neuropeptide-y and icatibant

The ability of scorpion toxins to produce hemodynamic alterations is well documented but all mediators implied in cardiovascular disturbances are not known. In the present investigation we studied the effect of North African Androctonus australis garzonii scorpion toxin on neuropeptide Y (NPY) release from rat atria and kidneys by a perifusion system in vitro. To further understand the mechanisms of the scorpion toxin action on NPY release, the effects of icatibant (HOE 140, a selective bradykinin-B2 receptor antagonist), tetrodotoxin (TTX, a sodium channel antagonist) and diltiazem (a calcium channel antagonist), and the effect of the scorpion toxin on bradykinin (BK, a potent vasorelaxant peptide of the kinin group) release were studied in both tissues. We showed that the scorpion toxin (10(-6)M) increased the NPY release from both atria (35%) and kidneys (40%). This increase was significantly (p<0.001) inhibited by HOE 140 (10(-5)M). The scorpion toxin (10(-6)M) enhanced BK secretion in both atria (52%) and kidneys (55%). Diltiazem (10(-5)M) and TTX (10(-5)M) decreased by 45-75% NPY levels induced by scorpion toxin in both organs. The results show that A. australis garzonii scorpion toxin stimulates NPY release from both rat atria and kidneys, and suggest that the toxin induces NPY release via BK stimulation through B2 receptors. This effect appears to involve calcium and sodium channel activation.

Topics: Animals; Bradykinin; Bradykinin B2 Receptor Antagonists; Diltiazem; Heart Atria; Kidney; Male; Neuropeptide Y; Radioimmunoassay; Rats; Rats, Sprague-Dawley; Scorpion Venoms; Sodium Channel Blockers; Tetrodotoxin

Neuropeptide Y (NPY) and noradrenaline (NA) are frequently co-localized and co-released in the sympathetic nervous system. Since bradykinin (BK) is known to stimulate neurotransmitter release as NA in adrenal glands, we therefore hypothesized that BK might also be involved in the release of NPY. The effect of BK(1-9) on immunoreactive NPY (Ir-NPY) release was investigated in superfused human pheochromocytoma tissue. BK(1-9) (10(-7)-10(-5) M) was shown to induce a rapid Ir-NPY release in a concentration-dependent manner. This effect of BK(1-9) (10(-6) M) was mimicked by the B2 agonist [Phe(8)(CH(2)NH)Arg(9)]-bradykinin (10(-5) M) and blocked by the selective B2-receptor antagonist HOE140 (10(-5) M). Increasing Ir-NPY release was probably not mediated by nitric oxide (NO) since the outflow of Ir-NPY was not influenced by the NO synthase inhibitor N-omega-nitro-L-arginine methyl ester (L-NAME) (10(-4) M). In presence of bapta-AM (10(-5) M), a chelator of cytosolic calcium, W7 (10(-5) M), a calmodulin inhibitor, TMB-8 (10(-5) M), a blocker of intracellular calcium mobilization and ryanodine (10(-5) M), a selective inhibitor of the Ca(2+)-induced release mechanism, the NPY release by BK(1-9) was significantly inhibited by 126%, 98%, 91%, and 94%, respectively. These results indicate that BK increased the release of NPY by the tumor acting through the interaction with the BK-B2 receptor and request intracellular calcium mobilization independently of a NO mechanism.

Topics: Adrenal Gland Neoplasms; Bradykinin; Calcium; Dose-Response Relationship, Drug; Enzyme Inhibitors; Humans; In Vitro Techniques; Neuropeptide Y; NG-Nitroarginine Methyl Ester; Nitric Oxide Synthase; Pheochromocytoma; Receptor, Bradykinin B2; Receptors, Bradykinin; Stimulation, Chemical

Neuropeptide Y (NPY) is an established modulator of renal function. Although NPY reduces renal blood flow and does not alter glomerular filtration rate, it enhances diuresis and natriuresis. Although initial studies on natriuresis did not detect kaliuresis, we now report that a retrospective analysis of previous studies regarding natriuresis demonstrates NPY-induced kaliuresis under several experimental conditions. Kaliuresis was observed despite a marked reduction in urinary potassium concentrations, which may explain why it has not been noted in some initial studies. In a direct comparison of NPY-induced kaliuresis and natriuresis, both effects were slow in onset (requiring >45 min to develop fully) and blocked by the cyclooxygenase inhibitor indomethacin. While natriuresis occurred solely via a Y5 receptor, kaliuresis involved a Y1 receptor and an additional receptor subtype, possibly Y2. The L-type Ca2+ entry blocker nifedipine abolished natriuresis but did not inhibit kaliuresis. A combination of experiments with the bradykinin B2 receptor antagonist icatibant, the angiotensin II receptor antagonist losartan, and the converting enzyme inhibitor ramiprilat revealed that NPY-induced natriuresis involves bradykinin while kaliuresis involves angiotensin II. We conclude that NPY-induced kaliuresis is much less pronounced than natriuresis and is mediated by distinct mechanisms.

Topics: Aldosterone; Animals; Bradykinin; Humans; Indomethacin; Losartan; Male; Neuropeptide Y; Nifedipine; Potassium; Rats; Rats, Wistar; Sodium

Neuropeptide Y (NPY) can cause diuresis, natriuresis, and calciuresis in rats independently of the pressure-natriuresis mechanism (A. Bischoff and M. C. Michel. Pflügers Arch. 435: 443-453, 1998). Because this is seen in systemic but not intrarenal NPY infusion, we have investigated the possible mediator of tubular NPY effects in anesthetized rats. In the present study, infusion of NPY (2 micrograms . kg-1 . min-1) enhanced renovascular resistance by approximately 8 mmHg . ml-1 . min and enhanced urine and sodium excretion by approximately 450 microliter/15 min and approximately 60-85 micromol/15 min, respectively. Acute renal denervation did not alter renovascular or tubular NPY effects, indicating that a neuronally released mediator is not involved. Treatment with the angiotensin II-receptor antagonist losartan prevented the decline of the renovascular response with time but did not modify tubular NPY effects. The bradykinin B2-receptor antagonist icatibant accelerated the decline of the renovascular NPY effects with time; concomitantly, it attenuated NPY-induced diuresis and natriuresis and abolished NPY-induced calciuresis. The converting-enzyme inhibitor ramiprilat prevented the decline of the renovascular response with time; concomitantly, it magnified the NPY-induced diuresis, natriuresis, and calciuresis. We conclude that bradykinin may be involved in NPY-induced diuresis, natriuresis, and, in particular, calciuresis.

Topics: Angiotensin-Converting Enzyme Inhibitors; Animals; Bradykinin; Bradykinin Receptor Antagonists; Calcium; Creatinine; Denervation; Diuresis; Infusions, Intravenous; Kidney; Losartan; Male; Natriuresis; Neuropeptide Y; Ramipril; Rats; Rats, Wistar; Receptor, Bradykinin B2; Regional Blood Flow; Renal Circulation; Vascular Resistance