Most solid malignancies display interstitial hypertension and a poor uptake of anticancer drugs. Platelet-derived growth factor (PDGF) and the cognate tyrosine kinase receptors are expressed in many tumors. Signaling through PDGFbeta receptors was shown recently to increase interstitial fluid pressure (IFP) in dermis after anaphylaxis-induced lowering of IFP. In this study, we show that treatment with the selective PDGF receptor kinase inhibitor, STI571, formerly known as CGP57148B, decreased the interstitial hypertension and increased capillary-to-interstitium transport of 51Cr-EDTA in s.c. growing rat PROb colonic carcinomas. Furthermore, treatment with an antagonistic PDGF-B oligonucleotide aptamer decreased interstitial hypertension in these tumors. PDGFbeta receptors were expressed in blood vessels and stromal cells but not in the tumor cells of PROb colonic carcinomas. Our study indicates a previously unrecognized role of PDGF receptors in tumor biology, although similar effects of PDGF on IFP have been demonstrated previously in the dermis. The data suggest interference with PDGF receptors, or their ligands, as a novel strategy to increase drug uptake and therapeutic effectiveness of cancer chemotherapy.
Background. C-peptide has been shown to reduce glomerular hyperfiltration, glomerular hypertrophy and urinary albumin excretion in type 1 diabetes, but its effect has not been compared with that of an angiotensin-converting enzyme inhibitor (ACEI) in the early stage of renal involvement in diabetes.
Infusion of hypertonic sodium chloride solution into the third cerebral ventricle results in a marked increase in renal sodium output, indicating an important regulator of extracellular volume homeostasis. The intrarenal events governing the enhanced excretion have not been thoroughly studied previously. In 12 anaesthetized male rats a stainless steel cannula was introduced stereotaxically into the right lateral cerebral ventricle. Urine volume and excretion rates of Na, K, and osmotically active particles were measured during control infusion of artificial cerebrospinal fluid and during stimulation of central mechanisms with 1 M NaCl (520 nl min“ 1 ). At the end of the stimulation period, regional renal plasma flow ( 86 RbCl) and glomerular filtration rate ( 51 Cr‐EDTA) were measured with single injection techniques. A second group of 12 non‐stimulated rats served as controls. During ICV stimulation, the urine flow rate increased from 1.8 ± 0.1910 6.4 ± 1.01 μl min ‐1 ( P < 0.001). The urinary concentrations of Na and K increased, leading to a rise in the excretion rates of these ions from 0.12 ± 0.025 to 0.96 ± 0.352 μmol min ‐1 ( P < 0.001) and 0.40 ± 0.083 to 1.70 ± 0.196 ( P < 0.001), respectively. The osmolar excretion rate was 2.9 ± 0.35 μOsm min ‐1 before stimulation and 9.6 ± 1.09 higher ( P < 0.001) during stimulation. Simultaneously the inner medullary plasma flow rose two‐fold from 0.7 ± 0.06 to 1.4 ± 0.12 μl min _1 mg ‐1 tissue ( P < 0.008). This increase was accompanied by a significant increase ( P < 0.001) in the single nephron glomerular filtration rate (SNGFR) in the inner cortex (to 37 ± 1.4 nl min ‐1 g _1 kidney wt) compared with the value in control rats (26 ± 2.7), while SNGFR in the outer cortex remained almost unaltered (24 ± 1.2 compared with 20 ± 2.0 in control rats). In summary, ICV stimulation with hypertonic NaCl solution induced a marked increase in electrolyte excretion. The stimulation affected inner cortical nephrons substantially more than outer cortical ones.
There is accumulating evidence that C-peptide exerts beneficial renal effects in type-1 diabetes by reducing glomerular hyperfiltration, albuminuria and glomerular hypertrophy in the early stage of nephropathy. The aim of this study was to clarify further the effects of C-peptide on renal structural changes in type-1 diabetic rats.The effects of C-peptide or placebo on glomerular volume, mesangial expansion, glomerular basement membrane thickness, albuminuria and glomerular filtration rate (GFR) were studied in three groups of rats: a non-diabetic group (N, n=9) and two groups that, during 8 weeks of diabetes, were left untreated for 4 weeks and then given a subcutaneous infusion of either placebo (D, n=11) or C-peptide (DCp, n=11) during the next 4 weeks. Furthermore, GFR was studied after 4 weeks of diabetes in an additional diabetic group (D-early, n=9) and in an age-matched non-diabetic group (N-early, n=9).After 4 weeks, GFR in the D-early group was 102% higher than in the N-early group. GFR after 8 weeks did not differ between the study groups. The D group presented with a 33% larger glomerular volume than the N group (P<0.001), while glomerular volume in the DCp group was similar to that in the N-group. Total mesangial and mesangial matrix fractions were increased by 46% (P<0.001) and 133% (P<0.001), respectively, in the D group. The corresponding values in the DCp group did not differ from those for the non-diabetic animals. Neither the thickness of the glomerular basement membrane nor the level of albuminuria differed significantly between the study groups.C-peptide administration in replacement dose to streptozotocin-diabetic rats serves to limit or prevent the glomerular hypertrophy and the mesangial matrix expansion seen in the post-hyperfiltration phase of early diabetic nephropathy.
Journal Article Macrovascular Changes in Mice Overexpressing Human Semicarbazide-Sensitive Amine Oxidase in Smooth Muscle Cells: Get access Camilla Gokturk, Camilla Gokturk 1Section of Pharmacology, Department of Neuroscience, Uppsala, Sweden Address correspondence and reprint requests to Dr. C. Gokturk, Department of Neuroscience (Unit of Pharmacology), Box 593, BMC, SE-751 24 Uppsala, Sweden E-mail: Camilla.Gokturk@neuro.uu.se Search for other works by this author on: Oxford Academic PubMed Google Scholar Haruyo Sugimoto, Haruyo Sugimoto 4Tokyo Medical Dental University School of Medicine, Department of Molecular Virology, Tokyo, Japan Search for other works by this author on: Oxford Academic PubMed Google Scholar Bo Blomgren, Bo Blomgren 5Safety Assessment, AstraZeneca R&D Södertälje, Södertälje, Sweden. Search for other works by this author on: Oxford Academic PubMed Google Scholar Godfried M. Roomans, Godfried M. Roomans 2Department of Medical Cell Biology, Uppsala, Sweden Search for other works by this author on: Oxford Academic PubMed Google Scholar Karin Forsberg-Nilsson, Karin Forsberg-Nilsson 3Department of Medical Biochemistry and Microbiology, Uppsala, Sweden Search for other works by this author on: Oxford Academic PubMed Google Scholar Lars Oreland, Lars Oreland 1Section of Pharmacology, Department of Neuroscience, Uppsala, Sweden Search for other works by this author on: Oxford Academic PubMed Google Scholar Mats Sjoquist Mats Sjoquist 5Safety Assessment, AstraZeneca R&D Södertälje, Södertälje, Sweden. Search for other works by this author on: Oxford Academic PubMed Google Scholar American Journal of Hypertension, Volume 20, Issue 7, July 2007, Pages 743–750, https://doi.org/10.1016/j.amjhyper.2007.02.011 Published: 01 July 2007 Article history Received: 24 August 2006 Accepted: 20 February 2007 Published: 01 July 2007
H ansell , P. & S jöquist , M. 1992. Dopamine receptor blockade and synthesis inhibition during exaggerated natriuresis in spontaneously hypertensive rats. Acta Physiol Scand 144 , 269–276. Received 21 September 1990, accepted 11 October 1991. ISSN 0001–6772. Department of Physiology and Medical Biophysics, Biomedical Centre, University of Uppsala, Sweden. The influence of dopamine receptor blockade and synthesis inhibition on natriuresis induced by isotonic saline volume expansion was investigated in anaesthetized spontaneously hypertensive rats and normotensive Wistar‐Kyoto rats. The aim of the study was to elucidate the mechanisms underlying the phenomenon of exaggerated natriuresis during volume expansion that has been observed in spontaneously hypertensive rats. Volume expansion, at 5 % of body weight, resulted in a larger and faster natriuretic response in spontaneously hypertensive rats than in Wistar‐Kyoto rats. Sixty minutes after commencement of volume expansion the natriuretic response (accumulated sodium excretion) in Wistar‐Kyoto rats ( n = 8) was only 24% of that in spontaneously hypertensive rats ( n = 17). When spontaneously hypertensive rats were pretreated with the dopamine receptor blockers haloperidol ( n = 14, 1 mg kg ‐1 ), SCH23390 ( n = 8, 30 μ g h ‐1 kg ‐1 ) or the dopamine synthesis inhibitor benserazide ( n = 8, 50 mg kg ‐1 ; n = 5, 100 mg kg ‐1 ), the natriuretic response to volume expansion was only 16, 35, 59 and 42%, respectively, of that in untreated SHR. The corresponding proportion in the haloperidol‐treated ( n = 8) compared with untreated Wistar‐Kyoto rats was 22%. In conclusion, isotonic volume loading results in more pronounced natriuresis in spontaneously hypertensive than in Wistar‐Kyoto rats. Dopamine receptor blockade and synthesis inhibition attenuate the expansion of exaggerated natriuresis in spontaneously hypertensive rats and reduces the volume expansion natriuresis in Wistar‐Kyoto rats, indicating that the dopamine system plays an important role.
The permeability characteristics of the peritubular capillary membrane in the rat kidney were investigated on the basis of the transport of hippuran, inulin, myoglobin, horseradish peroxidase, albumin, and gamma-globulin from peritubular capillary blood to renal hilar lymph. Data obtained in a previous investigation on single-nephron plasma flow, filtration fraction, net driving force, and fluid reabsorption along the peritubular capillary were also used. The data were analyzed in a computer-based model taking into account the transport both by diffusion and by convection. The results show that the membrane contains a few large pores through which the plasma proteins leak out into the renal interstitium and a system of several smaller pores responsible for the fluid reabsorption. The mean equivalent radius of the large pores was estimated from the larger molecular probes to be approximately 180 A (range 150-225 A), and the corresponding total pore area over pore length was estimated at 3 X 10(-4) cm (range 6 X 10(-4) to 1 X 10(-4) cm). The small-pore system was analyzed from the transport of hippuran, inulin, and myoglobin and from fluid reabsorption and showed a pore radius of somewhat below 20 A and pore areas over pore length of 50 cm. Here, the fluid reabsorption and the transport of hippuran turned out to be a sensitive marker of the pore area and the transport of inulin and myoglobin of the pore radius.
The dopamine receptor antagonist haloperidol blocks natriuretic but not hypotensive effects of the atrial natriuretic factor. Acta Physiol Scand 130 , 401–407. Received 11 December 1986, accepted 10 February 1987. ISSN 0001–6772. Department of Physiology & Medical Biophysics and Department of Pharmacology, Biomedical Centre, University of Uppsala, Sweden. Studies were performed on anaesthetized male Münich‐Wistar rats to investigate the influence of the dopamine (DA) receptor antagonist haloperidol on the natriuretic response to infusion of a synthetic atrial natriuretic factor. The whole kidney glomerular filtration rate (GFR), urinary excretion of electrolytes, and arterial blood pressure (BP) were therefore measured in groups of animals pretreated with haloperidol or vehicle and given a continuous intravenous infusion of atrial natriuretic peptide (ANP; 28 amino acids). Forty‐five minutes of ANP infusion at 10 μg h ‐1 kg ‐1 body wt did not increase GFR (change from 1.14 ± 0.08 to 1.15 ± 0.05 ml min ‐1 g ‐1 kidney wt). Sodium excretion ( U Na V ) increased more than four‐fold from 0.037 ± 0.008 to 0.165 ± 0.070 μmol min ‐1 g ‐1 kidney wt ( P 0.01). Potassium excretion ( U K V ) increased by 86% ( P 0.001) and the urine flow rate ( V ) increased transiently by 63% ( P 0.05) and did not differ from the control value during the last 15 min of ANP infusion. The urinary sodium concentration ( U Na ) increased almost three‐fold, while BP decreased by 14%. There was no change in urine osmolality. In animals pretreated with haloperidol (I mg kg ‐1 body wt), 45 min of ANP infusion did not significantly alter GFR (from 1.10 ± 0.08 to 0.98 ± o.09 ml min ‐l g ‐1 kidney wt). The U Na V did not increase significantly (change from 0.026 ± 0.006 to 0.030 ± 0.009 μ mol min ‐1 g ‐l kidney wt). The U K V was not elevated by ANF infusion. The urine flow rate was transiently elevated by 45% but was not different from the control during the last 15 min of infusion. Both U Na and U osm remained unchanged, but BP was reduced by 11%. In conclusion, the DA receptor blocking agent haloperidol blunts the natriuretic effect of ANP. This action is probably exerted by inhibiting the postulated tubular effects of ANP through an unknown mechanism, but not the vascular ones, since the hypotensive effect of ANP is unaltered. Atrial natriuretic peptide increases sodium excretion not, mainly, by increasing GFR but by affecting tubular transport processes.
