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.