System In Conscious Rats Research Articles

Changes in cardiovascular parameters in rats exposed to chronic widespread mechanical allodynia induced by hind limb cast immobilization.

To elucidate the relationship between chronic pain conditions with cast immobilization and autonomic function, we investigated the functional changes of the autonomic nervous system in conscious rats with chronic post-cast pain (CPCP) induced by a two-week cast immobilization of one hind limb. We telemetrically examined the time courses of systolic arterial blood pressure (SBP), heart rate (HR), and the middle-frequency (MF) component obtained from the power spectral analysis of SBP variability as a vasomotor sympathetic index. We also investigated the baroreflex sensitivity to phentolamine, an α-adrenoceptor antagonist, and the SBP and HR responses to a low ambient temperature (LT; 9.0 ± 0.2°C) exposure, a sympathetic stimulant. Rats exposed to cast immobilization exhibited mechanical allodynia lasting for at least 10 weeks after cast removal in the calf area (skin and muscle) of the bilateral hind limbs. Under resting conditions, the SBP, HR, and MF components were significantly increased during cast immobilization (all p < 0.001). Following cast removal, these parameters gradually decreased and within 1 week reached lower than baseline levels, lasting for over 10 weeks. Phentolamine administration (10 mg/kg, intraperitoneally) significantly decreased the SBP before and during cast immobilization (before, p < 0.001; during, p = 0.001) but did not lower the SBP after cast removal. The baroreflex gain after phentolamine administration, calculated as the HR increase divided by the SBP reduction, was significantly increased after cast removal (p = 0.002). The SBP increase on LT exposure was significantly greater after cast removal than that before cast immobilization, suggesting hypersensitivity to sympathetic neurotransmitters. These results revealed that, in the CPCP model, sympathetic activation was augmented during cast immobilization, which then decreased after cast removal and remained below normal levels with persisting pain behaviors. Additionally, the responsiveness of the autonomic nervous system was impaired in the CPCP model.

Central oxytocin signaling mediates the central orexin-induced visceral antinociception through the opioid system in conscious rats

Central oxytocin is implicated in a wide variety of physiological functions. With regard to gastrointestinal functions, oxytocin acts centrally to regulate gastrointestinal motility. Visceral sensation is also known as one of key gastrointestinal functions which are controlled by the central nervous system (CNS). Little is, however, known about a role of central oxytocin in visceral sensation. The present study was therefore performed to clarify whether oxytocin in the CNS may be involved in visceral sensation. Visceral sensation was evaluated by colonic distension-induced abdominal withdrawal reflex (AWR) in conscious rats. Intracisternally administered oxytocin increased the threshold volume of colonic distension-induced AWR while intraperitoneal injection of oxytocin did not alter the threshold volume. Pretreatment with subcutaneous injection of naloxone hydrochloride, a peripheral and central opioid antagonist, blocked the oxytocin-induced visceral antinociception while neither subcutaneous injection of naloxone methiodide, a peripheral selective opioid antagonist, sulpiride, a dopamine D2 receptor antagonist, DPCPX, an adenosine A1 receptor antagonist, AM251, a cannabinoid 1 receptor antagonist nor AM630, a cannabinoid 2 receptor antagonist blocked the antinociception. Intracisternally administered oxytocin antagonist, L368,899 significantly blocked the intracisternal orexin-A-induced visceral antinociception. These results suggest that oxytocin specifically acts in the CNS to enhance antinociceptive response to colonic distension through the central opioid system. The oxytocin signaling may mediate the central orexin-induced visceral antinociception.

Endothelin-1 Elicits TRP-Mediated Pain in an Acid-Induced Oral Ulcer Model

Oral ulcer is the most common oral disease and leads to pain during meals and speaking, reducing the quality of life of patients. Recent evidence using animal models suggests that oral ulcers induce cyclooxygenase-dependent spontaneous pain and cyclooxygenase-independent mechanical allodynia. Endothelin-1 is upregulated in oral mucosal inflammation, although it has not been shown to induce pain in oral ulcers. In the present study, we investigated the involvement of endothelin-1 signaling with oral ulcer–induced pain using our proprietary assay system in conscious rats. Endothelin-1 was significantly upregulated in oral ulcers experimentally induced by topical acetic acid treatment, while endothelin-1 production was suppressed by antibacterial pretreatment. Spontaneous nociceptive behavior in oral ulcer model rats was inhibited by swab applications of BQ-788 (ETB receptor antagonist), ONO-8711 (prostanoid receptor EP1 antagonist), and HC-030031 (TRPA1 antagonist). Prostaglandin E2 production in the ulcers was suppressed by BQ-788. Mechanical allodynia in the model was inhibited not only by BQ-788 and HC-030031 but also by BQ-123 (ETA receptor antagonist), SB-366791 (TRPV1 antagonist), and RN-1734 (TRPV4 antagonist). In naive rats, submucosal injection of endothelin-1 caused mechanical allodynia that was sensitive to HC-030031 and SB-366791 but not to RN-1734. These results suggest that endothelin-1 production following oral bacterial invasion via ulcerative regions elicits TRPA1-mediated spontaneous pain. This pain likely occurs through an indirect route that involves ETB receptor-accelerated prostanoid production. Endothelin-1 elicits directly TRPA1- and TRPV1-mediated mechanical allodynia via both ETA and ETB receptors on nociceptive fibers. The TRPV4-mediated allodynia component seems to be independent of endothelin signaling. These findings highlight the potential of endothelin signaling blockers as effective analgesic approaches for oral ulcer patients.

Non-invasive Method for Evaluation of Gastrocecal Transit Time by Using a Breath Test in Conscious Rats

The aim of this study was to establish a method for evaluating gastrocecal transit time using a simple and noninvasive 13C breath-test system in conscious rats. After fasting, rats were orally administered lactose-[13C]ureide. 13CO2 level in the expired air was measured at appropriate intervals. It was confirmed that priming dose of lactose-ureide was necessary for determining gastrocecal transit time. The level of 13CO2 in the expired air increased in a lactose-[13C]ureide dose-dependent manner. The gastrocecal transit time determined with 30 mg/kg of lactose-[13C]ureide was 160+/-24.5 min. This method is expected to contribute to the further understanding of intestinal pathophysiology.

Sildenafil acts on the central nervous system increasing sympathetic activity

Sildenafil induces vasodilation and is used for treating erectile dysfunction. Although its influence on resting heart function appears to be minimal, recent studies suggest that sildenafil can increase sympathetic activity. We therefore tested whether sildenafil injected into the central nervous system alters the autonomic control of the cardiovascular system in conscious rats. The effect of sildenafil citrate injected into the lateral cerebral ventricle was evaluated in conscious rats by means of the recording of lumbar sympathetic nerve activity (LSNA), spectral analysis of systolic arterial pressure and heart rate variability, spontaneous baroreflex sensitivity, and baroreflex control of LSNA. Intracerebroventricular (ICV, 100 microg /5 microl) administration of sildenafil caused remarkable tachycardia without significant change in basal arterial pressure and was associated with a conspicuous increase (47 +/- 14%) in LSNA. Spectral analysis demonstrated that systolic arterial pressure oscillations in the low frequency (LF) range were increased (from 6.3 +/- 1.5 to 12.8 +/- 3.8 mmHg(2)), whereas the high frequency (HF) range was not affected by ICV administration of sildenafil. Sildenafil increased pulse interval oscillations at LF and decreased them at HF. The LF-HF ratio increased from 0.04 +/- 0.01 to 0.17 +/- 0.06. Spontaneous baroreflex sensitivity measured by the sequence method and the baroreflex relationship between mean arterial pressure and LSNA were not affected by ICV administration of sildenafil. In conclusion, sildenafil elicited an increase in sympathetic nerve activity that is not baroreflex mediated, suggesting that this drug is able to elicit an autonomic imbalance of central origin. This finding may have implications for understanding the cardiovascular outcomes associated with the clinical use of this drug.

INCREASED CARDIAC SYMPATHETIC DRIVE AND REDUCED VAGAL MODULATION FOLLOWING ENDOTHELIN RECEPTOR ANTAGONISM IN HEALTHY CONSCIOUS RATS

1. The present study evaluated changes in autonomic control of the cardiovascular system in conscious rats following blockade of endothelin (ET) receptors with bosentan. 2. Rats were treated with bosentan or vehicle (5% gum arabic) for 7 days by gavage. 3. Baseline heart rate (HR) was higher in the bosentan-treated group compared with the control group (418 +/- 5 vs 357 +/- 4 b.p.m., respectively; P < 0.001). This baseline tachycardia was associated with a lower baroreflex sensitivity of the bradycardiac and tachycardiac responses in the bosentan-treated group compared with the control group. Sequential blockade of the parasympathetic and sympathetic autonomic nervous system with methylatropine and propranolol showed a higher intrinsic HR in the bosentan-treated group compared with the control group (411 +/- 5 vs 381 +/- 4 b.p.m., respectively; P < 0.05). This was accompanied by a higher cardiac sympathetic tone (31 +/- 1 vs 13 +/- 1%, respectively; P < 0.01) and a lower vagal parasympathetic tone (69 +/- 2 vs 87 +/- 2%, respectively; P < 0.01) in the bosentan-treated group compared with the control group. Variance and high-frequency oscillations of pulse interval (PI) variability in absolute and normalized units were lower in the bosentan-treated group than in the control group. Conversely, low-frequency (LF) oscillations of PI variability in absolute and normalized units, as well as variance and LF oscillations of systolic arterial pressure variability, were greater in the bosentan-treated group than the control group. 4. Overall, the data indicate an increased cardiac sympathetic drive, as well as lower vagal parasympathetic activity and baroreflex sensitivity, in conscious rats after chronic blockade of ET receptors with bosentan.

Partial hindlimb occlusion during coronary artery occlusion reduces the susceptibility to ventricular arrhythmias via the intrinsic adenosine receptor system in conscious rats

Temporary occlusion of coronary arteries can lead to potentially lethal arrhythmias. The arrhythmias are triggered directly by ischemia or during the reperfusion phase. Remote conditioning induced by ischemia in distant organs protects the heart from ischemic/reperfusion injury. However, the effect of remote conditioning on ischemia‐induced ventricular arrhythmias is unknown. Therefore, we tested the hypothesis that partial hindlimb occlusion during coronary artery occlusion reduces the susceptibility to ventricular arrhythmias. To test this hypothesis, 7 rats were instrumented for recording arterial pressure and ECG. A Doppler ultrasonic flow probe and vascular occluder were placed around the terminal aorta. Finally, a snare was placed around the left main coronary artery. The response to coronary artery occlusion during partial hindlimb occlusion was determined in conscious rats. Occlusion of the left main coronary artery resulted in tachy‐arrhythmias that culminated in ventricular fibrillation within 4.56 ± 0.15 min. Partial hindlimb occlusion during coronary artery occlusion culminated in ventricular fibrillation within 6.29 ± 0.49 min. Adenosine receptor blockade (theophylline, 10 mg/kg) attenuated the cardioprotective effects of remote conditioning (4.62 ± 0.79 min). Supported by HL67713

Effects of centrally administered adrenomedullin 5 on cardiovascular system in conscious rats

Effects of centrally administered adrenomedullin 5 on cardiovascular system in conscious rats

Whole Body Plethysmograph法を用いた非拘束ラットの呼吸機能測定における薬物評価

Whole Body Plethysmograph法を用いた非拘束ラットの呼吸機能測定における薬物評価

Effects of Urocortin, Corticotropin-Releasing Factor (CRF) Receptor Agonist, and Astressin, CRF Receptor Antagonist, on the Sleep-Wake Pattern: Analysis by Radiotelemetry in Conscious Rats

Stress has been known to release corticotropin-releasing factor (CRF) and have an affect on sleep-wake patterns. However, there is no direct evidence of CRF receptor agonist and antagonist on sleep-wake patterns. Therefore, this study aimed to clarify this point by using radiotelemetry system in conscious rats. Wake, non-rapid eye-moving (NREM) sleep and rapid eye-moving (REM) sleep were analyzed by computer software, simultaneously measuring electroencephalogram and electromyogram. In the light period, urocortin (CRF receptor agonist: i.v.) significantly increased wake duration, and decreased NREM sleep duration. REM sleep was not affected. Astressin (CRF receptor antagonist: i.p.) significantly attenuated the changes induced by urocortin, although astressin itself did not affect the sleep-wake pattern in the light period at this dosage. These findings show that urocortin changes the sleep-wake pattern in the light period. Moreover, urocortin was found to change the sleep-wake pattern by acting on CRF receptor, as astressin significantly attenuated the urocortin-induced changes on sleep-wake patterns.

Orexin a elicits arousal electroencephalography without sympathetic cardiovascular activation in isoflurane-anesthetized rats.

We studied the effects of intracerebroventricular injection of the novel neuropeptide orexin A on electroencephalogram (EEG) and autonomic nervous system activity in rats under isoflurane anesthesia. The administration of orexin A changed burst suppression patterns to arousal patterns on the EEG at 1.0 minimum alveolar anesthetic concentration (MAC) isoflurane and decreased the burst suppression ratio at 1.5 MAC isoflurane. However, orexin A did not influence the heart rate or mean arterial blood pressure at either isoflurane concentration. These findings demonstrated that orexin A elicited anesthetic arousal under isoflurane anesthesia in terms of EEG pattern without sympathetic cardiovascular activation in the rat. The novel neuropeptides orexins induce arousal associated with activation of the sympathetic nervous system in conscious rats. It is not known whether orexins affect the electroencephalogram (EEG), autonomic nerve activity, or both under anesthesia. Orexin A induced EEG arousal without sympathetic cardiovascular activation in the isoflurane-anesthetized rat. Orexin A might influence the depth of anesthesia.

Serotonin 1A Receptor Agonists Reverse Respiratory Abnormalities in Spinal Cord-Injured Rats

Contusion spinal cord injury (SCI) at T8 produces respiratory abnormalities in conscious rats breathing room air and challenged with CO2. In seeking ways to improve respiration after SCI, we tested drugs that stimulate serotonin 1A (5-HT1A) receptors, based on our previous findings that these agents can counteract respiratory depression produced by morphine overdose. Respiratory function was measured with a head-out plethysmograph system in conscious rats. T8 SCI rats (n = 5) showed decreased tidal volume (Vt; 0.90 +/- 0.02-0.66 +/- 0.03 ml; p < 0.05) and increased respiratory rate (f;91 +/- 3.7-132 +/- 5.7 breaths/min; p < 0.05) with room air ventilation at 24 hr after injury. They also exhibited a diminished response to the respiratory stimulating effect of 7% CO2; minute ventilation increased to 250 +/- 17 ml/min before, but only to 162 +/- 15 ml/min at 24 hr after SCI (p < 0.05). Respiratory deficits during room air ventilation were also observed at 7 d after injury (n = 3). Treatment with the 5-HT1A receptor agonist 8-hydroxy-2-(di-n-propylmino)tetralin (8-OH-DPAT; 250 microg/kg, i.p.) at 24 hr (n = 5) or 7 d (n = 3) after injury normalized Vt, f, and the respiratory response to 7% CO2. Identical results were obtained with another 5-HT1A receptor agonist, buspirone (1.5 mg/kg, i.p.; n = 3). In contrast, intraperitoneal saline vehicle administration (n = 5) showed no beneficial effects on SCI-impaired respiration. Finally, pretreatment with a specific antagonist of 5-HT1A receptors, 4-iodo-N-[2-[4-(methoxyphenyl)-1-piperazinyl]ethyl]-N-2-pyridinyl-benzamide (3 mg/kg, i.p.; n = 3) given 20 min before 8-OH-DPAT, prevented 8-OH-DPAT from restoring respiration to normal. Our results demonstrate that drugs that stimulate 5-HT1A receptors counteract respiratory abnormalities in conscious rats after SCI.

Effects of β3‐adrenoceptor stimulation on prostaglandin E2–induced bladder hyperactivity and on the cardiovascular system in conscious rats

To investigate the effects of selective beta(2)- and selective beta(3)-adrenoceptor (AR) agonists on prostaglandin (PG) E(2)-induced bladder hyperactivity in conscious free-moving rats. Female Sprague-Dawley rats were anesthetized for implantation of bladder, intravenous, and intra-arterial catheters. The effects of a beta(3)-AR agonist (CL316,243) on cystometric and cardiovascular parameters were assessed in conscious rats. Intravesical instillation of PGE(2) (20-60 microM, 6 mL/hr) in conscious rats produced a concentration-dependent increase in voiding frequency. In this model i.v. CL316,243 (beta(3)-AR agonist) reduced basal bladder pressure, increased micturition volume, and prolonged micturition interval in a dose-dependent manner, without affecting threshold pressure or micturition pressure. On the other hand, i.v. procaterol (beta(2)-AR agonist) did not counteract the bladder hyperactivity. Atropine (muscarinic antagonist) reduced micturition pressure and micturition volume, and shortened micturition interval. CL316,243 slightly decreased mean blood pressure and increased heart rate only when given at high doses (10 and 100 microg/kg, i.v.). In contrast, procaterol caused a significant decrease in mean blood pressure and a significant increase in heart rate. Atropine significantly increased heart rate. The present results clearly demonstrated that the beta(3)-AR agonist prolonged the micturition interval without producing significant cardiovascular side effects. The human detrusor, like the rat detrusor, relaxes on beta(3)-AR stimulation. Provided that these results are valid in humans, selective beta(3)-AR agonists might be clinically useful for controlling a certain type of bladder overactivity.

Effect of magnesium deficiency on neural regulation of cardiovascular system in conscious rats.

Effect of magnesium deficiency on neural regulation of cardiovascular system in conscious rats.

Interaction between endothelin and nitric oxide in sympathetic nerve modulation in hypertensive rats.

To test the hypothesis that endothelin (ET) and nitric oxide (NO) interact in modulating the sympathetic nervous system in conscious rats, as they do in the endothelium, mean arterial pressure (MAP), heart rate, and renal sympathetic nerve activity (RSNA) were recorded in Wistar-Kyoto (WKY) and spontaneously hypertensive rats (SHR) given losartan and compared before and during intravenous infusion of an NO synthase inhibitor, L-NMMA (0.25 mg/kg/min). The slope of the relation between RSNA and MAP to blood pressure reduction was increased in the presence of L-NMMA (from 0.6 +/- 0.1 to 2.8 +/- 0.2), suggesting that endogenous NO suppresses the reflex increase in RSNA. Since NO inhibits ET production in the endothelium, we speculated that the increase in MAP-RSNA slope was due partly to an unmasking of ET, and thus recorded MAP, heart rate, and RSNA during intravenous infusions of both L-NMMA and the ET-type-A-receptor antagonist BQ-485 (0.10 mg/kg/min). The slope decreased significantly in SHR when BQ-485 was added (1.5 +/- 0.2), but not in WKY, implying that unmasked ET enhanced the sympathetic increase via ETA receptors in hypertensive rats. An ETB-receptor antagonist potentiated the sympathetic response only in WKY rats. These results suggest that NO suppressed the reflex increase in RSNA to blood pressure reduction, while ET uncovered by L-NMMA enhanced the sympatho-activation, indicating an interaction between ET and NO in modulating the sympathetic nervous system in conscious hypertensive animals in vivo. In contrast, the interaction was not observed in normotensive rats.

Evaluation of a novel nimodipine delivery system in conscious rats that allows sustained release for 24 h

Methodologies that allow prolonged drug administration in animal models, while minimizing surgery and anesthesia, are an important contribution towards studies in awake conditions. Commercially available drug delivery systems like pellets can be customized for the evaluation of experimental therapies with minimal or no discomfort to animals. Our objective was to evaluate pharmacokinetic and physiologic parameters after subcutaneous implantation of rapid 24 h release nimodipine pellets in rats for their potential use as a delivery system for stroke therapeutics. A day prior to the study Sprague-Dawley rats were anesthetized (halothane, N 2O, O 2) for femoral vessel cannulation and later returned to their cages. On the day of the study the rats were briefly anesthetized (identical regimen as before), and assigned to two groups: nimodipine (NP) and placebo (PL). NP rats received either 0.5 ( n = 4), 1 ( n = 3), 2 ( n = 2), 4 ( n = 2), or 15 ( n = 5) mg pellets (Innovative Research of America Inc., Sarasota, FL, USA) and PL rats ( n = 5) received placebo pellets. Nimodipine plasma levels were measured at 1, 3, and 6 h. In addition, the 15 mg NP group was followed at 18 and 24 h. Immediately following decapitation the brain was removed for later determination of nimodipine tissue concentration. The NP 15 mg group showed a significant decline of 10% in MABP from base line to 24 h post implantation ( p < 0.001). All NP animals achieved at least 83% of their highest plasma concentration at 1 h and 94% at 3 h. A high degree of correspondence ( r 2 = 0.95, y = 0.36 + 0.28 x, n = 16) between the plasma and brain concentrations of nimodipine was present. Although a significant drop in MABP was observed the drop was no greater than 10% in 24 h. Plasma nimodipine levels for the 15 mg animals were within the cerebrovascular effective range. This is the first report to show that 24 h release nimodipine pellets subcutaneously implanted in rats are a reliable delivery system that allows rapid rise and constant nimodipine plasma levels. Therefore, 24 h release pellets are a suitable alternative to other delivery systems like osmotic pumps.

Distension of the proximal colon induces FOS in the central nervous system in conscious rats: Role of Capsaicin sensitive afferents: [formula omitted], L. Wang, J.-C. Marvizón, Y. Taché CURE/GBC, VA Med. Ctr., Brain Res. Inst. and Dept. med., UCLA. Los Angeles, CA 90073

Distension of the proximal colon induces FOS in the central nervous system in conscious rats: Role of Capsaicin sensitive afferents: [formula omitted], L. Wang, J.-C. Marvizón, Y. Taché CURE/GBC, VA Med. Ctr., Brain Res. Inst. and Dept. med., UCLA. Los Angeles, CA 90073

Mechanical stimulation of the colon delays gastric emptying and stimulates specific areas of the central nervous system in conscious rats

Mechanical stimulation of the colon delays gastric emptying and stimulates specific areas of the central nervous system in conscious rats

Opposite changes in the mesolimbic dopamine metabolism in the nerve terminal and cell body sites induced by locally infused baclofen in the rat

Infusion of baclofen (10 −4 M, 1 h) into the ventral tegmental area (VTA), the cell body site of mesolimbic dopamine (DA) neuron system in conscious rats, caused a decrease in both axonal and somatodendritic DA release in this neuron system, when monitored by in vivo microdialysis using two probes simultaneously placed in both the NAC and the VTA. Levels of the metabolite of DA, 3,4-dihydroxyphenylacetic acid (DOPAC) in the VTA decreased significantly in a similar manner following infused baclofen into the VTA, however, a pronounced increase in DOPAC outflow was observed in dialysates from the NAC. This dissociated changes in DA metabolism observed in the NAC may possibly be derived from regulatory mechanisms via an autoreceptor located in the DA nerve terminals.

Metabolic and neuroanatomical correlates of barrel-rolling and oculoclonic convulsions induced by intraventricular endothelin-1: a novel peptidergic signaling mechanism in visuovestibular and oculomotor regulation?

The neuroactive peptide endothelin-1 has receptors distributed abundantly among subdivisions and nuclei of the visuovestibular and oculomotor systems. In previous work, we and others described the convulsive manifestations resulting from central injection of this neuropeptide, including nystagmus, oculoclonus, exophthalmos, tonic hindlimb extension, and a generalized repetitive motor disturbance called barrel-rolling. We applied the quantitative, autoradiographic [14C]deoxyglucose method to examine the hypothesis that visuovestibular and oculomotor structures would become metabolically stimulated when endothelin was introduced into the brain via the ventricular system in conscious rats. Since previous work had demonstrated that hypermetabolic responses to endothelin in other neural systems were inhibited by an antagonist of neuronal calcium L-type channels, nimodipine, we further tested whether the increased function of vestibulooculomotor nuclei whose metabolic activity was sensitive to endothelin could be altered following nimodipine pretreatment via the ventricle. A single unilateral injection of endothelin (9 pmol in 3 microliters saline) into a lateral ventricle provoked significantly increased rates of glucose metabolism in 22 of 39 individual anatomical structures of the visuovestibular and oculomotor systems. Among those affected were the superficial stratum of the caudal superior colliculus (+25%), the optic tract bilaterally (+35 to 43%), the oculomotor cranial nerve nuclei (III, IV, VI; range of +21 to 47%), and the medial terminal nucleus of the accessory optic tract which harbors dense fields of endothelin binding sites (bilateral increase of +70 to 96%). Several other nuclei involved in the proprioceptive and visuovestibular disturbance caused by endothelin displayed increased metabolic activity, including the cuneate, gracile, sensory trigeminal, and prepositus hypoglossal nuclei, the vestibular subnuclear system, and the cerebellar flocculus. Identification of hypermetabolic responsivity to endothelin in these structures provides further information on the anatomical substrates mediating the behavioral phenomenology of endothelin-induced motor convulsions which involve the paroxysmal participation of the extraocular muscles and motor control systems producing barrel-rolling convulsions. Nimodipine pretreatment inhibited both the convulsive activity and the cerebral hypermetabolic responses to intraventricular endothelin. The results indicate that the neural systems sensitive to intraventricular endothelin become functionally active via a calcium-mediated process that may involve the neuropeptide as an intrinsic signaling molecule.