Involvement of kinins, mast cells and sensory neurons in the plasma exudation and paw oedema induced by staphylococcal enterotoxin B in the mouse

FAPESP - FUNDAÇÃO DE AMPARO À PESQUISA DO ESTADO DE SÃO PAULOIntraplantar injection of staphylococcal enterotoxin B induces long-lasting oedema mediated by both cyclooxygenase and lipoxygenase products as well as by neuropeptides from sensory nerves. This study was undertaken to further clarify the role of peripheral primary afferent sensory nerves in staphylococcal enterotoxin B (25 mu g/paw)-induced plasma extravasation and oedema formation. The tachykinin NK2 receptor antagonist (S)-1-[2-[3-(3,4-dichlorophenyl)-1 (3-isopropoxyphenylacetyl)piperidin-3-y] ethyl]4-phenyl-1 azoniabicyclo [2.2.2]octane cloride (SR140333; 120 nmol/kg, s.c. + 120 nmol/kg, i.v.) significantly inhibited plasma exudation and paw oedema evoked by staphylococcal enterotoxin B. The tachykinin NK, receptor antagonist (S)-N-methyl-N[4-(4-acetylamino-4-phenyl piperidino)-2-(3,4-dichlorophenyl)butyl] (SR48968) had no effect on the staphylococcal enterotoxin B-induced responses. The bradykinin B-2 receptor antagonist D-Arg-[Hyp(3),Thi(5),D-TiC7,OiC(8)]bradykinin (Hoe 140; 400 nmol/kg, i.v.) significantly reduced staphylococcal enterotoxin B-induced responses. The magnitude of the inhibition observed with Hoe 140 alone was similar to that caused by concomitant treatment of animals with SR140333 and Hoe 140, suggesting that there is a final common pathway. Additionally, SR140333 given alone reduced bradykinin (3 nmol/paw)-induced paw oedema. The vanilloid receptor antagonist N-[2-(4-chlorophenyl) ethyl]-1,3,4,5-tetrahydro-7,8-dihydroxy-2H-2-benzazepine-2-carbothioamide (capsazepine; 100 mu mol/kg) significantly reduced staphylococcal enterotoxin B-induced responses. The 5-HT receptor antagonist methysergide (10 mg/kg, i.v.) and the histamine H-1 receptor antagonist mepyramine (10 mg/kg, i.v.) produced a significant reduction in paw oedema whereas plasma exudation was reduced only by methysergide. In diabetic mice, exudation and oedema evoked by staphylococcal enterotoxin B were markedly reduced. Acute administration of insulin (20 UI/kg, s.c., 30 min before) did not restore the increased permeability induced by staphylococcal enterotoxin B. We conclude that plasma exudation and paw oedema in response to staphylococcal enterotoxin B are a consequence of a complex neurogenic response involving direct activation of vanilloid receptors on sensory nerves, release of kinins and subsequent activation of bradykinin B-2 receptors at a prejunctional level, and direct or indirect degranulation of mast cells3992-3235242FAPESP - FUNDAÇÃO DE AMPARO À PESQUISA DO ESTADO DE SÃO PAULOFAPESP - FUNDAÇÃO DE AMPARO À PESQUISA DO ESTADO DE SÃO PAULOsem informaçã

Phoneutria nigriventer spider venom induces oedema in rat skin by activation of capsaicin sensitive sensory nerves

FAPESP - FUNDAÇÃO DE AMPARO À PESQUISA DO ESTADO DE SÃO PAULOPhoneeutria nigriventer venom induces oedema formation when injected in the rat dorsal skin and such oedema is, in part, dependent on the stimulation of tachykinin NK1 receptors. This study investigated whether Phoneutria nigriventer venom acts directly on tachykinin NK1 receptors, or indirectly to activate sensory neurones which in turn release a tachykinin NK1 receptor agonist. The plasma extravasation induced by Phoneutria nigriventer venom (1-10 mu g/site) in neonatally capsaicin (8-methyl N-vanillyl-6-nonenamide)-pretreated rats was substantially attenuated (P < 0.05) but the response to either the tachykinin NK1 receptor agonist GR73632 ((delta Ava[L-Pro(9), N-MeLeu10] substance P-(7-11) 30 pmol/site) or bradykinin (0.3-3 nmol/site) was not affected. These results indicate that Phoneutria nigriventer venom stimulates sensory nerves indirectly. The lack of effect of capsaicin-pretreatment on the GR73632 and bradykinin responses indicated that the tachykinin NK1 and bradykinin B-2 receptors remained functional. There was no evidence to suggest that Phoneutria nigriventer venom contains a tachykinin NK1 receptor agonist3392-3223226FAPESP - FUNDAÇÃO DE AMPARO À PESQUISA DO ESTADO DE SÃO PAULOFAPESP - FUNDAÇÃO DE AMPARO À PESQUISA DO ESTADO DE SÃO PAULOsem informaçã

Involvement of vanilloid receptors and purinoceptors in the phoneutria nigriventer spider venom-induced plasma extravasation in rat skin

FAPESP - FUNDAÇÃO DE AMPARO À PESQUISA DO ESTADO DE SÃO PAULOPhoneutria nigriventer venom causes stimulation of capsaicin-sensitive primary afferent neurons in the rat dorsal skin, leading to neurogenic plasma protein extravasation due to the release of tachykinin NK1 receptor agonist. In this study we further investigated the mechanisms involved in the venom-induced activation of capsaicin-sensitive primary afferent neurons. The plasma extravasation in response to venom intradermally injected was measured in Wistar rats as the local accumulation of i.v. injected I-125-labelled human serum albumin into skin sites. The tachykinin NK1 receptor agonist, D-Ala-[L-Pro(9),Me-Leu(8)]substance P-(7-11) (GR73632; 10-100 pmol/site), induced a significant plasma leakage that was abolished by the selective tachykinin NK1 receptor antagonist, (S)-1-[2-[3-(3,4-dichlorphenyl)-1 (3-isopropoxyphenylacetyl) piperidin-3-yl] ethyl]-4-phenyl-1 azaniabicyclo [2.2.2]octane chloride (SR140333; 1 nmol/site), whereas the leakage after venom (1-10 mu g/site) was significantly inhibited (but not abolished) by SR140333. The calcitonin gene-related peptide (CGRP) receptor antagonist, CGRP-(8-37), failed to further reduce the residual plasma extravasation induced by venom plus SR140333, The mu-opioid receptor agonist, [D-Ala(2),Me-Phe(4),Gly-ol(5)]enkephalin (DAMGO), and the local anaesthetic, Lignocaine, had no effect on the venom-induced plasma extravasation. Similarly, the L-, N- and P/Q-type voltage-sensitive Ca2+ channel blockers (verapamil, omega-conotoxin MVIIA and MVIIC, respectively) as well as the Na+ channel blockers, tetrodotoxin and carbamazepine, had no effect on the venom-induced effect. Neither the systemic treatment nor the local injection of ruthenium red prevented the venom-induced plasma extravasation. However, the vanilloid receptor antagonist, N-[2-(4-chlorophenyl) ethyl]-1,3,4,5-tetrahydro7,8-dihydroxy-2H-2-benzazepine-2-carbothioamide (capsazepine; 120 mu mol/kg, i.v.), reduced by 48% (P <0.05) the venom (10 mu g/site)-induced plasma extravasation. A significant inhibitory effect was also observed with the P, purinoceptor agonists, adenosine 5'-triphosphate (ATP; 10 and 30 nmol/site) and adenosine 5'-diphosphate (ADP; 10 nmol/site). The involvement of histamine and/or 5-hydroxytryptamine (5-HT) in the venom-induced plasma extravasation was ruled out since neither histamine and 5-HT receptor antagonists nor depletion of mast cells by compound 48/80 affected the venom response. This was further supported by the failure of venom to degranulate in vitro peritoneal mast cells. In conclusion, only vanilloid receptors and P, prejunctional purinoceptors had an inhibitory effect on the neurogenic plasma extravasation evoked by P. nigriventer venom in rat dorsal skin3913305315FAPESP - FUNDAÇÃO DE AMPARO À PESQUISA DO ESTADO DE SÃO PAULOFAPESP - FUNDAÇÃO DE AMPARO À PESQUISA DO ESTADO DE SÃO PAULOsem informaçã

The effect of Phoneutria nigriventer (armed spider) venom on arterial blood pressure of anaesthetised rats

CNPQ – CONSELHO NACIONAL DE DESENVOLVIMENTO CIENTÍFICO E TECNOLÓGICOThe changes induced in the mean arterial blood pressure of anaesthetised rats following the administration of armed spider (Phoneutria nigrinventer) venom have been investigated. The intravenous injection of Phoneuhria nigriventer venom (0.1 mg/kg) evoked a brief and reversible decrease in the mean arterial blood pressure whereas a higher dose of venom (0.3 mg/kg) caused a biphasic response characterized by a short-lasting hypotension followed by a sustained and prolonged hypertension (40-50 min). These changes were accompanied by tachycardia, salivation, fasciculations, defecation and respiratory disturbances. Pretreatment of the animals with atropine (10 mg/kg), propranolol (100 mg/kg), phenoxybenzamine (100 mg/kg) and indomethacin (4 mg/kg) did not significantly affect the mean arterial blood pressure changes induced by Phoneutria nigriventer venom. Similarly, the bradykinin B-2 receptor antagonist Hoe 140 (D-Arg-[Hyp(3),Thi(5),DTic(7),Oic(8)]-bradykinin (0.6 mg/kg), the PAF receptor antagonist WEB 2086 (3-(4-(2-chlorophenyl)-9-methyl-6 H-thieno-(3,2f) (1,2,4)-triazolo-(4,3-a) (1,4)aiazepine-2-yl)-(4-morpholinyl)-1-propanone) (20 mg/kg), the tachykinin NK2 receptor antagonist SR 140333 ((S)1-(2-[3-(3,4-dichlorophenyl)-1-(3-iso-propoxyphenyl acetyl) piperidin-3-yl] ethyl)-4-phenyl-1-azoniabicyclo[2.2.2] octane, chloride) (0.5 mg/kg), the tachykinin NK2 receptor antagonist SR 48968 ((S)-N-methyl-N[4-(4-acetylamino-4-phenylpiperidino)-2-(3,4-d (0.5 mg/kg) and the nitric oxide synthase inhibitor N-omega-nitro-L-arginine methyl ester (10 mg/kg) had no significant effect on the mean arterial blood pressure changes induced by Phoneutria nigriventer venom. The increase in the blood pressure induced by Phoneutria nigriventer venom was also not significantly affected by either the angiotensin II receptor antagonist losartan (10 mg/kg) or the endothelin ET(A) receptor antagonist FR 139317 ((R)2-[(R)-2-[[1(hexahydro-1H-azepinyl]carbonyl]amino-4-methyl-pentanoyl[amino-3-[3-(1-methyl-1H-indoyl)lpropionyl] amino-3-(2-pyridyl) propionic acid) (30 mg/kg). The ATP-dependent K+ channel antagonist glibenclamide (50 mg/kg) reduced by 40% the hypotension induced by Phoneutria nigriventer venom without affecting the hypertensive response. Pretreatment of the animals with L-type Ca2+ channel antagonists such as verapamil (10-100 mu g/kg/min), diltiazem (40-120 mu g/kg/min) and nifedipine (0.3-10 mg/kg) markedly attenuated the hypertension induced by Phoneutria nigriventer venom. Verapamil (30 mu g/kg/min) and diltiazem (120 mu g/kg/min) also promptly reversed the established hypertension induced by Phoneutria nigriventer venom when infused 8 min after venom injection. Our results indicate that the brief decrease of blood pressure induced by Phoneutria nigriventer venom.is partially due to ATP-dependent K+ channel activation. The prolonged hypertension seems to result from direct Ca2+ entry into vascular and/or cardiac muscles2982113120CNPQ – CONSELHO NACIONAL DE DESENVOLVIMENTO CIENTÍFICO E TECNOLÓGICOCNPQ – CONSELHO NACIONAL DE DESENVOLVIMENTO CIENTÍFICO E TECNOLÓGICOsem informaçã

Comparative effect of phoneutria nigriventer spider venom and capsaicin on the rat paw oedema

FAPESP - FUNDAÇÃO DE AMPARO À PESQUISA DO ESTADO DE SÃO PAULOCapsaicin, the pungent component of hot peppers, and the venom of the spider Phoneutria nigriventer are able to activate sensory nerves resulting in cutaneous neurogenic plasma extravasation. This study was undertaken to compare the ability of these substances to evoke oedema in the rat hind-paw and mechanisms underlying this effect. Subplantar injection of either Phoneutria nigriventer venom (PNV; 1-100 mug/paw) or capsaicin (10-200 mug/paw) caused a significant paw oedema that was potentiated by CGRP (10 pmol/paw). In rats treated neonatally with capsaicin to deplete neuropeptides. the paw oedema induced by either PNV (100 mug/paw) or capsaicin (100 mug/paw) was partially reduced (P <0.05). The tachykinin NKI receptor antagonist SR140333 (0.2 mu mol/kg; i.v.) prevented the paw oedema induced by the tachykinin NK1 receptor agonist GR73632 (30 pmol/paw) and partially reduced paw oedema induced by PNV or capsaicin. Treatment of rats with compound 48/80 (5 mg/kg; s.c. 3 days) or with both HI receptor antagonist (mepyramine; 1 nmol/paw) and 5-HT receptor antagonist (methysergide; I nmol/paw) significantly inhibited PNV- or capsaicin-induced paw oedema. The combined treatment with mepyramine and methysergide and SR140333 further reduced PNV- and capsaicin-induced paw oedema. The bradykinin B-2 receptor antagonist Hoe 140 affected neither PNV- nor capsaicin-induced responses. Our results suggest that PNV and capsaicin each induce paw oedema that is partially mediated by activation of sensory fibers culminating in the release of substance P as well as by activation of mast cells which in turn release amines such as histamine and 5-HT691315731585FAPESP - FUNDAÇÃO DE AMPARO À PESQUISA DO ESTADO DE SÃO PAULOFAPESP - FUNDAÇÃO DE AMPARO À PESQUISA DO ESTADO DE SÃO PAULOsem informaçã

Enalapril Does Not Prevent The Myocardial Ischemia Caused By The Chronic Inhibition Of Nitric Oxide Synthesis

In rats, chronic administration of the nitric oxide (NO) inhibitor Nω-nitro-l-arginine methyl ester (L-NAME) causes arterial hypertension, cardiac hypertrophy and myocardial ischemic alterations such as necrosis and fibrosis. In this study, we evaluated the effect of 8 weeks of treatment with enalapril maleate on cardiac weight and on the development of the histological alterations induced by L-NAME. Enalapril significantly inhibited the development of both arterial hypertension (117.2 ± 5.8, 161.8 ± 8.8 and 122.0 ± 10.6 mm Hg, for control, L-NAME- and L-NAME + enalapril-treated animals, respectively) and left ventricular hypertrophy (1.36 ± 0.13, 1.60 ± 0.04 and 1.48 ± 0.05 mg/g, for control, L-NAME- and L-NAME + enalapril-treated animals, respectively), but had no effect on the myocardial lesions. These findings demonstrate that although the renin-angiotensin system plays a major role in the development of arterial hypertension and cardiac hypertrophy, it does not modulate the ischemia-induced myocardial alterations observed in this model. © 1995.28719396Baylis, Mitruka, Deng, Chronic blockade of nitric oxide synthesis in the rat produces systemic hypertension and glomerular damage (1992) J. Clin. Invest., 90, p. 278Brush, Cannon, III, Schenke, Bonow, Leon, Maron, Epstein, Angina due to coronary microvascular disease in hypertensive patients without left ventricular hypertrophy (1988) New Engl. J. Med., 319, p. 1302Buttrick, Malhotra, McDermott, Lam, Brodman, Isomyosin distribution on overloaded human atrial myocardium (1986) J. Am. Coll. Cardiol., 7 (2), p. 86AChilds, Adams, Mak, Regression of cardiac hypertrophy in spontaneously hypertensive rats by enalapril and the expression of contractile proteins (1990) Hypertension, 16, pp. 662-668Dunn, Oigman, Ventura, Messerli, Kobrin, Frohlich, Enalapril improves systemic and renal hemodynamics and allows regression of left ventricular mass in essential hypertension (1984) Am. J. Cardiol., 53, p. 105Factor, Bhan, Minase, Wolinsky, Sonnenblick, Hypertensive-diabetic cardiopathy in the rat (1981) Am. J. Pathol., 102, p. 219Jover, Herizi, Ventre, Dupont, Mimran, Sodium and angiotensin in hypertension induced by long-term nitric oxide blockade (1993) Hypertension, 21, p. 944Lund, Tomanek, Myocardial morphology in spontaneously hypertensive and aortic-constricted rats (1978) Am. J. Anat., 152, p. 141Moore, Al Swayeh, Chong, Evans, Mirzazadeh, Gibson, l-NG-Nitroarginine (NOARG) inhibits endothelium-dependent vasodilatation in the rabbit aorta and perfused rat mesentery (1989) Br. J. Pharmacol., 176, p. 219Moreno, Jr., Metze, Antunes, Zatz, De Nucci, Chronic nitric oxide blockade causes cardiac ischemia but not cardiac hypertrophy: an experiment of four weeks in rats (1994) Verh. Dtsch. Ger. Path., 78, p. 459Nemoto, Matsuoka, Hasegawa, Ueki, Kimura, Kawamura, Masuda, Miura, Effect of enalapril and E4177 on the heart under chronic nitric oxide suppression in in vivo rat model (1994) J. Mol. Cell. Cardiol., 26, p. 228Ribeiro, Antunes, De Nucci, Lovisolo, Zatz, Chronic inhibition of nitric oxide synthesis: a new model of arterial hypertension (1992) Hypertension, 20, p. 298Tan, Jalil, Pick, Janicki, Weber, Cardiac myocyte necrosis induced by angiotensin II (1991) Circ. Res., 69, p. 1185Ueki, Matsuoka, Hasegawa, Nemoto, Kimura, Kawamura, Masuda, Miura, Comparison the effects of long-term nitric oxide suppression on the heart between young and old rats (1994) J. Mol. Cell. Cardiol., 26, p. 228Weber, Brilla, Janicki, Signals for the remodeling of the cardiac interstitium in systemic hypertension (1991) J. Cardiovasc. Pharmacol., 17, p. 14Zatz, A low cost tail-cuff method for the estimation of mean arterial pressure in conscious rats (1990) Lab. Anim. Sci., 40, p. 19

Chronotropic Response Of β-adrenergic-, Muscarinic-, And Calcitonin Gene-related Peptide-receptor Agonists In Right Atria From Neonatal Capsaicin-treated Rats

We evaluated the potency of isoproterenol, carbachol, pilocarpine and calcitonin gene-related peptide (CGRP) in the rat right atria at 30, 60 and 90 days after neonatal capsaicin treatment. Neonatal rats were pretreated on the second day of life with capsaicin (50 mg/kg). The capsaicin pretreatment caused a five-fold rightward shift at the pEC50 level on the concentration-response curves to isoproterenol in 30-day-old rats. Propranolol (10 mg/kg, given 15 min prior to capsaicin treatment) prevented this subsensitivity. No changes in the potency of isoproterenol were observed at 60 and 90 days after capsaicin pretreatment. The potency and maximal responses of CGRP in the right atria in 30-day-old rats were significantly higher than in 60- and 90-day-old rats; however, no differences were found between control and capsaicin groups. The potency and maximal responses to carbachol and pilocarpine were not changed in all groups. The neonatal capsaicin treatment reduced by about 74% the CGRP content in the heart in all groups. In summary, capsaicin treatment in newborn rats produces a desensitization of chronotropic response mediated by β-adrenoceptors in isolated right atria from 30-day-old rats possibly due to a massive release of catecholamines. © 2002 Elsevier Science Ireland Ltd. All rights reserved.3253147150Alving, K., Matran, R., Lundberg, J.M., Capsaicin-induced local effector responses, autonomic reflexes and sensory neuropeptide depletion in the pig (1991) Naunyn-Schmiedeberg's Arch. Pharmacol., 343, pp. 37-45Amerini, S., Rubino, A., Mantelli, L., Ledda, F., α-Adrenoceptor modulation of the efferent function of capsaicin-sensitive sensory neurones in guinea-pig isolated atria (1992) Br. J. Pharmacol., 105, pp. 947-953Armour, J.A., Yuan, B.X., Butler, C.K., Cardiac responses elicited by peptides administered to canine intrinsic cardiac neurons (1990) Peptides, 11, pp. 753-761Bonish, H., Further studies on the extraneuronal uptake and metabolism of isoprenaline in the perfused rat heart (1978) Naunyn-Schmiedeberg's Arch. Pharmacol., 303, pp. 121-131Hoover, D.B., Effects of substance P on rate and perfusion pressure in the isolated guinea pig heart (1989) J. Pharmacol. Exp. Ther., 252, pp. 179-184Jancsó, N., Kiraly, E., Jancsó-Gabor, A., Pharmacologically induced selective degeneration of chemosensitive primary sensory neurons (1977) Nature, 270, pp. 741-743Jancsó, N., Kiraly, E., Joo, F., Such, G., Nagy, A., Selective degeneration by capsaicin of a subpopulation of primary sensory neurons in the adult rat (1985) Neurosci. Lett., 59, pp. 209-214Marfurt, C.F., Ellis, L.C., Jones, M.A., Sensory and sympathetic nerve sprouting in the rat cornea following neonatal administration of capsaicin (1993) Somatosensory Motor Res., 10, pp. 377-398Miyake, H., Inaba, N., Kato, S., Takeuchi, K., Increased susceptibility of rat gastric mucosa to ulcerogenic stimulation with aging. Role of capsaicin-sensitive sensory neurons (1996) Dig. Dis. Sci., 41, pp. 339-345Rubino, A., Burnstock, G., Capsaicin-sensitive sensory-motor nerves in the control of cardiovascular function (1996) Cardiovasc. Res., 31, pp. 467-479Rubino, A., Ralevic, V., Burnstock, G., Sympathetic neurotransmission in isolated rat atria after sensory-motor denervation by neonatal treatment with capsaicin (1997) J. Pharmacol. Exp. Ther., 282, pp. 671-675Seyedi, N., Maruyama, R., Levi, R., Bradykinin activates a cross-signaling pathway between sensory and adrenergic nerve endings in the heart: A novel mechanism of ischemic norepinephrine release? (1999) J. Pharmacol. Exp. Ther., 290, pp. 656-663Simone, D.A., Nolano, M., Johnson, T., Wendelschafer-Crabb, G., Kennedy, W.R., Intradermal injection of capsaicin in humans produces degeneration and subsequent reinnervation of epidermal nerve fibers: Correlation with sensory function (1998) J. Neurosci., 18, pp. 8947-8959Stiles, G.L., Caron, M.G., Lefkowitz, R.J., Beta-adrenergic receptors: Biochemical mechanisms of physiological regulation (1984) Physiol. Rev., 64, pp. 661-743Szallasi, A., Blumberg, P.M., Vanilloid (capsaicin) receptors and mechanisms (1999) Pharmacol. Rev., 51, pp. 159-211Zanesco, A., Costa, S.K.P., Riado, S.R., Nathan, L.P., Oliveira, C.F., De Luca, I.M.S., Antunes, E., De Nucci, G., Modulation of coronary flow and cardiomyocytes size by sensory fibers (1999) Hypertension, 34, pp. 790-79

Non-specific inhibitors of nitric oxide synthase cause myocardial necrosis in the rat

FAPESP - FUNDAÇÃO DE AMPARO À PESQUISA DO ESTADO DE SÃO PAULOCNPQ – CONSELHO NACIONAL DE DESENVOLVIMENTO CIENTÍFICO E TECNOLÓGICOTo study the effect of acute nitric oxide (NO) inhibition on the rat heart both in vitro and in vivo, male Wistar rats received a single bolus injection of saline, N-omega-nitro-L-arginine methyl ester (L-NAME; 0.5, 1.5, 5.0, 15.0 and 45.0 mg/kg) and D-NAME (45.0 mg/kg). 2. Animals were killed 72 h after the bolus injection of L-NAME and the hearts were removed and studied under light microscopy. In other groups of animals, saline, L-NAME and D-NAME were administered as above and the mean arterial blood pressure (MABP/carotid) was recorded, Furthermore, L-NAME was also administered in the drinking water (20 mg/kg per day) for 72 h and animals were then killed and their hearts evaluated as described above, Hearts of control animals were perfused in vitro and coronary flow was measured following saline, L-NAME (45 mu g/heart) and D-NAME (45 mu g/heart). 3. Areas of necrosis were observed in the left ventricle of animals that had received L-NAME at 5.0, 15.0 and 45.0 mg/kg, Also, only doses higher than 1.5 mg/kg caused an important increase in MABP. The frequency and extent of the lesions paralleled the dose of L-NAME administered and no lesions were observed in D-NAME- and saline-treated animals. 4. The oral administration of L-NAME also caused myocardial lesions similar to those described above, but the frequency and extent of these lesions were more discrete compared with those observed following 5.0 mg/kg, i.v., L-NAME. 5. Bolus injection of L-NAME into control rat hearts in vitro resulted in a small and transient fall in coronary flow (17.2 +/- 1.4 and 12.2 +/- 1.2 mL/min before and after L-NAME administration, respectively) within 30 s and this was followed 4.5 min later by a further (11.5 +/- 1.6 mL/min) decrease. The administration of D-NAME to control hearts caused no change in coronary flow. 6. In conclusion, the acute inhibition of NO biosynthesis by L-NAME causes myocardial necrosis, Both high levels of MABP and a small but significant reduction in coronary flow (associated or not) can be responsible for the lesions we found245349352FAPESP - FUNDAÇÃO DE AMPARO À PESQUISA DO ESTADO DE SÃO PAULOCNPQ – CONSELHO NACIONAL DE DESENVOLVIMENTO CIENTÍFICO E TECNOLÓGICOFAPESP - FUNDAÇÃO DE AMPARO À PESQUISA DO ESTADO DE SÃO PAULOCNPQ – CONSELHO NACIONAL DE DESENVOLVIMENTO CIENTÍFICO E TECNOLÓGICOsem informaçãosem informaçã