Cardiovascular actions of centrally and peripherally administered trout urotensin-I in the trout

The cardiovascular effects of centrally and peripherally administered synthetic trout urotensin (U)-I, a member of the corticotropin-releasing hormone family of neuroendocrine peptides, were investigated in unanesthetized rainbow trout Oncorhynchus mykiss. Intracerebroventricular injections of U-I (5.0 and 12.5 pmol) produced a sustained increase in mean dorsal aortic blood pressure (P(DA)) without significant change in heart rate (HR). This elevation in P(DA) was associated with an increase in cardiac output, but systemic vascular resistance did not change. Intra-arterial injection of U-I (12.5-500 pmol) evoked a dose-dependent increase in P(DA), but in contrast to the hemodynamic effects of centrally administered U-I, the hypertensive effect was associated with an increase in systemic vascular resistance and an initial fall in cardiac output. HR did not change or underwent a delayed increase. Pretreatment of trout with prazosin, an alpha-adrenoreceptor antagonist, completely abolished the rise in arterial blood pressure after intra-arterial administration of U-I, which was replaced by a sustained hypotension and tachycardia. Trout U-I produced a dose-dependent (pD(2) = 7.74 +/- 0.08) relaxation of preconstricted rings of isolated trout arterial vascular smooth muscle, suggesting that the primary action of the peptide in the periphery is vasorelaxation that is rapidly reversed by release of catecholamines. Our results suggest that U-I may regulate blood pressure in trout by acting centrally as a neurotransmitter and/or neuromodulator and peripherally as a neurohormone functioning either as a locally acting vasodilator or as a potent secretagogue of catecholamines.     

Phosphoramidon inhibits the conversion of intracisternally administered big endothelin-1 to endothelin-1

It is suggested that endothelin-1 (ET-1), a potent vasoconstrictor peptide, is involved in the pathogenesis of cerebral vasospasm following subarachnoid hemorrhage (SAH). We examined the effects of intracisternal administration of big ET-1 on the cerebral arteries in the absence or presence of pretreatment with phosphoramidon, an inhibitor of ET converting enzyme, in anesthetized dogs. After intracisternal administration of big ET-1 (10 micrograms/dog), the caliber of the basilar artery on the angiogram was decreased to about 59% of the control. This was accompanied by a marked increase in immunoreactive ET in the cerebrospinal fluid. Systemic arterial pressure was markedly elevated following big ET-1 injection. All changes induced by big ET-1 were effectively prevented with phosphoramidon. These data suggest that intracisternally administered big ET-1 is converted to ET-1 and that the generated ET-1 produces cerebral vasospasm and hypertension. A phosphoramidon-sensitive metalloproteinase appears to contribute to this conversion.     

Analgesic and cardiovascular effects of centrally administered substance P

Substance P (SP) injected intracerebroventricularly (ICV) into rabbits caused dose-related thermal analgesia with the maximum effect after 2 micrograms. The analgesia was measured by timing the withdrawal of the rabbit's ear from an infrared beam. Equimolar amounts of the related peptides physalaemin and eledoisin-related peptide also caused analgesia, but the SP N-terminal fragment (1-9) was inactive. This suggests that the analgesic message of SP resides within the C-terminal fragment. The analgesia caused by each peptide developed more rapidly but did not last as long as that after central injection of beta-endorphin. In separate experiments, 2 micrograms SP injected ICV increased blood pressure and decreased heart rate. The analgesic, bradycardic and pressor responses to central administration of SP were opposite to effects of peripherally administered SP, described previously. These results indicate that the effect induced by SP depends upon its specific neuroanatomical site of action.     

Bosentan antagonizes the effects of endothelin-1 on rat gastric blood flow and mucosal integrity

Bosentan, a new type of orally effective, mixed (ETA+ETs) endothehn receptor antagonist has been recently introduced and tested in a variety of experimental models. We studied the effect of bosentan on the changes in gastric mucosal hemodynamics and mucosal integrity, induced by the exogenous application of endothelin-1, in rats. Bosentan (10 mg/kg iv) pretreated rats were injected with endothelin-1 (500-1000-2000 pmol/kg, iv) and gastric mucosal hemodynamics were monitored. After combined oral (30 mg/kg) and systemic pretreatment with bosentan we studied the effects of submucosal injection of endothelin-1 (50 pmol) on blood flow and gastric mucosa. Bosentan antagonized the vasodilator, vasoconstrictor and ulcerogenic effects of endothelin-1 in the rat gastric mucosa. These results show that bosentan can be a useful probe in the study of endogenous endothelin in the gastrointestinal tract.     

Regional cerebral blood flow changes during hypothermia

1. 1. When brain temperature was decreased from 38 to 22 °C using selective hypothermia, tissue blood flow decreased significantly in cerebral cortex, cerebellum, and thalamus, but did not significantly change in hypothalamic or brain stem tissue.

2. 2. A further decrease in brain temperature to 8 °C produced an increase in blood flow in all tissues except cerebral cortex compared to tissue blood flow measured at 22 °C. Compared to normothermic values, blood flow remained significantly decreased at 8 °C in cerebral and cerebellar cortex and was increased in brain stem.

3. 3. After rewarming, tissue blood flow returned to original baseline values in all tissues except cerebral cortex where blood flow was slightly but significantly decreased and brain stem, where blood flow was increased.

4. 4. These results indicate that the cerebrovascular effects of selective brain cooling are regionally specific. These changes appear to be due to both direct and indirect effects of cerebral hypothermia since brain tissue blood flow changes are apparent, compared to control values, after rewarming of the brain.

     

Hypothermic and antipyretic effects of centrally administered ACTH (1--24) and alpha-melanotropin

ACTH (1--24) and alpha-melanotropin (alpha-MSH), peptides previously shown to influence body temperature when administered centrally and to occur naturally in brain regions important to temperature control, were injected intracerebroventricularly (ICV) in rabbits. The peptides in doses of 1.25, 2.5 and 5.0 micrograms produced dose-related hypothermias in a 23 degrees C environment, and greater decreases in body temperature when the experiments were repeated in the cold (10 degrees C), but the largest dose had no effect on temperature in the heat (30 degrees C). These results indicate that the peptides do not reduce the central set-point of temperature control. Rather, they appear to selectively inhibit heat conservation and production responses. Five microgram of ACTH reversed vasoconstriction and inhibited rises in temperature caused by leukocytic pyrogen (LP) given IV and ICV. The same dose of alpha-MSH also reduced fever produced by IV and ICV LP, but the reduction was not as great as after ACTH. Both peptides (5 micrograms) also reduced temperature rises and vasoconstriction caused by ICV PGE2. ACTH reduced d-amphetamine-induced hyperthermia without altering vasoconstriction which suggests that this peptide can reduce temperature rises by inhibiting heat production alone. One of the most important findings was that the peptides are antipyretic in that they reduce fever at doses (0.25 microgram, ICV) that do not affect normal temperature. The powerful effects of these peptides on resting body temperature, hyperthermia and fever, together with their presence in brain tissue important to temperature control, suggest that the endogenous central peptides participate in thermoregulation, perhaps by limiting fever and influencing normal temperature.     

Hemodynamic effects of centrally administered, norcocaine in the rat.

Norcocaine is the N-demethylated metabolite of cocaine. It is present in the CNS and is reported to be pharmacologically active. The present study was designed to evaluate the cardiovascular actions of norcocaine following central administration. Wistar Kyoto (WKY) rats were anesthetized with pentobarbital and instrumented for measurement of blood pressure and renal and hindlimb blood flow (via Doppler flowprobes). A cerebroventricular cannula was placed in the lateral ventricle for drug administration. Cocaine or norcocaine was administered centrally in a dose range of 0.025 to 4.0 mg/kg. Under the above experimental conditions, 4.0 mg/kg of norcocaine decreased blood pressure without a significant change in either hind limb or renal blood flow. Central administration of cocaine also produced a similar depressor response. In conscious, unrestrained rats, cocaine produced a pressor response while norcocaine did not significantly alter blood pressure. The depressor response to both cocaine and norcocaine in the anesthetized animal is speculated to be due to the local anesthetic properties of the drugs.     

Chronic effects of centrally administered adiponectin on appetite, metabolism and blood pressure regulation in normotensive and hypertensive rats

Acute studies suggest that adiponectin may reduce sympathetic activity and blood pressure (BP) via actions on the central nervous system (CNS). However, the chronic effects of adiponectin on energy expenditure and cardiovascular function are still poorly understood. We tested if chronic intracerebroventricular (ICV) infusion of adiponectin (1 or 7μg/day) in Sprague-Dawley rats fed a high fat diet (HFD) for 8 weeks and at the high dose (7μg/day) in spontaneously hypertensive rats (SHRs), a hypertensive model associated with sympathetic overactivity, evoked chronic reductions in BP and heart rate (HR). We also determined if chronic ICV adiponectin infusion alters appetite, whole body oxygen consumption (VO(2)), and insulin and leptin levels. Neither dose of adiponectin infused for 7 days significantly altered BP or HR in the HFD group (115±2 to 112±2mmHg and 384±6 to 379±6bpm at 1μg/day; 109±3 to 111±3mmHg and 366±5 and 367±5bpm at 7μg/day). The higher dose slightly reduced food intake (14±1 to 11±1g/day), whereas VO(2), insulin and leptin levels were not affected by the treatment. In SHRs, ICV adiponectin infusion reduced appetite (22±2 to 12±2g/day) and insulin levels (～55%), but did not alter BP (162±4 to 164±3mmHg) or HR (312±5 to 322±8bpm). These results suggest that adiponectin, acting via its direct actions on the CNS, has a small effect to reduce appetite and insulin levels, but it has no long-term action to reduce BP or HR, or to alter whole body metabolic rate.     

GLP-1 receptor signaling contributes to anorexigenic effect of centrally administered oxytocin in rats

The present study examined possible interactions between central glucagon-like peptide-1 (GLP-1) and oxytocin (OT) neural systems by determining whether blockade of GLP-1 receptors attenuates OT-induced anorexia and vice versa. Male rats were acclimated to daily 4-h food access. In the first experiment, rats were infused centrally with GLP-1 receptor antagonist or vehicle, followed by an anorexigenic dose of synthetic OT. Access to food began 20 min later. Cumulative food intake was measured every 30 min for 4 h. In the second experiment, rats were infused with OT receptor blocker or vehicle, followed by synthetic GLP-1 [(7-36) amide]. Subsequent food intake was monitored as before. The anorexigenic effect of OT was eliminated in rats pretreated with the GLP-1 receptor antagonist. Conversely, GLP-1-induced anorexia was not affected by blockade of OT receptors. In a separate immunocytochemical study, OT-positive terminals were found closely apposed to GLP-1-positive perikarya, and central infusion of OT activated c-Fos expression in GLP-1 neurons. These findings implicate endogenous GLP-1 receptor signaling as an important downstream mediator of anorexia in rats after activation of central OT neural pathways.     

Dexamethasone suppresses pituitary-adrenal but not behavioral effects of centrally administered CRF

Intracerebral ventricular (icv) administration of corticotropin-releasing factor (CRF) significantly enhances the expression of stress-related behaviors in the rat and also activates the pituitary-adrenal system. The pituitary-adrenal response can be blocked by pretreatment of animals with dexamethasone. The behavioral effects (motor activation, increased grooming and decreased eating) on the other hand are resistant to suppression by dexamethasone. The independence of the behavioral effects from activation of the pituitary-adrenal axis suggests that stress-induced release of CRF could contribute to behavioral alterations even in the presence of high concentrations of endogenous steroids.     

Synchronizing, sedative and anticonvulsive effects of centrally administered somatostatin in the conscious rabbit

The effects of intracerebroventricular injection of somatostatin-14 on the cortical and deep structure electrical activity, somatic behavior and rectal temperature, were studied in 45 unanesthetized rabbits. In addition the antiepileptic action of the peptide was tested in these models: pentamethylenetetrazole-induced cortical spikes and waves, epileptic focus by topical application of strychnine and voltage-threshold for amygdala after-discharge. The results indicate that somatostatin exerts synchronizing, sedative and weak antiepileptic effects when centrally administered to rabbits.     

Peripheral mechanisms involved in the pressor and bradycardic effects of centrally administered arachidonic acid

In the current study, we aimed to determine the cardiovascular effects of arachidonic acid and peripheral mechanisms mediated these effects in normotensive conscious rats. Studies were performed in male Sprague Dawley rats. Arachidonic acid was injected intracerebroventricularly (i.c.v.) at the doses of 75, 150 or 300 microg and it caused dose- and time-dependent increase in mean arterial pressure and decrease in heart rate in normal conditions. Maximal effects were observed 10 min after 150 and 300 microg dose of arachidonic acid and lasted within 30 min. In order to evaluate the role of main peripheral hormonal mechanisms in those cardiovascular effects, plasma adrenaline, noradrenaline, vasopressin levels and renin activity were measured after arachidonic acid (150 microg; i.c.v.) injection. Centrally injected arachidonic acid increased plasma levels of all these hormones and renin activity. Intravenous pretreatments with prazosin (0.5 mg/kg), an alpha1 adrenoceptor antagonist, [beta-mercapto-beta,beta-cyclopentamethylenepropionyl1, O-Me-Tyr2-Arg8]-vasopressin (10 microg/kg), a vasopressin V1 receptor antagonist, or saralasin (250 microg/kg), an angiotensin II receptor antagonist, partially blocked the pressor response to arachidonic acid (150 microg; i.c.v.) while combined administration of these three antagonists completely abolished the effect. Moreover, both individual and combined antagonist pretreatments fully blocked the bradycardic effect of arachidonic acid. In conclusion, our findings show that centrally administered arachidonic acid increases mean arterial pressure and decreases heart rate in normotensive conscious rats and the increases in plasma adrenaline, noradrenaline, vasopressin levels and renin activity appear to mediate the cardiovascular effects of the drug.     

Propranolol prevents cerebral blood flow changes and pain-related behaviors in migraine model mice

Propranolol, a β-adrenergic receptor blocker, is one of the most commonly used prophylactic drugs for migraines. Cortical spreading depression (CSD) is the propagation wave of neuronal excitation along with cerebral blood flow (CBF) changes over the cerebral cortex and has been implicated in the pathological process of migraine auras and its pain response. However, the effect of propranolol on CSD-related CBF changes and behavioral responses remains poorly understood. In this study, we measured CSD-related CBF responses using a micro-device with a green light emitting diode (LED) and micro-complementary-metal-oxide-semiconductor (CMOS) image sensor and evaluated pain-related reduced locomotor activity in mice. An injection of KCl into the visual cortex led to CSD-related CBF changes; however, propranolol prevented the increase in CBF as well as delayed the propagation velocity in KCl-induced CSD. Furthermore, an injection of KCl reduced locomotor activity and induced freezing behavior in awake and freely moving mice, which were prevented by propranolol treatment. These results suggest that the modulation of CSD-related CBF responses by the blockade of β-adrenergic receptor contributes to its prophylactic effects on migraines.     

Renal, cardiovascular and endocrine effects of centrally administered galanin in the anaesthetised rat.

Several studies implicate galanin as a central neuromodulator with an ability to influence hypothalamic and pituitary secretion. Central galanin content is also sensitive to the state of body hydration. Cardiovascular, renal and peripheral endocrine changes evoked by intracerebroventricular administration of galanin have been examined in the anaesthetized rat. Central galanin infusion consistently induced a transitory diuresis, the increase in urine flow being associated with a reduction in urine osmolality. There was no demonstrable change in plasma vasopressin concentration at the end of a 40 min galanin infusion. However, plasma aldosterone and corticosterone concentrations were significantly reduced by comparison with time-matched vehicle infused controls. There were no clear changes in renal electrolyte excretion or in heart rate or mean arterial blood pressure during the study period. The findings of this study support a participatory role for galanin in body fluid homeostasis, though the mechanisms responsible for mediating its central action on urine production remain unclear.     

Comparison of the hemodynamic effects of endothelin-1 and big endothelin-1 in the rat

We compared the hemodynamic effects of continuous i.v. infusion of endothelin-1 and big endothelin-1 in anesthetized rats. Big endothelin-1 was fivefold less potent than endothelin-1 in decreasing cardiac output, heart rate, and stroke volume. However, big endothelin-1 produced a significantly larger increase in mean arterial pressure compared to endothelin-1 at doses that produced identical decreases in cardiac output. These findings support the hypothesis that the hypertensive effects of big endothelin-1 and endothelin-1 are produced by differential effects on systemic vascular resistances.     

Intermedin1-53对大鼠心血管功能的影响及机制探讨

目的：研究Intermedin1-53（IMD1—53）对大鼠心脏及血管功能的影响及其作用机制。方法：采用Langendorff方法灌流离体心脏,记录IMD1—53灌流下心功能的变化,并以静脉注射给药方法观察IMD1—53对动脉血压的影响,同时检测心脏及血管组织cAMP含量。结果：IMD1—53灌注明显增强心功能,LVSP,＋dp／dtmax和．dp／dtmax较对照组分别增加45％,51％和37％,并增加冠脉流量。IMD1—53增强心功能的作用可被PKA抑制刺H-89阻断。IMD1-53灌流后的心肌组织cAMP含量升高131％。此外,IMD1—53静脉注射可降低大鼠动脉血压和心率,同时经IMD1-53孵育的血管组织cAMP含量升高236％。结论：IMD1—53有明显的增强心功能及降压作用,该作用可能与cAMP途径有关。