Almorris Lynch

THE EFFECT OF PRESSURE AND STRETCHING ON THE PASSAGE OF LABELED ALBUMIN INTO CANINE AORTIC WALL

Summary The passage of labeled albumin from serum into canine aortic wall was studied in vitro under conditions which permitted the pressure exerted on the serum and the amount of aortic stretching to be varied independently. The rate at which albumin entered the inner layer of the aortic wall was not appreciably affected by pressure exerted on the serum. However, the passage of albumin into that layer was greatly accelerated by stretching the aortic wall. Hypertension has previously been observed to accelerate the passage of albumin into the inner layer of the aortic wall in the living dog. The present study suggests that it does so mainly by stretching the aortic wall. Albumin has previously been observed to enter the inner layer of the aortic wall fastest proximally and progressively less rapidly down the length of the aorta. This gradient was observed in the present study in aortas, the different regions of which were stretched the same amount. This indicates that the gradient that occurs in the intact dog is due in part to regional variations in the nature of the aortic wall. However, in the living dog, greater stretching of proximal than distal aorta by blood pressure probably also contributes to the occurrence of the gradient.

Lipoprotein Movement through Canine Aortic Wail

Low-density (1.019 to 1.063) lipoprotein labeled with radioiodine enters the inner layer of the canine aortic wall directly from the aortic lumen. Its rate of entry is greatest in the proximal aorta and decreases progressively down the length of the aorta. A similar gradient was observed previously for the accumulation of cholesterol early in experimental atherosclerosis.

Hyperprolactinemia in monkeys: Induction by an estrogen-progesterone synergy

To evaluate the synergistic effect of estrogens and progesterone on prolactin secretion, rhesus and cynomolgus monkeys in the early follicular phase received estradiol benzoate (100 microgram/kg/day, sc) alone for 14 days, then in combination with progesterone (subcutaneous silastic capsule) for an additional 14 days. Blood was drawn daily by femoral venipuncture under ketamine hydrochloride anesthesia (15 mg/kg). Similarly, this protocol for exogenous steroid treatment was employed in a monkey having a chronically indwelling (femoral insertion into the vena cava) cannula maintained by a vest and mobile tether apparatus; however, no anesthesia was used to obtain serum specimens. In addition, this assembly was applied to six monkeys to determine the acute effects of ketamine hydrochloride on prolactin secretion. Concentrations of prolactin, estradiol-17 beta, and progesterone in serum were determined by conventional radioimmunoassays. Under estrogen therapy alone, mean circulating prolactin levels declined from approximately 15 to less than 5 ng/ml; in contrast, the addition of progesterone caused an abrupt serum prolactin elevation, approximately 8-12 fold. This estradiol-progesterone course led to sustained hyperprolactinemia in the chronically catheterized monkey, whereas ketamine administration raised serum prolactin only briefly, the elevation lasting less than three hours after injection. These findings establish that an estrogen-progesterone synergy, separate from the transient effects of ketamine, induced hyperprolactinemia in cycling monkeys having prevailing levels of estrogen and progesterone near those characteristic of late gestation, when sustained prolactin elevations are observed normally.

Passage of Labeled Cholesterol into the Aortic Wall of the Normal Dog

In the normal dog the rate of movement of cholesterol from the serum into the inner layer of the aortic wall is greatest at the proximal end of the aorta and decreases progressively along the length of the aorta until in the terminal aorta the rate is only about one sixth that in the proximal aorta. A similar gradient of rates was previously demonstrated for albumin which enters the aortic wall about three times as fast as cholesterol. The similarity of the gradients and the relative magnitude of the rates for cholesterol and albumin support the concept that cholesterol is carried into the aortic wall of the normal dog by the passage of the lipoproteins of which it is a part.

Glycogen Regulation in Isolated Perfused Near Term Monkey Liver

Extract: Glycogen metabolism was studied in the isolated perfused liver of the monkey conceptus at 90% of gestation using an in situ recirculating perfusion system. Net uptake of glucose and galactose and the activities of the enzymes, glycogen synthetase and phosphorylase, were studied in response to varied perfusate composition. Synthetase activity was expressed as %1, the percentage of total synthetase activity in the active form. Perfusate glucose concentrations as high as 700 mg/100 ml did not lead to net glucose uptake or to an increase in the baseline %I synthetase (4 ± 1, mean ± SEM). In the presence of 300 mg/100 ml glucose, insulin at 10-7 M increased %I to 8 ± 2, and galactose > 75 mg/100 ml increased %I to 8 ± 1. The combination of galactose, glucose, and insulin increased %I to 40 ± 5. With this latter combination, synthetase activity was proportional to perfusale glucose concentration above 100 mg/100 ml. Phosphorylase activity was diminished by either galactose or insulin, and phosphorylase activity was lowest in the group receiving galactose, glucose, and insulin. Galactose was taken up by all livers, but net glucose uptake was not observed under any condition; net hexose uptake was observed in perfusions with galactose. Glycogen levels did not vary significantly with varied perfusate composition during the 30-min perfusion periods.Speculation: We speculate that galactose may be uniquely important for neonatal liver glycogen synthesis, and that its action is mediated through reciprocal changes in the activities of the enzymes, glycogen synthetase and phosphorylase. If liver glycogen is important for acute neonatal glucose homeostasis, then galactose may also be essential for maintaining circulating glucose concentration by ensuring glycogen synthesis during feeding.

Regulation of rat liver glycogen synthesis and activities of glycogen cycle enzymes by glucose and galactose

Direct regulation of rat liver glycogen metabolism by glucose and galactose was studied using an isolated liver perfusion system. Activation of glycogen synthase and net glycogen synthesis increased linearly when perfusate glucose concentration was increased from 125 to 500 mg/100 ml. Galactose, rapidly taken up by isolated rat liver regardless of circulating glucose concentration, increased these responses to glucose. In the presence of galactose (greater than or equal to 5 mg/100 ml), activation of synthase and glycogen synthesis were 1.5-fold higher at any given glucose concentration. The addition of insulin did not appreciably after synthase activation by glucose and galactose. Phosphorylase activity, low at circulating glucose levels above 125 mg/100 ml, was further decreased as glucose was increased or when galactose was added to the perfusate. Release of glucose into the perfusate in response to aglycemia was increased in the presence of galactose.

Glucose Regulation by Isolated Near Term Fetal Monkey Liver

Extract: Near term fetal monkey livers were perfused with a closed recirculating system and a defined perfusion medium. Livers from normal fetal animals were able to release glucose rapidly into the perfusate when they were exposed to glucagon, cyclic AMP, or an aglycemic perfusate, but they did not remove glucose rapidly from the perfusate, synthesize glycogen, or activate liver glycogen synthetase in response to hyperglycemia (Figs. 1, 2, and 3; Table 1). Insulin decreased glucose mobilization in response to aglycemia, but did not stimulate glucose uptake during hyperglycemia; insulin activated glycogen synthetase (Table 1; Figs. 1 and 3). Livers from fetuses of streptozotocin-treated mothers and livers from 2-week-old neonates released more glucose into the perfusate in response to aglycemia then did livers from normal fetal monkeys (Fig. 4). These observations support the possibility that neonatal monkey liver is capable of rapidly mobilizing glucose during periods of hypo-glycemia but is unable to take up glucose and store glycogen rapidly during periods of hyperglycemia.Speculation: Incomplete development of glycogen synthetic mechanisms in early postnatal life may contribute to decreased liver glycogen reserves. These decreased reserves may then be inadequate for maintaining normoglycemia during periods of increased glucose uptake or utilization by peripheral tissue.

Quantitative Analysis of the Development of Experimental Atherosclerosis in the Dog

Atherosclerosis was produced in dogs by feeding them thiouracil and cholesterol. The increments in cholesterol concentration at sites along the length of the aortas of these dogs Avere determined by subtracting from the value for each site the corresponding value obtained from normal dogs. After about 1 month on the experimental regimen the cholesterol increments along the length of the aorta formed a gradient. The increment was greatest in the proximal aorta and progressively less down the length of the aorta. After about 5 months on the regimen, the gradient no longer existed. Instead, the cholesterol increment in the abdominal aorta exceeded that in the thoracic aorta. Albumin is known to enter aortic wall with a gradient of rates that is similar to the gradient of cholesterol increments early in the course of experimental atherosclerosis. The foregoing facts are consistent with the following theory: In the development of atherosclerosis, intact low-density lipoproteins containing cholesterol enter the aortic wall with a gradient of rates. They enter fastest in the proximal aorta and progressively less rapidly down the length of the aorta. However, cholesterol is removed from the abdominal aorta much more slowly than from the thoracic aorta. Thus, the increment in cholesterol concentration in the abdominal aorta eventually exceeds that in the thoracic aorta.

Pulsatile Progesterone Secretion: Its Relevance to Clinical Evaluation of Corpus Luteum Function

Pulsatile progesterone (P) secretory patterns were characterized in rhesus macaques (n = 13) during the midluteal phase (cycle days 18 to 20) of the normal ovarian/menstrual cycle. Sixty high-amplitude (greater than 1 ng/ml) P pulses were observed during a total of 169 hours of sampling. Typically, P pulses had an ultradian periodicity of 2 hours and were independent of detectable luteinizing hormone (LH) and prolactin (PRL) pulses in 70% of instances. LH pulses were associated with a concomitant P and PRL pulse in 100% to 80% of occasions, respectively. Pulsatile P release was augmented by exogenous cynomolgus monkey LH and suppressed by administration of a gonadotropin-releasing hormone antagonist. Two individuals with apparently normal ovulation and once daily plasma P concentrations within the normal range demonstrated a nonpulsatile P profile. These findings encourage clinical investigations to characterize pulsatile P secretion in normal women and patients in whom corpus luteum dysfunction is suspected.

Selective inhibition of follicle-stimulating hormone by porcine follicular fluid extracts in the monkey: effects on midcycle surges and pulsatile secretion**Supported in part by Ford Foundation grant 810-0293.††Presented in part at the Society of Gynecologic Investigation, Dallas, Texas, March 29, 1982 (Abstract 59).

Nonsteroidal factor(s) in porcine follicular fluid (pFF) can selectively suppress tonic follicle-stimulating hormone (FSH) concentrations when administered in the follicular phase to monkeys. Here it is demonstrated that when administered in either the early follicular phase or in the midst of the spontaneous preovulatory estradiol (E2) surge (E2 greater than or equal to 200 pg/ml), pFF preferentially inhibits FSH or blocks the FSH surge, respectively, whereas immunoassayable and bioassayable luteinizing hormone (LH) surges persist. Delay in the timing of ovulation uniformly follows follicular phase pFF administration, and corpus luteal insufficiency is often seen. The inhibitions of FSH in circulation were achieved by a decrease in amplitude and frequency of FSH pulses. No discernible effect on LH pulsatility was observed.