capsazepine and Hypotension

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.

Topics: Acetanilides; Acyclic Monoterpenes; Animals; Aorta; Atropine Derivatives; Blood Pressure; Bradycardia; Capsaicin; Hypotension; In Vitro Techniques; Lauraceae; Male; Monoterpenes; Oils, Volatile; Ondansetron; Phenylephrine; Plant Oils; Purines; Rats; Rats, Wistar; Reflex

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.

Topics: Animals; Aorta; Atropine Derivatives; Benzene Derivatives; Bradycardia; Capsaicin; Cryptocarya; Dose-Response Relationship, Drug; Herb-Drug Interactions; Hypotension; In Vitro Techniques; Male; Oils, Volatile; Ondansetron; Phenylephrine; Rats; Rats, Wistar; Reflex; Vagus Nerve; Vasoconstriction

To test the hypothesis that activation of the transient receptor potential vanilloid 4 (TRPV4) channel conveys a hypotensive effect that is enhanced during salt load, male Wistar rats fed a normal-sodium (0.5%) or high-sodium (HS; 4%) diet for 3 weeks were given 4 alpha-phorbol 12,13-didecanoate (4 alpha-PDD), a specific TRPV4 activator, in the presence or absence of capsazepine, a selective TRPV1 blocker, ruthenium red, a TRPV4 blocker, or TRPV4 small hairpin RNA that selectively knockdowns TRPV4. 4 alpha-PDD (1, 2.5, or 5 mg/kg IV) dose-dependently decreased mean arterial pressure (P<0.05). HS enhanced 4 alpha-PDD-induced depressor effects as well as 4 alpha-PDD-mediated release of calcitonin gene-related peptide and substance P (P<0.001). Ruthenium red markedly blunted (P<0.001), whereas capsazepine slightly attenuated (P<0.05) 4 alpha-PDD-induced depressor effects in HS and normal-sodium diet rats. Ruthenium red alone increased baseline mean arterial pressure in both HS and normal-sodium diet rats with a greater magnitude in the former (P<0.05). Western blot analysis showed that HS increased TRPV4 expression in dorsal root ganglia and mesenteric arteries (P<0.05) but not the renal cortex and medulla. Gene-silencing approach revealed that TRPV4 small hairpin RNA downregulated TRPV4 expression leading to blunted 4 alpha-PDD-induced hypotension (P<0.05). Thus, TRPV4 activation decreases blood pressure in rats given a normal-sodium diet. HS enhances TRPV4 expression in sensory nerves/mesenteric arteries and TRPV4-mediated depressor effects and calcitonin gene-related peptide/substance P release such that HS causes a greater increase in blood pressure when TRPV4 is blocked. Our data indicate that TRPV4 activation may constitute a compensatory mechanism in preventing salt-induced increases in blood pressure.

Topics: Animals; Blood Pressure; Calcitonin Gene-Related Peptide; Capsaicin; Disease Models, Animal; Dose-Response Relationship, Drug; Ganglia, Spinal; Hypertension; Hypotension; Kidney; Male; Mesenteric Arteries; Phorbol Esters; Rats; Rats, Wistar; Ruthenium Red; Salt Tolerance; Sodium Chloride, Dietary; Substance P; TRPV Cation Channels

This study was designed to test the hypothesis that the transient receptor potential vanilloid type 1 (TRPV1) channel, expressed primarily in sensory nerves, and substance P (SP), released by sensory nerves, play a protective role against lipopolysaccharide (LPS)-induced hypotension. LPS (10 mg/kg iv) elicited tachycardia and hypotension in anesthetized male Wistar rats, which peaked at 10 min and gradually recovered 1 h after the injection. Blockade of TRPV1 with its selective antagonist capsazepine (CAPZ, 3 mg/kg iv) impaired recovery given that the fall in mean arterial pressure (MAP) was greater 1 h after CAPZ plus LPS injections compared with LPS injection alone (45 +/- 5 vs. 25 +/- 4 mmHg, P < 0.05). Blockade of the neurokinin 1 (NK1) receptor with its selective antagonists RP-67580 (5 mg/kg iv) or L-733,060 (4 mg/kg iv) prevented recovery, considering that falls in MAP were not different 1 h after injections of NK1 antagonists plus LPS from their peak decreases (66 +/- 9 vs. 74 +/- 5 mmHg or 60 +/- 7 vs. 69 +/- 3 mmHg, respectively, P > 0.05). LPS increased plasma SP, norepinephrine (NE), and epinephrine (Epi) levels compared with vehicles, and the increases in plasma SP, NE, and Epi were significantly inhibited by CAPZ or RP-67580. The survival rate at 24 or 48 h after LPS injection (20 mg/kg ip) was lower in conscious rats pretreated with CAPZ or RP-67580 compared with rats treated with LPS alone (P < 0.05). Thus our results show that the TRPV1, possibly via triggering release of SP which activates the NK1 and stimulates the sympathetic axis, plays a protective role against endotoxin-induced hypotension and mortality, suggesting that TRPV1 receptors are essential in protecting vital organ perfusion and survival during the endotoxic condition.

Topics: Animals; Blood Pressure; Capsaicin; Catecholamines; Endotoxins; Heart Rate; Hypotension; Isoindoles; Lipopolysaccharides; Male; Neurons, Afferent; Rats; Rats, Wistar; Receptors, Neurokinin-1; Substance P; TRPV Cation Channels

We recently demonstrated that activation of the pulmonary sensory neurons plays a critical role in prevention of endotoxin-induced shock by releasing calcitonin gene-related peptide (CGRP) in rats. CGRP increased the endothelial production of prostacyclin (PGI(2)) in the lungs, thereby preventing endotoxin-induced shock response by inhibiting tumor necrosis factor-alpha (TNF-alpha) production. Since antithrombin (AT) enhances sensory neuron activation, we hypothesized that AT might reduce endotoxin-induced hypotension by enhancing the activation of pulmonary sensory neurons in rats. We examined this possibility using a rat model of endotoxin shock. AT-induced effects including reduction of hypotension (n = 5) and inhibition of induction of iNOS (n = 4 or 5) and TNF- alpha (n = 5) in the lungs of endotoxin-treated animals were completely reversed by pretreatment with capsazepine (CPZ) (n = 4 or 5), a vanilloid receptor antagonist, or CGRP(8-37), a CGRP receptor antagonist (n = 4 or 5). AT enhanced endotoxin-induced increases in lung tissue levels of CGRP (n = 4), but this effect of AT was not seen in animals pretreated with CPZ (n = 4). CGRP produced therapeutic effects (n = 5) similar to those induced by AT, and such therapeutic effects were completely abrogated by pretreatment with indomethacin (n = 4). AT increased CGRP release from cultured dorsal root ganglion neurons only in the presence of anandamide (n = 5), and AT-induced increase in CGRP release was not observed in the presence KT5720, an inhibitor of protein kinase A (n = 5). AT markedly increased intracellular levels of cAMP in the presence of anandamide (n = 5). These results strongly suggested that AT might reduce endotoxin-induced hypotension in rats by enhancing activation of sensory neurons via activation of protein kinase A.

Topics: Animals; Antithrombins; Arachidonic Acids; Blood Pressure; Calcitonin Gene-Related Peptide; Calcitonin Gene-Related Peptide Receptor Antagonists; Capsaicin; Carbazoles; Cells, Cultured; Cyclic AMP; Cyclic AMP-Dependent Protein Kinase Type II; Cyclic AMP-Dependent Protein Kinases; Cyclooxygenase Inhibitors; Disease Models, Animal; Endocannabinoids; Endotoxins; Ganglia, Spinal; Gene Expression Regulation; Hypotension; Indoles; Indomethacin; Lung; Male; Neurons, Afferent; Nitrates; Nitric Oxide Synthase Type II; Nitrites; Peptide Fragments; Polyunsaturated Alkamides; Protein Kinase Inhibitors; Pyrroles; Rats; Rats, Wistar; Receptors, Calcitonin Gene-Related Peptide; RNA, Messenger; TRPV Cation Channels; Tumor Necrosis Factor-alpha

We attempted to determine whether activation of the sensory neuron contributes to reduction of endotoxin-induced hypotension by inhibiting tumor necrosis factor (TNF)-alpha production via calcitonin gene-related peptide (CGRP) release in rats.. Prospective, randomized, controlled study.. Research laboratory at a university medical center.. Wistar rats weighing 220-280 g.. Mean arterial blood pressure was measured in rats administered endotoxin intravenously. Animals were pretreated with capsazepine (a vanilloid receptor antagonist), CGRP(8-37) (a CGRP receptor antagonist), and indomethacin before endotoxin administration. Levels of CGRP, 6-keto-prostaglandin F1alpha, TNF-alpha, and cytokine-induced neutrophil chemoattractant (CINC) were measured by enzyme immunoassay methods. The concentration of NO2/NO3 was measured using the Griess reagent. Tissue levels of messenger RNA of the inducible form of nitric oxide synthase (iNOS) and TNF-alpha were determined by reverse transcription polymerase chain reaction.. Both lung levels of CGRP and plasma levels of 6-keto-prostaglandin F1alpha were increased after intravenous administration of endotoxin (5 mg/kg), peaking at 90 mins after endotoxin administration. Increases in plasma levels of 6-keto-prostaglandin F1alpha at 90 mins after endotoxin administration (766 +/- 134 pg/mL) were inhibited by pretreatment with capsazepine (373 +/- 44 pg/mL, p < .05), CGRP(8-37) (406 +/- 64 pg/mL, p < .05), and indomethacin (154 +/- 40 pg/mL, p < .05). Although none of the pretreatments affected a series of endotoxin-induced responses, including increases in lung tissue levels of TNF-alpha, CINC, and iNOS and the resultant hypotension in animals given 5 mg/kg endotoxin, such pretreatments enhanced these pathologic responses in animals given a smaller dose of endotoxin (1 mg/kg) to the same extent as those induced by 5 mg/kg of endotoxin, suggesting that shock responses induced by 5 mg/kg endotoxin are maximum responses and activation of sensory neurons in endotoxin-treated rats is essentially a reparative response.. Activation of sensory neurons might contribute to reduction of endotoxin-induced hypotension by releasing CGRP, which is capable of promoting endothelial production of prostacyclin.

Topics: 6-Ketoprostaglandin F1 alpha; Animals; Blood Pressure; Calcitonin Gene-Related Peptide; Capsaicin; Cyclooxygenase Inhibitors; Disease Models, Animal; Dose-Response Relationship, Drug; Endotoxins; Hypotension; Iloprost; Indomethacin; Interleukin-16; Lung; Neurons, Afferent; Nitric Oxide Synthase; Prospective Studies; Rats; Rats, Wistar; Reference Values; Tumor Necrosis Factor-alpha; Vasodilator Agents