role of sex hormones in the gender differences in these hypoxic responses. After 40 days of exposure to simulated high altitude (5,500 m; barometric pressure of 370 Torr and inspired Po2 of 73 Torr), both sham-gonadectomized male and female rats developed polycythemia and had increased RV peak systolic pressure and RV hypertrophy. The hematocrit was slightly but significantly higher in males than in females. Orchiectomy did not affect these hypoxic responses, although total ventricular weight was less in the castrated high-altitude rats. At high altitude, the mortality rates were 67% in the sham-operated male rats and 50% in the castrated animals. In contrast, ovariectomy aggravated the high-altitude-associated polycythemia and increased RV peak systolic pressure and RV weight compared with the sham-operated high-altitude female rats. Both sham-operated control and ovariectomized females suffered negligible mortality at high altitude. The present study demonstrated that 1) the male sex hormones play no role in the development of the excessive polycythemia, pulmonary hypertension, and RV hypertrophy during chronic hypoxic exposure or in the associated high mortality and 2) the female sex hormones suppressed both the polycythemic and cardiopulmonary responses in vivo during chronic hypoxic exposure.

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Enhanced gene expression of Na+/Ca2+exchanger attenuates ischemic and hypoxic contractile dysfunction

AJP Heart and Circulatory Physiology ◽

10.1152/ajpheart.2000.279.6.h2846 ◽

2000 ◽

Vol 279 (6) ◽

pp. H2846-H2854 ◽

Cited By ~ 11

Author(s):

Thomas G. Hampton ◽

Ju-Feng Wang ◽

Joseph DeAngelis ◽

Ivo Amende ◽

Kenneth D. Philipson ◽

...

Keyword(s):

Gene Expression ◽

Sarcoplasmic Reticulum ◽

Cardiac Function ◽

Intracellular Calcium ◽

Systolic Pressure ◽

Contractile Dysfunction ◽

Compensatory Mechanism ◽

Wild Type ◽

Generating Capacity ◽

And Function

Enhanced gene expression of the Na+/Ca2+exchanger in failing hearts may be a compensatory mechanism to promote influx and efflux of Ca2+, despite impairment of the sarcoplasmic reticulum (SR). To explore this, we monitored intracellular calcium (Cai 2+) and cardiac function in mouse hearts engineered to overexpress the Na+/Ca2+ exchanger and subjected to ischemia and hypoxia, conditions known to impair SR Cai 2+transport and contractility. Although baseline Cai 2+and function were similar between transgenic and wild-type hearts, significant differences were observed during ischemia and hypoxia. During early ischemia, Cai 2+ was preserved in transgenic hearts but significantly altered in wild-type hearts. Transgenic hearts maintained 40% of pressure-generating capacity during early ischemia, whereas wild-type hearts maintained only 25% ( P < 0.01). During hypoxia, neither peak nor diastolic Cai 2+ decreased in transgenic hearts. In contrast, both peak and diastolic Cai 2+ decreased significantly in wild-type hearts. The decline of Cai 2+ was abbreviated in hypoxic transgenic hearts but prolonged in wild-type hearts. Peak systolic pressure decreased by nearly 10% in hypoxic transgenic hearts and >25% in wild-type hearts ( P < 0.001). These data demonstrate that enhanced gene expression of the Na+/Ca2+ exchanger preserves Cai 2+ homeostasis during ischemia and hypoxia, thereby preserving cardiac function in the acutely failing heart.

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Left ventricular function during lethal and sublethal endotoxemia in swine

AJP Heart and Circulatory Physiology ◽

10.1152/ajpheart.1986.251.2.h364 ◽

1986 ◽

Vol 251 (2) ◽

pp. H364-H373 ◽

Cited By ~ 2

Author(s):

R. D. Goldfarb ◽

L. M. Nightingale ◽

P. Kish ◽

P. B. Weber ◽

D. J. Loegering

Keyword(s):

Low Dose ◽

Diastolic Pressure ◽

Contractile Function ◽

Lethal Dose ◽

Cardiac Contractility ◽

Systolic Pressure ◽

Left Ventricular ◽

High Dose ◽

Adrenergic Stimulation ◽

And Function

Our previous studies suggested that after a median lethal dose (LD50) of endotoxin, cardiac contractility was depressed in nonsurviving dogs. The canine cardiovascular system is unlike humans in that dogs have a hepatic vein sphincter that is susceptible to adrenergic stimulation capable of raising hepatic and splanchnic venous pressures. We retested the hypothesis that lethality after endotoxin administration is associated with cardiac contractile depression in pigs, because the hepatic circulation in this species is similar to that of humans. We compared cardiac mechanical function of pigs administered a high dose (250 micrograms/kg) or a low dose (100 micrograms/kg) endotoxin by use of the slope of the end-systolic pressure-diameter relationship (ESPDR) as well as other measurements of cardiac performance. In all the pigs administered a high dose, ESPDR demonstrated a marked, time-dependent depression, whereas we observed no significant ESPDR changes after low endotoxin doses. The other cardiodynamic variables were uninterpretable, due to the significant changes in heart rate, end-diastolic diameter (preload), and aortic diastolic pressure (afterload). Plasma myocardial depressant factor activity accumulated in all endotoxin-administered animals, tending to be greater in the high-dose group. In this group, both subendocardial blood flow and global function were depressed, whereas pigs administered the low dose of endotoxin demonstrated slight, but nonsignificant, increases in flow and function. These observations indicate that myocardial contractile depression is associated with a lethal outcome to high doses of endotoxin. One possible mechanism for this loss of contractile function may be a relative hypoperfusion of the subendocardium.

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SOME ASPECTS OF ZONATION AND FUNCTION OF THE ADRENAL CORTEX

Journal of Endocrinology ◽

10.1677/joe.0.0100266 ◽

1954 ◽

Vol 10 (3) ◽

pp. 266-NP ◽

Cited By ~ 17

Author(s):

I. CHESTER JONES ◽

A. WRIGHT

Keyword(s):

Outer Part ◽

Outer Region ◽

Pituitary Hormones ◽

Zona Glomerulosa ◽

Female Rats ◽

Zona Fasciculata ◽

Zona Reticularis ◽

Male And Female Rats ◽

Glomerulosa Cells ◽

And Function

SUMMARY The adrenal of male and female rats with persistent diabetes insipidus showed a prominent zona fasciculata and zona reticularis. The zona glomerulosa was narrow or absent. The results from this and the preceding three papers are here reviewed together. It is concluded that control of salt-electrolyte metabolism cannot be ascribed to the zona glomerulosa. It is probable that the zona fasciculata is reponsible for most of the adrenocortical secretions. The zona glomerulosa is a vegetative back-water of cells, which is able to produce minimal amounts of adrenocortical secretions without stimulation by pituitary hormones, but is only of significance when the latter are absent. Rising amounts of circulating adrenocorticotrophic hormone (ACTH) can transform the zona glomerulosa into actively secreting cells of the zona fasciculata type. After cessation of such activity the zona glomerulosa re-forms, as the amount of ACTH will maintain only a certain volume of zona fasciculata (and zona reticularis) against the rigid limiting inner circumference formed by the medulla; some of the cells derived from the chief area of cell division in the outer part of the zona fasciculata do not mature to cells of the zona fasciculata type, but form zona glomerulosa cells. It is thought that cell migration occurs from the cells of the outer region of the zona fasciculata to the zona reticularis and that this is, normally, a slow process.

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Decreased cardiac SERCA2 expression, SR Ca uptake, and contractile function in hypothyroidism are attenuated in SERCA2 overexpressing transgenic rats

AJP Heart and Circulatory Physiology ◽

10.1152/ajpheart.00490.2010 ◽

2011 ◽

Vol 300 (3) ◽

pp. H943-H950 ◽

Cited By ~ 4

Author(s):

Roland Vetter ◽

Uwe Rehfeld ◽

Christoph Reissfelder ◽

Henry Fechner ◽

Enn Seppet ◽

...

Keyword(s):

Contractile Function ◽

Heart Function ◽

Systolic Pressure ◽

Left Ventricular ◽

Cardiac Contraction ◽

Loss Of Function ◽

Transgenic Rats ◽

Mrna Ratio ◽

And Function

The sarco/endoplasmic reticulum (SR) Ca2+-ATPase SERCA2a has a key role in controlling cardiac contraction and relaxation. In hypothyroidism, decreased expression of the thyroid hormone (TH)-responsive SERCA2 gene contributes to slowed SR Ca2+ reuptake and relaxation. We investigated whether cardiac expression of a TH-insensitive SERCA2a cDNA minigene can rescue SR Ca2+ handling and contractile function in female SERCA2a-transgenic rats (TG) with experimental hypothyroidism. Wild-type rats (WT) and TG were rendered hypothyroid by 6- N-propyl-2-thiouracil treatment for 6 wk; control rats received no treatment. In vivo measured left ventricular (LV) hemodynamic parameters were compared with SERCA2a expression and function in LV tissue. Hypothyroidism decreased LV peak systolic pressure, dP/d tmax, and dP/d tmin in both WT and TG. However, loss of function was less in TG. Thus slowed relaxation in hypothyroidism was found to be 1.5-fold faster in TG compared with WT ( P < 0.05). In parallel, a 1.4-fold higher Vmax value of homogenate SR Ca2+ uptake was observed in hypothyroid TG ( P < 0.05 vs. hypothyroid WT), and the hypothyroidism-caused decline of LV SERCA2a mRNA expression in TG by −24% was markedly less than the decrease of −49% in WT ( P < 0.05). A linear relationship was observed between the SERCA2a/PLB mRNA ratio values and the Vmax values of SR Ca2+ uptake when the respective data of all experimental groups were plotted together ( r = 0.90). The data show that expression of the TH-insensitive SERCA2a minigene compensates for loss of expressional activity of the TH-responsive native SERCA2a gene in the female hypothyroid rat heart. However, SR Ca2+ uptake and in vivo heart function were only partially rescued.

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