Desensitization of catecholamine release. The novel catecholamine release-inhibitory peptide catestatin (chromogranin a344-364) acts at the receptor to prevent nicotinic cholinergic tolerance

Nicotinic cholinergic receptors undergo desensitization upon repeated or prolonged exposure to agonist. We investigated the effects of a novel chromogranin A catecholamine release-inhibitory fragment, catestatin (chromogranin A344-364), on agonist-induced desensitization of catecholamine release from pheochromocytoma cells. In a dose-dependent fashion, the nicotinic antagonist catestatin blocked agonist desensitization of both catecholamine release (IC50 approximately 0.24 microM) and 22Na+ uptake (IC50 approximately 0.31 microM), the initial step in nicotinic cationic signal transduction; both secretion inhibition and blockade of desensitization were noncompetitive with agonist. Desensitizing effects of the nicotinic agonists nicotine and epibatidine were blocked. This antagonist action was specific to desensitization by nicotinic agonists, since catestatin did not block desensitization of catecholamine release induced by agents which bypass the nicotinic receptor. Hill plots with slopes near unity suggested noncooperativity for catestatin effects on both nicotinic responses (secretory antagonism and blockade of desensitization). Human, bovine, and rat catestatins (as well as substance P) had similar potencies. IC50 values for secretion inhibition and blockade of desensitization paralleled each other (r = 0.76, n = 10 antagonists, p = 0.01) for several noncompetitive nicotinic antagonists. Peptide nicotinic antagonists (catestatins, substance P) were far more potent inhibitors of both secretion (p = 0.019) and desensitization (p = 0.005) than nonpeptide antagonists (trimethaphan, hexamethonium, procaine, phencyclidine, cocaine, or clonidine), and the peptides displayed enhanced selectivity to block desensitization versus secretion (p = 0.003). We conclude that catestatin is a highly potent, dose-dependent, noncompetitive, noncooperative, specific inhibitor of nicotinic desensitization, an effect which may have implications for control of catecholamine release.     

Novel autocrine feedback control of catecholamine release. A discrete chromogranin a fragment is a noncompetitive nicotinic cholinergic antagonist

Catecholamine secretory vesicle core proteins (chromogranins) contain an activity that inhibits catecholamine release, but the identity of the responsible peptide has been elusive. Size-fractionated chromogranins antagonized nicotinic cholinergic-stimulated catecholamine secretion; the inhibitor was enriched in processed chromogranin fragments, and was liberated from purified chromogranin A. Of 15 synthetic peptides spanning approximately 80% of chromogranin A, one (bovine chromogranin A344-364 [RSMRLSFRARGYGFRGPGLQL], or catestatin) was a potent, dose-dependent (IC50 approximately 200 nM), reversible secretory inhibitor on pheochromocytoma and adrenal chromaffin cells, as well as noradrenergic neurites. An antibody directed against this peptide blocked the inhibitory effect of chromogranin A proteolytic fragments on nicotinic-stimulated catecholamine secretion. This region of chromogranin A is extensively processed within chromaffin vesicles in vivo. The inhibitory effect was specific for nicotinic cholinergic stimulation of catecholamine release, and was shared by this chromogranin A region from several species. Nicotinic cationic (Na+, Ca2+) signal transduction was specifically disrupted by catestatin. Even high-dose nicotine failed to overcome the inhibition, suggesting noncompetitive nicotinic antagonism. This small domain within chromogranin A may contribute to a novel, autocrine, homeostatic (negative-feedback) mechanism controlling catecholamine release from chromaffin cells and neurons.     

Paradigms for clinical ethics consultation practice

The effects of lipoproteins on ion channel-mediated catecholamine secretion were investigated in cultured bovine adrenal medullary cells. Low density lipoprotein (LDL: 20-80 mg/dl) and lipoprotein(a) [Lp(a); 10-80 mg/dl] inhibited catecholamine secretion induced by carbachol, an activator of nicotinic acetylcholine receptor-ion channels. LDL and Lp(a) suppressed carbachol-induced 22Na+ influx as well as 45Ca2+ influx in a concentration-dependent manner similar to that of catecholamine secretion. The inhibition of catecholamine secretion by Lp(a) was not overcome by increasing the concentration of carbachol. On the other hand, high density lipoprotein (HDL; < 150 mg/dl) had no effect on 22Na+ influx, 45Ca2+ influx, and catecholamine secretion. Like LDL and Lp(a), a synthetic peptide homologous to human plasma apolipoprotein B (apoB), apoB fragment(3358-3372)-amide (3-60 microM), attenuated 22Na+ influx, 45Ca2+ influx, and catecholamine secretion caused by carbachol. The apoB fragment also suppressed 22Na+ influx induced by veratridine (an activator of voltage-dependent Na+ channels) and 45Ca2+ influx induced by 56 mM K+ (an indirect activator of voltage-dependent Ca2+ channels). These findings suggest that atherogenic lipoproteins such as LDL and Lp(a) suppress catecholamine secretion by interfering with Na+ influx through nicotinic acetylcholine receptor-ion channels, in which apoB, a structural component common to both LDL and Lp(a), plays an important role. The inhibition by atherogenic lipoproteins of catecholamine secretion may influence the progression of atherosclerosis induced by these lipoproteins.     

Determination of diarrheic shellfish toxins in mussels by microliquid chromatography-tandem mass spectrometry

Treatment of cultured bovine adrenal medullary cells with carbamazepine (CBZ) for 5 days caused an increase in catecholamine secretion induced by veratridine, an activator of voltage-dependent Na+ channels. However, no increase was stimulated by carbachol, an agonist of nicotinic receptors, or by 56 mM K+, a depolarizing agent that activates voltage-dependent Ca++ channels. CBZ (30 microg/ml) treatment enhanced veratridine-induced catecholamine secretion in a time-dependent manner (increases of 25%, 65% and 70% for 3, 5 and 7 days of treatment, respectively). CBZ treatment (5 days) increased veratridine-induced catecholamine secretion in a concentration-dependent manner (increases of 27%, 36%, 45% and 55% at 10, 15, 20 and 30 microgram/ml of CBZ, respectively). CBZ treatment also increased 22Na+ influx and 45Ca++ influx stimulated by veratridine. The stimulatory effect of CBZ treatment on catecholamine secretion was blocked by either actinomycin D or cycloheximide, an inhibitor of protein synthesis. Additive responses of catecholamine secretion and 22Na+ influx induced by veratridine were associated with combined exposure of the cells to CBZ and dibutyryl cyclic AMP. CBZ treatment (30 microg/ml, 5 days) significantly increased the specific binding of [3H]saxitoxin to cell membranes. A Scatchard analysis of [3H]saxitoxin binding revealed that CBZ increased the Bmax value without any change in the dissociation constant. These findings suggest that CBZ up-regulates the density and activity of voltage-dependent Na+ channels.     

Cholestatic liver diseases--diagnosis and therapy. 3: Therapy of primary biliary cirrhosis

Preproadrenomedullin, the precursor of proadrenomedullin N-terminal 20 peptide (PAMP), is produced by rat zona glomerulosa cells. The actions of PAMP on the rat adrenal have been investigated. PAMP was found to stimulate aldosterone secretion and cAMP release by intact capsules, in a dose-dependent manner, but had only a minor effect on dispersed cells. The effects of PAMP on aldosterone secretion were inhibited by HA1004, an inhibitor of protein kinase A. The difference between tissue preparations does not appear to be due to the actions of PAMP on local release of catecholamines as PAMP inhibited the release of catecholamines from rat capsular preparations. These data suggest that PAMP is a novel zona glomerulosa stimulant in intact capsular tissue, acting through cAMP.     

Uptake of [3H]dopamine in isolated chromaffin cells of the mouse: modulation by intra- and extra-adrenal peptides and other secretagogues

The effects of intra- and extra-adrenal peptides on [3H]dopamine uptake in adrenal chromaffin cells of the mouse were examined in vitro. Dopamine uptake was inhibited by acetylcholine, high potassium, reserpine, imipramine and desmethylimipramine as was in noradrenaline uptake. Among the intra-adrenal peptides, vasoactive intestinal peptide (VIP, 100 pmol/l) and neurotensin inhibited [3H]dopamine uptake by approximately 25%. Somatostatin, enkephalin, and neuropeptide Y did not cause any significant inhibition. An extra-adrenal peptide, bradykinin, inhibited the uptake while angiotensin II showed no significant effect. Intra-adrenal peptides which cause catecholamine secretion inhibit catecholamine uptake probably to extend its effect. Extra-adrenal peptide which causes catecholamine secretion also inhibits catecholamine uptake.     

Evidence for two types of nicotinic receptors in the cat carotid body chemoreceptor cells

Current concepts on the location and functional significance of nicotinic receptors in the carotid body rest on alpha-bungarotoxin binding and autoradiographic studies. Using an in vitro preparation of the cat carotid body whose catecholamine deposits have been labeled by prior incubation with the tritiated natural precursor [3H]tyrosine, we have found that nicotine induces release of [3H]catecholamines in a dose-dependent manner (IC50 = 9.81 microM). We also found that mecamylamine (50 microM) completely abolished the nicotine-induced release, while alpha-bungarotoxin (100 nM; approximately 20 times its binding Kd) only reduced the release by 56%. These findings indicate that chemoreceptor cells, and perhaps other carotid body structures, contain nicotinic receptors that are not sensitive to alpha-bungarotoxin and force a revision of the current concepts on cholinergic mechanisms in the carotid body chemoreception.     

Genetic risk of neuropsychological impairment in schizophrenia: a study of monozygotic twins discordant and concordant for the disorder

We investigated the effect of the adenosine receptor agonist 5'-(N-ethylcarboxamido)adenosine (NECA) in catecholamine secretion from adrenal chromaffin cells that exhibit only the A2b subtype adenosine receptor. NECA reduced catecholamine release evoked by the nicotinic agonist 1,1-dimethyl-4-phenylpiperazinium (DMPP) in a time-dependent manner. Inhibition reached 25% after 30-40-min exposure to NECA. This effect on DMPP-evoked catecholamine secretion was mirrored by a similar (27.7 +/- 3.3%), slowly developing inhibition of [Ca2+]i transients induced by DMPP that peaked at 30-min preincubation with NECA. The capacity of the chromaffin cells to buffer Ca2+ load was not affected by the treatment with NECA. Short-term treatment with NECA failed both to modify [Ca2+]i levels and to increase endogenous diacylglycerol production, showing that NECA does not activate the intracellular Ca2+/protein kinase C signaling pathway. The inhibitory effects of NECA were accompanied by a 30% increase of protein phosphatase activity in chromaffin cell cytosol. We suggest that dephosphorylation of a protein involved in DMPP-evoked Ca2+ influx pathway (e.g., L-type Ca2+ channels) could be the mechanism of the inhibitory action of adenosine receptor stimulation on catecholamine secretion from adrenal chromaffin cells.     

Cardiovascular and sympathetic effects of proadrenomedullin NH2-terminal 20 peptide in conscious rats

Proadrenomedullin NH2-terminal 20 peptide (PAMP) and adrenomedullin (AM), which are derived from the same gene, are novel vasodilative peptides and have been shown to exhibit hypotensive action in anesthetized animals. To avoid the modification via anesthesia, we investigated the effects of intravenously administered PAMP on mean arterial pressure, heart rate (HR), and renal sympathetic nerve activity (RSNA) relative to those of AM in conscious unrestrained rats. We also examined whether the arterial baroreceptor reflex was altered with the two peptides. Intravenous injection of rat PAMP (rPAMP) (10, 20 and 50 nmol/kg) and rat AM (rAM) (0.3, 1.0 and 3.0 nmol/kg) similarly elicited dose-related hypotension accompanied by increases in HR and RSNA. However, the responses to rPAMP were less potent in magnitude and shorter in duration than those to rAM. Moreover, rAM facilitated baroreflex control, whereas rPAMP attenuated it. These findings indicate that although PAMP, as well as AM, may play an important role as a circulating hormone in the systemic circulation of conscious rats, the two peptides derived from an identical origin might have different mechanisms responsible for their cardiovascular and RSNA actions.     

Proadrenomedullin-derived peptides

Posttranslational processing of the adrenomedullin gene product results in the formation of at least two biologically active peptides, adrenomedullin (AM) and proadrenomedullin N-20 terminal peptide (PAMP). Produced predominantly in the vasculature, both peptides are potent hypotensive agents, albeit via unique mechanisms of action. The gene is transcribed in a variety of other tissues including brain, pituitary, and kidney. Numerous actions have been reported most related to the physiologic control of fluid and electrolyte homeostasis. In the kidney, AM is diuretic and natriuretic, and both AM and PAMP inhibit aldosterone secretion by direct adrenal actions. In pituitary gland, both peptides at physiologically relevant doses inhibit basal ACTH secretion, again by apparently differing mechanisms. Additionally, AM antagonizes CRH-stimulated ACTH release. The peptides are produced in numerous brain sites, including hypothalamus and brainstem. Inhibition of AVP release has been reported and the physiologic significance of AM's ability to inhibit water drinking and salt appetite has been established. Thus the peptides appear to act in brain and pituitary gland to facilitate the loss of plasma volume, actions which complement their hypotensive effects in the blood vessel. Interestingly, direct cardiac effects (positive inotropism and chronotropism) and CNS actions (sympathostimulation) have been reported, leading to the hypothesis that these peptides also can exert important cardioprotective effects, helping to prevent vascular collapse during states of high AM secretion such as sepsis.     

High degree of occult tumor contamination in bone marrow and peripheral blood stem cells of patients undergoing autologous transplantation for non-Hodgkin''s lymphoma

Treatment of cultured bovine adrenal chromaffin cells with dbcAMP increased [3H]STX binding with an EC50 of 126 microM and a half-effective time of 12 h; dbcAMP (1 mM x 18 h) raised the Bmax approximately 1.5-fold without altering the Kd value. Forskolin (0.1 mM) or IBMX (0.3 mM) also increased [3H]STX binding, while dbcGMP had no effect. Effects of dbcAMP and forskolin were abolished by H-89, an inhibitor of cAMP-dependent protein kinase. Cycloheximide (10 microgram/ml) and actinomycin D (10 microgram/ml), inhibitors of protein synthesis, nullified the stimulatory effect of dbcAMP, whereas tunicamycin, an inhibitor of protein glycosylation, had no effect. Treatment with dbcAMP augmented veratridine-induced 22Na influx, 45Ca influx via voltage-dependent Ca channels and catecholamine secretion, while the same treatment did not alter 45Ca influx and catecholamine secretion caused by high K (a direct activation of voltage-dependent Ca channels) [25]. Na influx via single Na channel calculated from 22Na influx and [3H]STX binding was quantitatively similar between non-treated and dbcAMP-treated cells. Brevetoxin allosterically enhanced veratridine-induced 22Na influx approximately 3-fold in dbcAMP-treated cells as in non-treated cells. These results suggest that cAMP-dependent protein kinase is involved in the modulation of Na channel expression in adrenal medulla.     

Use-dependent suppression of the nicotinic acetylcholine receptor response by the proadrenomedullin N-terminal 20-amino acid peptide in rat locus coeruleus neurons

The effects of the proadrenomedullin N-terminal 20-amino acid peptide (PAMP) on the nicotinic acetylcholine (ACh) receptor (nAChR)-mediated inward current were investigated in neurons acutely dissociated from the rat locus coeruleus using whole-cell recording under voltage clamp. Nicotine and cytidine mimicked the ACh response, whereas the maximal response to dimethylphenylpiperazinium was lower in amplitude compared with that to ACh. Nicotine-induced current (I[nic]) was suppressed more effectively by mecamylamine than by hexamethonium. In addition, neither atropine nor alpha-bungarotoxin affected the I(nic). PAMP reversibly and noncompetitively suppressed the peak amplitude of 10(-4) M I(nic). PAMP concentrations for the threshold, half-maximal inhibition, and maximal inhibition of 10(-4) M I(nic) were 10(-8), 2.6 x 10(-7), and 10(-5) M, respectively. The peak amplitudes of 10(-4) M I(nic) elicited at 2-min intervals showed a gradual decline in the presence of 10(-7) M PAMP. This decline in the I(nic) was independent of the period of PAMP pretreatment. The suppression of I(nic) by PAMP did not show any voltage dependency at a holding potential (VH) of <0 mV, although the inhibitory effect was masked by the marked inward rectification of I(nic) at a VH of >0 mV. These results suggest that PAMP could thus be a unique endogenous peptide that antagonizes the nAChR in the CNS.     

Potentiation of histamine-induced catecholamine secretion by ouabain in cultured bovine adrenal chromaffin cells is dependent on calcium and sodium influx

The effects of histamine on catecholamine secretion from cultured bovine adrenal chromaffin cells were studied in the presence of ouabain, an inhibitor of Na+-K+ ATPase. The purpose of this study was to determine whether Na+, as well as Ca2+, was involved in histamine receptor-mediated catecholamine secretion. Histamine (10(-8)-10(-5) M)-induced catecholamine secretion was markedly potentiated by addition of ouabain (10(-5) M) and was inhibited by a histamine-H1 receptor antagonist or incubation in a Ca2+-free medium. Histamine-induced 45Ca2+ influx was also potentiated by addition of ouabain. Ouabain alone or in the presence of histamine increased 22Na+ influx into the cells. In an additional set of experiments, cells were preincubated in the presence or absence of Na+ for 30 min (+/- histamine and ouabain), washed and then catecholamine secretion was measured following exposure to 2.2 mM Ca2+ for 15 min. Preincubation with histamine alone with or without Na+ had no effect of Ca2+-induced secretion of catecholamine. Preincubation with ouabain alone or with ouabain plus histamine produced a slight stimulation of catecholamine secretion in Na+-free medium and a large stimulation in Na+-containing medium. These results suggested that stimulation of the histamine-H1 receptor and inhibition of the Na+ pump both increase intracellular Na+ levels, resulting in increases in Ca2+ influx and catecholamine secretion.     

Catecholamine concentrations in rat nasal mucus are modulated by trigeminal stimulation of the nasal cavity

Olfactory mucus provides the perireceptor environment in which the initial steps of olfactory signal transduction occur [5]. Extrinsic autonomic and trigeminal innervation controls mucus secretion and may release neurotransmitters into nasal mucus [13]. We quantitated catecholamines in rat nasal mucus and found that catecholamine levels first increased and then declined with trigeminal stimulation. These data indicate that catecholamine levels are regulated in nasal mucus and could modulate the odor sensitivity of olfactory sensory neurons.     

Derivatives of 2-mercaptobenzenesulphonamide. XVIII. Syntheses and cardiovascular effects of some S- and S,N-substituted 4-chloro-2-mercapto-5-methyl-N-(5-amino-1,2,4-triazol-3-yl) benzenesulphonamide derivatives

The effect of peptide YY on contractility, acetylcholine release and noradrenaline release was examined in the isolated guinea-pig colon, and findings were compared with those for neuropeptide Y. Peptide YY and neuropeptide Y inhibited the twitch contractions mediated by the stimulation of cholinergic neurons. Peptide YY, neuropeptide Y, [Leu31,Pro34]neuropeptide Y and neuropeptide Y-(13-36) inhibited the electrically stimulated release of acetylcholine. Neuropeptide Y, but not peptide YY, inhibited the high K(+)-stimulated tetrodotoxin-resistant release of acetylcholine, while the inhibitory effect of neuropeptide Y disappeared after treatment with yohimbine. Neuropeptide Y, but not peptide YY or neuropeptide Y analogues, evoked the release of noradrenaline. After desensitization to the effects of neuropeptide Y, peptide YY inhibited electrically stimulated acetylcholine release. Thus, peptide YY inhibits acetylcholine release through stimulation of a receptor, distinct from the site of action of neuropeptide Y, located on cholinergic neurons as well as the neuropeptide Y Y1 and Y2 receptors in the guinea-pig colon. Neuropeptide Y inhibits acetylcholine release due to the noradrenaline release mediated by stimulation of a receptor distinct from neuropeptide Y Y1 and Y2 receptors, located on adrenergic neurons.     

Protein phosphorylation at a postreceptor site can block desensitization and induce potentiation of secretion in chromaffin cells

Desensitization or habituation to repeated or prolonged stimulation is a common property of secretory cells. Phosphorylation of receptors mediates some desensitization processes, but the relationship of phosphorylation to desensitization at postreceptor sites is not well understood. We have tested the effect of protein phosphorylation on desensitization in bovine chromaffin cells. To increase protein phosphorylation, we have used the protein phosphatase inhibitor okadaic acid at 12.5 nM, 100 microM 8-bromo-cyclic AMP to activate protein kinase A, and 10 nM phorbol 12,13-dibutyrate to activate protein kinase C. During repeated 6-s stimulation at 5-min intervals, catecholamine secretion from control cells decreases. Cells exposed to 8-bromo-cyclic AMP or okadaic acid alone show slightly decreased rates of desensitization. In cells pretreated with phorbol 12,13-dibutyrate, desensitization is blocked. Okadaic acid-treated cells stimulated in the presence of 8-bromo-cyclic AMP show potentiation of secretion with repeated stimulation. The protein kinase inhibitor 1-(5-isoquinolinylsulfonyl)-2-methylpiperazine (H7) increases the desensitization rate. Because these phenomena are observed during secretion evoked with elevated K+ as well as by a nicotinic agonist, the effect of phosphorylation is at a postreceptor site. In contrast to desensitization to the repeated stimulations, desensitization to prolonged stimulation with high K+ is not altered by the above protocols in chromaffin cells.     

Potentiation by ouabain of catecholamine secretion from bovine adrenal chromaffin cells in culture induced by pituitary adenylate cyclase-activating polypeptide: evidence for involvements of Na+ and Ca2+ movements

The effect of pituitary adenylate cyclase-activating polypeptide (PACAP) on catecholamine secretion with ouabain, an inhibitor of Na(+)-K+ ATPase, in cultured bovine adrenal chromaffin cells was examined, to determine whether movement of Na+, as well as Ca2+, is involved in the secretory process. PACAP (10(-10)-10(-6)M)-induced catecholamine secretion was markedly potentiated by addition of ouabain (10(-5)M). When cultured cells were preincubated with PACAP for 30 min in Ca(2+)-free medium in the presence of ouabain and then stimulated for 15 min with Ca(2+)-containing medium without PACAP or ouabain, their catecholamine secretion was dependent on the external Ca2+ concentration, and 45Ca2+ influx into the cells was increased. When the cells had been preincubated with PACAP and ouabain in Na(+)-free sucrose medium, their Ca(2+)-induced catecholamine secretion was greatly reduced. PACAP increased 22Na+ influx into cells treated with ouabain. These results suggest that stimulation by PACAP and inhibition of the Na(+)-pump both increase the intracellular Na+ level, resulting in increase in Ca2+ influx and catecholamine secretion.     

The relationship between apolipoprotein E, dementia, and vascular illness

In an effort to determine mechanisms of action of the putative anti-addictive agent ibogaine, we have measured its effects on catecholamine release in a model neuronal system, cultured bovine chromaffin cells. Various modes of stimulating catecholamine release were used including nicotinic ACh receptor activation, membrane depolarization with elevated K+ and Na+ channel activation with veratridine. In addition, because ibogaine has been reported to interact with kappa opioid receptors, we tested whether kappa receptor antagonists could reverse ibogaine's effects on catecholamine release. Ibogaine, at low concentration (<10 microM) was found to selectively inhibit nicotinic receptor-mediated catecholamine release, while having no significant effect on release evoked by either veratridine or membrane depolarization with elevated K+. The inhibitory actions of ibogaine and the kappa agonists were not reversed by preincubation with the opioid antagonists nor-binaltorphimine or naltrexone, suggesting that these inhibitory effects are not mediated by the kappa opioid receptor. The effects of low dose (10 microM) ibogaine were rapidly reversible, while the inhibitory effects of higher ibogaine doses persisted for at least 19 h following ibogaine washout. The results provide evidence for a mechanism of action ibogaine at the nicotinic ACh receptor. The results are consistent with a model in which the initial high transient brain concentrations (100 microM) of ibogaine act at multiple cellular sites and then have a selective action at the nicotinic ACh receptor cation channel following its metabolism to lower brain concentrations. The present findings are relevant to potential anti-addictive actions of ibogaine and to the development of drugs to combat nicotine addiction.     

Mechanism of cardiovascular actions of the chromogranin A fragment catestatin in vivo

Catestatin (bovine chromogranin A(344-364); RSMRLSFRARGYGFRGPGLQL), reduces catecholamine secretion from chromaffin cells in vitro. We investigated the effects of this peptide on catecholamine release and blood pressure in vivo. Intravenous catestatin reduced pressor responses to activation of sympathetic outflow by electrical stimulation in rats, and the catestatin effect persisted even after adrenergic (alpha plus beta) blockade. Catestatin did not alter plasma norepinephrine levels, but increased plasma epinephrine 11-fold. Catestatin also blunted pressor responses to exogenous neuropeptide Y agonists. A control peptide (chromogranin A(141-160)) did not alter pressor or catecholamine responses to electrical stimulation. Pretreatment with a histamine H1 receptor antagonist blocked both the vasodepressor response to catestatin and the elevation in plasma epinephrine. Catestatin elevated endogenous circulating histamine 21-fold, and exogenous histamine mimicked both the epinephrine elevation and the vasodepressor actions of catestatin. We conclude that catestatin is a potent vasodilator in vivo whose actions appear to be mediated, at least in part, by histamine release and action at H1 receptors.