Rodrigo José Bezerra de Siqueira

1-Nitro-2-phenylethane, the main constituent of the essential oil of Aniba canelilla, elicits a vago-vagal bradycardiac and depressor reflex in normotensive rats

Previously, it was shown that intravenous (i.v.) treatment with the essential oil of Aniba canelilla (EOAC) elicited a hypotensive response that is due to active vascular relaxation rather than to the withdrawal of sympathetic tone. The present study investigated mechanisms underlying the cardiovascular responses to 1-nitro-2-phenylethane, the main constituent of the EOAC. In pentobarbital-anesthetized normotensive rats, 1-nitro-2-phenylethane (1-10mg/kg, i.v.) elicited dose-dependent hypotensive and bradycardiac effects which were characterized in two periods (phases 1 and 2). The first rapid component (phase 1) evoked by 1-nitro-2-phenylethane (10mg/kg) was fully abolished by bilateral vagotomy, perineural treatment of both cervical vagus nerves with capsaicin (250 microg/ml) and was absent after left ventricle injection. However, pretreatment with capsazepine (1mg/kg, i.v.) or ondansetron (30 microg/kg, i.v.) did not alter phase 1 of the cardiovascular responses to 1-nitro-2-phenylethane (10mg/kg, i.v.). In conscious rats, 1-nitro-2-phenylethane (1-10mg/kg, i.v.) evoked rapid hypotensive and bradycardiac (phase 1) effects that were fully abolished by methylatropine (1mg/kg, i.v.). It is concluded that 1-nitro-2-phenylethane induces a vago-vagal bradycardiac and depressor reflex (phase 1) that apparently results from the stimulation of vagal pulmonary rather than cardiac C-fiber afferents. The transduction mechanism of the 1-nitro-2-phenylethane excitation of C-fiber endings is not fully understood and does not appear to involve activation of either Vanilloid TPRV(1) or 5-HT(3) receptors. The phase 2 hypotensive response to 1-nitro-2-phenylethane seems to result, at least in part, from a direct vasodilatory effect since 1-nitro-2-phenylethane (1-300 microg/ml) induced a concentration-dependent reduction of phenylephrine-induced contraction in rat endothelium-containing aorta preparations.

Vasorelaxant effects of 1-nitro-2-phenylethane, the main constituent of the essential oil of Aniba canelilla, in superior mesenteric arteries from spontaneously hypertensive rats.

The present study investigated the mechanisms underlying the vasorelaxant effects of the essential oil of Aniba canelilla (EOAC) and its main constituent 1-nitro-2-phenylethane (NP) in isolated superior mesenteric artery from spontaneously hypertensive rats (SHRs). At 0.1-1000 μg/mL, EOAC and NP relaxed SMA preparations pre-contracted with 75 mMKCl with IC(50) (geometric mean [95% confidence interval]) values of 294.19 [158.20-94.64] and 501.27 [378.60-624.00] μg/mL, respectively); or with phenylephrine (PHE) (IC(50)s=11.07 [6.40-15.68] and 7.91 [4.08-11.74) μg/mL, respectively). All these effects were reversible and remained unaltered by vascular endothelium removal. In preparations maintained under Ca(2+)-free conditions, EOAC and NP (both at 600 μg/mL) reduced the PHE-, but not the caffeine-induced contraction. In Ca(2+)-free and high K(+) (75 mM) medium, the contractions produced by CaCl(2) or BaCl(2) were reduced or even abolished by EOAC and NP at 100 and 600 μg/mL, respectively. EOAC and NP (both at 10-1000 μg/mL) also relaxed the contraction evoked by phorbol dibutyrate (IC(50)=52.66 [10.82-94.64] and 39.13 [31.55-46.72] μg/mL, respectively). It is concluded that NP has a myogenic endothelium-independent vasorelaxant effects and appears to be the active principle of the EOAC. Vasorelaxant effect induced by both EOAC and NP is preferential to receptor-activated pathways and it appears to occur intracellularly more than a superficial action restricted to the membrane environment such as a simple blocking activity on a given receptor or ion channel.

Cardiovascular effects of 1-nitro-2-phenylethane, the main constituent of the essential oil of Aniba canelilla, in spontaneously hypertensive rats.

This study investigated the cardiovascular responses to the essential oil of Aniba canelilla (EOAC) and its main constituent 1‐nitro‐2‐phenylethane (NP) in spontaneously hypertensive rats (SHRs). In anesthetized SHRs, intravenous (i.v.) bolus injections of EOAC (1–20 mg/kg) or NP (1–10 mg/kg) elicited dose‐dependent hypotensive and bradycardiac effects, which were characterized in two periods (phases 1 and 2). The first rapid component (phase 1) evoked by EOAC and NP both at 10 mg/kg was absent after left ventricle injection, fully abolished by bilateral vagotomy and perineural treatment of both cervical vagus nerves with capsaicin (250 μg/mL) while remained unaltered by i.v. pretreatment with capsazepine (1 mg/kg) or ondansetron (30 μg/kg). In conscious SHRs, NP (5 and 10 mg/kg, i.v.) evoked rapid hypotensive and bradycardiac effects (phase 1) that were fully abolished by methylatropine (1 mg/kg, i.v.) pretreatment. In rat endothelium‐containing mesenteric preparations, increasing concentrations (0.1–1000 μg/mL) of EOAC and NP relaxed the phenylephrine‐induced contraction in a concentration‐dependent manner. It is concluded that NP induces a vago‐vagal bradycardiac and depressor reflex (phase 1) that apparently results from the stimulation of vagal pulmonary rather than cardiac C‐fiber afferents. This effect does not appear to involve activation of either vanilloid TPRV1 or 5‐HT3 receptors located on vagal sensory nerves. The phase 2 hypotensive response to i.v. NP seems to result, at least in part, from its direct vasodilatory effect on the peripheral smooth muscle. All in vivo and in vitro effects of EOAC are mostly attributed to the actions of its main constituent NP.

Linalool-rich rosewood oil induces vago-vagal bradycardic and depressor reflex in rats.

Cardiovascular effects of the linalool‐rich essential oil of Aniba rosaeodora (here named as EOAR) in normotensive rats were investigated. In anesthetized rats, intravenous (i.v.) injection of EOAR induced dose‐dependent biphasic hypotension and bradycardia. Emphasis was given to the first phase (phase 1) of the cardiovascular effects, which is rapid (onset time of 1–3 s) and not observed in animals submitted to bilateral vagotomy or selective blockade of neural conduction of vagal C‐fibre afferents by perineural treatment with capsaicin. Phase 1 was also absent when EOAR was directly injected into the left ventricle injection, but it was unaltered by i.v. pretreatment with capsazepine, ondansetron or HC030031. In conscious rats, EOAR induced rapid and monophasic hypotensive and bradycardiac (phase 1) effects that were abolished by i.v. methylatropine. In endothelium‐intact aortic rings, EOAR fully relaxed phenylephrine‐induced contractions in a concentration‐dependent manner. The present findings reveal that phase 1 of the bradycardiac and depressor responses induced by EOAR has a vago‐vagal reflex origin resulting from the vagal pulmonary afferents stimulation. Such phenomenon appears not to involve the recruitment of C‐fibre afferents expressing 5HT3 receptors or the two chemosensory ion channels TRPV1 and TRPA1. Phase 2 hypotensive response appears resulting from a direct vasodilatory action. Copyright

Inhibitory effects of sertraline in rat isolated perfused kidneys and in isolated ring preparations of rat arteries.

Objectives  Sertraline is often prescribed to patients suffering with end stage renal disease, but its action on kidney has not been investigated. We aimed to investigate the pharmacological action of sertraline on rat kidney with emphasis on the underlying mechanisms involved in the vascular actions of the drug.

Reações adversas causadas por fármacos que atuam no sistema nervoso: análise de registros de um centro de farmacovigilância do Brasil

BACKGROUND: The morbi-mortality by the use of medicines is a major health problem. The drug adverse reactions may result in death, increased hospitalizations and healthcare costs. OBJECTIVES: Describe and analyze reports of suspected adverse reactions caused by drugs that act on the nervous system (SN-ADR), registered in the database of the Pharmacovigilance Centre of Ceara, from January 1997 to March 2008. METHODS: All the NS-ADRs were classified according to criteria of the World Health Organization. The causality between the drug administered and the adverse reaction was established, as well as the analysis regarding to the severity of the reaction. RESULTS: The Centre recorded 176 notifications of RAM-SN. The most of the reactions occurred in the hospital. The main reporter was the pharmacist. All the RAM-SN were classified as possible (n = 110), probable (n = 37) and definite (n = 17). With regard to severity, the NS-ADRs were considered: light (n = 21), moderate (n = 127), serious (n = 15) and fatal (n = 1). The fatal case was reported by physician, and involved anesthetic drugs. In general the adverse reactions observed were caused predominantly by analgesics, anesthetics and antiepileptics. DISCUSSION: The data demonstrate the potential values of accessing to a local system of pharmacovigilance to report possible risks with the use of nervous system drugs.CONTEXTO: A morbimortalidade por uso de medicamentos e um grande problema de saude. As reacoes adversas a medicamentos podem resultar em obito, aumento de internacoes hospitalares e dos custos com a saude. OBJETIVOS: Descrever e analisar as notificacoes de suspeitas de reacoes adversas causadas por medicamentos que atuam no sistema nervoso (RAM-SN), registradas no Centro de Farmacovigilância do Ceara, de janeiro de 1997 a marco de 2008. METODOS: As RAM-SN foram classificadas segundo os criterios da Organizacao Mundial da Saude. Uma relacao de causalidade entre o farmaco administrado e a reacao adversa identificada foi realizada, bem como a analise da reacao quanto a gravidade. RESULTADOS: Foram registradas 176 notificacoes de RAM-SN. A maioria (n = 145; 82,4%) ocorreu no ambiente hospitalar. O principal notificador foi o farmaceutico. As RAM-SN foram classificadas como: possiveis (n = 110), provaveis (n = 37) e definidas (n = 17). Quanto a gravidade, foram consideradas: leves (n = 21), moderadas (n = 127), graves (n = 15) e fatais (n = 1). O caso fatal foi notificado por medico e envolveu medicamentos anestesicos. Geralmente, as reacoes adversas observadas foram causadas predominantemente por analgesicos, anestesicos e antiepilepticos. DISCUSSAO: Os dados demonstram o valor potencial de se ter acesso a sistemas de farmacovigilância local para registrar possiveis riscos com o uso de farmacos.

Endothelium-independent vasodilator effect of 2-nitro-1-phenyl-1-propanol on mesenteric resistance vessels in rats

Abstract 2‐Nitro‐1‐phenyl‐1‐propanol (NPP) is a nitro alcohol with vasodilator activity in the rat aorta. The present study investigated the vasodilator properties of NPP in small vessels of the mesenteric bed, which, contrary to the aorta, contains resistance vessels. Using myography, isometric contractions were recorded in rings of second‐ and third‐order branches from the rat mesenteric artery. NPP relaxed mesenteric ring preparations that were contracted with phenylephrine, U‐46619, and KCl (40 mM), resulting in significantly different EC50 values (0.41 &mgr;M [0.31–0.55 &mgr;M], 0.16 &mgr;M [0.10–0.24 &mgr;M], and 4.50 &mgr;M [1.86–10.81 &mgr;M], respectively). NPP‐induced vasodilation decreased as the extracellular K+ concentration increased. The pharmacological blockade of K+ channels with tetraethylammonium, BaCl2, CsCl, and apamin also blunted NPP‐induced vasorelaxation. In contrast, NPP‐induced vasodilation was resistant to indomethacin, L‐NG‐nitroarginine methyl ester (L‐NAME), and endothelium removal, indicating that neither prostaglandins nor the endothelial release of nitric oxide is involved in the relaxant effects of NPP. Conversely, 1H‐[1,2,4]oxadiazolo[4,3‐a]quinoxalin‐1‐one (ODQ), cis‐N‐(2‐phenylcyclopentyl)‐azacyclotridec‐1‐en‐2‐amine hydrochloride (MDL‐12,330 A), and H‐89 reduced NPP‐induced vasodilation. Under Ca2+‐free conditions, NPP did not alter transient contractions that were evoked by caffeine, but it reduced transient contractions that were evoked by phenylephrine. In mesenteric rings that were loaded with the fluorescent Ca2+ indicator Fluo‐4 AM and stimulated with phenylephrine, NPP blunted both contractions and fluorescence signals that were related to cytosolic Ca2+ levels. In conclusion, the vasodilatory actions NPP on mesenteric vessel resistance involved the participation of cyclic nucleotides and the opening of K+ channels.

Cardiovascular Effects of the Essential Oil of Croton argyrophylloides in Normotensive Rats: Role of the Autonomic Nervous System.

Cardiovascular effects of the essential oil of Croton argyrophylloides Muell. Arg. (EOCA) were investigated in normotensive rats. In saline-pretreated anesthetized or conscious rats, intravenous (i.v.) injection of the EOCA induced dose-dependent hypotension. Dose-dependent tachycardia was observed only in conscious rats. In anesthetized rats, cervical bivagotomy failed to enhance EOCA-induced hypotension but unmasked significant bradycardia. In conscious rats, i.v. pretreatment with methylatropine, but not with atenolol or L-NAME, reduced both hypotensive and tachycardiac responses to EOCA. However, hexamethonium pretreatment reverted the EOCA-induced tachycardia into significant bradycardia without affecting the hypotension. In aortic ring preparations precontracted with phenylephrine, EOCA induced a concentration-dependent relaxation that was significantly reduced by vascular endothelium removal and pretreatment with atropine, indomethacin, or glibenclamide but remained unaffected by pretreatment with L-NAME or TEA. It is concluded that i.v. treatment with EOAC decreased blood pressure probably through an active vascular relaxation rather than withdrawal of sympathetic tone. Muscarinic receptor stimulation, liberation of the endothelium-derived prostacyclin, and opening KATP channels are partially involved in the aortic relaxation induced by EOCA and in turn in the mediation of EOCA-induced hypotension. EOCA-induced tachycardia in conscious rats appears to be mediated reflexly through inhibition of vagal drive to the heart.

Cardiovascular effects of a labdenic diterpene isolated from Moldenhawera nutans in conscious, spontaneously hypertensive rats

Abstract Context: The labdenic diterpene labd-8(17)-en-15-oic acid (labd-8) isolated from a methanolic extract of Moldenhawera nutans Queiroz & Alkin (Leguminosae) has hypotensive and tachycardiac properties in normotensive rats. A part of the hypotensive effect was due to a reduction in the sympathetic nerve drive to vessels, an event admittedly enhanced in spontaneously hypertensive rats (SHRs). Objectives: We assessed whether the cardiovascular effects induced by labd-8 could be enhanced in SHRs. Materials and methods: For in vivo experiments, arterial and venous catheters were implanted under anesthesia for blood pressure recording and drug administration, respectively. For in vitro experiments, thoracic aorta rings were suspended in organ baths containing warm (37 °C) perfusion medium that was continuously bubbled with carbogen. Results: Intravenous injection of labd-8 (1, 3, 5, and 10 mg/kg) induced similar dose-dependent hypotension and tachycardia in both SHRs and Wistar–Kyoto rats (WKY). In SHRs, only the tachycardia response to labd-8 was significantly reduced by pretreatment with methylatropine or propranolol. However, both cardiovascular effects of labd-8 were reduced by hexamethonium while remained unchanged by l-NAME. In isolated aortic preparations from SHRs, labd-8 (1–1000 µg/mL) relaxed potassium-induced contractions with an IC50 (geometric mean [95% confidence interval]) value (536.5 [441.0–631.9] µg/mL) significantly greater than that (157.6 [99.1–250.5] µg/mL) obtained in preparations from WKY rats. Conclusion: In SHRs, the hypotension induced by labd-8 is associated with a reflex tachycardia and seems mediated partly through withdrawal of sympathetic vasomotor tone and partly through an active vasorelaxation. Its magnitude was not enhanced when compared with WKY rats likely because of impaired vasorelaxant effects of labd-8 in preparations from SHRs.