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Neuropeptide Y (NPY) is a 36-amino-acid polypeptide which coexists with catecholamines in many adrenergic and noradrenergic neurons. It has been demonstrated to exert pressor effects in the perfused guinea pig heart and to constrict large cerebral and coronary blood vessels in animal studies. To determine if NPY might be a human coronary vasoconstrictor, the authors studied its effect on postmortem human coronary arteries. Proximal epicardial coronary rings were studied in a superfusion apparatus in Krebs-Ringer bicarbonate buffer (37 degrees C, pH 7.4) presaturated with 95% O2-5% CO2. Concentration-response curves were obtained using NPY in 0.1% bovine serum albumin in buffer and the responses were compared to those obtained in the presence of alpha 1, beta, and cyclooxygenase antagonists. A dose-related constrictor effect was obtained with NPY, which was significantly more potent than noradrenaline, constriction often being seen at 10(-12) M concentration. A vasorelaxant effect was seen in nonatherosclerotic vessels at higher concentrations. The vasoconstriction produced by noradrenaline was potentiated by subthreshold concentrations of NPY. The vasoconstrictor effect of NPY was not inhibited by prazosin (10(-6) M), and the vasodilatory effect was not inhibited by propranolol (10(-5) M). Indomethacin (3 X 10(-6) M) did not alter either vasoconstriction or vasorelaxation. The authors conclude that NPY is a potent constrictor of the human coronary artery at concentrations that may be achievable in vivo; it may thus be a contributor to sympathetic enhancement of coronary artery tone.
Serotonin (5HT) stimulates phosphoinositide turnover in a number of tissues, but it is not known whether this effect is due to activation of a 5HT receptor which is coupled to phosphoinositide hydrolysis or if the effect is secondary to 5HT stimulated arachidonate metabolism or to the release of another neurotransmitter. In the present study we show that neither indomethacin nor BW 755C inhibits 5HT stimulated phosphoinositide hydrolysis in rat cerebral cortex, suggesting that neither cyclooxygenase nor lipoxygenase activity is required for the response to 5HT. Proteinase inhibitors do not potentiate the response to 5HT, suggesting that 5HT's effect is not due to stimulation of release of a peptide neurotransmitter. Tetrodotoxin does not inhibit the effect of 5HT and 5HT's effect is additive with that of KCl and veratrine. These data suggest that 5HT stimulated phosphoinositide hydrolysis is not dependent upon release of another neurotransmitter.
Leucine (LEU) kinetics were assessed using a primed-continuous infusion of L-[1-14C]LEU in normal overnight-fasted male volunteers during a basal period and an experimental period where insulin (INS) was infused at either 0.6, 1.2, 2.5, 5.0, 10, or 20 mU.kg-1.min-1 with euglycemia maintained. Two protocols were used: 1) subjects were allowed to develop hypoaminoacidemia or 2) plasma essential amino acids (AA) were maintained near basal levels by frequently monitoring plasma LEU in conjunction with variable infusions of an AA solution (LEU infused = 0.41, 0.72, 0.93, 1.03, 1.31, and 1.35 mumol.kg-1.min-1 at escalating INS doses, respectively). Basal rates of LEU appearance (Ra), nonoxidative disappearance (NORd) and oxidative disappearance (OXRd) were similar in both protocols (means = 1.74, 1.40, and 0.36 mumol.kg-1.min-1, respectively). INS infusions without AA resulted in a progressive decrement in LEU Ra (14 to 45%), NORd (16-41%), and OXRd (3-56%) compared with basal values. The infusion of AA resulted in an additional reduction in endogenous Ra (P less than 0.01; approximately 100% suppression achieved at plasma INS greater than 1,000 microU/ml) and a blunting of NORd reduction (P less than 0.05) at each dose of INS. Observed differences in INS's suppression of LEU Ra between the two protocols suggests the existence of a component of whole body proteolysis that is highly dependent on circulating plasma AA. Therefore, hypoaminoacidemia associated with INS treatment would appear to blunt the responsiveness of INS's suppression of protein breakdown and in the presence of near basal plasma AA, proteolytic suppression by INS is enhanced.
Adenosine is a potent inhibitor of renin release. It has therefore been suggested that endogenous adenosine may play a role in the regulation of renin release. Sodium-chloride transport at the level of the macula densa has been proposed as the primary source of endogenous adenosine. Evidence to support a modulatory role of adenosine on renin release in vivo is, however, limited. We therefore wanted to determine if: 1) adenosine modulates furosemide-induced renin release and 2) sodium-chloride reabsorption at the macula densa is essential for adenosine actions. To test these hypotheses, three groups of rats were pretreated either with saline or the adenosine receptor antagonists caffeine or 1,3-dipropyl-8-(p-sulfophenyl)xanthine (both at a dose of 30 mg/kg followed by 450 micrograms/kg/min). Rats then received furosemide (50 mg/kg i.v.). In the vehicle group, furosemide increased urinary volume, sodium and potassium excretion and increased plasma renin activity from 6 +/- 1 to 45 +/- 11 ngAl/ml/hr. Caffeine and 1,3-dipropyl-8-(p-sulfophenyl)xanthine potentiated the increase in plasma renin activity produced by furosemide (to 120 +/- 15 and 147 +/- 21 ng Al/ml/hr, respectively), whereas having no significant effects on urinary volume, sodium excretion or blood pressure. These results suggest that furosemide-induced renin release in vivo is restrained by endogenous adenosine. In as much as furosemide blocks sodium-chloride transport in the thick ascending limb of Henle's loop and the macula densa cells, it appears that under the conditions of this study sodium transport across these segments is not essential to initiate adenosine-mediated mechanisms.
In the rat and dog, exogenous adenosine inhibits renin release and adenosine receptor blockade augments stimulated renin release, suggesting that endogenous adenosine contributes to the regulation of renin release. The present study examines the role of endogenous adenosine in the regulation of renin in humans. The ability of the adenosine receptor blocker, caffeine, to augment renin release in response to the vasodilator, diazoxide, has been investigated in eight normal subjects in a double-blind, placebo-controlled, cross-over study. During each arm of the study, subjects on a 150 mEq of sodium, xanthine-free diet received caffeine (250 mg 3 times daily) or placebo for 3 days before and on the study day, when they were given an i.v. loading dose of diazoxide (4 mg/kg) followed by a 3-hr continuous infusion (0.67 mg/kg/hour). PRA, caffeine and diazoxide levels were measured before, during and after the diazoxide infusion. PRA measurements were repeated with subjects standing, 6 hr after starting diazoxide. Administration of diazoxide resulted in a modest tachycardia and a small, but significant, decrease in BP. Supine PRA was elevated during and after the diazoxide infusion and rose further with standing. Although there was no difference in plasma diazoxide levels, maximal pulse or BP response to diazoxide between the two arms of the study, the renin response was significantly greater in the presence of caffeine. These data confirm that caffeine augments the PRA response to diazoxide and suggest that endogenous adenosine inhibits stimulated renin response in humans.
Nitroglycerin potently dilates large coronary arteries but has minimal effect on coronary resistance vessels. Thus, nitroglycerin is not likely to be converted to vasoactive intermediates in small coronary microvessels (less than 100 microns diameter). Because nitroglycerin biotransformation may involve sulfhydryl groups, the effect of L-cysteine on the dilation caused by nitroglycerin (1 nM to 10 microM) was examined in small (80-100 microns in diameter) and large (190-300 microns in diameter) porcine coronary microvessels. Vessels were pressurized in a no-flow state and preconstricted with acetylcholine, then visualized by means of an in vitro microvessel imaging apparatus. Under control conditions, nitroglycerin caused potent dilations of large coronary microvessels, while having minimal effects on small coronary microvessels [peak relaxations 90 +/- 3 vs. 20 +/- 7% (mean +/- S.E.M.) of preconstricted diameter, respectively]. L-Cysteine (100 microM) markedly enhanced relaxations of small coronary microvessels (peak relaxation 96 +/- 2%), while having no effect on relaxations of large coronary microvessels. Ethacrynic acid, which alkylates sulfhydryl groups, markedly inhibited relaxations of large coronary microvessels (peak relaxation = 31 +/- 9%) yet had a minimal effect on the small relaxations of small coronary microvessels to nitroglycerin. Thus, when sulfhydryl groups are made available, small coronary microvessels are markedly responsive to nitroglycerin. This suggests that small coronary microvessels normally lack the reductive capacity to convert nitroglycerin to its active metabolites. Prussian blue stains of sulfhydryl groups in large and small coronary microvessels were qualitatively similar. Thus, small coronary microvessels do not lack sulfhydryl groups but may be deficient in a critical pool necessary for nitroglycerin biotransformation.
Vasoactive intestinal polypeptide (VIP) is a gut neuroendocrine polypeptide that increases cyclic adenosine monophosphate (cAMP) production in cells with VIP receptors. Some gastrointestinal cancer cells possess functional receptors for VIP; however, the role of VIP in regulation of growth of gastric cancer cells has not been determined. The purpose of this study was to determine whether VIP and other agents that increase cAMP regulate growth of a human gastric cancer cell line (AGS) and whether these agents regulate expression of c-myc proto-oncogene, which is required for cell proliferation. We measured levels of cAMP by radioimmunoassay, and we used Northern blot analysis to examine c-myc messenger RNA expression. Cell-growth studies were carried out in media supplemented with 3% serum, and cells were counted with a Coulter counter. We found that VIP significantly increased cAMP production of AGS cells in a dose-dependent manner, whereas secretin, glucagon, and peptide histidine methionine (PHM) did not stimulate cAMP production. Exogenous cAMP (8-bromo-cAMP) inhibited AGS cell growth in a dose-dependent manner. VIP acted synergistically with either isobutylmethyl-xanthine or forskolin to inhibit AGS cell proliferation. The increased c-myc expression, which was induced by serum, was inhibited by simultaneous treatment with VIP and isobutylmethyl-xanthine. We have found that AGS cells have specific, functional VIP receptors (activation of which are negatively correlated with cell growth) and that the mechanism by which VIP acts to inhibit cell growth appears to be due, in part, to cAMP-dependent regulation of c-myc proto-oncogene expression.
About 50% of Helicobacter pylori isolates produce a vacuolating toxin in vitro, which may be an important determinant of virulence. Because ammonium salts potentiate H. pylori toxin activity, the effect of other weak bases upon toxin activity was determined. Vacuolation of HeLa cells was quantitated using a neutral red uptake assay. As expected, ammonium chloride, trimethylamine, triethanolamine, and nicotine each induced vacuolation of HeLa cells when tested independently. In addition, each of these weak bases potentiated H. pylori vacuolating toxin activity, whereas sodium chloride or sodium hydroxide did not. Sequential incubation of cells with toxin followed by nicotine resulted in potentiation of vacuolation, whereas sequential incubation in the reverse order did not lead to potentiation. Monensin inhibited the formation of vacuoles by either H. pylori vacuolating toxin or nicotine. The potentiation of H. pylori toxin activity by ammonia and nicotine may contribute to gastroduodenal mucosal injury associated with this infection.