SUMMARYCockroach salivary glands are innervated by dopaminergic and serotonergic neurons. Both transmitters elicit saliva secretion. We studied the distribution pattern of neurons containing ␥-aminobutyric acid (GABA) and their physiological role . Immunofluorescence revealed a GABA-immunoreactive axon that originates within the subesophageal ganglion at the salivary neuron 2 (SN2) and this extends within the salivary duct nerve towards the salivary gland. GABA-positive fibers form a network on most acinar lobules and a dense plexus in the interior of a minor fraction of acinar lobules. Co-staining with anti-synapsin revealed that some putative GABAergic terminals seem to make pre-synaptic contacts with GABA-negative release sites. Many putative GABAergic release sites are at some distance from other synapses and at distance from the acinar tissue. Intracellular recordings from isolated salivary glands have revealed that GABA does not affect the basolateral membrane potential of the acinar cells directly. When applied during salivary duct nerve stimulation, GABA enhances the electrical response of the acinar cells and increases the rates of fluid and protein secretion. The effect on electrical cell responses is mimicked by the GABA B receptor agonists baclofen and SKF97541, and blocked by the GABA B receptor antagonists CGP52432 and CGP54626. These findings indicate that GABA has a modulatory role in the control of salivation, acting presynaptically on serotonergic and/or dopaminergic neurotransmission.

Circulation Journal Official Journal of the Japanese Circulation Society http://www. j-circ.or.jp (LV) dilation. 1 This subgroup (ie, those with dilated cardiomyopathy: DCM) constitutes the third most common type of heart failure and is the most frequent indication for heart transplantation. 2 Etiological aspects of LV dilation in DCM are under intense current investigation. 3-5 Among other factors, imbalance in the cardiac extracellular matrix (ECM) is believed to be a key pathogenic factor of ventricular chamber dilation in heart failure. This includes increased accumulation of collagens, disturbance in ECM-regulating factors such as metalloecent-onset cardiomyopathy (ROCM), described as nonischemic and nonvalvular ventricular dysfunction with cardiac symptoms of less than 6 months' duration, is a relevant cause of heart failure and includes increased morbidity and mortality. 1 Patients with ROCM show great variation in the clinical course, which ranges from sufficient myocardial recovery to end-stage heart failure and increased mortality. Background: Ventricular dilation is known as a pivotal predictor in recent-onset cardiomyopathy (ROCM), but its pathophysiology is not fully understood. In the present study we investigated whether single-cell stiffness of right and left ventricular-derived fibroblasts has an effect on cardiac phenotype in patients with ROCM.

ENaC-dependent and thiazide-sensitive sodium-retaining mechanisms are not overactive in sunitinib-induced hypertension but ENaC blockers and in particular thiazides may be suitable for its treatment.

No abstract

BackgroundThe tyrosine kinase inhibitor sunitinib causes hypertension associated with reduced nitric oxide (NO) availability, elevated renal vascular resistance, and decreased fractional sodium excretion. We tested whether (1) nitrate supplementation mitigates sunitinib‐induced hypertension and NO contributes less to renal vascular resistance as well as fractional sodium excretion regulation in sunitinib‐treated rats than in controls; and (2) renal soluble guanylate cyclase (sGC) is downregulated and sGC activation lowers arterial pressure in rats with sunitinib‐induced hypertension.Methods and ResultsArterial pressure responses to nitrate supplementation and the effects of systemic and intrarenal NO synthase (NOS) inhibition on renal hemodynamics and fractional sodium excretion were assessed in sunitinib‐treated rats and controls. Renal NOS and sGC mRNA as well as protein abundances were determined by quantitative polymerase chain reaction and Western blot. The effect of the sGC activator cinaciguat on arterial pressure was investigated in sunitinib‐treated rats. Nitrate supplementation did not mitigate sunitinib‐induced hypertension. Endothelium‐dependent reductions in renal vascular resistance were similar in control and sunitinib‐treated animals without and with systemic NOS inhibition. Selective intrarenal NOS inhibition lowered renal medullary blood flow in control but not in sunitinib‐treated rats without significant effects on fractional sodium excretion. Renal cortical sGC mRNA and sGC α1‐subunit protein abundance were less in sunitinib‐treated rats than in controls, and cinaciguat effectively lowered arterial pressure by 15‐20 mm Hg in sunitinib‐treated rats.ConclusionsRenal cortical sGC is downregulated in the presence of intact endothelium‐dependent renal vascular resistance regulation in developing sunitinib‐induced hypertension. This suggests that sGC downregulation occurs outside the renal vasculature, increases renal sodium retention, and contributes to nitrate resistance of sunitinib‐induced hypertension.

We report the effects of sublingual absorption of a single dose (0.5 mg) of oestradiol-17\g=b\(E2) in 8 post-menopausal women, on plasma E2 and oestrone (E1), urine elimination of total E2 + E1 and on plasma FSH and LH.The results show that sublingual absorption of E2 occurs and that plasma concentrations of E2 obtained (between 133.2 to 320 pmol/1) in this way were higher than those obtained after percutaneous absorption of a single dose (3 mg)of E2. The ratio E1/E2 in plasma is close to that of pre-menopausal women.Although synthetic forms of oestrogen are effec¬ tive in treating menopausal symptoms, they are now less commonly used because of side-effects in the liver (Kern et al. 1978) and cardiovascular system (Irey & Norris 1973; Gammal 1976), and the natural oestrogen oestradiol-I7ß (E2) is con¬ sidered preferable. Nevertheless, its concentration in the patients plasma after administration, as well as that of its chief metabolite oestrone (Ei) should both remain as close as possible to pre-menopausal physiological levels. Many absorption routes have been studied for E2, including the percutaneous (Basdevant & De Lignieres 1980), oral (Yen et al. 1975, vaginal (Rigg et al. 1978), intramuscular (Sommerville 1975) and implantation pathways (Greenblatt et al. 1977). Apart from one very recent paper (Burnier et al. 1981), however, no description exists of absorption by the sublingual route.Our aim was to determine whether E2 can be absorbed sublingually. 'Glossettes1' of E2 were administered in single doses to 8 post-menopausal women and plasma concentration of E2, E^F SH and LH were measured, in addition to the sum of the Et and E2 excreted in the urine.Finally, for purposes of comparison, 6 of the 8 women were given a percutaneous application of E2 one week after the sublingual dose and the same parameters were measured. Materials and Methods PatientsOur series was of 9 post-menopausal women, but we excluded one 70-year-old patient with very high levels of basal E2. Investigation revealed that she was using beauty creams containing oestrogen.The ages of the 8 patients studied ranged from 47 to 69 years and their mean weight was 55 kg. Six patients had experienced a natural menopause and 2 had under¬ gone hysterectomy with bilateral ovariectomy. The time elapsing between the onset of menopause and the in¬ vestigation ranged from 4 to 24 years. No patient had received oestrogen treatment during that time. None was suffering from kidney, liver or thyroid complaints or disturbed salivation. All medication was stopped during the trial. »Laboratoire Fournier, BP 130, 21004 DIJON cédex,

The renal renin-angiotensin system (RAS) is involved in the development of chronic kidney disease. Here, we investigated whether mice with reduced renal angiotensin I-converting enzyme (ACE−/−) are protected against aristolochic acid nephropathy (AAN). To further elucidate potential molecular mechanisms, we assessed the renal abundances of several major RAS components. AAN was induced using aristolochic acid I (AAI). Glomerular filtration rate (GFR) was determined using inulin clearance and renal protein abundances of renin, angiotensinogen, angiotensin I-converting enzyme (ACE) 2, and Mas receptor (Mas) were determined in ACE−/− and C57BL/6J control mice by Western blot analyses. Renal ACE activity was determined using a colorimetric assay and renal angiotensin (Ang) (1–7) concentration was determined by ELISA. GFR was similar in vehicle-treated mice of both strains. AAI decreased GFR in controls but not in ACE−/− mice. Furthermore, AAI decreased renal ACE activity in controls but not in ACE−/− mice. Vehicle-treated ACE−/− mice had significantly higher renal ACE2 and Mas protein abundances than controls. AAI decreased renal ACE2 protein abundance in both strains. Furthermore, AAI increased renal Mas protein abundance, although the latter effect did not reach statistical significance in the ACE−/− mice. Renal Ang(1–7) concentration was similar in vehicle-treated mice of both strains. AAI increased renal Ang(1–7) concentration in the ACE−/− mice but not in the controls. Mice with reduced renal ACE are protected against AAN. Our data suggest that in the face of renal ACE deficiency, AAI may activate the ACE2/Ang(1–7)/Mas axis, which in turn may deploy its reno-protective effects.

Sunitinib is an antiangiogenic receptor tyrosine kinase inhibitor used in cancer treatment. A major adverse effect of sunitinib is a rapidly developing hypertension associated with reduced renal nitric oxide (NO) availability and increased renal fractional sodium reabsorption (FRNa). We tested if NO‐dependent regulation of renal hemodynamics and FRNa are compromised and if nitrate supplementation has antihypertensive effects in early sunitinib‐induced hypertension.Male Wistar rats were treated with sunitinib at 15 mg/(kg*d). Four days after initiation of sunitinib treatment, renal hemodynamics and renal sodium excretion were investigated. Radiotelemetric experiments were performed to study the effects of nitrate supplementation and soluble guanylate cyclase (sGC) activation on arterial pressure. Nitric oxide synthase (NOS) as well as sGC mRNA and protein abundances were studied in renal tissue.Within four days, sunitinib elicited a 20–25 mmHg arterial pressure rise. NOS inhibition elicited similar reductions in total and renal medullary blood flow in sunitinib‐ and vehicle‐treated rats. NO‐dependent and independent components of endothelium‐dependent renal vasodilation were not compromised in early sunitinib‐induced hypertension. Low dose intrarenal NOS inhibition did not differentially affect FRNa in sunitinib‐ and vehicle‐treated rats. In sunitinib‐treated rats, renal nitrite/nitrate excretion was 60 per cent less than in controls (p < 0.05). However, nitrate supplementation did not reduce arterial pressure and renal sodium balance in sunitinib‐treated rats. While sunitinib treatment had no effects on renal NOS mRNA abundances, it significantly reduced renal cortical sGC α‐ and β‐subunit mRNA abundances as well as renal cortical guanylate cyclase protein expression. Pharmacological sGC activation caused a rapid 15–20 mmHg arterial pressure fall in sunitinib‐treated rats (p < 0.05).We conclude that the NO‐dependent regulation of renal hemodynamics is largely unaltered in early sunitinib‐induced hypertension despite evidence for reduced NO formation. Reduced renal sGC expression and activity may contribute to the early arterial pressure rise in sunitinib‐induced hypertension and cause its nitrate resistance.Support or Funding InformationSupported by the German Research Foundation, Grant‐No. KO 4936/2‐1.This abstract is from the Experimental Biology 2018 Meeting. There is no full text article associated with this abstract published in The FASEB Journal.