Brown Norway Katholiek rats, which have very low levels of plasma kininogens, excreted a much smaller amount of kinin in the urine than normal rats of the same strain. The systolic blood pressure of 7-week-old kininogen-deficient rats fed low (0.3%) NaCI diets (131±4 mm Hg, n=12) was not different from that in normal rats. Two percent NaCI diets given from 7 weeks of age for 4 weeks caused rapid increases in blood pressure (167±4 mm Hg, n=12, 9 weeks old) in deficient rats, although the same diets induced no blood pressure increase in normal rats. Urinary excretion of active kallikrein and prokallikrein remained constant in both rat groups throughout NaCI loading. During this period, the deficient rats secreted less urine (9 weeks old, P<.05) and less urinary sodium (11 weeks old, P<.05). Serum levels of sodium in deficient rats were higher (/ > <.O5) than in normal rats at 9 weeks of age. Intracellular concentrations of sodium in the erythrocytes of deficient rats were higher (P<.05) than in normal rats throughout NaCI loading. Subcutaneous infusion of bovine low molecular weight kininogen with an osmotic pump in NaCI-loaded deficient rats induced a reduction (P<.01) in blood pressure and increases (P<.05) in urine volume and urinary sodium and kinin levels. By contrast, subcutaneous infusion of the bradykinin antagonist Hoe 140 or of aprotinin in NaCI-loaded normal rats induced a hypertensive response. This antagonist treatment reduced urine volume and urinary sodium. These results indicate that the lack of kinin generation observed in the kininogen-deficient rats was related through sodium retention to the hypertensive response to NaCI loading. (Hypertension. 1993;22:705-714.) KEY WORDS • hypertension, sodium-dependent • sodium, dietary • kininogens • bradykinin • aprotininT he blood pressure-lowering effects of urinary kallikrein injected intravenously have been described for more than six decades,' and bradykinin is well known to induce vasodilatation and an increase in renal blood flow and excretion of water and sodium from the kidney.2 Urinary kallikrein therefore has been thought to be involved in hypertension, and its reduction has been reported in human 36 and animal 717 experiments. On the other hand, it is widely accepted that sodium retention may be related to the pathogenesis of hypertension, although the precise mechanisms of its contribution to the elevation of blood pressure are still unclear. The causal relation between these three factors -urinary kallikrein, sodium retention, and hypertension-has not been verified. Recently, we reported that the kallikrein-kinin system may play a suppressive role in deoxycorticosterone acetate (DOCA)-salt hypertension.18 Using kininogendeficient Brown Norway Katholiek (BN-Ka) rats and normal rats of the same strain (Brown Norway Kitasato [BN-Ki]), we were able to demonstrate that the urinary kallikrein-kinin system may contribute to lowering of systemic blood pressure in the initial phase of the development of DOCA-salt hypertension in uninephrectomized ...

Non-technical summary In the oesophagus the ion channel TRPV4 senses multiple stimuli, including heat and mechanical stimulation. TRPV4 activation causes ATP release from oesophageal cells, which could be important in oesophageal disease mechanisms.Abstract Gastro-oesophageal reflux disease (GERD) is a multi-factorial disease that may involve oesophageal hypersensitivity to mechanical or heat stimulus as well as acids. Intraganglionic laminar endings (IGLEs) are the most prominent terminal structures of oesophageal vagal mechanosensitive afferents and may modulate mechanotransduction via purinergic receptors. Transient receptor potential channel vanilloid 4 (TRPV4) can detect various stimuli such as warm temperature, stretch and some chemicals, including 4α-phorbol 12,13-didecanoate (4α-PDD) and GSK1016790A. TRPV4 is expressed in many tissues, including renal epithelium, skin keratinocytes and urinary bladder epithelium, but its expression and function in the oesophagus is poorly understood. Here, we show anatomical and functional TRPV4 expression in mouse oesophagus and its involvement in ATP release. TRPV4 mRNA and protein were detected in oesophageal keratinocytes. Several known TRPV4 activators (chemicals, heat and stretch stimulus) increased cytosolic Ca 2+ concentrations in cultured WT keratinocytes but not in TRPV4 knockout (KO) cells. Moreover, the TRPV4 agonist GSK1016790A and heat stimulus evoked TRPV4-like current responses in isolated WT keratinocytes, but not in TRPV4KO cells. GSK1016790A and heat stimulus also significantly increased ATP release from WT oesophageal keratinocytes compared to TRPV4KO cells. The vesicle-trafficking inhibitor brefeldin A (BFA) inhibited the ATP release. This ATP release could be mediated by the newly identified vesicle ATP transporter, VNUT, which is expressed by oesophageal keratinocytes at the mRNA and protein levels. In conclusion, in response to heat, chemical and possibly mechanical stimuli, TRPV4 contributes to ATP release in the oesophagus. Thus, TRPV4 could be involved in oesophageal mechano-and heat hypersensitivity.