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.     

Cardiovascular effects of delta 9- and delta 9(11)-tetrahydrocannabinol and their interaction with epinephrine

The administration of delta-9-tetrahydrocannabinol (delta 9-THC, 0.078-5.0 mg/kg, i.v.) to rats anesthetized with pentobarbital caused as much as a 50% decrease in mean arterial blood pressure, heart rate and respiratory rate in a dose-dependent manner. Delta-9(11)-tetrahydrocannabinol (delta 9(11)-THC) was approximately 8-fold less potent than delta 9-THC in its hypotensive effect and had smaller effects on heart and respiratory rates that were not dose-related at doses below 5 mg/kg. Alternate injections of epinephrine (2 micrograms/kg) with vehicle and increasing cannabinoid doses (1.25-5.0 mg/kg) indicated a potentiation of both the duration of the pressor effect and the magnitude of the reflex bradycardic effect of epinephrine by both delta 9- and delta 9(11)-THC. Epinephrine also produced arrhythmias in rats receiving cannabinoids, but not in rats receiving alternate injections of vehicle. It is concluded that both cannabinoids have adverse effects on the cardiovascular system and adverse interactions with epinephrine in rats anesthetized with pentobarbital.     

Reduction by atropine of phencyclidine hypertension and apneusis

The aim of this study was to assess the possible role of a central cholinergic component phencyclidine (PCP)-induced hypertension. Sprague-Dawley rats, lightly anesthetized with urethane, exhibited a dose related pressor response following 0.1–1.0 mg/kg PCP i.v. After i.v. atropine pre-treatment, the PCP dose-response curve was shifted to the right, and the magnitude of the pressor responses was reduced by about 50%. In addition, atropine reduced the incidence of apneusis, but had no effect on the bradycardia that accompanied the pressor responses. Methylatropine (i.v.) did not reduce the PCP pressor responses, nor did it prevent the apneusis induced by PCP. These results suggest that in addition to its direct pressor effects the activation of central cholinergic systems contribute significantly to the cardiovascular and respiratory toxicity induced by PCP.     

Cardiovascular effect of intravenously administered thyrotropin-releasing hormone and its concentration in push-pull perfusion of the fourth ventricle in conscious and pentobarbital-anesthetized rats

Changes in the concentration of thyrotropin-releasing hormone (TRH) in cerebrospinal fluid (CSF) were examined by the push-pull perfusion method after intravenous (i.v.) administration of the peptide in conscious and pentobarbital-anesthetized rats. The concentration of endogenous TRH in the perfusate was not changed during the 160-min perfusion period and was similar to that in the CSF (0.92 +/- 0.26 ng/ml) collected before the perfusion in conscious as well as in anesthetized rats. After i.v. administration of TRH (5 mg/kg) to the conscious rats, the peptide concentration in the perfusate increased to 42.23 +/- 14.33 ng/ml during the first 20 min and gradually returned to the basal level 2 hr after administration. The total amount of TRH detected in the perfusate was 20.0 ng. It was reduced by 75% in the anesthetized animals. The increases in blood pressure and heart rate, seen after i.v. as well as intracerebroventricular administration of TRH in the conscious rats, was significantly inhibited in the anesthetized rats. These results indicate that systemically administered TRH exerts its cardiovascular effect at central site(s), and that the transportation and the effect of the peptide is suppressed by pentobarbital anesthesia.     

Effects of nitric oxide synthesis inhibition with or without nitric oxide inhalation on responses to systemic cocaine administration in rats

The effects of N^ω-nitro-L-arginine methyl ester (L-NAME) i.v. and nitric oxide (NO) inhalation on integrated systemic responses to cocaine were studied in lightly anesthetized, paralyzed, and mechanically ventilated rats. Cocaine (4 mg/kg/min i.v.) produced seizures then isoelectric electrocephalographic (isoEEG) activity as well as an initial increase in systolic blood pressure and heart rate, then progressive cardiovascular system depression culminating in asystole. Pretreatment with L-NAME (2 mg/kg/min i.v.) for 30 min significantly reduced the incidence of seizure as compared to saline treated animals (saline 7/8; L-NAME 3/8). Doses of cocaine that produced arrhythmias, isoEEG and asystole were significantly lower in the L-NAME treated animals as compared to the saline group. L-NAME did not affect peak systolic blood pressure and heart rate responses to cocaine. NO inhalation (80 ppm) did not affect CNS and cardiovascular responses to cocaine in control animals but enhanced the effects of L-NAME on cocaine toxicity. The results show that pretreatment with L-NAME reduces the central nervous system stimulatory effect of cocaine (reduced seizure incidence) and enhances its depressant effect on both the central nervous system (lower does for isoEEG) and the cardiovascular system (lower dose for arrhythmias and asystole), but does not affect the cardiovascular stimulatory action of cocaine. NO inhalation does not protect against any of the systemic effects of cocaine in animals with normal or suppressed NO production.     

Cardiovascular effects of centrally administered endothelin-1 and its relationship to changes in cerebral blood flow

Intracerebroventricular (i.c.v.) injection of endothelin-1 (ET-1; 100 ng, i.c.v.) produced an initial pressor (24%) (peak at 3 min following ET-1 administration) and a delayed depressor (−40%) (30 and 60 min following ET-1 administration) effects in urethane anesthetized rats. The pressor effect of ET-1 was due to an increase (21%) in cardiac output, while the depressor effect of ET-1 was associated with a marked decrease (−46%) in cardiac output. Stroke volume significantly decreased at 30 and 60 min after the administration of ET-1. No change in total peripheral vascular resistance and heart rate was observed following central administration of ET-1. The effects of ET-1 on blood pressure, cardiac output and stroke volume were not observed in BQ123 (10 μg, i.c.v.) treated rats. Blood flow to the cerebral hemispheres, cerebellum, midbrain and brain stem was not affected at 3 min, but a significant decrease in blood flow to all the regions of the brain was observed at 30 and 60 min following central administration of ET-1. BQ123 pretreatment completely blocked the central ET-1 induced decrease in blood flow to the brain regions. It is concluded that the pressor effect of centrally administered ET-1 is not accompanied by a severe decrease in brain blood flow, however, a subsequent decrease in blood pressure is associated with a decrease in blood flow to the brain. The cardiovascular effects of ET-1 including decrease in brain blood flow are mediated through central ET_A receptors.     

Potentials evoked in the intermediolateral column by hypothalamic stimulation - suppression by delta 9-tetrahydrocannabinol

Δ⁹-Tetrahydrocannabinol (THC), the primary psychoactive component of marihuana produces pronounced effects on the cardiovascular system including bradycardia and hypotension. A decrease in sympathetic activity may contribute to these actions. In chloralose urethane anesthetized cats, THC (2 mg/kg, i.v.) produced significant bradycardia, hypotension and attenuation of threshold pressor responses induced by hypothalamic stimulation. Evoked potentials recorded in the intermediolateral cell column (ILC) by stimulation of these hypothalamic pressor sites were significantly altered after THC. Hypotension induced by histamine administration (5 μg/kg, i.v.) altered ILC potentials before and after THC. These results support the hypothesis that THC reduces sympathetic outflow and reversibly resets the level of central cardiovascular homeostasis.     

Cardiovascular responses to V1-vasopressinergic antagonism in conscious versus anesthetized rats

Experiments were performed to compare the possible effect of endogenous arginine vasopressin on renal hemodynamics between anesthetized, surgically stressed rats and conscious rats. Animals were instrumented with arterial and venous catheters as well as with a pulsed Doppler flow probe on the left renal artery. The rats were studied under the following conditions: (1) conscious and unrestrained; (2) anesthetized only; (3) anesthetized with minor surgical stress; and (4) anesthetized with major surgical stress. Two anesthetic agents were also compared, a mixture of ketamine (110 mg/kg i.m.) and acepromazine (1 mg/kg i.m.), and sodium pentobarbital (50 mg/kg i.p.). Baseline mean arterial blood pressure was significantly higher in pentobarbital-anesthetized rats following surgical stress compared with conscious animals, but blood pressure was not affected by ketamine-acepromazine anesthesia. After baseline measurements of blood pressure, heart rate, and renal blood flow, a specific V1-vasopressinergic antagonist (d(CH2)5Tyr(Me) arginine vasopressin, 10 mg/kg i.v.) was administered to each group. Mean arterial blood pressure, heart rate, and renal blood flow were monitored for an additional 15 min. Mean arterial blood pressure and renal blood flow decreased after V1 antagonism in ketamine-acepromazine-anesthetized rats with major surgical stress, but were not affected in pentobarbital-anesthetized animals. Heart rate and renal vascular resistance were not affected following V1 blockade with either anesthetic agent. These data suggest that arginine vasopressin plays a role in maintaining blood pressure and renal perfusion in ketamine-acepromazine-anesthetized rats following surgical stress, but does not have a significant effect on renal hemodynamics under pentobarbital anesthesia.     

The involvement of central cholinergic mechanisms in cardiovascular responses to intracerebroventricular and intravenous administration of thyrotropin-releasing hormone

Intracerebroventricular (i.c.v.) administration of thyrotropin-releasing hormone (TRH) in a range from 0.1 to 100 micrograms induced a dose-related increase in blood pressure in conscious rats, whereas TRH-free acid (TRH-OH) and histidyl-proline diketopiperazine (His-Pro-DKP), metabolites of TRH, did not. The blood pressure responses to intravenous (i.v.) injection of 5 mg/Kg TRH were similar to those induced by TRH (i.c.v.). Pretreatment with atropine (50 micrograms, i.c.v.) significantly reduced the pressor effect of TRH administered through either route. Hemicholinium-3 (50 micrograms, i.c.v.), an inhibitor of choline uptake, also prevented the increase in blood pressure induced by TRH (10 micrograms, i.c.v.). These results indicate that both centrally and peripherally administered TRH have pressor effects that are mediated by central cholinergic mechanisms, probably by activating cholinergic neurons.     

Central nervous system actions of corticotropin-releasing factor on cardiovascular function in the absence of locomotor activity

Studies were performed in conscious and anesthetized Sprague-Dawley rats to examine whether the cardiovascular responses to intracerebroventricular (i.c.v.) administration of corticotropin-releasing factor (CRF) required concomitant locomotor activation. I.c.v. administration of CRF to conscious animals elicited significant increases in arterial pressure, heart rate, mesenteric resistance, and iliac blood flow, as well as intermittent locomotor, grooming and chewing activity. Intravenous infusion of the anesthetic agent, Saffan, at the minimal dose required to abolish locomotor activity caused slight but significant elevations of heart rate and mesenteric vascular resistance. I.c.v. administration of CRF to anesthetized animals produced delayed, yet significant and sustained increases in the heart rate and arterial pressure, without altering regional blood flow. These results demonstrate that locomotor activation is not requisite for the expression of CRF-induced pressor and tachycardic responses. It is concluded that CRF acts within the central nervous system to influence cardiovascular function in the absence of locomotor activity.     

Central mechanisms of action involved in cocaine-induced tachycardia

The present study was designed to determine the central effects of cocaine on heart rate and blood pressure in Wistar Kyoto rats (WKY) and to evaluate mechanisms involved in the response. Cocaine (0.025-4 mg/kg) was administered to unanesthetized, unrestrained rats via a cannula placed into the lateral ventricle. Procaine (0.1 and 4 mg/kg) was also administered centrally. Cocaine did not significantly alter blood pressure at doses of 0.025, 0.1, or 0.5 mg/kg, icv. Only the highest dose, 4 mg/kg, icv produced a significant pressor response. Cocaine produced significant dose-dependent tachycardia, with the maximum increase in heart rate occurring within 5 min. Procaine (4 mg/kg, icv) produced tachycardia, but the effect was significantly less than that produced by cocaine (4 mg/kg, icv). Cocaine also produced tachycardia at a dose of 0.1 mg/kg, but procaine did not significantly alter heart rate at the same dose. Central phentolamine pretreatment (0.1 mg/kg, icv) significantly attenuated the increase in heart rate produced by cocaine. These results indicate that the centrally mediated tachycardia produced by cocaine is partly due to its local anesthetic activity and to indirect stimulation of alpha receptors.     

Effects of cocaine on the electrical activity of single noradrenergic neurons from locus coeruleus

The effects of intravenous (i.v.) cocaine HCl on single identified spontaneously firing noradrenergic neurons in the nucleus locus coeruleus (LC) were studied in rats in vivo. Cocaine (0.25-1 mg/kg) produced inhibition of spontaneously firing LC neurons, which was reversed by the administration of the selective alpha 2-adrenoceptor antagonist, piperoxane (250 micrograms/kg, i.v.). Procaine, a local anesthetic that is structurally related to cocaine, did not inhibit LC neurons in doses up to 4 mg/kg, i.v. These results suggest that cocaine in low doses has significant central sympathomimetic effects at the single noradrenergic neuron level and that the inhibition of spontaneous activity may be mediated by alpha 2-adrenoceptors. Our results also indicate that cocaine in pharmacologically relevant doses, can significantly affect central alpha 2-adrenoceptor regulatory processes.     

Central mechanism underlying pressor and bradycardic effect of intracerebroventricularly injected arachidonic acid

The aim of the current study was to determine the central cyclooxygenase (COX) pathway and central thromboxane signaling in the cardiovascular effects evoked by arachidonic acid (AA). As a main control for the study, different doses of AA (75, 150, or 300?μg) were administered intracerebroventricularly (i.c.v.). Centrally injected AA dose- and time-dependently increased mean arterial pressure and decreased heart rate in conscious normotensive Sprague-Dawley rats. The maximal cardiovascular effects of AA were observed at min 10 of the injection and lasted almost 30?min. To investigate the central mechanism of the AA-induced cardiovascular effect in conscious normotensive animals, pretreatment with nonselective COX inhibitor indomethacin (200?μg; i.c.v.), thromboxane A2 (TXA2) synthesis inhibitor furegrelate (250 or 500?μg; i.c.v.), or TXA2 receptor antagonist SQ-29548 (8 or 16?μg; i.c.v.) was carried out 15?min before AA (150?μg; i.c.v.) injection. While indomethacin completely prevented the pressor and bradycardic responses to AA, furegrelate and SQ-29548 attenuated these effects in part in awake normotensive rats. In conclusion, these findings suggest that the pressor and bradycardic cardiovascular effects of centrally injected AA are dependent on COX activity being totally central and the TXA2 signaling pathway being subsequently central, at least in part.     

Variations in the effect of clonidine on arterial pressure in rats in the presence of various anesthetics]

The central hypotensive agent, clonidine (30 microgram/kg i.v.) has been injected in normotensive rats anesthetized with various agents. This dose of clonidine elicits usually a biphasic blood pressure response, i.e. a transient increase due to peripheral vasoconstriction, followed by a long lasting decrease. This has been observed in the animals anesthetized with pentobarbitone as well as with urethane. The hypotensive effect is abolished during chloralose, ketamine or Alfatésine anesthesia. These data emphasize that some anesthetics mays particularly modify the effects of centrally acting cardiovascular drugs.     

Cardiovascular effects of 1,8-cineole,a terpenoid oxide present in many plant essential oils,in normotensive rats

The cardiovascular effects of i.v. treatment with 1,8-cineole, a monoterpenic oxide present in many plant essential oils, were investigated in normotensive rats. This study examined (i) whether the autonomic nervous system is involved in the mediation of 1,8-cineole-induced changes in mean aortic pressure (MAP) and heart rate (HR) and (ii) whether the hypotensive effects of 1,8-cineole could result from its vasodilatory effects directly upon vascular smooth muscle. In both pentobarbital-anesthetized and conscious, freely moving rats, bolus injections of 1,8-cineole (0.3-10 mg/kg, i.v.) elicited similar and dose-dependent decreases in MAP. Concomitantly, 1,8-cineole significantly decreased HR only at the highest dose (10 mg/kg). Pretreatment of anesthetized rats with bilateral vagotomy significantly reduced the bradycardic responses to 1,8-cineole (10 mg/kg) without affecting hypotension. In conscious rats, i.v. pretreatment with methylatropine (1 mg/kg), atenolol (1.5 mg/kg), or hexamethonium (30 mg/kg) had no significant effects on the 1,8-cineole-induced hypotension, while bradycardic responses to 1,8-cineole (10 mg/kg) were significantly reduced by methylatropine. In rat isolated thoracic aorta preparations, 1,8-cineole (0.006-2.6 mM) induced a concentration-dependent reduction of the contraction induced by potassium (60 mM). This is the first physiological evidence that i.v. treatment with 1,8-cineole in either anesthetized or conscious rats elicits hypotension; this effect seems related to an active vascular relaxation rather than withdrawal of sympathetic tone.     

Cardiovascular effects of methyleugenol, a natural constituent of many plant essential oils, in normotensive rats

Cardiovascular effects of intravenous (i.v.) treatment with methyleugenol (ME), a natural constituent of many plant essential oils, were investigated in normotensive rats. Additionally this study examined (I) whether the autonomic nervous system is involved in the mediation of ME-induced changes in mean aortic pressure (MAP) and heart rate (HR), and (II) whether the hypotensive effects of ME could result from its vasodilatory effects directly upon vascular smooth muscle. In both pentobarbital-anesthetized and conscious rats, i.v. bolus injections of ME (1 to 10 mg/kg) elicited similar and dose-dependent decreases in MAP. In anesthetized rats, ME decreased HR only at the highest dose (10 mg/kg), while changes of this parameter were not uniform in conscious rats. Pretreatment of anesthetized rats with bilateral vagotomy significantly reduced the bradycardia response to ME (10 mg/kg) without affecting the hypotension. In conscious rats, i.v. pretreatment with methylatropine (1 mg/kg) or hexamethonium (30 mg/kg) had no significant effect on ME-induced hypotension. In rat isolated thoracic aorta preparations, ME (0.006-1.68 mM) induced a concentration-dependent reduction of potassium (60 mM)-induced contraction. This is the first physiological evidence that i.v. treatment with ME in either anesthetized or conscious rats elicits hypotension; an effect that seems related to an active vascular relaxation rather than withdrawal of sympathetic tone.     

Effects of cocaine alone and in combination with haloperidol and SCH 23390 on cardiovascular function in squirrel monkeys

The potential involvement of D1 and D2 dopamine receptors in the effects of cocaine on cardiovascular function in squirrel monkeys was evaluated. A low dose of cocaine (0.1 mg/kg i.v.) produced increases in both blood pressure and heart rate. At the higher doses of cocaine (1.0-3.0 mg/kg) the heart rate response was biphasic, consisting of an early decrease followed by an increase in heart rate 10-20 min following injection. The dopamine D2 antagonist haloperidol (0.1 mg/kg i.m.) attenuated the heart rate increasing effect of cocaine, but doses as high as 0.03 mg/kg did not alter the blood pressure increase. The D1 antagonist SCH 23390 (0.01-0.03 mg/kg i.m.) did not attenuate either the blood pressure or heart rate increasing effects of cocaine. The D2 agonist quinpirole (1.0 mg/kg i.v.) produced increases in heart rate similar to cocaine, with little effect on blood pressure. Although effective against the heart rate increasing effect of cocaine, haloperidol (0.01 mg/kg) did not antagonize the heart rate increasing effects of quinpirole. The D1 agonist SKF 38393 (3.0 mg/kg i.v.) decreased heart rate and increased blood pressure. The blood pressure increasing effect of SKF 38393 was antagonized by 0.01 mg/kg SCH 23390. Haloperidol's ability to partially antagonize the tachycardiac response to cocaine suggests the involvement of D2 receptors in that response. However, the failure of haloperidol to antagonize quinpirole's tachycardiac effect suggests that non-dopaminergic mechanisms may also be involved in haloperidol's antagonism of cocaine's tachycardiac effect. The pressor effects of cocaine do not appear to be controlled by selective dopamine receptors.     

Adrenoceptor mechanisms in the cardiovascular effects of cocaine in conscious squirrel monkeys.

The purpose of the current experiment was to study the role of various adrenoceptor subtypes in the cardiovascular response to cocaine in conscious squirrel monkeys. A variety of adrenoceptor antagonists were administered i.v. prior to the administration of 0.3 mg/kg cocaine (i.v.). Cocaine alone produced an increase in both blood pressure and heart rate. The non-selective alpha adrenoceptor antagonist phentolamine produced a dose-dependent antagonism of the pressor effect of cocaine, as did the alpha-1 selective antagonist prazosin. The alpha-2 selective antagonist yohimbine had no effect on the pressor effect of cocaine. The non-selective beta antagonist propranolol enhanced the pressor effect of cocaine as did the beta-1 selective antagonist atenolol. However, the effect of atenolol was not dose-dependent. The beta-2 selective antagonist ICI 118,551 and labetalol, which blocks both alpha and beta adrenoceptors, did not alter the pressor effect of cocaine. Propranolol, atenolol, and labetalol all antagonized the tachycardiac effect of cocaine in a dose-dependent manner, while the beta-2 antagonist ICI 118,551 did not. Phentolamine, prazosin and yohimbine also reduced the tachycardiac effect of cocaine, although these effects were dose-dependent only for yohimbine, which also significantly elevated baseline heart rate. These results indicate that alpha-1 adrenoceptor mechanisms mediate the pressor effect of cocaine, while beta-1 adrenoceptor mechanisms are involved in the tachycardiac effect of cocaine in squirrel monkeys. Propranolol potentiated cocaine's pressor effect through beta-2 independent mechanisms. Thus, neither alpha-2 nor beta-2 adrenoceptor mechanisms appear to be involved in cocaine's cardiovascular effects.     

Differential depressant effects of general anesthetics on the cardiovascular response to cocaine in mice.

In recent years, murine models have gained increasing importance for studies of cardiovascular physiology and pharmacology, largely due to the development of transgenic strains with specific alterations in phenotype. Differential effects of general anesthetic agents on the cardiovascular responses to cocaine have been reported in larger mammals; therefore, we studied the effects of commonly used anesthetics on heart function and on blood pressure responses to cocaine in Swiss Webster mice. We positioned a polyethylene catheter (PE-10) in the right carotid artery or left ventricle of mice anesthetized with equivalent anesthetic dose of either ketamine-xylazine (KX, 40 mg/kg + 5 mg/kg), pentobarbital (PEN, 40 mg/kg) or alpha-chloralose-urethane (CU, 80 mg/kg + 100 mg/kg). Cocaine (0.3 mg/kg, 1 mg/kg and 3 mg/kg) was administrated via the left jugular vein by bolus injection. In the KX group, the basal mean arterial pressure (MAP) and systolic left ventricular pressure (LVP) were 110 +/- 12 and 120 +/- 13 mmHg, respectively, close to conscious values. However, PEN and CU significantly decreased the basal parameters (P < 0.01 compared to the KX group). The lowest dose of cocaine (0.3 mg/kg) elicited minimal changes. Significant responses were obtained with a 1-mg/kg dose of cocaine (P < 0.01 compared to baseline). However, at 3 mg/kg, a toxic effect of cocaine appeared in all three anesthetic groups. Compared to published conscious animal data, anesthetic agents attenuated the cardiovascular effects of cocaine. Taken together, our results indicate that minimally effective doses of general anesthetics may significantly alter the basal hemodynamic state and the responses to sympathomimetic agents in the murine model, as has been reported in larger mammalian species. We concluded that anesthesia with ketamine-xylazine provides baseline hemodynamic values close to reported values in conscious animals, but also attenuates the hemodynamic response to cocaine.     

Cardiorespiratory effects of μ and δ opiate agonists following third or fourth ventricular injections

The cardiorespiratory effects of prototype μ (morphine and β-casomorphine 1–4) and δ (D-Ala²-D-Leu⁵Enkephalin—DADLE) opioid ligands were compared following microinjection into third and fourth ventricular spaces in conscious and anesthetized rats. The direction of change in arterial pressure produced by ventricular opioid injections varied according to ligand, site of administration, and state of consciousness of the animal. In general, pentobarbital anesthesia blocked or reversed the pressor response to these opiate agonists; depressor responses became magnified following pentobarbital. Qualitatively, the predominant effect of third ventricular DADLE in anesthetized rats was to produce a depression of arterial pressure and pulse pressure, suggesting an involvement of hypothalamic δ opioid receptors in decreasing sympathetic outflow. By contrast, morphine exerted pronounced bradycardic effects following fourth ventricular administration, suggesting an action at μ opioid receptors which influence vagal parasympathetic activity. Both ligands lowered respiratory rates upon fourth ventricular injection, indicating a possible involvement of either opioid receptor subtype in the depression of brainstem respiratory centers. These depressant effects of opioids upon cardiorespiratory function were readily reversed by naloxone. The qualitative similarity between the cardiovascular effects of third ventricular DADLE administration and various forms of circulatory shock may indicate that both phenomena involve delta opioid receptors at hypothalamic sites.