Shree Mulay

Cortisol receptors in rabbit fetal lung

Abstract Rabbit fetal lung nuclei contain macromolecules which have the properties of physiological receptors for cortisol by the criteria of specificity of binding and saturation of binding sites at low concentrations of the hormone The number of nuclear receptor sites is relatively low at 20 days of gestation, reaches a maximum at about 28–30 days of gestation and drops slightly after birth. These results correlate well with previously reported changes in pulmonary epithelial cell maturation and surfactant concentrations in rabbit fetal lung extracts. Preliminary evidence for the presence of cytoplasmic cortisol-binding components in fetal lung cells is also presented.

Inverse agonist activities of β‐adrenoceptor antagonists in rat myocardium

Negative inotropic effects of several β‐adrenoceptor (βAR) antagonists on electrically‐stimulated right atria, left atria, right ventricles and left ventricular papillary muscles from reserpine‐treated rats were used as a measure of their inverse agonist activities. β1AR antagonists acebutolol, atenolol and metoprolol, β2AR antagonist ICI‐181,551 and nonselective βAR antagonists alprenolol, nadolol, propranolol and timolol produced negative inotropic effects, which were most marked on the right atria. The nonselective βAR antagonist pindolol did not exhibit inverse agonist activity but inhibited the negative inotropic activities of ICI‐118,551, atenolol and propranolol. The negative inotropic effects of lidocaine, nifedipine and pentobarbitone were similar on all the four myocardial preparations. The positive inotropic efficacy of salbutamol on right and left atria but not on right ventricles and papillary muscles was comparable to that of isoprenaline. The antagonist activity of ICI‐118,551 against isoprenaline was greater on right atria than on other cardiac regions. β1AR proteins were expressed in all regions of the heart but of β2AR were primarily localized in the right atrium. It is concluded that β2AR play a greater role in right atria than in other cardiac regions and almost all βAR antagonists behave as inverse agonists.

Hormonal modulation of atrial natriuretic factor receptors and effects on adrenal glomerulosa cells of female rats

This study was done to determine if a decrease in the aldosterone-suppressant effect of atrial natriuretic factor (ANF) by progesterone and an increase by estrogen was caused by modulation of adrenal zona glomerulosa ANF receptors. Freshly dispersed glomerulosa cells from virgin, 13-15 day pregnant, ovariectomized (OVX) estradiol-17 beta-treated and OVX progesterone-treated rats were used. Competitive displacement of specifically bound [125I]ANF1-28 with unlabelled ANF1-28 yielded concentrations of guanylate cyclase-linked ANF-R1 plus ANF-R2 (clearance) receptors and the displacement with unlabelled ANF4-23 yielded ANF-R2 receptors; the difference between the two was treated as the concentration of ANF-R1 receptors. Pregnancy and progesterone decreased and estrogen increased the number of glomerulosa ANF-R1 receptors. ANF produced a significantly greater suppression of potassium-induced aldosterone secretion in cells from OVX estradiol-treated rats than in cells from OVX progesterone-treated animals. These data suggest that the inhibition of the aldosterone-suppressant activity of ANF by progesterone is the result of a downregulation of ANF-R1 receptors.

Differential effects of rat pregnancy on uterine and lung atrial natriuretic factor receptors

We investigated if the refractoriness to the tocolytic effects of atrial natriuretic factor (ANF) during rat pregnancy is due to a downregulation of one or both guanylyl cyclase (GC)-coupled GC-A and GC-B ANF receptors; lungs were used as controls. Uteri and lungs of virgin, pregnant ( days 7, 16, and 21), and day 2postpartum rats expressed mRNAs for GC-A and GC-B as well as GC-uncoupled ANF-C receptors. GC-B receptor protein was more abundant than GC-A in uteri; the reverse was the case in lungs. Pregnancy decreased uterine mRNAs and proteins for GC-A and GC-B receptors as well as the effects of ANF and C-type natriuretic peptide (CNP) on uterine GC activity; lung ANF receptors and effects of ANF and CNP on lung GC activity were not modulated by pregnancy. It is concluded that pregnancy induces organ-specific modulation of ANF receptors and a downregulation of ANF-GC receptors would minimize interference with uterine motility during pregnancy.

Inhibition of the aldosterone-suppressant activity of atrial natriuretic factor by progesterone and pregnancy in rats

Angiotensin II (AII) caused concentration-dependent increase in aldosterone secretion by dispersed zona glomerulosa cells from non-ovariectomized (non-OVX) and ovariectomized (OVX) rats treated with the vehicle (peanut oil), beta-estradiol (0.1 mg/kg/d x 3) or progesterone (2 mg/kg/d x 3); this effect of AII was greater on cells from progesterone- than from estrogen-treated animals. In contrast, atrial natriuretic factor (ANF) was 100- to 1,000-fold less effective in suppressing AII-stimulated aldosterone production by cells from progesterone-treated (both non-OVX and OVX) and pregnant (17-20 day) rats than by cells from nonpregnant controls and estrogen-treated animals. To our knowledge, this is the first demonstration of an inhibition of an important action of ANF by another hormone and our data suggest that increased circulating levels of progesterone during pregnancy produce a relative refractoriness to the aldosterone-suppressant activity of ANF, which favors fluid/salt expansion.

Fetal lung development in streptozotocin-induced experimental diabetes: Cytidylyl transferase activity, disaturated phosphatidyl choline and glycogen levels

The influence of streptozotocin-induced maternal diabetes on choline phosphate cytidylyltransferase activity (EC.2.7.7.15) glycogen content and disaturated phosphatidyl choline in fetal lung was studied between 19 and 21 days of gestation. In this experimental model, induction of maternal diabetes two days after mating, resulted in fetal hyperglycemia and hyperinsulinemia; the fetuses were neither macrosomic nor showed any evidence of fetal growth retardation. The glycogen content of lungs on days 19 and 20, but not on day 21 of gestation was significantly higher in fetuses of diabetic rats than in controls. The pulmonary cytosol cytidylyltransferase activity was similar in the two groups of fetuses on days 19 and 20. On day 21 of gestation the enzyme activity was significantly lower in fetuses of diabetic rats than in those of controls. On day 21 of gestation and in newborns of diabetic mothers, although there was no difference in the total pulmonary phospholipids, the levels of disaturated phosphatidyl cholines were significantly lower than in controls.

Carbon Monoxide: From Public Health Risk to Painless Killer

The omnipresent colorless and odorless carbon monoxide (CO), generated by combustion, is the leading cause of unintentional death worldwide. CO binds to hemoglobin with affinity more than 200-times greater than oxygen and forms carboxyhemoglobin (COHb). The source of the endogenous CO is the breakdown of heme by heme oxygenase (HO), yielding CO, biliverdin, and iron; endogenous CO is similar to another endogenous gas, nitric oxide (NO), and both activate guanylyl cyclase and increase cGMP, which mediates many of their physiological effects. The toxicity of CO is primarily attributable to formation of COHb and resultant hypoxia, which in turn leads to rebound hyperperfusion and generation of oxidant radicals; these oxidants can produce their own toxicity and add to that of CO. The toxicity of CO ranges from mild headache at COHb less than 10% to death at COHb more than 70%. CO is more toxic in subjects with cardiovascular diseases than in healthy individuals, and it increases maternal and fetal morbidity and mortality. Nonfatal exposure to CO can result in delayed neurological, myocardial, and other toxicities. At the same time, there is some adaptation to effects of CO on low level chronic exposure. Hyperbaric oxygen is the main therapy against CO poisoning. Determined public health measures are needed to decrease atmospheric CO, which is already quite high in places such as Mexico City and Los Angeles.

Chapter 21 – Carbon Monoxide: From Public Health Risk to Painless Killer

The omnipresent colorless and odorless carbon monoxide (CO), generated by combustion, is the leading cause of unintentional death worldwide. CO binds to hemoglobin with affinity more than 200-times greater than oxygen and forms carboxyhemoglobin (COHb). The source of the endogenous CO is the breakdown of heme by heme oxygenase (HO), yielding CO, biliverdin, and iron; endogenous CO is similar to another endogenous gas, nitric oxide (NO), and both activate guanylyl cyclase and increase cGMP, which mediates many of their physiological effects. The toxicity of CO is primarily attributable to formation of COHb and resultant hypoxia, which in turn leads to rebound hyperperfusion and generation of oxidant radicals; these oxidants can produce their own toxicity and add to that of CO. The toxicity of CO ranges from mild headache at COHb less than 10% to death at COHb more than 70%. CO is more toxic in subjects with cardiovascular diseases than in healthy individuals, and it increases maternal and fetal morbidity and mortality. Nonfatal exposure to CO can result in delayed neurological, myocardial, and other toxicities. At the same time, there is some adaptation to effects of CO on low level chronic exposure. Hyperbaric oxygen is the main therapy against CO poisoning. Determined public health measures are needed to decrease atmospheric CO, which is already quite high in places such as Mexico City and Los Angeles.

CHAPTER 7 – The Bhopal Accident and Methyl Isocyanate Toxicity

Publisher Summary The chapter discusses acute and chronic toxicities of methyl isocyanate (MIC), and the possible mechanisms. The effect of the accident on the environment, the consequences of consuming polluted underground water, the cause of the accident, legal aspects of the tragedy, and the issues of compensation and rehabilitation of the population are extremely important. The chemistry and toxicity of MIC are studied in relation to other members of the isocyanate family, all of which are toxic. The cyanide-sodium thiosulfate controversy is also briefly discussed. The exposure of Bhopal population to MIC caused thousands of deaths and long-term effects of varying severity. Although chemically-induced acute-respiratory-distress syndrome was probably the cause of deaths, the magnitude and the underlying mechanisms of long-term effects with the exception of pulmonary complications have yet to be identified. Animal studies corroborate some of the clinical findings, but they neither offer an explanation nor disclose the underlying mechanism of long-term effects. It is safe to say that the full dimension of the toxicity of a chemical (and also its therapeutic potential) cannot be predicted from its chemical structure, but can be approximated by careful and painstaking studies. Such an enquiry into MIC would be well deserved not because it will disclose an astounding rational therapeutic approach, but because it will be a fitting conclusion to the speculative assertions one way or another.

High Performance Liquid Chromatography of Rat Globin Chains of Fetal Liver During the Switch from Embryonic to Adult Hemoglobin

A reversed-phase high performance liquid chromatography (HPLC) method for the direct separation of globin chains from cell lysates of peripheral blood and fetal liver from rat fetuses is described. Partial amino acid analysis of the globins eluted from the HPLC columns as well as comparison with the known elution positions of the adult globin chains in carboxymethyl cellulose chromatography indicated that alpha-chains are eluted first, followed by adult beta chains. The last chains to be eluted are considered as embryonic globins because of their absence in adult rats and their rapid disappearance from the liver after the 14th day of gestation. Liver erythroid cells isolated from rat fetuses on day 14 of gestation mainly synthesized alpha-chains and embryonic globin chains, whereas cells prepared from 16-day old fetuses synthesized almost exclusively alpha-chains and adult beta chains. When the fetal rat liver cells were cultured for 20h with erythropoietin there was a significant stimulation in the synthesis of alpha-globins and adult beta chains but not on the synthesis of embryonic globin chains. It is concluded that HPLC can be useful for the study of rat globin chain synthesis during fetal development, because it separates the globin chains in the three groups of globins, namely alpha, beta and embryonic chains which are important in the switch occurring in the liver.