Effects on blood pressure after treatment of obstructive sleep apnoea with a mandibular advancement appliance - a three-year follow-up.

Obstructive sleep apnoea (OSA) is a highly prevalent sleep disorder; it affects 4% of males and 2% of females. Hypertension has been shown to occur in 28-57% of OSA patients. There is a steady increase in evidence linking OSA to long-term cardiovascular morbidity including hypertension. The purpose of this study was to investigate whether mandibular advancement oral appliance (OA) treatment of OSA affects the patient's blood pressure (BP) in a 3-month and a 3-year perspective. Twenty-nine consecutive patients, with verified OSA defined as apnoea index (AI) >5 per hour and/or apnoea/hypopnoea index (AHI) > or =10 per hour, received an OA as treatment. BP was measured on three occasions; before treatment, after 3 months of treatment, and after 3 years of treatment. BP was measured with an electronic blood pressure monitor. The treatment effect of OA was measured after 3 months by repeated somnographic registration while the patient was wearing the OA. A treatment response was defined as AHI < 10; this was achieved in 25 of 29 patients (86%) at the 3-month evaluation. Significant reductions in blood pressure were attained between baseline and the 3-month evaluation (P < 0.001) and these changes remained at the 3-year follow-up in both systolic BP of -15.4 +/- 18.7 mm Hg and diastolic BP of -10.3 +/- 10.0 mm Hg. OA therapy reduced blood pressure in both a 3-month and a 3-year perspective in patients with OSA.

Inhibition of platelet-derived growth factor receptors reduces interstitial hypertension and increases transcapillary transport in tumors.

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.

Increase of bikunin and alpha1-microglobulin concentrations in urine of rats during pregnancy is due to decreased tubular reabsorption.

Bikunin and alpha1-microglobulin are two plasma proteins of about 25 kDa which are made in the liver from a common precursor. The concentration of bikunin in human urine has been shown to increase several fold during various conditions of stress. The mechanism behind this increase is unknown. We have studied pregnant rats and found that the bikunin and alpha1-microglobulin levels in their urine increased 3-fold towards the end of the pregnancy, whereas those of albumin and orosomucoid did not. There were no significant changes in either the bikunin/alpha1-microglobulin mRNA level or the concentrations of the two proteins in serum. These findings imply that the synthesis and the clearance rates of bikunin and alpha1-microglobulin are normal during pregnancy but that the tubular reabsorption of these proteins is decreased.

Sodium excretion and renin secretion after continuous versus pulsatile infusion of oxytocin in rats.

Neurohypophyseal oxytocin (OT), secreted continuously under conditions of hyperosmolality, is a potent natriuretic hormone in rats. In contrast, OT secretion during lactation is pulsatile and is not accompanied by increased urinary Na+ excretion. The present experiments compared the effects of continuous and pulsatile infusion of OT on natriuresis in rats. In male rats anesthetized with Inactin, continuous infusion of OT (125 ng/kg x h) increased plasma OT to about 70 pg/ml; renal Na+ excretion increased 10-fold, and urine volume and K+ excretion also were elevated. However, when OT was administered i.v. in the same amount but in pulses given once every 5 or 10 min, to simulate the pattern of OT secretion during lactation, rats did not excrete significantly more urine, Na+, or K+ than did vehicle-treated animals. The plasma renin concentration, measured in these experiments because OT receptors are present in the macula densa, increased 2-fold when OT was infused either continuously or in pulses. These results indicate that the effects of OT administration on urinary Na+ excretion in rats varies depending on whether the infusion is pulsatile or continuous, whereas the effects of OT on renin secretion show no such difference.

Sodium and potassium load in the loop of Henle, measured with intact and blocked tubuloglomerular feedback mechanism in juxtamedullary nephrons.

For the juxtamedullary nephrons only the loop of Henle is easily accessible for micropuncture. We have shown that the tubuloglomerular feedback (TGF) mechanism is highly activated in these nephrons. Techniques have been developed for measurements on these nephrons without disrupting the normal flow to the macula densa. The tubular flow rate was measured by a real-time videodensitometric method in juxtamedullary nephrons in Lewis x DA rats. For the determination of tubular fluid composition a small fraction (less than 10%) of the fluid was sampled. Measurements were also performed according to the conventional technique, where all the tubular fluid was sampled. Despite a more than twofold increase in tubular flow rate when the flow to the macula densa region was interrupted, sodium concentration was only reduced by 25%, whereas potassium concentration was reduced by 40%. The results demonstrate that interruption of the urine flow to the macula densa results in a 52% increase in the tubular load of Na in the loop of Henle of juxtamedullary nephrons, and a corresponding increase of 24% for K. Thus, TGF exerts a strong influence on these nephrons which is why previous data on water and electrolyte loads, based on stop-flow measurements, greatly overestimate these loads.

Biochemical evidence for the GABA regulation of vasopressin levels in microdissected brain structures after servo-controlled hypotension.

Discrete brain structures were analysed for gamma-aminobutyric acid (GABA) and vasopressin content in normo- and hypotensive rats treated with the glutamic acid decarboxylase inhibitor, 3-mercaptopropionic acid (MPA) and the GABAA agonist muscimol. In the normotensive group treated with MPA only, the concentration of vasopressin increased in the supraoptic nucleus, indicating an inhibitory role for GABA. In the hypotensive group a rise in the vasopressin level in the nucleus of the solitary tract was detected and the GABA level decreased in the supraoptic nucleus. Muscimol decreased the concentration of vasopressin in the nucleus of the solitary tract. The changes in the concentration of vasopressin may be a result of increased or decreased activation of the GABAergic system. The results show that the GABA- and vasopressinergic systems somehow interact although the more precise way of action remains to be clarified.

Intrathecal injection of an oxytocin-receptor antagonist attenuated postnephrectomy natriuresis in the male rat.

We have previously shown that oxytocin (OT) is a major humoral mediator in postnephrectomy natriuresis. As immunoassayable OT has been demonstrated in the spinal cord, the aim of this investigation was to determine whether OT receptors in the spinal cord are also involved in this natriuresis. The experiments were performed on anesthetized male rats. Before acute unilateral nephrectomy, an oxytocin-receptor antagonist was injected intrathecally in the thoracolumbar region in rats. Postnephrectomy natriuresis was attenuated by this injection but not by intrathecal injection of artificial cerebrospinal fluid. Our results suggest that OT receptors within the spinal cord may influence the autonomic nervous regulation of renal function. In an additional experiment, intravenously infused hexamethonium did not prevent the adaptive natriuresis in the remaining kidney. We conclude that OT receptors in the spinal cord are involved in the postnephrectomy natriuresis, possibly as a component in the afferent signal pathway.

Tubuglomerular feedback control in long-looped nephrons. Topical minireview.

The tubuloglomerular feedback mechanism is highly activated in juxtamedullary nephrons and considered to play a major role in intrarenal regulation of glomerular filtration rate. The vasculature of juxtamedullary nephrons is highly vasoreactive with a high ability for vasodilation. This vasoreactivity is a prerequisite for an important influence of the tubuloglomerular feedback mechanism on the medullary blood flow and its regulation.

Improvement of insulin response in the streptozotocin model of insulin-dependent diabetes mellitus. Insulin response with and without a long-acting insulin treatment.

Streptozotocin-induced diabetes mellitus (STZ-DM) in rats is a model of type 1 diabetes, which is commonly used to study diabetes, but differs from human diabetic pathophysiology in its insulin resistance. An STZ-DM rat can be administered five times the dose of insulin compared to that of a diabetic patient. Thus, attaining normoglycaemia in STZ-DM rats with insulin injections is complicated, and it involves an obvious risk of overdosing before getting a response. This study was designed to investigate whether suboptimal treatment with long-acting insulin restores insulin sensitivity in the STZ-DM rat, and thus an approach to more closely mimic the human condition. Male Sprague-Dawley rats were made diabetic by means of a single intravenous injection of STZ (55 mg/kg body weight (BW)), resulting in an increase in blood glucose (BG) from 6.5 ± 0.2 to 22.5 ± 1.0 mmol/l (P 0.05) within 24 h. After treating the STZ-DM rats with vehicle for 14 days, BG was 26.1 ± 1.1 mmol/l, and the response to a single injection of fast-acting insulin (Humalog, 5 IE/kg BW) was a 23% reduction in BG. Thereafter, the rats were treated daily with a suboptimal dose of long-acting insulin for a total of 7 days (Insulatard, 5 IE/kg per day), which resulted in a BG level of 19.4 ± 2.7. The response to fast-acting insulin after the suboptimal treatment was a 61% reduction in BG. Thereafter, the animals were vehicle-treated for another 7 days, which resulted in a response to fast-acting insulin similar to the initial values (-34%). Furthermore, the group treated with suboptimal doses of long-acting insulin had a longer duration of the reduction in BG (150 min, as opposed to 90 min in the vehicle-treated groups). We conclude that the development of a decreased insulin response occurs rapidly within the first 2 weeks after the onset of diabetes in STZ-DM rats. This leads to a brief and significantly reduced decrease in BG when fast-acting insulin is administered. The insulin response is increased by treatment with suboptimal doses of long-acting insulin, but rapidly decreases again when treatment is withdrawn. Regular administration of suboptimal insulin doses may provide an approach to eliminate the effects of a lowered insulin response.

Time-dependent heterogeneity of filtration rate in the autoregulating rat kidney.

Experiments were performed to study the regulation of the single-nephron glomerular filtration rate (SNGFR) in superficial and juxtamedullary nephrons, as the left kidney of Sprague Dawley rats was submitted to a reduced arterial pressure of 70 mmHg by means of an aortic clamp. The SNGFR at different cortical levels was measured 0.5, 1, 5, 20 or 45 min after the reduction, in order to ascertain whether the effects of the regulatory mechanisms are modified with time. A Hanssen technique was used, which allows one determination of filtration rates per animal. At a renal arterial pressure (RAP) of 100 mmHg (= control animals) the SNGFR amounted to 20 +/- 1.2 and 23 +/- 0.8 nl X min-1 X g-1 kidney weight in the outer and inner cortical (OC, IC) nephrons. When RAP was further reduced to 70 mmHg, the autoregulation of SNGFR, determined after 0.5 min, was highly efficient for both OC and IC nephrons (19 +/- 2.0, 23 +/- 2.6). A prolonged reduction in RAP caused a gradual decline in SNGFR. The filtration rate measured after 5 min was 15 +/- 1.4 for OC and 20 +/- 1.8 for IC nephrons. The decline was most pronounced for OC nephrons, which led to a fractional redistribution in favour of IC nephrons. Thus, SNGFRIC/SNGFROC was 1.16 +/- 0.065 when RAP was 100 mmHg and 1.41 +/- 0.126 after 5 min with an RAP of 70 mmHg. It is well documented that suprarenal aortic occlusion is a powerful stimulus for the release of renin. This was manifested as an increase in the arterial pressure proximal to the aortic clamp.(ABSTRACT TRUNCATED AT 250 WORDS)

The effect of a converting enzyme inhibitor on autoregulation and intrarenal distribution of glomerular filtration in the rat.

The role of the renin-angiotensin system in the autoregulation and distribution of the single nephron glomerular filtration rate (SNGFR) in anaesthetized, normotensive rats was investigated. SNGFR in outer cortical (OC) and inner cortical (IC) nephrons of the left kidney were measured with a modified Hanssen technique at three levels of renal arterial pressure (RAP): at a spontaneous arterial pressure; at a value within the autoregulatory limit, 100 mmHg; and at the lower limit of the autoregulatory range, 70 mmHg. This was done in control rats and in rats given a continuous i.v. infusion of the converting enzyme inhibitor (CEI) captopril (3 mg . h-1 X kg-1 BW). In control rats there was complete autoregulation of SNGFR in both OC and IC nephrons when RAP was reduced to 100 mmHg. Further reduction to 70 mmHg elicited different responses among the cortical layers, associated with a decrease in SNGFR. A fractional redistribution of glomerular filtration rate towards IC nephrons was evident. Administration of CEI at spontaneous RAP increased SNGFR in IC nephrons compared with values in control rats, but did not notably alter SNGFR in OC nephrons. Reduction of RAP to 100 mmHg during CEI infusion caused SNGFR to decrease below control values in both OC and IC nephrons, and the autoregulation as found in control rats was impaired. When RAP was lowered to 70 mmHg during CEI administration there was a progressive decrease in SNGFR in all cortical layers, although absolute changes were much greater in IC nephrons than in OC nephrons.(ABSTRACT TRUNCATED AT 250 WORDS)

Dopamine receptor blockade and synthesis inhibition during exaggerated natriuresis in spontaneously hypertensive rats.

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 micrograms 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.

Natriuresis obtained by intracerebroventricular infusion of hypertonic NaCl in rats with papillary necrosis.

Raising the sodium concentration in the third cerebral ventricle increases renal sodium, potassium and water excretion. The identification and characterization of the factor(s) mediating the centrally evoked natriuresis would be greatly facilitated if the exact intrarenal effector site were known. We have assessed the importance of inner medullary structures for the effects of CNS stimulation by examining its ability to alter renal excretion in rats with papillary necrosis, induced 2 d earlier with 2-bromoethylamine hydrobromide (BEA), 250 mg kg-1 body wt i.v. Male Lewis x DA rats were divided into a BEA-treated group (n = 6) and a control group receiving vehicle alone (n = 6). In contrast to the white papillae normally seen, the papillae of BEA-treated animals were bright red and showed a clear line of demarcation at their base. The rats were anaesthetized i.p. with Inactin (120 mg kg-1 body wt). Artificial cerebrospinal fluid (CSF) was infused (520 nL min-1) via a cannula into the left lateral ventricle. After 45 min CSF containing 1 M NaCl was used. Stimulation of the control rats with hypertonic CSF increased urine flow rate five-fold (5.4 +/- 0.8 to 27.1 +/- 6.1 microL min-1), Na excretion 23-fold (0.4 +/- 0.1 to 7.6 +/- 1.8 mumol min-1) and K excretion fourfold (0.6 +/- 0.18 to 3.8 +/- 0.5 mumol min-1). When the concentration mechanisms were damaged with BEA, the basal excretion rates of water and Na increased. The natriuretic response to ICV stimulation was severely impaired in these rats, but the kaliuretic effect was sustained.(ABSTRACT TRUNCATED AT 250 WORDS)

The effect of pressor doses of Angiotensin II on autoregulation and intrarenal distribution of glomerular filtration rate in the rat.

This study was designed to investigate the effect of pressor doses of exogenous Angiotensin II (AII) on autoregulation and intrarenal distribution of single nephron glomerular filtration rate (SNGFR) in anesthetized, normotensive rats. SNGFR at all cortical levels of the left kidney was measured with a modified Hanssen technique at three renal arterial pressures (RAP): Spontaneous, 100 +/- 1 mmHg and 70 +/- 1 mmHg. In control rats, both outer cortical (OC) and inner cortical (IC) nephrons showed complete autoregulation of SNGFR when RAP was reduced to 100 +/- 1 mmHg. Further reduction to 70 +/- 1 mmHg resulted in different responses among the cortical layers, accompanying a decrease in SNGFR. The SNGFRIC/SNGFROC ratio increased from 1.36 +/- 0.053 to 1.52 +/- 0.047 and a fractional redistribution of glomerular filtration rate towards IC nephrons was seen. When the kidney was submitted to a RAP of 70 +/- 1 mmHg, there was a concomitant increase in central arterial pressure (CAP) from 120 +/- 4.3 to 134 +/- 3.2 mmHg. A continuous i.v. infusion of AII (0.5 microgram . min-1 . kg-1 BW) increased mean arterial pressure from 123 +/- 1.4 to 142 +/- 3.8 mmHg, an effect corresponding to that on peripheral vascular resistance during reduction of RAP to 70 +/- 1 mmHg in control rats. This dose reduced SNGFR at all cortical levels, but did not per se lead to redistribution of SNGFR. A reduction in RAP to 100 +/- 1 mmHg during AII administration resulted in impaired autoregulation of SNGFR in both OC and IC nephrons.(ABSTRACT TRUNCATED AT 250 WORDS)

Whole kidney response to reduced arterial pressure during converting enzyme inhibition in the rat.

Autoregulatory efficiency of renal blood flow (RBF) and glomerular filtration rate (GFR) was evaluated in male Sprague-Dawley rats during interference with the renin-angiotensin system by a converting enzyme inhibitor (CEI), captopril (3 mg X h-1 X kg-1 BW). RBF and GFR were approximately 25 (p less than 0.01) and 20% (p less than 0.02) higher, respectively, in rats infused with CEI than in control rats at spontaneous renal arterial pressure (RAP). A reduction of RAP to 100 mm Hg (within the autoregulatory range) resulted in effective autoregulation of GFR and RBF in control rats. In rats given CEI, however, the autoregulation of GFR was markedly impaired. GFR decreased by 35% (p less than 0.001), while RBF remained relatively unchanged. This caused the filtration fraction to decrease from 0.33 +/- 0.01 to 0.29 +/- 0.01 (p less than 0.001). RAP had a consistent effect on the urine flow rate, even though both GFR and RBF were well autoregulated in control rats. No significant decrease in electrolyte excretion was detected within the autoregulatory range in control rats, but during converting enzyme blockade this excretion decreased progressively as RAP was reduced, and the decrease correlated well to the reduction in GFR. In summary, these results suggest that the renin-angiotensin system plays an important intrarenal role in the autoregulation of GFR, probably through an efferent arteriolar mechanism. Furthermore, it is demonstrated that the contralateral kidney efficiently compensates in urinary electrolyte excretion for an acute unilateral reduction of RAP.(ABSTRACT TRUNCATED AT 250 WORDS)

Efferent renal nerve activity during intracarotid and intracerebroventricular infusions of hypertonic sodium chloride solutions and isotonic volume expansion in the rat.

The change in renal nerve activity under conditions known to increase renal sodium excretion was studied. In adult Sprague Dawley rats, anaesthetized with Inactin, normotonic and hypertonic NaCl solutions were infused into 1) a vein, 2) a carotid artery and 3) the third ventricle. The left kidney was freed and placed in a plastic cup. A renal nerve was dissected free and placed on a stainless bipolar electrode. The nerve was cut distal to the electrode. The nerve signals were amplified and recorded on a tape recorder. Simultaneously integrated nerve signals and also atrial and venous pressures were recorded. Intracarotid infusion of a 1 M NaCl solution increased sodium output and temporarily decreased renal nerve activity by some 35%. Corresponding intravenous (i.v.) infusion gave an increase in renal nerve activity and also in sodium output. The latter increase was delayed compared with that caused by the intracarotid infusion. No variations in blood pressure were noted. In control experiments with a slow i.v. infusion of physiological saline, renal nerve activity increased throughout the experiment, while sodium excretion remained constant. During infusion of a 1 M NaCl solution into the third ventricle, renal nerve activity decreased in about half of the cases. This reduction was often accompanied by an increased arterial blood pressure and an increased sodium output. Arterial blood pressure increases were especially pronounced at the highest infusion rats, i.e. 800 ml-min-1. Isotonic volume expansion of 2% of the body weight resulted in a transient decrease in renal nerve activity by about 30%. Venous blood pressure rose and sodium output increased six-fold. The decrease in nerve activity was observed both when the vagal nerves were intact and when they were cut.

Renal interstitial volume of the rat kidney.

The intravascular plasma volume and the interstitial volume of the rat kidney were determined by an indicator dilution method with a bolus injection of 125-I-labelled human serum albumin and 51-Cr-EDTA into the renal artery and subsequent recording of the indicator-dilution curves in the venous effluent, sampled at intervals of 0.33 s. The curves allowed determination of both the mean transit time of the two indicators and total renal plasma flow. The volumes of distribution were obtained by multiplying these two factors. Under control conditions the plasma volume was 93.0 +/- 11.2 microliters/100 g rat (mean +/- SE), which is 17.9% of the total kidney volume. The interstitial volume was 68.3 +/- 8.6 microliters/100 g, corresponding to 13.1% of the total kidney volume. During expansion with 0.15 M NaCl, 10% of body weight, the plasma and interstitial volumes were not significantly increased. The values for the two volumes were 101.6 +/- 9.7 and 72.8 +/- 6.8 microliters/100 g, respectively. The kidney weight showed, in contrast a clear increase from 539 to 670 mg/100 g, reflecting the expansion of the proximal and distal tubules due to the increased glomerular filtration rate. It is concluded that although the saline load produced a rise in the renal interstitial pressure, the expected expansion of the interstitium became small, due to the parallel expansion of both the vascular and tubular systems which compress the renal interstitium.

Effect of a converting-enzyme inhibitor on vasa recta blood flow in rat kidney.

In young anesthetized Munich-Wistar rats, red cell flux (Qrbc) was measured in the vasa recta of the exposed renal papilla by means of fluorescently labeled erythrocytes. To study the vasoreactivity of the juxtamedullary vasculature and its sensitivity to converting-enzyme inhibition, measurements of Qrbc were made before and after continuous intravenous infusion of the angiotensin I converting-enzyme inhibitor captopril (3 mg.h-1.kg body wt-1). A time control group that received vehicle alone was studied in parallel. Captopril acts as a vasodilator and reduces systemic arterial pressure. Captopril treatment increased Qrbc by 40 +/- 4% (n = 9, P less than 0.001) and decreased blood pressure by 9% (P less than 0.001). In the time control group no statistically significant change occurred in either Qrbc (+6 +/- 8%, n = 10) or blood pressure (-1%). Urine samples were taken from the papillary tip. In neither of the groups did the urine osmolality show a statistically significant change. In the time control group the values before and after intravenous infusion were 1,006 +/- 61 and 1,091 +/- 70 mosmol/kg H2O, respectively, and in the captopril-treated animals the corresponding values were 1,150 +/- 85 and 1,210 +/- 60 mosmol/kg H2O, respectively. These results confirm the suggestion that there is high vasoreactivity in the juxtamedullary vasculature and that this region is sensitive to inhibition of angiotensin I-converting enzyme, the latter sensitivity implying that angiotensin II plays a role in the regulation of juxtamedullary vascular resistance.(ABSTRACT TRUNCATED AT 250 WORDS)