RESUMEN
Serotonin (5-HT) takes a key position in regulating vital functions, such as cardio-ventilatory activity, locomotion and behaviour. Selective serotonin reuptake inhibitors (SSRIs) modulate the serotonergic system and thus affect these functions. Rhythmic behaviours, such as cardio-ventilatory activity, are controlled by central pattern generators, which in turn are regulated by 5-HT. In crustaceans, 5-HT also regulates the synthesis and secretion of crustacean hyperglycaemic hormone, a pleiotropic hormone involved in the mobilisation and release of glucose into the haemolymph, thus stimulating the animal's activity. As a matter of consequence, SSRIs may affect cardio-ventilatory activity. In order to examine how the SSRIs affect fundamental physiological parameters based on rhythmic behaviours in decapods, cardio-respiratory activity in the shore crab Carcinus maenas was assessed after pericardial injection of a single dose of either 0.5 µM, 0.75 µM or 1 µM fluoxetine, respectively. Simultaneous recordings of heart and scaphognathite movements in both brachial chambers were conducted by measuring impedance changes in the respective body compartments. Injection of 5-HT had an immediate effect on cardio-ventilatory activities and strongly upregulated both cardiac and ventilatory activities. Fluoxetine showed similar effects, entailing moderate tachycardia and increased ventilation rates. Compared to 5-HT, these effects were delayed in time and much less pronounced. Metabolism of fluoxetine into the active compound nor-fluoxetine might account for the delayed action, whereas compensatory regulation of cardio-ventilatory frequencies and amplitudes are likely to explain the attenuation of the responses compared to the strong and immediate increase by 5-HT. Overall, the results suggest increased 5-HT levels in invertebrates following fluoxetine exposure, which are able to disturb physiological functions regulated by 5-HT, such as cardiac and respiratory activity.
Asunto(s)
Braquiuros/fisiología , Fluoxetina/farmacología , Corazón/fisiología , Respiración/efectos de los fármacos , Serotonina/farmacología , Animales , Proteínas de Artrópodos/metabolismo , Braquiuros/efectos de los fármacos , Electrodos , Corazón/efectos de los fármacos , Hormonas de Invertebrados/metabolismo , Masculino , Proteínas del Tejido Nervioso/metabolismo , Serotonina/administración & dosificaciónRESUMEN
The baroreflex response is an essential component of the cardiovascular regulation that buffers abrupt changes in blood pressure to maintain homeostasis. Urotensin II (UII) and its receptor UT are present in the brain and in peripheral cardiovascular tissues of fish and mammals. Intracerebroventricular (ICV) injection of UII in these vertebrates provokes hypertension and tachycardia, suggesting that the cardio-inhibitory baroreflex response is impaired. Since nothing is known about the effect of UII on the cardiac baroreflex sensitivity (BRS), we decided to clarify the changes in spontaneous BRS using a cross spectral analysis technique of systolic blood pressure (SBP) and R-R interval variabilities after ICV and intra-arterial (IA) injections of trout UII in the unanesthetized trout. We contrasted the effects of UII with those observed for the UII-related peptides (URP), URP1 and URP2. Compared with vehicle-injected trout, ICV injection of UII (5-500 pmol) produced a gradual increase in SBP, a decrease in the R-R interval (reflecting a tachycardia) associated with a dose-dependent reduction of the BRS. The threshold dose for a significant effect on these parameters was 50 pmol (BRS; -55%; 1450 ± 165 ms/kPa vs. 3240 ± 300 ms/kPa; P < 0.05). Only the 500-pmol dose of URP2 caused a significant increase in SBP without changing significantly the R-R interval but reduced the BRS. IA injection of UII (5-500 pmol) caused a dose-dependent elevation of SBP. Contrasting with the ICV effects of UII, the R-R interval increased (reflecting a bradycardia) up to the 50-pmol dose while the BRS remained unchanged (50 pmol; 2530 ± 270 ms/kPa vs. 2600 ± 180 ms/kPa; P < 0.05). Nonetheless, the highest dose of UII reduced the BRS as did the highest dose of URP1. In conclusion, the contrasting effect of low picomolar doses of UII after central and peripheral injection on the BRS suggests that only the central urotensinergic system is involved in the attenuation of the BRS. The limited and quite divergent effects of URP1 and URP2 on the BRS, indicate that the action of UII is specific for this peptide. Further studies are required to elucidate the site(s) and mechanisms of action of UII on the baroreflex pathways. Whether such effects of central UII on the BRS exist in mammals including humans warrants further investigations.
RESUMEN
The QT interval of the electrocardiogram (ECG) is a measure of the duration of the ventricular depolarization and repolarization. In fish as in human, the QT interval is positively correlated with the RR interval of the ECG, a measure of the cardiac cycle length. Urotensin II (UII) is a neuropeptide that has been highly conserved from fish to human, and UII and its receptor (UT) are expressed in cardiovascular tissues including the heart. Although UII exerts potent cardiovascular actions, its possible effects on the QT interval have never been investigated. The goal of the present study was to provide insight into the potential effect of UII on the QT interval in an established in vivo trout model. To this end, the effects of UII on dorsal aortic blood pressure (PDA), RR, QT intervals and corrected QT (QTc) for RR interval, were investigated after intra-arterial (IA) injection of 5, 50 and 100 pmol UII. The effects of UII were compared to those of two structurally UII-related peptides (URPs), URP1 and URP2, and to those of arginine vasotocin (AVT), homolog of the mammalian arginine vasopressin. IA injection of vehicle or 5 pmol UII had no effect on the various parameters. At the 50-pmol dose, UII evoked its usual increase in PDA with a peak value observed 15 min after the injection (+22% from baseline, P<0.001). This hypertensive effect of UII was accompanied by a significant increase in the RR interval (+18%, P<0.001), i.e. a bradycardia, and these effects remained constant until the end of the recording. The highest dose of UII evoked similar hypertensive and bradycardic effects. Of interest, the QT interval did not change during the bradycardic action of UII (50 and 100 pmol) but the QTc interval significantly decreased. In trout pre-treated with urantide, a peptidic antagonist of UT, the hypertensive and bradycardic actions of 50 pmol UII were reduced 3-fold and no change occurred in the QT and QTc intervals. In trout pre-treated with blockers of the autonomic nervous system, the hypertensive effect of UII was maintained but no change appeared in RR, QT and QTc intervals. IA injections of 50 pmol URPs were without action on the preceding parameters. IA administration of 50 pmol AVT provoked quite similar increase in PDA, and elevation of the RR interval to those evoked by IA injection of UII but, in contrast to UII, AVT injection induced a highly significant and sustained prolongation of the QT interval compared to baseline (+7%, P<0.001) without change in QTc. Our results are indicative of a lack of QT interval change during UII-evoked bradycardia but not after AVT-induced bradycardia and suggest for the first time that some compensatory mechanism specific for the UII peptide is working to stabilize the QT interval. Further research is needed to elucidate the mechanism involved in this action of UII. The potential for UII to prevent detrimental prolongation of cardiac ventricular repolarization might be questioned.
Asunto(s)
Cardiotónicos/envenenamiento , Modelos Animales de Enfermedad , Proteínas de Peces/envenenamiento , Corazón/efectos de los fármacos , Síndrome de QT Prolongado/inducido químicamente , Urotensinas/envenenamiento , Vasotocina/envenenamiento , Animales , Acuicultura , Sistema Nervioso Autónomo/efectos de los fármacos , Sistema Nervioso Autónomo/fisiología , Sistema Nervioso Autónomo/fisiopatología , Bradicardia/inducido químicamente , Bradicardia/fisiopatología , Bradicardia/prevención & control , Cardiotónicos/administración & dosificación , Cardiotónicos/química , Cardiotónicos/farmacología , Relación Dosis-Respuesta a Droga , Electrocardiografía Ambulatoria/efectos de los fármacos , Electrocardiografía Ambulatoria/veterinaria , Femenino , Proteínas de Peces/administración & dosificación , Proteínas de Peces/química , Proteínas de Peces/farmacología , Corazón/inervación , Corazón/fisiología , Corazón/fisiopatología , Hipertensión/inducido químicamente , Hipertensión/fisiopatología , Hipertensión/prevención & control , Inyecciones Intraarteriales , Síndrome de QT Prolongado/fisiopatología , Síndrome de QT Prolongado/prevención & control , Masculino , Oncorhynchus mykiss , Fragmentos de Péptidos/uso terapéutico , Urotensinas/administración & dosificación , Urotensinas/antagonistas & inhibidores , Urotensinas/química , Urotensinas/farmacología , Urotensinas/uso terapéutico , Vasotocina/administración & dosificación , Vasotocina/farmacologíaRESUMEN
The viability of single and coaxial electrospray techniques to encapsulate model peptide-angiotensin II into near mono-dispersed spherical, nanocarriers comprising N-octyl-O-sulphate chitosan and tristearin, respectively, was explored. The stability of peptide under controlled electric fields (during particle generation) was evaluated. Resulting nanocarriers were analysed using dynamic light scattering and electron microscopy. Cell toxicity assays were used to determine optimal peptide loading concentration (~1 mg/ml). A trout model was used to assess particle behaviour in vivo. A processing limit of 20 kV was determined. A range of electrosprayed nanoparticles were formed (between 100 and 300 nm) and these demonstrated encapsulation efficiencies of ~92 ± 1.8%. For the single needle process, particles were in matrix form and for the coaxial format particles demonstrated a clear core-shell encapsulation of peptide. The outcomes of in vitro experiments demonstrated triphasic activity. This included an initial slow activity period, followed by a rapid and finally a conventional diffusive phase. This was in contrast to results from in vivo cardiovascular activity in the trout model. The results are indicative of the substantial potential for single/coaxial electrospray techniques. The results also clearly indicate the need to investigate both in vitro and in vivo models for emerging drug delivery systems.
Asunto(s)
Nanopartículas , Animales , Línea Celular , Ratones , Microscopía Electrónica de Rastreo , Microscopía Electrónica de Transmisión , Oncorhynchus mykiss , Tamaño de la PartículaRESUMEN
The urotensin II (UII) gene family consists of four paralogous genes called UII, UII-related peptide (URP), URP1 and URP2. UII and URP peptides exhibit the same cyclic hexapeptide core sequence (CFWKYC) while the N- and C-terminal regions are variable. UII, URP1, and URP2 mRNAs are differentially expressed within the central nervous system of teleost fishes, suggesting that they may exert distinct functions. Although the cardiovascular, ventilatory and locomotor effects of UII have been described in teleosts, much less is known regarding the physiological actions of URPs. The goal of the present study was to compare the central and peripheral actions of picomolar doses (5-500 pmol) of trout UII, URP1, and URP2 on cardio-ventilatory variables and locomotor activity in the unanesthetized trout. Compared to vehicle, intracerebroventricular injection of UII, URP1 and URP2 evoked a gradual increase in total ventilation (V TOT) reaching statistical significance for doses of 50 and 500 pmol of UII and URP1 but for only 500 pmol of URP2. In addition, UII, URP1 and URP2 provoked an elevation of dorsal aortic blood pressure (P DA) accompanied with tachycardia. All peptides caused an increase in locomotor activity (A CT), at a threshold dose of 5 pmol for UII and URP1, and 50 pmol for URP2. After intra-arterial (IA) injection, and in contrast to their central effects, only the highest dose of UII and URP1 significantly elevated V TOT and A CT. UII produced a dose-dependent hypertensive effect with concomitant bradycardia while URP1 increased P DA and heart rate after injection of only the highest dose of peptide. URP2 did not evoke any cardio-ventilatory or locomotor effect after IA injection. Collectively, these findings support the hypothesis that endogenous UII, URP1 and URP2 in the trout brain may act as neurotransmitters and/or neuromodulators acting synergistically or differentially to control the cardio-respiratory and locomotor systems. In the periphery, the only physiological actions of these peptides might be those related to the well-known cardiovascular regulatory actions of UII. It remains to determine whether the observed divergent physiological effects of UII and URPs are due to differential interaction with the UT receptor or binding to distinct UT subtypes.
RESUMEN
Urotensin II (UII) is a cyclic neuropeptide that was first isolated from the urophysis of teleost fish on the basis of its ability to contract the hindgut. Subsequently, UII was characterized in tetrapods including humans. Phylogenetic studies and synteny analysis indicate that UII and its paralogous peptide urotensin II-related peptide (URP) belong to the somatostatin/cortistatin superfamily. In mammals, the UII and URP genes are primarily expressed in cholinergic neurons of the brainstem and spinal cord. UII and URP mRNAs are also present in various organs notably in the cardiovascular, renal, and endocrine systems. UII and URP activate a common G protein-coupled receptor, called UT, that exhibits relatively high sequence identity with somatostatin, opioid, and galanin receptors. The UT gene is widely expressed in the central nervous system (CNS) and in peripheral tissues including the retina, heart, vascular bed, lung, kidney, adrenal medulla, and skeletal muscle. Structure-activity relationship studies and NMR conformational analysis have led to the rational design of a number of peptidic and nonpeptidic UT agonists and antagonists. Consistent with the wide distribution of UT, UII has now been shown to exert a large array of biologic activities, in particular in the CNS, the cardiovascular system, and the kidney. Here, we review the current knowledge concerning the pleiotropic actions of UII and discusses the possible use of antagonists for future therapeutic applications.
Asunto(s)
Hormonas Peptídicas/metabolismo , Receptores Acoplados a Proteínas G/metabolismo , Urotensinas/metabolismo , Secuencia de Aminoácidos , Animales , Antagonistas de Hormonas/farmacología , Humanos , Péptidos y Proteínas de Señalización Intracelular , Ligandos , Datos de Secuencia Molecular , Hormonas Peptídicas/antagonistas & inhibidores , Hormonas Peptídicas/química , Hormonas Peptídicas/genética , Conformación Proteica , Receptores Acoplados a Proteínas G/antagonistas & inhibidores , Receptores Acoplados a Proteínas G/química , Receptores Acoplados a Proteínas G/genética , Transducción de Señal , Relación Estructura-Actividad , Urotensinas/antagonistas & inhibidores , Urotensinas/química , Urotensinas/genéticaRESUMEN
QT interval of the electrocardiogram (ECG) is a measure of the duration of the ventricular depolarization and repolarization. In humans, prolongation of the QT interval is a known clinical risk factor for the development of ventricular arrhythmias including 'Torsades de Pointes' and possible sudden cardiac death. After oral administration, fluoxetine (FLX), as well as other selective serotonin (5-hydroxytryptamine, 5-HT) reuptake inhibitors can affect cardiac autonomic control, including the QT interval. However, the action of centrally administered FLX on the QT interval has never been explored. Consequently, using the unanesthetized trout as an animal model, we sought to compare the effects of intracerebroventricular (i.c.v.) injection of FLX (5, 15 or 25 µg) on the QT interval of the ECG with the effects observed following i.c.v. injection of 5-HT (0.05, 0.5 or 5 nmol). The QT interval was corrected for the RR interval. The highest doses of centrally administered FLX and 5-HT induced a prolongation of the corrected QT (QTc) interval reaching a maximum value of 510 min after injection (+8% and +6% respectively, P < 0.05). The intra-arterial (i.a.) injections of 5-HT and FLX were without significant effect on the QTc. The i.a. injection of blockers of the autonomic nervous system indicated that the sympathetic nervous system modulated the QTc interval. In conclusion, our data demonstrate that for the first time in any animal species, cardiac electrophysiology is sensitive to central 5-HT and that FLX within the brain may disrupt the autonomic control of ventricular repolarization.
Asunto(s)
Arritmias Cardíacas/veterinaria , Electrocardiografía/efectos de los fármacos , Fluoxetina/farmacología , Oncorhynchus mykiss/fisiología , Serotonina/farmacología , Antagonistas Adrenérgicos beta/administración & dosificación , Antagonistas Adrenérgicos beta/farmacología , Animales , Arritmias Cardíacas/inducido químicamente , Vías de Administración de Medicamentos , Femenino , Enfermedades de los Peces/inducido químicamente , Fluoxetina/administración & dosificación , Masculino , Serotonina/administración & dosificación , Agonistas de Receptores de Serotonina/toxicidad , Inhibidores Selectivos de la Recaptación de Serotonina/toxicidad , Sotalol/administración & dosificación , Sotalol/farmacologíaRESUMEN
Fluoxetine (FLX) is a selective serotonin (5-HT) reuptake inhibitor present in the aquatic environment which is known to bioconcentrate in the brains of exposed fish. FLX acts as a disruptor of various neuroendocrine functions in the brain, but nothing is known about the possible consequence of FLX exposure on the cardio-ventilatory system in fish. Here we undertook to investigate the central actions of FLX on ventilatory and cardiovascular function in unanesthetized rainbow trout (Oncorhynchus mykiss). Intracerebroventricular (ICV) injection of FLX (dosed between 5 and 25 µg) resulted in a significantly elevated total ventilation (VTOT), with a maximum hyperventilation of +176% (at a dose of 25µg) compared with vehicle injected controls. This increase was due to an increase in ventilatory amplitude (VAMP: +126%) with minor effects on ventilatory frequency. The highest dose of FLX (25 µg) produced a significant increase in mean dorsal aortic blood pressure (PDA: +20%) without effects on heart rate (ƒH). In comparison, intra-arterial injections of FLX (500-2,500 µg) had no effect on ventilation but the highest doses increased both PDA and ƒH. The ICV and IA cardio-ventilatory effects of FLX were very similar to those previously observed following injections of 5-HT, indicating that FLX probably acts via stimulating endogenous 5-HT activity through inhibition of 5-HT transporter(s). Our results demonstrate for the first time in fish that FLX administered within the brain exerts potent stimulatory effects on ventilation and blood pressure increase. The doses of FLX given to fish in our study are higher than the brain concentrations of FLX in fish that result from acute exposure to FLX through the water. Nonetheless, our results indicate possible disrupting action of long term exposure to FLX discharged into the environment on central target sites sensitive to 5-HT involved in cardio-ventilatory control.
Asunto(s)
Fluoxetina/administración & dosificación , Fluoxetina/farmacología , Corazón/fisiología , Oncorhynchus mykiss/fisiología , Respiración/efectos de los fármacos , Anestesia , Animales , Corazón/efectos de los fármacos , Inyecciones Intraarteriales , Inyecciones Intraventriculares , Factores de TiempoRESUMEN
This study was undertaken to investigate the central actions of 5-HT on ventilatory and cardiovascular variables in the unanesthetized trout. Compared to vehicle, intracerebroventricular injection (ICV) of 5-HT elevated the total ventilation. This elevation was due to its stimulatory action on ventilatory amplitude. Moreover, 5-HT produced a dose-dependent increase in mean dorsal aortic blood pressure (PDA) without change in heart rate (fH). Methysergide, a 5-HT1/5-HT2 receptor antagonist, reduced the hyperventilatory and hypertensive actions of 5-HT. 8-OH-2-(di-n-propylamino) tetralin, a 5-HT1A receptor agonist, increased PDA while α-methyl-5-HT, a 5-HT2 receptor agonist, elevated all ventilatory variables and increased PDA without changing fH. Intra-arterial injection of 5-HT was without effect on ventilation, but 5-HT initially produced hypotension followed by hypertension. These changes were accompanied by tachycardia. It remains to be determined whether endogenous 5-HT within the brain of trout may act as a potent neuroregulator causing stimulatory effects on cardio-ventilatory functions. In the periphery, 5-HT may act as local modulator involved in vasoregulatory mechanisms.
Asunto(s)
Presión Sanguínea/efectos de los fármacos , Respiración/efectos de los fármacos , Serotoninérgicos/farmacología , Serotonina/farmacología , Análisis de Varianza , Animales , Interacciones Farmacológicas , Inyecciones Intraventriculares , TruchaRESUMEN
Gastrin-releasing peptide (GRP), a neuropeptide initially isolated from porcine stomach, shares sequence similarity with bombesin. GRP and its receptors are present in the brains and peripheral tissues of several species of teleost fish, but little is known about the ventilatory and cardiovascular effects of this peptide in these vertebrates. The goal of this study was to compare the central and peripheral actions of picomolar doses of trout GRP on ventilatory and cardiovascular variables in the unanesthetized rainbow trout. Compared to vehicle, intracerebroventricular (ICV) injection of GRP (1-50â pmol) significantly elevated the ventilation rate (ƒV) and the ventilation amplitude (VAMP), and consequently the total ventilation (VTOT). The maximum hyperventilatory effect of GRP (VTOT: +225%), observed at a dose of 50â pmol, was mostly due to its stimulatory action on VAMP (+170%) rather than ƒV (+20%). In addition, ICV GRP (50â pmol) produced a significant increase in mean dorsal aortic blood pressure (P DA) (+35%) and in heart rate (ƒH) (+25%). Intra-arterial injections of GRP (5-100â pmol) were without sustained effect on the ventilatory variables but produced sporadic and transient increases in ventilatory movement at doses of 50 and 100â pmol. At these doses, GRP elevated P DA by +20% but only the 50â pmol dose significantly increased HR (+15%). In conclusion, our study suggests that endogenous GRP within the brain of the trout may act as a potent neurotransmitter and/or neuromodulator in the regulation of cardio-ventilatory functions. In the periphery, endogenous GRP may act as locally-acting and/or circulating neurohormone with an involvement in vasoregulatory mechanisms.
RESUMEN
Many neuropeptides and their G-protein coupled receptors (GPCRs) are present within the brain area involved in ventilatory and cardiovascular regulation but only a few mammalian studies have focused on the integrative physiological actions of neuropeptides on these vital cardio-respiratory regulations. Because both the central neuroanatomical substrates that govern motor ventilatory and cardiovascular output and the primary sequence of regulatory peptides and their receptors have been mostly conserved through evolution, we have developed a trout model to study the central action of native neuropeptides on cardio-ventilatory regulation. In the present review, we summarize the most recent results obtained using this non-mammalian model with a focus on PACAP, VIP, tachykinins, CRF, urotensin-1, CGRP, angiotensin-related peptides, urotensin-II, NPY, and PYY. We propose hypotheses regarding the physiological relevance of the results obtained.
RESUMEN
In the brains of teleosts, angiotensin II (ANG II), one of the main effector peptides of the renin-angiotensin system, is implicated in various physiological functions notably body fluid and electrolyte homeostasis and cardiovascular regulation, but nothing is known regarding the potential action of ANG II and other angiotensin derivatives on ventilation. Consequently, the goal of the present study was to determine possible ventilatory and cardiovascular effects of intracerebroventricular injection of picomole doses (5-100 pmol) of trout [Asn(1)]-ANG II, [Asp(1)]-ANG II, ANG III, ANG IV, and ANG 1-7 into the third ventricle of unanesthetized trout. The central actions of these peptides were also compared with their ventilatory and cardiovascular actions when injected peripherally. Finally, we examined the presence of [Asn(1)]-ANG II, [Asp(1)]-ANG II, ANG III, and ANG IV in the brain and plasma using radioimmunoassay coupled with high-performance liquid chromatography. After intracerebroventricular injection, [Asn(1)]-ANG II and [Asp(1)]-ANG II two ANG IIs, elevated the total ventilation through a selective stimulatory action on the ventilation amplitude. However, the hyperventilatory effect of [Asn(1)]-ANG II was threefold higher than the effect of [Asp(1)]-ANG II at the 50-pmol dose. ANG III, ANG IV, and ANG 1-7 were without effect. In addition, ANG IIs and ANG III increased dorsal aortic blood pressure (P(DA)) and heart rate (HR). After intra-arterial injections, none of the ANG II peptides affected the ventilation but [Asn(1)]-ANG II, [Asp(1)]-ANG II, and ANG III elevated P(DA) (50 pmol: +80%, +58% and +48%, respectively) without significant decrease in HR. In brain tissue, comparable amounts of [Asn(1)]-ANG II and [Asp(1)]-ANG II were detected (ca. 40 fmol/mg brain tissue), but ANG III was not detected, and the amount of ANG IV was about eightfold lower than the content of the ANG IIs. In plasma, ANG IIs were also the major angiotensins (ca. 110 fmol/ml plasma), while significant but lower amounts of ANG III and ANG IV were present in plasma. In conclusion, our study suggests that the two ANG II isoforms produced within the brain may act as a neurotransmitter and/or neuromodulator to regulate the cardioventilatory functions in trout. In the periphery, two ANG IIs and their COOH-terminal peptides may act as a circulating hormone preferentially involved in cardiovascular regulations.
Asunto(s)
Angiotensina III/farmacología , Angiotensina II/análogos & derivados , Angiotensina II/farmacología , Angiotensina I/farmacología , Fenómenos Fisiológicos Cardiovasculares/efectos de los fármacos , Branquias/efectos de los fármacos , Fragmentos de Péptidos/farmacología , Trucha/fisiología , Angiotensina I/administración & dosificación , Angiotensina II/administración & dosificación , Angiotensina III/administración & dosificación , Animales , Presión Sanguínea/efectos de los fármacos , Presión Sanguínea/fisiología , Relación Dosis-Respuesta a Droga , Femenino , Branquias/fisiología , Frecuencia Cardíaca/efectos de los fármacos , Frecuencia Cardíaca/fisiología , Inyecciones Intraventriculares , Masculino , Fragmentos de Péptidos/administración & dosificación , Factores de TiempoRESUMEN
Calcitonin gene-related peptide (CGRP) and its receptors are widely distributed in the tissues of teleost fish, including the brain, but little is known about the ventilatory and cardiovascular effects of the peptide in these vertebrates. The present study was undertaken to compare the central and peripheral actions of graded doses (5-50 pmol) of trout CGRP on ventilatory and cardiovascular variables in unanesthetized rainbow trout. Compared with vehicle, intracerebroventricular injection of CGRP significantly elevated the ventilation frequency (f(V)) and the ventilation amplitude (V(AMP)) and, consequently, the total ventilation (V(TOT)). The maximum hyperventilatory effect of CGRP (V(TOT): +300%), observed at a dose of 50 pmol, was mostly due to its stimulatory action on V(AMP) (+200%) rather than f(V) (+30%). In addition, CGRP produced a significant and dose-dependent increase in mean dorsal aortic blood pressure (P(DA)) (50 pmol: +40%) but the increase in heart rate (f(H)) was not significant. Intra-arterial injections of CGRP were without effect on the ventilatory variables but significantly and dose-dependently elevated P(DA) (50 pmol: +36%) without changing f(H). At the highest dose tested, this hypertensive phase was preceded by a rapid and transient hypotensive response. In conclusion, our study suggests that endogenous CGRP within the brain of the trout may act as a potent neurotransmitter and/or neuromodulator in the regulation of cardio-ventilatory functions. In the periphery, endogenous CGRP may act as a local and/or circulating hormone preferentially involved in vasoregulatory mechanisms.
Asunto(s)
Péptido Relacionado con Gen de Calcitonina/farmacología , Oncorhynchus mykiss/fisiología , Animales , Presión Sanguínea/efectos de los fármacos , Presión Sanguínea/fisiología , Encéfalo/efectos de los fármacos , Encéfalo/fisiología , Péptido Relacionado con Gen de Calcitonina/administración & dosificación , Péptido Relacionado con Gen de Calcitonina/fisiología , Relación Dosis-Respuesta a Droga , Femenino , Frecuencia Cardíaca/efectos de los fármacos , Frecuencia Cardíaca/fisiología , Inyecciones Intraarteriales , Inyecciones Intraventriculares , Masculino , Respiración/efectos de los fármacosRESUMEN
Although PACAP and VIP exert diverse actions on heart and blood vessels along the vertebrate phylum, no information is currently available concerning the potential role of these peptides on the regulation of the baroreflex response, a major mechanism for blood pressure homeostasis. Consequently, the goal of this study was to examine in our experimental model, the unanesthetized rainbow trout Oncorhynchus mykiss, whether PACAP and VIP are involved in the regulation of the cardiac baroreflex sensitivity (BRS). Cross-spectral analysis techniques using a fast Fourier transform algorithm were employed to calculate the coherence, phase and gain of the transfer function between spontaneous fluctuations of systolic arterial blood pressure and R-R intervals of the electrocardiogram. The BRS was estimated as the mean of the gain of the transfer function when the coherence between the two signals was high and the phase negative. Compared with vehicle, intracerebroventricular (i.c.v.) injections of trout PACAP-27 and trout VIP (25-100 pmol) dose-dependently reduced the cardiac BRS to the same extent with a threshold dose of 50 pmol for a significant effect. When injected intra-arterially at the same doses as for i.c.v. injections, only the highest dose of VIP (100 pmol) significantly attenuated the BRS. These results suggest that the endogenous peptides PACAP and VIP might be implicated in the central control of cardiac baroreflex functions in trout.
Asunto(s)
Barorreflejo/efectos de los fármacos , Polipéptido Hipofisario Activador de la Adenilato-Ciclasa/farmacología , Péptido Intestinal Vasoactivo/farmacología , Animales , TruchaRESUMEN
The cyclic peptide urotensin II (UII) was originally isolated from the urophysis of teleost fish on the basis of its ability to contract intestinal smooth muscle. The UII peptide has subsequently been isolated from frog brain and, later on, the pre-proUII cDNA has been characterized in mammals, including humans. A UII paralog called urotensin II-related peptide (URP) has been identified in the rat brain. The UII and URP genes originate from the same ancestral gene as the somatostatin and cortistatin genes. In the central nervous system (CNS) of tetrapods, UII is expressed primarily in motoneurons of the brainstem and spinal cord. The biological actions of UII and URP are mediated through a G protein-coupled receptor, termed UT, that exhibits high sequence similarity with the somatostatin receptors. The UT gene is widely expressed in the CNS and in peripheral organs. Consistent with the broad distribution of UT, UII and URP exert a large array of behavioral effects and regulate endocrine, cardiovascular, renal, and immune functions.
Asunto(s)
Peces/genética , Urotensinas/genética , Secuencia de Aminoácidos , Animales , Humanos , Datos de Secuencia Molecular , Relación Estructura-Actividad , Urotensinas/química , Urotensinas/fisiologíaRESUMEN
Recent studies in trout have shown that tachykinins might be selectively implicated in important neuroregulatory functions related to the central control of ventilation. In teleost fish, cardiorespiratory coupling probably contributes to heart rate variability (HRV), and the hypoventilatory effects observed after central injection of tachykinins suggest that these peptides also may produce changes in HRV. Consequently, the present study was undertaken to compare the central actions of picomolar doses (25-250 pmol) of trout neuropeptide gamma (NPgamma), substance P (SP), and neurokinin A (NKA) on HRV in unanesthetized rainbow trout. Compared to vehicle-injected trout, Poincaré plot analysis of HRV demonstrated that intracerebroventricular injection of NPgamma dose dependently increased HRV. SP evoked a significant elevation of HRV but only at the highest dose (250 pmol). In contrast, NKA was without any effect on HRV. In conclusion, these results suggest that NPgamma may be selectively implicated in the central control of HRV in trout.
Asunto(s)
Frecuencia Cardíaca/efectos de los fármacos , Fragmentos de Péptidos/farmacología , Taquicininas/farmacología , Trucha/fisiología , AnimalesRESUMEN
The stress-related neurohormonal peptides corticotropin-releasing factor (CRF) and urotensin-I (U-I), an ortholog of mammalian urocortin 1, are widely distributed in the central nervous systems of teleost fish but little is known about their possible central neurotropic actions. In the present study, we investigated the effect of intracerebroventricular (ICV) injection of CRF and U-I (1-10pmol) on ventilatory and cardiovascular variables in our established unanaesthetized trout model. CRF and U-I produced a significant dose-dependent and long-lasting increase in the ventilatory frequency (VF) and the ventilatory amplitude (VA). Consequently the net effect of these peptides was a hyperventilatory response since the total ventilation (VTOT) was significantly elevated. However, CRF evoked a significant hyperventilatory response 5-10min sooner than that observed after ICV administration of U-I and the hyperventilatory effect of 10pmol CRF was twofold higher than that of equimolar dose of U-I. Pre-treatment of the trout with the antagonist, alpha-helical CRF(9-41), significantly reduced by about threefold the CRF-induced increase in VF, VA and VTOT. The most significant cardiovascular action of central CRF and U-I was to evoke a hypertensive response without changing the heart rate. Peripheral injection of CRF and U-I at doses of 5 and 50pmol produced no change in VF, VA or VTOT. Only a transient hypertensive response without change in heart rate was observed after the injection of the highest dose of U-I. Our results demonstrate that in a teleost fish, CRF and U-I produce a potent hyperventilatory response only when injected centrally. The two endogenous stress-related neuropeptides may play an important stimulatory role acting as neurotransmitters and/or neuromodulators in the central control of ventilatory apparatus during stress.
Asunto(s)
Hormona Liberadora de Corticotropina/farmacología , Oncorhynchus mykiss/metabolismo , Urotensinas/farmacología , Animales , Encéfalo/anatomía & histología , Encéfalo/efectos de los fármacos , Encéfalo/metabolismo , Sistema Cardiovascular/efectos de los fármacos , Hormona Liberadora de Corticotropina/administración & dosificación , Hormona Liberadora de Corticotropina/metabolismo , Femenino , Frecuencia Cardíaca/efectos de los fármacos , Humanos , Inyecciones Intraventriculares , Masculino , Modelos Biológicos , Estrés Fisiológico/fisiología , Urotensinas/administración & dosificación , Urotensinas/metabolismoRESUMEN
In mammals, a large body of evidence supports the existence of a brain renin-angiotensin system (RAS) acting independently or synergistically with the endocrine RAS to maintain diverse physiological functions, notably cardiovascular homeostasis. The RAS is of ancient origin and although most components of the RAS are present within the brain of teleost fishes, little is known regarding the central physiological actions of the RAS in these vertebrates. The present review encompasses the most relevant functional data for a role of the brain RAS in cardiovascular regulations in our experimental animal model, the unanesthetized trout Oncorhynchus mykiss. This paper mainly focuses on the central effect of angiotensin II (ANG II) on heart rate, blood pressure, heart rate variability and cardiac baroreflex, after intracerebroventricular injection or local microinjection of the peptide within the dorsal vagal motor nucleus. The probable implications of the parasympathetic nervous system in ANG II-evoked changes in the cardiac responses are also discussed.
Asunto(s)
Angiotensina II/farmacología , Fenómenos Fisiológicos Cardiovasculares/efectos de los fármacos , Trucha/fisiología , Animales , Presión Sanguínea/efectos de los fármacos , Frecuencia Cardíaca/efectos de los fármacos , Sistema Nervioso Parasimpático/efectos de los fármacos , Sistema Renina-Angiotensina/efectos de los fármacosRESUMEN
Urotensin-II (U-II) was originally considered to be exclusively the product of the caudal neurosecretory system (CNSS) of teleost fish, but it has now been demonstrated that U-II is widely expressed in peripheral tissues and nervous structures of species from lampreys to mammals. However, very little is known regarding the physiological effects of this peptide in its species of origin. In the present review, we summarize the most significant results relating to the cardiovascular, ventilatory, and motor effects of centrally and peripherally administered synthetic trout U-II in our experimental animal model, the unanesthetized trout Oncorhynchus mykiss. In addition, we compare the actions of U-II with those of other neurohormonal peptides, particularly with the actions of urotensin-I, a 41-amino acid residue peptide paralogous to corticotropin-releasing hormone that is co-localized with U-II within neurons of the CNSS.
Asunto(s)
Sistema Cardiovascular/efectos de los fármacos , Actividad Motora/efectos de los fármacos , Oncorhynchus mykiss/fisiología , Sistema Respiratorio/efectos de los fármacos , Urotensinas/farmacología , Animales , Sistema Nervioso Central/anatomía & histología , Sistema Nervioso Central/efectos de los fármacos , Sistema Nervioso Central/fisiologíaRESUMEN
The brains of teleost fish contain members of the tachykinin family that are the products of orthologous genes expressed in mammalian nervous tissues, but little is known regarding the physiological effects of these peptides in their species of origin. The present study compares the central actions of trout neuropeptide gamma (NPgamma), substance P (SP) and neurokinin A (NKA) (5-250 pmol) on ventilatory and cardiovascular parameters in the unanesthetized rainbow trout Oncorhynchus mykiss. Intracerebroventricular (ICV) injection of NPgamma evoked a dose-dependent elevation of the ventilation rate (f(V)) but a reduction of the ventilation amplitude (V(AMP)) that was caused by a reduction of the magnitude of the adduction phase of the ventilatory signal. The net effect of NPgamma was to produce an hypoventilatory response since the total ventilation (V(TOT)) was significantly reduced. The minimum effective dose for a significant effect of NPgamma on f(V) and V(AMP) was 50 pmol. SP evoked a significant elevation of f(V), a concomitant depression of V(AMP), and a resultant decrease in V(TOT) but only at the highest dose (250 pmol). NKA was without action on f(V) but significantly decreased V(AMP) at only the highest dose tested. In this case also, the net effect of NKA was to reduce V(TOT). When injected centrally, none of the three peptides, at any dose tested, produced changes in heart rate or mean dorsal aortic blood pressure (P(DA)). Intra-arterial injection of the three tachykinins (250 pmol) produced a significant (P<0.05) increase in P(DA), but only SP and NKA induced concomitant bradycardia. None of the three peptides produced any change in f(V) or V(AMP). In conclusion, our results demonstrate that centrally injected tachykinins, particularly NPgamma, produce a strong hypoventilatory response in a teleost fish and so suggest that endogenous tachykinins may be differentially implicated in neuroregulatory control of ventilation.