Human pancreatic tumor GH-releasing factor

Summary Within the past year, three similar peptides with specific growth hormone (GH) releasing effects have been extracted from human tissue, identified, and synthesized. Human pancreatic tumor GH releasing factor (1–40)-OH (hpGRF-40) was the sole hpGRF isolated from the pancreatic tumor of a patient in Charlottesville and was the predominant peptide isolated from the pancreatic tumor of a patient in Lyon. The Lyon tumor also contained hpGRF(1–37)-OH and hpGRF(1–44)-NH₂. Both immunological and biochemical data suggest that hpGRF-40 and hpGRF-44 are present in the human hypothalamus and may be the human GH releasing hormone(s) (GHRH).In cultures of rat pituitary cells, hpGRF stimulates GH but affects neither basal and dopamine-inhibited prolactin release nor basal and gonadotropin releasing hormone (GnRH)-stimulated luteinizing hormone (LH) release. hpGRF stimulates cyclic AMP production within seconds, an effect which is blocked by somatostatin. In contrast, while hpGRF stimulates phosphatidylinositol turnover in the pituitary, the effect is not inhibited by somatostatin.In the human, hpGRF-40 (1 g/kg) given intravenously (i.v.) stimulates GH release within 5 minutes. hpGRF-40 does not elevate serum prolactin levels, thyrotropin (TSH), LH, or corticotropin (measured indirectly through plasma cortisol), or blood glucose or plasma concentrations of insulin, glucagon, pancreatic polypeptide, cholecystokinin, gastrin, gastric inhibitory peptide, motilin, or somatostatin. When graded doses of hpGRF (0.1–10 g/kg) are given i.v., no differences are noted in the maximal levels of serum GH achieved. Doses of 1, 3.3 and 10 g/kg hpGRF-40 elicits a prolonged and biphasic pattern of GH release. Twenty-four hours after hpGRF-40 administration, serum somatomedin C is increased in 66% of subjects tested. Side effects including a feeling of warmth and facial flushing are observed in 66% (3.3 gmg/kg) and 100% (10 g/kg) of men given hpGRF-40. hpGRF-40 (3.3 g/kg, i.v.) selectively stimulates GH release and somatomedin C production in normal women, although no differences are found in GH responsivity during the menstrual cycle. hpGRF-40 given intranasally to normal men (30 g/kg) stimulates GH release within 30 minutes. The calculated metabolic clearance rate for hpGRF-40 is 194±17.51/m²/d; the disappearance rate occurs as two phases: an initial equilibration phase (7.6±1.2 minutes) and a subsequent elimination phase (51.8±5.4 minutes). hpGRF-40 administered i.v. stimulates the release of GH in some adult patients with GH deficiency documented in childhood. Serum somatomedin C concentrations may increase in patients in whom hpGRF-40 fails to stimulate GH release. If patients with GH deficiency who do not respond to hpGRF-40 administration (10 g/kg i. v.) are given the peptide (0.33 g/kg i. v. every 3 hours) for five days, some will respond to a subsequent 10 g/kg challenge. Of those who do respond initially, the response to the subsequent challenge may be greater. Serum somatomedin C increases significantly following the 5 days of intermittent administration of hpGRF-40.hpGRF-40 and/or hpGRF-44 may be the long sought GHRH. Clinical studies with hpGRF suggest that GH deficiency may often result from hypothalamic GHRH deficiency rather than pituitary disease. hpGRF and its analogues and antagonists may find therapeutic application in the treatment of GH deficiency and in other disorders in which an increase or decrease in the secretion of GH would be beneficial.     

Denervation and outlet obstruction induce a net synthesis of contractile and cytoskeletal proteins in the urinary bladder of the male rat

The concentrations of the contractile proteins actin and myosin and the cytoskeletal protein desmin were determined in urinary bladders from normal rats, and from rats with bladder outlet obstruction or denervation. Ten days of obstruction or total denervation by bilateral removal of the pelvic ganglia resulted in an almost fourfold increase in bladder weight. Actin and myosin concentrations did not change significantly. The total amount of actin was 1624±235 g in the control bladder. In the obstructed and denervated bladders it increased significantly to 6277±648 g and 7671±835 g, respectively. The desmin/actin ratio was 0.237±0.012 in the control bladders, and increased significantly to 0.369±0.015 in the obstructed and 0.343±0.022 in the denervated bladders. Partial denervation by removal of the pelvic ganglion on one side only increased bladder weight by 52%, but did not increase the desmin/actin ratio. The content of actin in such bladders increased by 82%. Both obstruction (which increases the functional load of the detrusor muscle cells) and denervation (which produces bladder paralysis) are known to induce hypertrophy of the detrusor smooth muscle cells. The study shows that the desmin/actin ratio and the total amount of contractile proteins increase in response to the hypertrophy as such, and not to the work performed by the smooth muscle cells, and that the nerves have no trophic influence on the growth response. Also, even a limited lesion of the bladder innervation is associated with growth and a net increase in the amount of contractile proteins.     

The rabbit as an intracavernous injection study model

We investigated the feasibility of using the rabbit as an animal model for intracavernous injection studies. The rabbit, having a penile structure rather similar to that of humans, offers the advantage of being a strain-specific, adequately sized, and easily controlled experimental animal. Using intracavernous injections of the two vasoactive drugs prostaglandin E₁ (PGE₁, 0.2–1.6 g/kg) and papaverine (PAP, 0.25–1 mg/kg), which have been commonly used in the management of erectile dysfunction in man, increases intracavernous injection of PGE₁m the maximal ICP ranged from 18 to 44 mmHg (mean 29.25±7.85 mmHg) with a duration of tumescence from 3.1 to 13.3 min (mean 8.61±3.71 min). Intracavernous injection of PAP also induced increases in ICP, with a maximal ICP ranging from 24 to 56 mmHg (mean 43.5±11.35 mmHg) and a duration of tumescence from 5.3 to 15 min (mean 10.25±3.39 min). The systemic blood pressures were unchanged after all intracavernous injections. In addition, administration of cAMP antagonist in combination with PGE₁ inhibited the relaxing effects of PGE₁ in a dose-dependent manner. Our results suggest that the effects of vasoactive drugs on the rabbit's corpus cavernosum are similar to those in humans; thus the rabbit model is a suitable alternative for further physiological and pharmacological studies of penile erection.     

Diffusion theory of isotropic light dosimetry probe response

For the measurements of light energy fluence rate in tissues in vitro and in vivo we have developed an isotropic probe. The response of such a probe depends on the refractive index (n) of the medium. This has been measured in a collimated light beam with the probe in air, water (n=1.33), ehtylene glycol (n=1.43) and glycerin (n=1.46). The response as a function of n has also been calculated using diffusion theory, taking into account reflection at the boundaries. Simple formulas are proposed which very well approximate Fresnel reflection of unpolarized light, facilitating mathematical calculations. For a probe of 3.2 mm diameter with little light absorption the theoretical result depends only on n and differs from the experimental data by not more than 6 %. For a probe of 0.8 mm diameter with some light absorption excellent agreement between theory and experiment could be obtained by adjusting the (unknown) absorption and scattering coefficients ( _a, _s) of the probe material. However, a good fit was only possible within certain limits for _a, i.e. 0.35 mm^–1< _a<0.40 mm^–1, whereas _s (1-g) could be varied between at least 5 and 20 mm^–1 (g is the asymmetry parameter of the scattering function).     

Tetracycline double-labeling of iliac trabecular bone in 41 normal adults

Summary A histomorphometric evaluation of the iliac crest trabecular bone remodeling was performed after tetracycline double-labeling in 41 normal Danes (12 males and 29 females) aged 19 to 56 years. The fraction of formative (osteoid covered) and resorptive surfaces was unrelated to age but higher in males than in females (P<0.02 andP<0.05, respectively). The appositional rate (0.65±0.12 m/day) was unrelated to age and sex, whereas the fractional labeled surfaces were higher (P<0.01) in the males (0.18±0.08 m²/m²) than in the females (0.12±0.05 m²/m²), and among the females inversely related to age (R=–0.38,P<0.05). The bone formation rate at BMU level (0.50±0.20 m³/m²/day) was unrelated to sex, but among the females inversely related to age R=–0.49,P<0.01). The bone formation rate at tissue level was higher (P<0.02) in the males (0.13±0.07 m³/m²/day) than in the females (0.07±0.03 m³/m²/day) and among the females inversely correlated to age (R=–0.43,P<0.05). The age- and sex-dependent variations in the dynamic parameters underline the importance of a more elaborated normal material.     

Pharmacokinetics of ganciclovir in pediatric renal transplant recipients

Ganciclovir (GCV) is effective in preventing and treating cytomegalovirus (CMV) infection in solid organ transplant recipients. The aims of the present study were to determine the pharmacokinetics of GCV administered intravenously (IV) and orally (p.o.) as pre-emptive anti-CMV therapy in pediatric renal transplant recipients and to monitor trough levels and side-effects during pre-emptive therapy. Eleven pediatric renal transplant recipients (aged 11.0±3.9 years) were included. The diagnosis of CMV infection, based on two positive pp-65 CMV blood antigen tests at 1 week apart, was made at 39±12 days post renal transplantation. They received IV GCV at a dose of 5.0±0.3 mg/kg per 12 h for 15 days, followed by GCV p.o. at a dose of 46.7±8.2 mg/kg per 12 h for 3 months. Pharmacokinetics (PK) were studied at steady state and GCV plasma concentrations were measured by high-performance liquid chromatography. After IV GCV administration, PK parameters were: C₀=0.84±0.66 g/ml; C_max=11.77±2.82 g/ml; AUC_{0–12 h}=42.29±17.57 g/ml per hour; Cl=0.13±0.05 l/h per kg. After p.o. GCV administration, PK parameters were: C₀=1.08±0.68 g/ml; C_max=2.70±1.07 g/ml; AUC_{0–12 h}=18.97±9.36 g/ml per hour; Cl/F=2.97±1.42 l/h per kg. Bioavailability (F) was 4.9±1.2%. Pre-dose concentrations (C₀) measured under p.o. GCV (n=51) were 1.29±0.80 g/ml (8 C₀ values were below 0.5 µg/ml). Pp-65 CMV blood antigen tests became negative after 16±11 days of treatment. GCV was well tolerated. Because of the limited bioavailability, the recommended high doses of p.o. GCV (50 mg/kg per 12 h) were administered and were associated with trough levels over 0.5 µg/ml. In 1 patient who received an erroneously low dosage p.o., CMV resistance to GCV appeared, requiring foscarnet.     

Serum levels of bone GLA protein (osteocalcin,BGP) and carboxyterminal propeptide of type I procollagen (PICP) in acromegly: Effects of long-term octreotide treatment

Summary We measured serum concentrations of bone Glaprotein (osteocalcin, BGP) and carboxyterminal propeptide of type I procollagen (PICP) in 14 patients with active acromegaly. Blood was collected at 0800 for measurement of bone Gla-protein (BGP), carboxyterminal propeptide of type I procollagen (PICP), and insulin-like growth factor I (IGF-I); growth hormone (GH) was then determined at 15-minute intervals for 3 hours and the integrated mean was calculated. The same protocol was repeated at regular intervals during treatment with the long-acting somatostatin analog, octreotide, 150–450 g/day for 6–33 months (median 15). In a case-control analysis, serum BGP concentrations recorded in the acromegalic patients were significantly elevated (14.2±4.2 g/liter versus 8.0±3.3 g/liter, P<0.001). Octreotide treatment induced a roughly parallel reduction in serum GH, IGF-I, and BGP. We found a significant positive correlation between BGP levels recorded before and during therapy and the logarithm of corresponding mean GH levels (r=0.67, P<0.001). Also IGF-I concentrations were positively correlated with BGP (r=0.66, P<0.001). On the other hand, PICP levels recorded in the acromegalics did not differ from control subjects (146±46 g/liter versus 127±44 g/liter, NS) and no correlation was found between either GH and PICP or IGF-I and PICP. To conclude, the present data are compatible with the view that GH and IGF-I play an important role in the control of BGP but not PICP production. It could be that BGP and PICP are submitted to different hormonal modulation.     

Effects of lead on osteoclast-like cell formation in mouse bone marrow cell cultures

To examine an effect of lead (Pb) on the process of osteoclast-like cell formation from its progenitors, we used a mouse bone marrow culture system in which osteoclast-like multinucleated cells (MNCs) were formed in response to bone-resorbing agents. In a 9-day culture period, Pb dose-dependently stimulated MNC formation over the concentration range 2–10 M, whereas at 40 M Pb, MNC formation declined. In an 11-day culture period, MNC formation reached a maximum at 5 M Pb and decreased with increasing concentration of Pb at 10–40 M. Pb-stimulated MNC formation was inhibited by both indomethacin and SC19220, an antagonist of prostaglandin E₂ (PGE₂) receptor. Pb stimulated the production of PGE₂ in marrow cell cultures, suggesting that Pb-stimulated MNC formation is dependent on the production of PGE₂. 3-Isobutyl-1-methylxanthine potentiated Pb-stimulated MNC formation and 2,5-dideoxyadenosine, an inhibitor of adenylate cyclase, inhibited it. A calcium ionophore A23187 increased Pb-induced MNC formation and verapamil, a calcium channel blocker, depressed it. It is possible that a PGE₂-induced increase in the levels of cyclic adenosine 3,5-monophosphate (cAMP) and calcium ions in marrow cells is involved in Pb-induced MNC formation. Pb and parathyroid hormone showed a synergistic stimulation on MNC formation. From these results, Pb is thought to induce osteoclast-like cell formation by a mechanism involving PGE₂ which increases the intracellular levels of cAMP and calcium ions.     

Experience with a new solid phase enzyme immunoassay for prostatic acid phosphatase

Summary In recent years, the value of prostatic acid phosphatase (PAP) as a tumor marker for early prostatic cancer (CaP) has been the subject of controversial discussion. Investigation of sera from patients with pathohistologically proven localized CaP and from those with benign prostatic hyperplasia (BPH) has demonstrated a lack of discrimination between these groups of patients. Earlier investigations have demonstrated that the turnover rate of PAP in a conventional enzyme immunoassay (EIA) was limited by the release of the phosphate from the active center of the enzyme. However, a transfer of the activated phosphate on n-butanol or n-pentanol could increase the turnover rate to about 150%. Based on these observations 1-butanol was added to a solid-phase direct EIA in order to increase the sensitivity. PAP was assayed in 177 healthy male donors, 33 patients with benign prostatic hyperplasia and 33 patients with CaP. In 10 out of 21 patients with localized CaP (T1-3N0M0), the tumor stage was based on pathohistological examination. The upper limit of discriminative normal value was set at 0.65 g/l. The values of normal donors ranged between 0.07 and 0.6 g/l (mean 0.27 g/l), while the values for patients with BPH were slightly higher (mean 0.5 g/l). Only one patient with BPH had an elevated serum level (0.7 g/l). Out of 33 patients with CaP, 31 were found to have PAP values higher than 0.65 g/l. In one patient with CaP, pT2pN0M0 and one other patient with CaP T1N0M0, serum PAP levels were slightly lower than 0.65 g/l. This study indicates that an increase in the sensitivity of PAP determination might yield a valuable tool even in the diagnosis of early CaP.     

Effects of increased intracranial pressure in brain surface microcirculation in rats

Summary The effects of increased intracranial pressure (ICP) on pial vessel diameters were investigated in rats using a cranial window and fluorescence microscopy. The brain surface was superfused with mock cerebro-spinal fluid (CSF) at a constant rate (5 ml/h), and the ICP was raised up to 20 mmHg by elevating a CSF-reservoir connected to the CSF-outlet of the window.Arterioles dilated as the ICP increased (+12% dilation at 20 mmHg ICP). Following a rapid reduction of the raised ICP to normal, arteriolar diameters did not return to control values (+ 7% dilatation), while venules dilated (+ 3%), indicating reactive hyperaemia. At this time, CO₂ inhalation induced a low response in the arterioles (+ 0.4%/mmHg P_aCO₂ increase) and an over-response in the venules (+ 0.3%/mmHg). The CO₂ response decreased in smaller arterioles (30–40 m ). In addition, a few animals showed extravasation of Na⁺-fluorescein administered intravenously.Our results indicate that reactive hyperaemia can take place following a rapid return from an increased ICP to an normal level, even in cases of mild intracranial hypertension; a disruption of the blood-brain barrier may follow.     

Pattern of elevation of urine catecholamines in intracerebral haemorrhage

Summary Autonomic nervous system dysfunction is a common complication of severe intracranial disease. The aim of this study was to reveal the autonomic changes in patients suffering from acute intracerebral haemorrhage (ICH). 25 patients with spontaneous ICH within 24 hours of onset of symptoms were included. All patients were treated with standardised medical management and the meta- and normetanephrines were detected by high performance liquid chromatography (HPLC) in 24-hour urine every day.The mean level of normetanephrine (709±579 g/day) and metanephrine (244±161 mg/day) were significantly elevated in comparison with a control group, p0,01. The norepinephrine elevation was of greater diagnostic and prognostic importance. Maximum urinary catecholamine metabolite levels occurred between day 3 to 10 after the bleeding.Normetanephrines correlated with the prognosis and the complications of ICH: intraventricular involvement resulted in significantly elevated normetanephrine levels (896±520 g/day versus 311±78 g/day) p0,01. Patients with a great volume of haematoma developed severe autonomic dysregulation (normetanephrines 1114±493 g/day), whereas patients with smaller haematoma did not (339±125 g/day) p0,0001; patients with bad outcome (1014±620 mg/day) had higher levels of normetanephrines than those with a good prognosis (322±110 g/day) p0,001. A close relationship to elevated intracranial pressure was established.This study demonstrated the feasibility of detecting autonomic nervous system dysfunction in neurological intensive care patients by means of examination of the metabolites of the catecholamines in the urine. The pattern of elevation in ICH and the relation to the clinical situation is presented. Norepinephrine offers the chance of simple and feasible monitoring of autonomic dysfunction.     

S-100 protein plasma levels after aneurysmal subarachnoid haemorrhage

Summary We investigated the level of S-100 protein in blood as an indicator of brain damage in 71 patients suffering from subarachnoid haemorrhage (SAH) due to ruptured aneurysms.Concentrations of S-100 protein were determined by micro-titre based immunofluorometic assay detecting predominantly S-100_b on blood samples obtained 24 hours, 3 days and 7 days after onset of symptoms in patients with SAH and from 120 healthy control subjects. Neurological status was assessed using the Hunt and Hess (HH) scale on admission and by the Glasgow Outcome Scale (GOS) 6 months later.Mean concentrations of S-100 protein in blood were significantly (p<0.0001) higher in patients 24 hours (0.263±0.387 g/l), 3 days (0.192±0.288 g/l) and 7 days (0.256±0.442 g/l) after onset of SAH symptoms compared to controls (0.050±0.081 g/l). More severe neurological symptoms (higher HH scale scores) on admission correlated with higher S-100 levels on admission (R=0.70) and Day 3 (R=0.66) (p<0.0001). Worse outcome (lower GOS score) 6 months after SAH was also associated with higher plasma concentration of S-100 in the first week after SAH.In summary, this study showed that in patients with SAH due to ruptured aneurysm, S-100 protein levels correlate with early neurological deficit and are as sensitive as HH scores in predicting neurological outcome (GOS scores). Measurement of S-100 protein in blood is a reliable non-invasive method and may be clinically useful to screen for and monitor progression of central nervous system diseases of various origins.     

Local application of basic fibroblast growth factor into the bone increases bone mass at the applied site in rabbits

The effect of basic fibroblast growth factor (bFGF) applied locally into the bone under physiological conditions was investigated. An aqueous solution containing Og (vehicle), 100 g or 400 g recombinant human bFGF was percutaneously applied through a needle into the right ilium in rabbit, and the ilia were harvested 4 weeks after the application. Compared with vehicle-treated animals, bone mineral density measured by dual-energy X-ray increased in the 400 g bFGF group. The width of trabeculae in the bFGF-treated groups was greater than in the vehicle group. These results showed that bFGF applied locally into the bone under physiological conditions affected bone formation, and suggested that such an application might have potential for increasing bone.     

The effects of vasopressin on hepatic haemodynamics in the cirrhotic and non-cirrhotic rat

Summary Liver blood flow (xenon-133 clearance method) and portal venous flow were mesured in cirrhotic and non cirrhotic rats following the infusion of vasopressin at varying rates. At low rates of infusion, vasopressin had no significant effect on portal venous flow or liver blood flow in cirrhotic or noncirrhotic rats. Infusion of vasopressin at a rate of 0.08 U/g body wt/min in non-cirrhotic rats and 0.04 and 0.08 U/g body wt/min in cirrhotic rats decreased portal venous flow and increased liver blood flow. At higher rates of infusion (0.2 U/g body wt/min in non-cirrhotic rats and 0.16 U/g body wt/min in cirrhotic rats) these effects were reversed. Furthermore, an infusion of 0.08 U/g body wt/min vasopressin significantly reduced portal pressure in the cirrhotic rat. However, portal pressure was not significantly altered following an infusion of 0.16 U/g body wt vasopressin. The implications of these findings in relation to the possible deleterious effects of high rates of vasopressin infusion in the management of portal hypertension and bleeding oesophageal varices is discussed.

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Der Effekt von Vasopressin auf die Leberdurchblutung in cirrhotischen und nicht-cirrhotischen Ratten

Zusammenfassung Die Leberdurchblutung (Xenon₁₃₃ clearance Methode) sowie der portale Fluß werden nach Vasopressin-Infusion verschiedener Geschwindigkeiten, an cirrhotischen und nicht cirrhotischen Ratten gemessen. Bei langsamer Infusion hatte Vasopressin keine signifikante Wirkung auf den portal-venösen oder auf den Leberblutfluß in cirrhotischen oder nicht cirrhotischen Ratten. Die Infusion von Vasopressin mit einer Geschwindigkeit von 0,08 U/g KG/min in nicht cirrhotischen Ratten und mit 0,04 bzw. 0,08 U/g KG/min in cirrhotischen Ratten reduziert den portal venösen aber steigert den Leberblutfluß. Bei höherer Infusionsrate (0,2 ,U/g KG/min in nicht cirrhotischen Ratten und 0,16 U/g KG/min in cirrhotischen Ratten) wurde dieser Effekt umgekehrt. Darüber hinaus konnte eine VasopressinInfusion von 0,08 U/g KG/min den portalen Druck bei cirrhotischen Ratten signifikant senken. Dagegen wurde der portale Druck durch Infusion von 0,16 U/g KG/min Vasopressin nicht signifikant beeinflußt. Die Bedeutung dieser Befunde für eine mögliche deletäre Wirkung hoher Raten von Vasopressin-Infusion in der Behandlung der portalen Hypertension mit blutenden Oesophagus-Varicen wird diskutiert.

     

Urinary thromboxane B2 as an indicator of acute rejection in human liver transplantation

Urinary thromboxane B₂ (u-TXB₂) was measured and analyzed after a human liver transplantation in 28 patients (30 transplantations) who underwent an orthotopic liver transplantation. Our results showed that the u-TXB₂ levels exceeded 3.0g/mmol creatinine in only 2 of the 13 cases that had a favorable postoperative course. In 10 of the 11 episodes of acute rejection, the u-TXB₂ levels exceeded 3.0g/mmol creatinine. In 6 episodes of acute rejection, the TXB₂ levels were more than 5.0. In 4 out of 6 episodes of infection unassociated with rejection, the u-TXB₂ values were between 3.0 and 4.9g/mmol creatinine. In 2 episodes of liver necrosis the TXB₂ value reached 5.3 in one and 0.9 in the other. In conclusion, the u-TXB₂ level was observed to be elevated in cases of acute rejection, infection, or necrosis. The diagnosis of acute rejection on the basis of u-TXB₂ showed a sensitivity of 58.8%, a specificity of 93.3%, and an accuracy of 75.0% for a threshold level of 3.0g/mmol creatinine, and a sensitivity of 85.7%, a specificity of 79.2%, and an accuracy of 80.6% for a threshold level of TXB₂ of 5.0g/mmol creatinine. These results indicate that the serial determination of u-TXB₂ is a useful diagnostic means for predicting acute rejection after liver transplantation.     

Glomerular adaptation in uninephrectomized young rats

To study the glomerular adaptation during compensatory renal growth starting in infancy, we assessed afferent effective ultrafiltration pressure (P_UF), glomerular filtration area and hydraulic conductivity in rats uninephrectomized (Nx) or sham-operated (S) at 5 days of age. Rats were fed a normal protein diet and studied at 20 and 60 days of age. Single nephron glomerular filtration rate was significantly higher in Nx than in S rats both at 20 days of age (mean ± SEM: 15.0±1.5 vs 7.4±0.7 nl/min) and 60 days of age (80.7±4.6 vs 43.5±3.2 nl/min). Afferent effective P_UF, estimated by the stop-flow method, was significantly higher in Nx than in S rats both at 20 days (22.5±0.8 vs 18.3±0.4 mmHg) and 60 days (28.3±1.0 vs 23.2±1.1 mmHg). The filtering area per glomerulus, calculated as the area of the glomerular basement membrane facing both the endothelial and the epithelial cells, but not the mesangial cells, was not different in Nx and in S rats at 20 days (3.0±0.3 vs 2.8±0.1 10⁴ m²), but it was significantly greater in Nx than in S rats at 60 days (23.3±3.7 vs 9.9±0.9 10⁴ m²). The hydraulic conductivity determined in isolated glomeruli was similar in Nx and in S rats at 20 days of age (1.40±0.11 vs 1.69±0.23 l/min·mmHg· cm²) but was significantly decreased in 60-day-old Nx rats, compared with S rats of the same age (1.52±0.11 vs 2.35±0.17 l/min·mmHg·cm²). In summary, this study showed that the glomerular response to the ablation of renal tissue in infancy is characterized by an immediate increase in P_UF, a slow increase in filtration area and a lower hydraulic conductivity.     

Changes in venous capacitance during prostaglandin E1-induced hypotension; Comparisons with trinitroglycerin

The purpose of this study was to examine the effects of prostaglandin E₁ (PGE₁) on venous capacitance during controlled hypotension. Trinitroglycerin (TNG) was used as a control agent. In rats anesthetized with ketamine, mean arterial pressure was lowered to 70mmHg and subsequently 50mmHg by intravenous infusion of PGE₁ or TNG. Venous capacitance was assessed before and during induced hypotension by measuring the mean circulatory filling pressure (MCFP). MCFP was measured after briefly arresting the circulation by inflating an indwelling balloon in the right atrium. MCFP was significantly decreased by PGE₁ from 7.9 ± 0.3 to 6.9 ± 0.3mmHg at mean arterial pressure of 70mmHg and to 6.9 ± 0.2mmHg at mean arterial pressure of 50mmHg. The decrease in MCFP by PGE₁ at mean arterial pressure of 70mmHg was not significantly different from TNG. However, the decrease in MCFP by PGE₁ at mean arterial pressure of 50mmHg was significantly less than that by TNG. The results suggest that the venous capacitance may be increased by PGE₁ to a similar degree with TNG at doses to produce a comparable level of moderate hypotension, but the increase in venous capacitance may be less in PGE₁ than TNG at doses to produce deep hypotension.(Liang J, Hoka S, Okamoto H, et al.: Changes in venous capacitance during prostaglandin E₁-induced hypotension; comparisons with trinitroglycerin. J Anesth 7: 303–307, 1993)     

The role of bradykinin in the etiology of vasogenic brain edema and perilesional brain dysfunction

Summary The feline infusion model of brain edema was used to evaluate the role of bradykinin in the etiology and pathophysiology of vasogenic brain edema. Bradykinin (3 or 90 ug in 600 L saline) did not alter normocapnic regional cerebral blood flow (rCBF) nor induce specific changes in either the somatosensory (SEP) or motor (MEP) evoked potentials. The mean increases in ICP (from 4.5 to 16.1 mmHg) and peri-infusion white matter water content (from 69.4 to 79.8 ml/100 g tissue), mean decrease in lumped craniospinal compliance (from 0.040 to 0.014 ml/mmHg) and local histological changes were all similar to those after 600 L saline infusion. The interstitial bradykinin infusion caused focal blood-brain-barrier (BBB) opening to Evans Blue dye and was chemotaxic for granulocytes. After the infusion there was a global loss of rCBF CO₂ reactivity but there was no ischemia at normocapnia. These results show that bradykinin in brain edema fluid, at concentrations greater than those found in neuropathological conditions, can open the BBB of normal cerebral parenchymal capillaries and cause vascular dysregulation. In neuropathological conditions bradykinin may therefore potentiate formation of vasogenic brain edema but does not contribute to perilesional brain dysfunction.This work was presented in part at the Brain Edema VIII Meeting, Berne, Switzerland, June, 1990.     

Developmental changes in the renal capacity for sulfate reabsorption in the guinea pig

During growth, immature guinea pigs maintain a positive inorganic sulfate balance. In the present study, renal clearance techniques were used to determine the maximum renal capacity for sulfate reabsorption [T_mR_si/glomerular filtration rate (GFR)] in three groups of guinea pigs at different stages of development (10–34 days, 35–80 days and >120 days of age). These ages are comparable to infant, adolescent, and adult guinea pigs. The guinea pigs were weaned at 10 days and then maintained on normal guinea pig chow (0.13% sulfate). The T_mR_si/GFR was determined by infusions of increasing concentrations of sulfate (0–16.8 mol/min). T_mR_si/GFR was significantly greater in young (infant and adolescent) than in older (adult) guinea pigs (2.20±0.26mol/ml and 1.80±0.27 mol/ml vs 0.942±0.08 mol/ml,P<0.05). These results demonstrate that the tubular capacity for inorganic sulfate reabsorption per milliliter of glomerular filtrate is enhanced in immature guinea pigs and decreases with age.     

Renal tubular differentiation in mouse and mouse metanephric culture

Sodium-potassium adenosine triphosphatase (Na-K-ATPase) activity was measured by microassay, and the surface density of basolateral membranes was measured morphometrically in postglomerular segments of single tubules isolated from normally developing, intact mouse kidneys and from transfilter metanephric cultures. Proximal tubule Na-K-ATPase activity was 1092±480 pmol/mm per hour in newborn mice, increasing to 2462±258 in 1-week-old and 3470–578 pmol/mm per hour in adult mice. The Na-K-ATPase activity in newborn mice was approximately one-third of the activity in adult mice. Tubular Na-K-ATPase in transfilter metanephric culture was 972±536 pmol/mm per hour, a mean value almost identical to that in newborn mice. The surface density of basolateral cell membranes was 1.36±0.60 m²/m³ in newborn mice and 1.34±0.45 m²/m³ in 1-week-old mice, increasing to 2.70±0.98 m²/m³ in 4-week-old mice and 2.89±0.51 m²/m³ in adult mice. The surface density of tubular basolateral cell membranes in transfilter metanephric culture was 1.13±0.51 m²/m³, not significantly different from the surface density in newborn mice. The calculated mean surface area of basolateral membranes per unit tubular length was greater in cultures than in newborns, however, because total epithelial volume per unit length was significantly larger in the cultured tubules. Membrane surface area in intact mice increased with age, the surface area per unit length of tubule in adults being 4.6 times the area in newborn animals. The ratio of enzyme activity to membrane surface area more than doubled in the 1st week of life without any increase in the density or surface area of basolateral membranes. The ratio fell thereafter, as membrane area increased with maturation, to a value in the adult animal three-fourths of that in the newborn. The early postnatal increase in enzyme activity, beginning almost immediately after birth, possibly relates to an increased density of enzyme sites on the membrane. The postnatal spurt in enzyme activity, without a corresponding increase in membrane area, suggests that tubules have considerable functional reserve in generating a complement of sodium pumps. The studies of proximal tubules grown in metanephric culture show that the basolateral membranes and the sodium pump are initiated independently of renal blood flow and tubular fluid flow, presumably as inherent characteristics. The functional data confirm the similarity, already shown by morphometric studies, between natural tubules and those grown in culture.