Biomedical subjects

G de Nucci

Publications and source records attributed to G de Nucci.

At least 55 records · Page 3Linked to original sources

PubMed1996

Bioequivalence study of two enalapril maleate tablet formulations in healthy male volunteers. Pharmacokinetic versus pharmacodynamic approach.

OBJECTIVE: Two different conventional release enalapril maleate tablet formulations were evaluated for their relative bioavailability (Eupressin tablets 10 mg, Biosintética as the test formulation vs Renitec tablets 10 mg Merck Sharp & Dhome, as the reference formulation). A single 20 mg oral dose of each preparation was administered to 18 healthy male adult volunteers and their bioequivalence was assessed by comparing the serum enalaprilat and total enalapril (enalaprilat plus enalapril maleate) concentration-time curves. Angiotensin converting enzyme (ACE) activity was also quantified in each serum sample. RESULTS: The pharmacokinetic parameters obtained for each formation were the area under the time-concentration curve from 0 to 24 h (AUC[0-24]), maximum concentration Cmax and the time at which it occurred (tmax). When serum enalaprilat concentration-time curves were employed to assess bioequivalence, the formulations were bioequivalent in the extent but not in the rate of absorption. However, no difference in either the extent or the rate of absorption were observed when serum total enalapril vs time curves were analysed. ACE activity-time curves were similar for both formulations and showed that ACE was 90% inhibited for 3-5 h after enalapril administration, and till approximately 50% after 24 h. At that time, circulating enalaprilat and total enalapril levels were less than the tenth of Cmax. CONCLUSION: The results show that complete bioequivalence of the two formulations can be concluded from serum total enalapril concentration data, and that serum ACE activity is not a suitable pharmacodynamic variable for assessing bioequivalence.

Adult↗

PubMed1996

Pharmacological characterization of novel tissue kallikrein inhibitors in vivo.

In this study we have investigated the effect of novel tissue kallikreins on the plasma protein exudation induced by porcine pancreatic kallikrein (PPK) in the rabbit skin in vivo. The tissue kallikrein inhibitors here described were synthesized based on analogues of peptide substrates for tissue kallikreins. The intradermal injection of PPK and rabbit urinary kallikrein, but not of rabbit plasma kallikrein, significantly increased the microvascular permeability leading to local oedema formation in the rabbit skin. At the dose of 3-200 nmol/site, the intradermal co-administration of the tissue kallikrein inhibitors Bz-F-F-S-R-EDDnp (Ki = 0.1 microM; ESP5), PAC-F-S-R-EDDnp (Ki = 0.7 microM; ESP6), Bz-F-F-A-P-R-NH2 (Ki = 7.8 microM; ESP8), PAC-F-F-R-P-R-NH2 (Ki = 0.3 microM; ESP9) and Bz-F-F-S-R-NH2 (Ki = 0.3 microM; ESP11) dose-dependently inhibited the plasma protein exudation induced by PPK. The most potent compound was ESP6 (IC25 = 7.8 nmol/site) followed by ESP5 (IC25 = 14.2 nmol/site), ESP8 (IC25 = 25 nmol/site), ESP9 (IC25 = 30 nmol/site) and ESP11 (IC25 = 50.4 nmol/site). The compounds Bz-F-F-R-P-R-NH2 (Ki = 0.5 microM; ESP1), Bz-F-F-pNa (Ki = 0.4 microM; ESP3), Bz-F(NH2)-F-R-P-R-NH2 (Ki = 1.1 microM; ESP7) and Bz-F-F-S-P-R-NH2 (Ki = 4.6 microM; ESP10) had no significant effect on the PPK-induced plasma protein exudation in doses up to 200 nmol/site. ESP6 also inhibited the PPK-induced plasma protein exudation when administered systemically. This compound may constitute a useful tool to further investigate both the physiological and pathological role of tissue kallikreins.

Animals↗

PubMed1996

Involvement of nitric oxide in the smooth muscle tone of the isolated canine spleen and the responses to acetylcholine and substance P.

1. The canine isolated spleen was perfused at constant flow with warmed (37 degrees C) Krebs solution while the splenic arterial perfusion pressure (SAPP) and spleen weight were recorded continuously. An augmented smooth muscle tone was maintained by a continuous intra-arterial infusion of noradrenaline (0.01-0.1 mumol min-1) throughout the experiment. 2. Intra-arterial infusion of indomethacin (5.6 microM) significantly elevated (P < 0.05) the augmented vascular tone and the subsequent infusion of L-NAME (10 microM) further raised this vascular tone significantly (P < 0.01). 3. The splenic vasoconstrictor response to L-NAME was significantly (P < 0.05) reduced by the subsequent infusion of L-arginine (300 microM) but not of D-arginine (300 microM). 4. Neither L-NAME nor D-NAME had any effect on the basal vascular tone or the spleen weight in conditions of either basal or augmented tone. 5. Bolus injection of acetylcholine, substance P, sodium nitroprusside and isoprenaline caused short-lasting reductions in the SAPP. 6. The splenic vasodilator responses to ACh and SP, but not those to SNP and ISO, were significantly (P < 0.05) reduced by the infusion of L-NAME (10 microM), methylene blue (30 microM) but not of D-NAME (10 microM). 7. The reductions in the vasodilator responses to ACh and SP caused by L-NAME were partially reversed by L-arginine (300 microM), but not by D-arginine (300 microM). 8. The results demonstrate the contribution of nitric oxide (NO) release to the maintenance of the augmented splenic vascular tone and also the contribution of NO to the splenic vasodilator responses to ACh and SP.

Acetylcholine↗

PubMed1996

The effect of a tachykinin NK1 receptor antagonist, SR140333, on oedema formation induced in rat skin by venom from the Phoneutria nigriventer spider.

1. The possibility that tachykinin NK1 receptors are involved in the plasma extravasation evoked by intradermal (i.d.) injection of Phoneutria nigriventer venom (PNV) in rat dorsal skin in vivo has been investigated. 2. Local oedema formation induced by the i.d. injection of test agents was measured by the extravascular accumulation of intravenously (i.v.) injected 125I-labelled human serum albumin over a 30 min period. 3. The tachykinin NK1 agonist, GR73632 (30 pmol per site), induced local oedema formation which was potentiated by co-injection with the neuropeptide vasodilator, calcitonin gene-related peptide (CGRP, 10 pmol per site). The non-peptide tachykinin NK1 receptor antagonist, SR140333 (0.03-1 nmol per site co-injected, i.d.) significantly inhibited (0.3 nmol per site, P < 0.05; 1 nmol per site, P < 0.001) local oedema formation induced by GR73632 with CGRP but not that induced by histamine (10 nmol per site) with CGRP. 4. PNV (0.03-0.3 microgram per site) injected i.d. induced dose-dependent local oedema formation. SR140333 (1 nmol per site, co-injected i.d.) inhibited oedema formation; with complete inhibition observed at doses of 0.03 microgram (P < 0.05) and 0.1 microgram (P < 0.001); and partial inhibition (50%) observed with the highest dose of PNV, 0.3 microgram (P < 0.05). 5. Local oedema formation induced by PNV was not affected by systemic pretreatment with the bradykinin B2 receptor antagonist, Hoe 140 (80 nmol kg-1, i.v.), which was used at a dose which significantly inhibited oedema formation by bradykinin (1 nmol per site). 6. Local oedema formation induced by PNV was significantly inhibited (P < 0.01) by co-injection of the histamine H1 receptor antagonist, mepyramine (2.5 nmol per site), together with the 5-hydroxytryptamine (5-HT) antagonist, methysergide (2.8 nmol per site). 7. In the presence of all three antagonists (mepyramine 2.5 nmol per site; methysergide, 2.8 nmol per site and SR140333 1 nmol per site), the plasma extravasation induced by PNV was further significantly inhibited (P < 0.001, when compared with PNV injected i.d. alone; P < 0.05 when compared with PNV co-injected with mepyramine and methysergide and P < 0.01, when compared with PNV co-injected with SR140333). 8. These results suggest that oedema formation evoked by i.d. PNV in rat skin may be partially mediated via a mechanism involving tachykinin NK1 receptors and that this effect is independent of histamine and 5-HT.

Animals↗

PubMed1996

Role of chondroitin 4-sulphate as a receptor for polycation induced human platelet aggregation.

1. Proteoglycans provide negatively charged sites on the surface of platelets, leukocytes and endothelial cells. Since chondroitin 4-sulphate is the main proteoglycan present on the platelet surface, the role of this molecule in mediating the activation of human platelets by polylysine was studied. 2. Platelets were desensitized with phorbol 12-myristate 13-acetate (PMA, 10 nM) 5 min before the addition of polylysine to platelet-rich plasma (PRP). Changes in the intracellular Ca2+ concentration were measured in fura2-am (2 microM) loaded platelets and protein phosphorylation was assessed by autoradiography of the electrophoretic profile obtained from [32P]-phosphate labelled platelets. The release of dense granule contents was measured in [14C]-5-hydroxytryptamine loaded platelets and the synthesis of thromboxane (TXA2) was assessed by radioimmunoassay. Surface chondroitin 4-sulphate proteoglycan was degraded by incubating platelets with different concentrations of chondroitinase AC (3 min, 37 degrees C). The amount of chondroitin 4-sulphate remaining in the platelets was then quantified after proteolysis and agarose gel electrophoresis. 3. The addition of PMA to PRP before polylysine inhibited the aggregation by 88 +/- 18% (n = 3). Staurosporine (1 microM, 5 min) prevented the PMA-induced inhibition. Chondroitinase AC (4 pu ml-1 to 400 muu ml-1, 3 min) abolished the polylysine-induced aggregation in PRP but caused only a discrete inhibition of ADP-induced aggregation. The concentration of chrondroitin 4-sulphate in PRP (0.96 +/- 0.2 microgram/10(8) platelets, n = 3) and in washed platelets (WP; 0.35 +/- 0.1 microgram/10(8) platelets, n = 3) was significantly reduced following incubation with chondroitinase AC (PRP = 0.63 +/- 0.1 microgram/10(8) platelets and WP = 0.08 +/- 0.06 microgram/10(8) platelets). 4. Washed platelets had a significantly lower concentration of chondroitin 4-sulphate than platelets in PRP. The addition of polylysine to WP induced a rapid increase in light transmission which was not accompanied by TXA2 synthesis or the release of dense granule contents. This effect was not inhibited by sodium nitroprusside (SNP), iloprost, EDTA or the peptide RGDS. This event was accompanied by the discrete phosphorylation of plekstrin and myosin light chain, which were inhibited by staurosporine (10 microM, 10 min). The hydrolysis of platelet surface chondroitin 4-sulphate strongly reduced the polylysine-induced phosphorylation. 5. Our results indicate that polylysine activates platelets through a specific receptor which could be the proteoglycan chondroitin 4-sulphate present on the platelet membrane.

Blood Platelets↗

PubMed1996

Renal effects of acute and chronic nitric oxide inhibition in experimental diabetes.

We investigated whether nitric oxide (NO) contributes to glomerular hyperfiltration in experimental diabetes. Thirty-five adult male Munich-Wistar streptozocin-diabetic rats and 39 nondiabetic controls were distributed among 4 groups: C, normal control; C + L-NAME, controls receiving the NO inhibitor N omega-nitro-L-arginine methyl ester (L-NAME), 40 mg/dl in drinking water; DM, diabetic rats; DM + L-NAME, diabetic rats receiving L-NAME, 15 mg/dl in drinking water. After 1 month of treatment, the DM + L-NAME group exhibited renal vasoconstriction and lacked hyperfiltration. Acute administration of L-NAME, 2.5 mg/kg, depressed the glomerular filtration rate and promoted renal vasoconstriction to a much greater extent in the DM than in the C group. Acute administration of endothelin 1 (600 ng/kg, bolus) or angiotensin II (25 micrograms/kg/min, continuous infusion) exerted similar hemodynamic effects in the C and DM groups, suggesting that the enhanced response of DM to L-NAME reflected specific sensitivity to NO inhibition. Urinary excretion of nitrites and nitrates was fourfold higher in DM compared to C. These results support the notion that augmented NO production may contribute to renal hyperfiltration and hyperperfusion in diabetes.

Angiotensin II↗

PubMed1995

Dissimilarity between prostaglandin E1 and nitric oxide donors as potentiators of plasma exudation in the rabbit skin in vivo.

The ability of prostaglandin E1 (PGE1) and nitric oxide (NO) donor compounds such as sodium nitroprusside (SNP), glyceryl trinitrate (GTN), and 3-morpholino-sydnonimine (SIN-1) to modulate the histamine- and bradykinin-induced increase in microvascular permeability have been investigated in rabbit skin. The effect of the NO synthesis inhibitor N omega-nitro-L-arginine methyl ester (L-NAME) on the plasma exudation induced by histamine and bradykinin was also studied. Local edema formation was evaluated using [125I]human serum albumin. New Zealand white rabbits received an intravenous injection of [125I]human albumin followed immediately by the intradermal injection of edematogenic agents into the shaved dorsolateral skin. PGE1 (0.1 nmol/site) significantly potentiated both histamine- and bradykinin-induced edema. In contrast, SNP (0.4-400 nmol/site), SIN-1 (0.4-400 nmol/site), and GTN (0.4-40 nmol/site) did not affect the edematogenic response induced by either histamine or bradykinin. GTN (0.4-40 nmol/site) also had no effect on the increase in plasma exudation induced by histamine and bradykinin in the presence of PGE1. L-NAME (50-400 nmol/site, but not its enantiomer D-NAME, dose-dependently reduced the edema formation induced by a combination of either histamine or bradykinin with PGE1. This inhibition was significantly reversed by SNP (4-400 nmol/site) and by high doses (2.5 mumol/site) of L-arginine (but not by D-arginine). Our results thus demonstrate that PGE1, but not nitrovasodilators, can actually potentiate histamine- and bradykinin-induced edema in rabbit skin.(ABSTRACT TRUNCATED AT 250 WORDS)

Alprostadil↗

PubMed1995

Inhibition of carrageenin-induced rat paw oedema by crotapotin, a polypeptide complexed with phospholipase A2.

1. The effect of purified crotapotin, a non-toxic non-enzymatic chaperon protein normally complexed to a phospholipase A2 (PLA2) in South America rattlesnake venom, was studied in the acute inflammatory response induced by carrageenin (1 mg/paw), compound 48/80 (3 micrograms/paw) and 5-hydroxytryptamine (5-HT) (3 micrograms/paw) in the rat hind-paw. The effects of crotapotin on platelet aggregation, mast cell degranulation and eicosanoid release from guinea-pig isolated lung were also investigated. 2. Subplantar co-injection of crotapotin (1 and 10 micrograms/paw) with carrageenin or injection of crotapotin (10 micrograms/paw) into the contralateral paw significantly inhibited the carrageenin-induced oedema. This inhibition was also observed when crotapotin (10-30 micrograms/paw) was administered either intraperitoneally or orally. Subplantar injection of heated crotapotin (15 min at 60 degrees C) failed to inhibit carrageenin-induced oedema. Subplantar injection of crotapotin (10 micrograms/paw) also significantly inhibited the rat paw oedema induced by compound 48/80, but it did not affect 5-HT-induced oedema. 3. In adrenalectomized animals, subplantar injection of crotapotin markedly inhibited the oedema induced by carrageenin. The inhibitory effect of crotapotin was also observed in rats depleted of histamine and 5-HT stores. 4. Crotapotin (30 micrograms/paw) had no effect on either the histamine release induced by compound 48/80 in vitro or on the platelet aggregation induced by both arachidonic acid (1 nM) and platelet activating factor (1 microM) in human platelet-rich plasma. The platelet aggregation and thromboxane B2 (TXB2) release induced by thrombin (100 mu ml-1) in washed human platelets were also not affected by crotapotin. In addition, crotapotin (10 microg/paw) did not affect the release of 6-oxo-prostaglandin Fla, and TXB2 induced by ovalbumin in sensitized guinea-pig isolated lungs.5. Our results indicate that the anti-inflammatory activity of crotapotin is not due to endogenous corticosteroid release or inhibition of cyclo-oxygenase activity. It is possible that crotapotin may interact with extracellular PLA2 generated during the inflammatory process thereby reducing its hydrolytic activity.

6-Ketoprostaglandin F1 alpha↗

PubMed1995

Comparative bioavailability of single doses of tablet formulations of cetirizine dihydrochloride in healthy male volunteers.

The bioavailability of two tablet formulations of cetirizine (Zetir from Abbott and Zyrtek from UCB) were compared in 14 healthy male volunteers who received a single dose of 10 mg of cetirizine dihydrochloride in an open randomized two-period crossover design with a 7-day washout period between doses. Plasma samples were obtained over a 24 h interval and cetirizine concentrations were determined by HPLC with ultraviolet detection. From the plasma cetirizine concentration vs. time curves, AUC(0-24) (area under the concentration vs. time curves from 0 to 24 h), Cmax (maximum achieved concentration), Tmax (time to achieve Cmax), Ke (terminal first order elimination constant), elimination half-life (t1/2) and AUC(0-infinity) (area under the concentration vs. time curves extrapolated to infinity) were obtained. The two cetirizine dihydrochloride tablet brands did not show statistically significant differences in bioavailability as assessed by analysis of AUC(0-24), AUC(0-infinity), Cmax, Tmax, Ke and t1/2 values. Based on these results and on the U.S. Food and Drug Administration requirements [1985, 1993], we conclude that both formulations are bioequivalent.

Adult↗

PubMed1995

Role of endothelin ETA and ETB receptors in the arterial vasculature of the isolated canine liver.

The vascular effects of endothelin-1 (ET-1; ETA/ETB agonist), sarafotoxin 6b (S6b; ETA agonist), and IRL 1620 (ETB agonist) were investigated in the isolated canine liver arterial circuit before and after infusions of indomethacin (cyclo-oxygenase inhibitor) and N omega L-nitro arginine methyl ester (L-NAME; nitric oxide synthesis inhibitor). Norepinephrine (NE) was used as vasconstrictor control agent. The portal vein, hepatic artery, and vena cava were cannulated in vitro and the liver was perfused via the hepatic artery and portal vein with oxygenated (95%) O2/5% CO2) Krebs solution at 37 degrees C. Intra-arterial bolus injections of either ET-1 (0.4-400 pmol) or S6b (0.4-400 pmol) induced dose-dependent and long-lasting vasoconstriction accompanied by significant prostacyclin release. The vasoconstrictor responses to these peptides were slightly increased during infusion of indomethacin. Subsequent infusion of L-NAME potentiated both ET-1- and S6b-induced vasoconstriction (p < 0.05). IRL 1620 (up to 1.2 nmol) had no effect on the hepatic arterial vascular resistance even during indomethacin and L-NAME infusions. Infusion of the ETA receptor antagonist FR-139317 (0.3 microM) markedly reduced both ET-1- and S6b-induced vasoconstriction without affecting that evoked by NE. Our results indicate that pressor responses to ET-1 and S6b in the isolated canine liver are modulated by concomitant release of vasodilator mediators, including prostacyclin and nitric oxide. These effects appear to depend primarily on the activation of ETA receptor subtypes. IRL 1620 (but not ET-1) induced a significant release of hemoglobin into the venous effluent, suggesting that ETB receptors are located in the venous side of the intrahepatic circulation.

Animals↗

PubMed1994

Crotoxin induces aggregation of human washed platelets.

Crotoxin, the main toxic component isolated from the venom of the South American rattlesnake Crotalus durissus terrificus, is a reversible protein complex composed of a non-toxic non-enzymatic acidic polypeptide (crotapotin) and a toxic basic phospholipase A2 (PLA2). In this study, we have evaluated the ability of crotoxin to induced aggregation in human washed platelets. Human washed platelet aggregation was monitored in a Payton aggregometer and thromboxane B2 (TXB2) release measured by direct radioimmunoassay (RIA). Crotoxin (15-50 micrograms/ml) produced dose-dependent and irreversible human washed platelet aggregation, which was inhibited by pre-incubation of the platelets with sodium nitroprusside (50-500 microM) or iloprost (8-80 nM). Crotoxin also induced TXB2 release (207 +/- 8 ng/ml, n = 6), and although indomethacin significantly reduced the release of TXB2 (to 23.5 +/- 5 ng/ml, P < 0.001, n = 6), it did not inhibit crotoxin-induced aggregation. Our results clearly demonstrate that crotoxin induces human washed platelet aggregation and that this phenomenon is independent of the formation of pro-aggregatory arachidonic acid metabolites.

Amino Acid Sequence↗

PubMed1994

The effects and molar potency of iloprost, U46619 and sodium nitroprusside on capsular and vascular smooth muscle of the isolated perfused canine spleen.

The isolated canine spleen was perfused at constant flow with continuous recording of splenic arterial perfusion pressure (SAPP) and spleen weight. Intra-arterial injections of the thromboxane A2 (TXA2) mimetic U46619 caused dose-related increases in splenic arterial perfusion pressure (SAPP) of short duration (ED50 0.31 nmol). There were very small changes in spleen weight accompanying any of the vasoconstrictor responses to U46619. The stable analogue of prostacyclin, iloprost, caused dose-dependent reductions in SAPP (ED50 1.3 nmol) indicating vasodilation. There were no changes in spleen weight to any doses of iloprost indicating a lack of action on capsular smooth muscle. Similarly, the nitric oxide (NO) mimetic sodium nitroprusside caused dose-related reductions in SAPP of short duration (ED50 5.8 nmol). No changes in spleen weight accompanied splenic vasodilator responses to any dose of sodium nitroprusside (SNP). The results indicate the potential actions and intrinsic potency of three endogenous vasoactive substances and provide information about their relative roles in the control of the splenic microcirculation in situations when they are released.

15-Hydroxy-11 alpha,9 alpha-(epoxymethano)prosta-5↗

PubMed1994

Pharmacological characterization of rabbit corpus cavernosum relaxation mediated by the tissue kallikrein-kinin system.

1. The roles of the tissue kallikrein-kinin system and nitric oxide (NO) release in Phoneutria nigriventer venom-induced relaxations of rabbit corpus cavernosum (RbCC) smooth muscle have been investigated by use of a bioassay cascade. 2. Phoneutria nigriventer venom (10-30 micrograms), porcine pancreatic kallikrein (100 mu), rabbit urinary kallikrein (10 mu), bradykinin (BK, 0.3-3 nmol), acetylcholine (ACh, 0.3-30 nmol) and glyceryl trinitrate (GTN, 0.5-10 nmol) caused relaxations of the RbCC strips. Captopril (1 microM) substantially potentiated Phoneutria nigriventer venom- and BK-induced RbCC relaxations without affecting those elicited by GTN. 3. The bradykinin B2 receptor antagonist, Hoe 140 (D-Arg-[Hyp3,Thi5,D- Tic7,Oic8]-BK, 50 nM), aprotinin (10 micrograms ml-1) and the tissue kallikrein inhibitor, Pro-Phe-Aph-Ser-Val- Gln-NH2 (KIZD-06, 1.3 microM) significantly inhibited Phoneutria nigriventer venom-induced RbCC relaxations, without affecting those provoked by GTN and ACh. The B1 receptor antagonist, [Leu9]des Arg10BK (0.5 microM) and soybean trypsin inhibitor (SBTI, 10 micrograms ml-1) had no effect on Phoneutria nigriventer venom-induced RbCC relaxations. 4. The relaxations induced by Phoneutria nigriventer venom, porcine pancreas kallikrein, BK and ACh were significantly inhibited by N omega-nitro-L-arginine methyl ester (L-NAME, 10 microM) but not by D-NAME (10 microM). L-NAME did not affect GTN-induced relaxations. L-Arginine (300 microM), but not D-arginine (300 microM), significantly reversed the inhibitory effect of L-NAME. 5. Our results indicate that Phoneutria nigriventer venom activates the tissue kallikrein-kininogen-kinin system in RbCC strips leading to NO release and suggest a functional role for this system in penile erection.

Adrenergic beta-Antagonists↗

PubMed1994

Modulation by endogenous prostanoids of the vasoconstrictor activity of endothelin-1 in the canine isolated, perfused spleen.

1. Endothelin-1 (ET-1, 0.4-200 pmol) was injected into the arterial circuit of the isolated perfused spleen of the dog in which splenic arterial perfusion pressure and spleen weight were recorded continuously. 2. Serial collection was made of splenic venous effluent before and after intra-arterial injection of ET-1 and assayed by direct radioimmunoassay for prostaglandin E2 (PGE2), 6-oxo-PGF1 alpha and thromboxane B2 (TXB2). 3. ET-1 caused graded arterial vasoconstriction of prolonged duration with small reductions in spleen weight at higher doses. 4. ET-1 cause a dose-related release of PGE2, 6-oxo-PGF1 alpha and TXB2 into the splenic venous effluent. The mean peak increase above the basal levels following 200 pmol of ET-1 was 800% for PGE2, 233% for 6-oxo-PGF1 alpha and 205% for TXB2. 5. Intra-arterial infusion of indomethacin significantly reduced the basal release of all three eicosanoids and significantly elevated the basal splenic vascular resistance. The release of all three eicosanoids in response to ET-1 and adrenaline (Ad) was significantly reduced by indomethacin and the accompanying increases in the splenic arterial vascular resistance were significantly potentiated at low doses of ET-1. The splenic arterial vascular responses to Ad were unchanged by indomethacin infusion. 6. These results indicate that the release of eicosanoids may modulate the splenic vascular responses to ET-1.

Animals↗

PubMed1994

Sodium excess aggravates hypertension and renal parenchymal injury in rats with chronic NO inhibition.

Chronic nitric oxide (NO) inhibition promotes hypertension and ischemic glomerular injury with only minor glomerulosclerosis (GS). We evaluated the effect of superimposed salt overload, which has been shown to aggravate GS in other models. Fifteen days of treatment with the NO inhibitor N omega-nitro-L-arginine methyl ester (L-NAME) promoted marked arterial and glomerular hypertension, hyporeninemia, and slight renal interstitial expansion, but no glomerular injury. Salt overload slightly exacerbated systemic and glomerular hypertension, promoted albuminuria, interstitial expansion, and glomerular ischemia, and paradoxically reversed hyporeninemia. The angiotensin II inhibitor losartan attenuated glomerular and systemic hypertension and prevented renal injury in these rats. Thirty days of treatment with L-NAME resulted in marked hypertension, hyperreninemia, interstitial expansion, and glomerular ischemia. Concomitant salt overload exacerbated hypertension, interstitial expansion, and ischemia and promoted massive albuminuria, GS, and creatinine retention. Losartan attenuated these effects. Sodium overload aggravates the renal and systemic consequences of chronic NO inhibition by mechanisms that may include paradoxical activation of renin secretion. Interstitial expansion and glomerular ischemia, rather than GS, constitute the chief modalities of renal injury in this model.

Animals↗

PubMed1994

The kinetics of chondroitin 4-sulfate release from stimulated platelets and its relation to thromboxane A2 formation and granule secretion.

1. In platelet rich plasma (PRP), chondroitin 4-sulfate release from platelets occurred after stimulation with ADP (5 microM), collagen (5-10 micrograms/ml), or adrenaline (10 microM). Release started within 60 s and maximum release (0.7-2.0 mg/l) was reached within 180 s. TXA2 formation and dense granule release reached a maximum within 90 s after stimulation. 2. Using washed platelets (1.5 x 10(8) cells/ml), the platelet responses were faster. Release of chondroitin 4-sulfate and TXA2 started within 20-30 s after thrombin addition (100 mU/ml). Maximum release was reached within 60 s in both cases. Dense granule release started in the first 5 s of stimulation (34.6 +/- 12.4%) reaching maximum secretion (74.4 +/- 8.7%) within 60 s. 3. Our results demonstrate that maximal chondroitin 4-sulfate release occurs after the dense granule release reaction in both PRP and washed platelets. This observation suggests that chondroitin 4-sulfate is unlikely to be stored in the dense granules but may be stored in the alpha-granules.

Adenosine Diphosphate↗

PubMed1994

Comparative bioavailability of two suspension formulations of potassium diclofenac in healthy male volunteers.

The bioavailability of two suspension formulations of potassium diclofenac (Flogan, Merck and Cataflam, Ciba-Geigy) were compared in eighteen healthy male volunteers who received a single dose of 7 ml of each suspension (equivalent to 105 mg of potassium diclofenac) in an open randomized two period crossover design, with a fourteen-day washout period between doses. Serum samples were obtained over a 24 hour interval and diclofenac concentrations were determined by HPLC with ultraviolet detection. From the serum diclofenac concentration vs time curves, AUC[0-24] (area under the concentration vs time curves from 0-24 h), Cmax (maximum achieved concentration), Tmax (time to achieve Cmax) and Ke (terminal first order elimination constant) were obtained. Overlapping of Tmax intervals for both formulations was observed, but the important inter-subject variation observed in Cmax ratios did not allow equivalence conclusion for the rate of absorption. Equivalence in the extent of bioavailability between both potassium diclofenac suspension brands was concluded from the analysis of AUC[0-24] ratios.

Adult↗

PubMed1993

Identification of a new vascular smooth muscle contracting polypeptide in Phoneutria nigriventer spider venom.

The fractionation of Phoneutria nigriventer spider venom by gel filtration (Sephadex G-10-120) followed by ion-exchange chromatography (microgranular CM-cellulose-52) resulted in sixteen fractions (CI to CXVI) from which CVII+VIII, CIX and CX+XI caused dose-dependent and short-lived contractions of both arterial and venous rabbit vessels. Fraction CX+XI was further purified by a reverse phase HPLC, and a contractile polypeptide (PNV2) was isolated. The amino terminal sequence of PNV2 (LAKRADICQPGKTSQRACET) indicated that it represents a pure polypeptide consisting of a single chain. Furthermore, the amino acid analysis of PNV2 revealed the presence of four disulfide bridges, a high content in Lys (14%), Glx (11%), and the absence of His. The global amino acid composition showed that this polypeptide is composed of 102 residues (Trp not included) with a calculated molecular weight of 12,114. Whether this peptide is responsible for the vascular alterations observed in Phoneutria envenomation, such as lung edema and priapism, remains to be further investigated.

Amino Acid Sequence↗