Angiotensin and NMDA receptors in the median preoptic nucleus mediate hemodynamic response patterns to stress

The brain renin-angiotensin system plays an important role in the regulation of arterial pressure in response to stress, in part due to activation of AT1 receptors in the hypothalamic median preoptic nucleus (MnPO) by endogenous angiotensin II (ANG II). N-methyl-d-aspartate (NMDA) receptors are also involved in the angiotensinergic signaling pathway through the MnPO. We investigated whether AT1 and NMDA receptors in the MnPO are responsible for variable hemodynamic response patterns to stress. Cocaine or startle with cold water evoked a pressor response in Sprague-Dawley rats due, in some rats [vascular responders (VR)], to a large increase in systemic vascular resistance (SVR) and, in other rats [mixed responders (MR)], to small increases in SVR and cardiac output (CO). Microinjection of the GABAA agonist muscimol into the MnPO to block synaptic transmission attenuated the cocaine- or stress-induced increase in SVR and the decrease in CO seen in VR without altering either response in MR. Likewise, administration of either an AT1 receptor antagonist, losartan, or an NMDA receptor antagonist, MK-801, attenuated the increase in SVR and the decrease in CO in VR in response to either cocaine (losartan and MK-801) or startle with cold water (losartan) without altering either response in MR. We propose that the MnPO is responsible for greater SVR responses in VR and that AT1 and NMDA receptors play an important role in greater SVR responses in VR. These data provide additional support for the critical role of the MnPO in cardiovascular responses to stress.     

Olfactory bulbectomy attenuates cardiovascular sympathoexcitatory reflexes in rats

Bilateral removal of the olfactory lobes in rats produces a number of behavioral, endocrine, and neurochemical alterations in the brain. Little is known, however, regarding the effects of this treatment on cardiovascular function and autonomic reflexes. Male Sprague-Dawley rats underwent bilateral surgical ablation of the olfactory bulbs (n = 10) or were sham operated (n = 8). After 3 wk of recovery, animals were instrumented with femoral catheters and a lumbar sympathetic nerve recording electrode. After 24 h of recovery, cardiovascular responses to arterial baroreflex manipulation, air jet stress, and smoke exposure were recorded. Olfactory bulbectomized rats demonstrated attenuated sympathoexcitatory responses to hypotension, air jet stress, and smoke exposure, as well as elevated basal blood pressure, compared with sham-operated rats. These data indicate that the integrity of the olfactory bulbs in rats is important for the elicitation of normal cardiovascular and autonomic responses to a number of evocative stimuli.     

Estrogen replacement suppresses stress-induced cardiovascular responses in ovariectomized rats

We assessed the hypothesis that chronic estrogen replacement in ovariectomized rats has the beneficial effect of suppressing stress-induced cardiovascular responses through endothelial nitric oxide synthase (eNOS). We employed a radiotelemetry system to measure blood pressure and heart rate (HR). Female Wistar rats aged 11 wk were ovariectomized and implanted with radiotelemetry devices. After 4 wk, the rats were assigned either to a placebo-treated group (Placebo; n=6) or a group treated with 17beta-estradiol (Estrogen; n=8) subcutaneously implanted with either placebo- or 17beta-estradiol (1.5 mg/60-day release) pellets under anesthesia. These rats underwent either of the two types of stress after 4 wk of estrogen or placebo treatment. Cage-switch stress and restraint stress rapidly and continuously elevated the mean arterial pressure (MAP) and HR both in the Placebo and Estrogen groups. However, the MAP and HR responses to cage-switch stress and the MAP but not HR response to restraint stress were attenuated significantly in the Estrogen group compared with the Placebo group. A NOS inhibitor, NG-nitro-L-arginine methyl ester, given in drinking water, reduced the difference in the pressor response to cage-switch between the Estrogen and Placebo groups. In addition, Western blot analysis showed that eNOS expression in the mesentery was increased in the Estrogen group compared with the Placebo group. Thus for the first time we showed that mesenteric eNOS overexpression could explain at least partly why chronic estrogen treatment suppressed the enhanced cardiovascular responses to psychological stress in the ovariectomized rat.     

Role of angiotensin II and corticotropin-releasing hormone in hemodynamic responses to cocaine and stress

Cocaine produces characteristic behavioral and autonomic responses due to its unique pharmacological properties. Many of the autonomic responses resemble those to acute behavioral stress. Both cocaine and behavioral stress have been shown to evoke an increase in sympathetic nerve activity that is primarily responsible for the peripheral cardiovascular responses. We noted varying hemodynamic and sympathetic response patterns to cocaine administration and to acute behavioral stress in rats that correlate with the predisposition to develop both a sustained increase in arterial pressure and cardiomyopathies. Several lines of evidence suggest that the autonomic response patterns are dependent on the actions of central peptides including angiotensin II (Ang II) and corticotropin-releasing hormone (CRH). This is based on observations demonstrating that intracerebroventricular (icv) administration of receptor antagonists for Ang II or CRH attenuated the decrease in cardiac output (CO) and increase in vascular resistance noted in some animals after cocaine administration or startle. In contrast, icv Ang II enhances the cardiodepression associated with cocaine administration or startle. Based on this and other evidence, we propose that the autonomic response patterns to startle and to cocaine are closely related and dependent on central Ang II and CRH. Furthermore, we suggest that these central peptides may be responsible for varying predisposition to cardiovascular disease.     

Concomitant Pavlovian conditioning of heart rate and leg flexion responses in the rat

Pavlovian conditioning was studied in male Fischer 344 rats using tones as the conditioned stimulus (CS) and footshock as the unconditioned stimulus (UCS). Different groups of animals received (a) contiguous CS-UCS pairings with a 0.5 sec CS, (b) contiguous CS-UCS pairings with a 4.0 sec CS, or (c) a random sequence of noncontiguous tones and shocks using either a 0.5 sec or a 4.0 sec CS. Heart rate (HR) and leg flexion (LF) responses were recorded. Leg flexion conditioning occurred only in the 0.5 sec contiguous group. Decelerative HR CRs occurred only in the 4.0 sec contiguous group. Accelerative HR changes occurred in the other two groups but were significantly greater in the 0.5 sec contiguous group. These results are similar to but not identical to those obtained during eyeblink or nictitating membrane conditioning in rabbits, and suggest that the topography of the Pavlovian HR CR is dependent on the simultaneous occurrence of other classically conditioned responses.     

Effects of apomorphine on the expression of learned helplessness behavior

Dopaminergic system and its D1 as well as D2 receptors are involved in the modulation of emotional behavior. This experiment investigated the role of dopaminergic activity in the inescapable stress-induced learned helplessness, a widely used depression animal model, by using the pharmacological manipulation through the apomorphine (APO), an agonist for D1 and D2 receptors, and sulpiride (SUL), a selective D2 antagonist. Male Sprague Dawley rats were used and tested in a shuttle box. In the day-1 session, the rats received a 10-trial (1 min/trial) inescapable stressor: a 3 sec conditioned stimulus (CS; 75 db sound and 250 lux red light) followed by a 10 sec unconditioned stimulus (UCS; electrical foot shock, 0.5 mA). In the day-2 session, a 15-trial active avoidance test, 3 sec CS followed by UCS, was performed 30 min after the administration of APO (0, 0.05, 0.5, 1, and 5 mg/kg, i.p.). The number of failures was counted and the UCS was stopped when the rats did not escape after 15 sec UCS. The results showed that APO at the dosage of 0.5 mg/kg had a tendency to enhance the avoidance behavior. In contrast, the treatment of higher dose of APO, 1 and 5 mg/kg, reduced the number of escape but increased the number of failure. Pretreatment of SUL (5 mg/kg, i.p.), 10 min before 1 mg/kg of APO, significantly enhanced the failure behavior. The present data suggest that the activity of D2 receptor may be associated with the adaptive or protective role in the prevention of escape deficits after exposure to inescapable stress. However, the excessive stimulation of D1 receptor may participate in the failure of coping behavior leading to learned helplessness and therefore in the pathophysiological mechanisms underling the development of depression.     

Discriminative behavior and Pavlovian conditioning in the mollusc Pleurobranchaea

The buccal motor system in the sea slug Pleurobranchaea californica is multifunctional; similar sets of neurons and muscles generate different behaviors through similar electrophysiological motor patterns. Such multifunctional systems compromise the traditional practice of identifying a motor pattern and then using that pattern to indicate the behavior in reduced preparations. We address this issue in a series of experiments leading to the comparison of differential Pavlovian conditioning in whole animals with the conditioned behavior of the same animals during electrophysiological recording. Because differential conditioning requires two conditioned stimuli (CSs), we show here that each of two CSs activated the conditioned response from animals after they received the stimulus (CS+) paired with an unconditioned stimulus (UCS). Conditioning sessions consisted of 5 training trials with a 2-h intertrial interval. In one study, experimental animals received a 60-s CS+, derived from beer (Sbr), paired with a 50-s electrical shock UCS whose onset occurred 10 s after the CS+ onset; control animals received the Sbr and UCS explicitly unpaired. In a second study, animals received similar procedures as in the first but with a CS+ consisting of squid homogenate (Ssq). Tests with both CSs showed that animals did not discriminate between Sbr and Ssq before beginning conditioning, but did so afterward. Experimental animals exhibited robust food aversion (withdrawal and suppressed feeding) to the CS+, but retained strong appetitive responses to the CS they did not receive in training; response thresholds to the CS+ changed as much as 1000-fold by comparison to the preconditioning values. Control animals exhibited similar though significantly smaller behavioral changes as the experimental animals. Both stimuli evoked associatively learned responses, but Sbr produced greater experimental-control differences than Ssq did. Two accompanying papers show the results of using both CSs in differential conditioning, and describe the behavioral/electrophysiological comparisons.     

Chewing reduces sympathetic nervous response to stress and prevents poststress arrhythmias in rats

Reducing stress is important in preventing sudden death in patients with cardiovascular disease, as stressful events may cause autonomic imbalance and trigger fatal arrhythmias. Since chewing has been shown to inhibit stress-induced neuronal responses in the hypothalamus, we hypothesized that chewing could ameliorate stress-induced autonomic imbalance and prevent arrhythmias. To test this hypothesis, we analyzed changes in radiotelemetered electrocardiograms in rats that were allowed to chew a wooden stick during a 1-h period of immobilization stress. Chewing significantly reduced the occurrence of ventricular premature beats (VPBs) and complex ventricular ectopy after immobilization and prevented stress-induced prolongation of the QT interval of VPBs throughout the 10-h experimental period. It also prevented prolongation of the QRS complex and fluctuations in the QT interval in normal sinus rhythm beats preceding VPBs during both immobilization and in the poststress period. Fast Fourier transform-based spectral analysis of heart-rate variability further showed that chewing significantly inhibited the stress-induced increase in the power ratio of low-to-high frequency activity (LF/HF: a marker of sympathetic activity) during immobilization and in addition was associated with blunting of the stress-induced increase in plasma noradrenaline observed at the termination of immobilization. Similar suppressive effects on the occurrence of VPBs and the LF/HF were observed in rats that were administered the β-adrenergic blocker propranolol before immobilization. These results indicate that chewing can ameliorate sympathetic hyperactivity during stress and prevent poststress arrhythmias and suggest that chewing may provide a nonpharmacological and cost-effective treatment option for patients with a high risk of stress-induced fatal arrhythmia.     

Cardiovascular alterations and autonomic imbalance in an experimental model of depression

Depressed patients with and without a history of cardiovascular pathology display signs, such as elevated heart rate, decreased heart rate variability, and increased physiological reactivity to environmental stressors, which may indicate a predisposition to cardiovascular disease. The specific physiological mechanisms associating depression with such altered cardiovascular parameters are presently unclear. The current study investigated cardiovascular regulation in the chronic mild stress rodent model of depression and examined the specific autonomic nervous system mechanisms underlying the responses. Sprague-Dawley rats exposed to a series of mild, unpredictable stressors over 4 wk displayed anhedonia (an essential feature of human depression), along with elevated resting heart rate, decreased heart rate variability, and exaggerated pressor and heart rate responses to air jet stress. Results obtained from experiments studying autonomic blockade suggest that cardiovascular alterations in the chronic mild stress model are mediated by elevated sympathetic tone to the heart. The present findings have implications for the study of pathophysiological links between affective disorders and cardiovascular disease.     

Effects of nicotine and dietary salt on a learned blood pressure response in Dahl-S rats

We examined the effects of chronic nicotine exposure and dietary salt on the arterial blood pressure (BP) changes learned in response to an acute behavioral stress in the Dahl salt-sensitive rat. Four groups were tested: low salt + vehicle; low salt + nicotine; high salt + vehicle; and high salt + nicotine. Rats were fed a low-salt (0.08% NaCl) or a high-salt (8% NaCl) diet for 4 wk; 2.4 mg. kg(-1). day(-1) nicotine or vehicle was given via an implanted osmotic minipump for the last 2 wk. All rats were conditioned by following one tone (CS+) with a 0.5-s tail shock; another tone (CS-) was never followed by shock. CS+ in low salt + vehicle and high salt + vehicle-treated rats evoked an initial arterial BP increase (C(1)), a component of the startle response, and an ensuing, smaller, but more sustained, pressor response (C(2)), which is acquired with training. In these rats, both C(1) and C(2) evoked by CS- were significantly smaller than those to CS+, demonstrating that these groups discriminated between the two tests. Conversely, although the low salt + nicotine-treated rats had both the C(1) and C(2) components of the conditional arterial pressure response, they did not discriminate between CS+ and CS-. Finally, the high salt + nicotine group failed to both discriminate between tones and acquire (i.e., learn) the C(2) response. The unconditional response to shock did not differ between groups. We conclude that combined exposure to high salt and to nicotine inhibits the salt-sensitive animal's acquisition of a learned conditional BP response, perhaps because nicotine acts preferentially on those central processes required for associative learning versus those involved in orientating to external stimuli.     

Effect of chronic stress during prepubertal period of life on development of inherited arterial hypertension

The immediate and long-lasting effects of environmental stress during prepubertal life on arterial blood pressure (AP) were studied in rats with inherited stress-induced arterial hypertension (ISIAH) and normotensive Wistar rats. Two models of chronic stress (the 21st-32nd postnatal days) were used: repeated handling and unpredictable stress of daily exposures to a variety of mild physical or psychoemotional stressors. Chronic prepubertal stress did not affect the basal or stress-induced AP levels in young or adult Wistar rats. In ISIAH rats, chronic stress during the early phase of hypertension development did not accelerate its formation and did not augment its manifestation in adults. Moreover, the basal AP was decreased in young and adult ISIAH rats exposed to prepubertal stress as compared to the age-matched controls. AP elevation under acute stress conditions was lower in young ISIAH rats exposed to unpredictable stress. No long-lasting effect of prepubertal stress on acute stress-induced AP elevation in adults was found. The conclusion was drawn that moderate physical and psychoemotional training at prehypertensive stage can positively affect the development of inherited arterial hypertension.     

Classical conditioning to visual stimuli in the housefly, Musca domestica

In the housefly, Musca domestica, classical conditioning to monochromatic light was demonstrated by using a proboscis extension response to labellar stimulation with sucrose solution as an unconditioned response. Sequential and temporal relationships between the conditioned stimulus (CS) and unconditioned stimulus (UCS) to form conditioning were studied; conditioning occurred most readily when the CS was presented before the UCS without an interstimulus interval. Spectral response curves, which were obtained by examining the responsiveness of flies conditioned for one colour to other colours, were divided into two groups; one was that of 462 nm-conditioned flies and the other those of 516 nm-, 579 nm-, and 642 nm-conditioned flies.     

Circulating leptin and stress-induced cardiovascular activity in humans

Obesity is associated with an elevated risk of hypertension and cardiovascular disease. The adipocyte hormone leptin, which stimulates energy expenditure in animals by activating the sympathetic nervous system (SNS), is believed to play a role in this association. However, evidence in humans remains sparse. We investigated the relationship between circulating leptin and cardiovascular and inflammatory responses to acute psychological stress in humans. Participants were 32 men and 62 women aged 18-25 years. Cardiovascular activity was assessed using impedance cardiography at baseline, during acute laboratory stress, and during a 45-min recovery period. Plasma cytokines were measured in blood drawn at baseline and 45-min poststress. In women only, baseline plasma leptin was significantly associated with stress-induced changes in heart rate (beta = 0.53, P = 0.006), heart rate variability (HRV) (beta = -0.44, P = 0.015), and cardiac preejection period (PEP) (beta = -0.51, P = 0.004), independent of age, adiposity, and smoking. Women's plasma leptin levels also correlated with stress-induced elevations in the proinflammatory cytokine interleukin-6 (IL-6) (beta = 0.35, P = 0.042). Circulating leptin is an independent predictor of sympathetic cardiovascular activity, parasympathetic withdrawal, and inflammatory responses to stress in women. Because cardiovascular and inflammatory stress responses are predictive of future cardiovascular disease, leptin may be a mechanism mediating the adverse effects of stress and obesity on women's cardiovascular health.     

Social buffering ameliorates conditioned fear responses in female rats

The stress experienced by an animal is ameliorated when the animal is exposed to distressing stimuli along with a conspecific animal(s). This is known as social buffering. Previously, we found that the presence of an unfamiliar male rat induced social buffering and ameliorated conditioned fear responses of a male rat subjected to an auditory conditioned stimulus (CS). However, because our knowledge of social buffering is highly biased towards findings in male subjects, analyses using female subjects are crucial for comprehensively understanding the social buffering phenomenon. In the present studies, we assessed social buffering of conditioned fear responses in female rats. We found that the estrus cycle did not affect the intensity of the rats' fear responses to the CS or their degree of vigilance due to the presence of a conspecific animal. Based on these findings, we then assessed whether social buffering ameliorated conditioned fear responses in female rats without taking into account their estrus cycles. When fear conditioned female rats were exposed to the CS without the presence of a conspecific, they exhibited behavioral responses, including freezing, and elevated corticosterone levels. By contrast, the presence of an unfamiliar female rat suppressed these responses. Based on these findings, we conclude that social buffering can ameliorate conditioned fear responses in female rats.     

Microinjection of muscimol into the periaqueductal gray suppresses cardiovascular and neuroendocrine response to air jet stress in conscious rats

Microinjection of the neuronal inhibitor muscimol into the dorsomedial hypothalamus (DMH) suppresses increases in heart rate (HR), mean arterial pressure (MAP), and circulating levels of adrenocorticotropic hormone (ACTH) evoked in air jet stress in conscious rats. Similar injection of muscimol into the caudal region of the lateral/dorsolateral periaqueductal gray (l/dlPAG) reduces autonomic responses evoked from the DMH, leading to the suggestion that neurons in the l/dlPAG may represent a descending relay for DMH-induced increases in HR and MAP. Here, we examined the role of neuronal activity in the caudal l/dlPAG on the increases in MAP, HR, and plasma ACTH seen in air jet stress in rats. Microinjection of muscimol into the caudal l/dlPAG reduced stress-induced increases in HR and MAP, while identical injections into sites just dorsal or into the rostral l/dlPAG had no effect. Microinjection of a combination of the glutamate receptor antagonists 2-amino-5-phosphonopentanoate (AP5) and 2,3-dihydroxy-6-nitro-7-sulfamoyl-benzo[f]quinoxaline-2,3-dione (NBQX) into the caudal l/dlPAG decreased stress-induced increases in HR alone only at the end of the 20-min stress period but significantly accelerated return to baseline. Surprisingly, microinjection of muscimol into the caudal l/dlPAG also reduced the stress-induced increase in plasma ACTH by 51%. Compared with unstressed control rats, rats exposed to air jet stress exhibited approximately 3 times the number of Fos-positive neurons in the l/dlPAG. These findings suggest that neurons in the l/dlPAG are activated in air jet stress and that this activity contributes to increases in HR, MAP, and plasma ACTH.     

Expression of freezing and fear‐potentiated startle during sustained fear in mice

Fear‐potentiated acoustic startle paradigms have been used to investigate phasic and sustained components of conditioned fear in rats and humans. This study describes a novel training protocol to assess phasic and sustained fear in freely behaving C57BL/6J mice, using freezing and/or fear‐potentiated startle as measures of fear, thereby, if needed, allowing in vivo application of various techniques, such as optogenetics, electrophysiology and pharmacological intervention, in freely behaving animals. An auditory Pavlovian fear conditioning paradigm, with pseudo‐randomized conditioned–unconditioned stimulus presentations at various durations, is combined with repetitive brief auditory white noise burst presentations during fear memory retrieval 24 h after fear conditioning. Major findings are that (1) a motion sensitive platform built on mechano‐electrical transducers enables measurement of startle responses in freely behaving mice, (2) absence or presence of startle stimuli during retrieval as well as unpredictability of a given threat determine phasic and sustained fear response profiles and (3) both freezing and startle responses indicate phasic and sustained components of behavioral fear, with sustained freezing reflecting unpredictability of conditioned stimulus (CS)/unconditioned stimulus (US) pairings. This paradigm and available genetically modified mouse lines will pave the way for investigation of the molecular and neural mechanisms relating to the transition from phasic to sustained fear.     

Hemodynamic effects of blood loss during a passive response to a stressor in the conscious rabbit

In the conscious rabbit, exposure to an air jet stressor increases arterial pressure, heart rate, and cardiac output. During hemorrhage, air jet exposure extends the blood loss necessary to produce hypotension. It is possible that this enhanced defense of arterial pressure is a general characteristic of stressors. However, some stressors such as oscillation (OSC), although they increase arterial pressure, do not change heart rate or cardiac output. The cardiovascular changes during OSC resemble those seen during freezing behavior. In the present study, our hypothesis was that, unlike air jet, OSC would not affect defense of arterial blood pressure during blood loss. Male New Zealand White rabbits were chronically prepared with arterial and venous catheters and Doppler flow probes. We removed venous blood until mean arterial pressure decreased to 40 mmHg. We repeated the experiment in each rabbit on separate days in the presence and absence (SHAM) of OSC. Compared with SHAM, OSC increased arterial pressure 14 +/- 1 mmHg, central venous pressure 3.3 +/- 0.4 mmHg, and hindquarter blood flow 34 +/- 4% while decreasing mesenteric conductance 32 +/- 3% and not changing heart rate or cardiac output. During normotensive hemorrhage, OSC enhanced hindquarter and renal vasoconstriction. Contrary to our hypothesis, OSC (23.5 +/- 0.6 ml/kg) increased the blood loss necessary to produce hypotension compared with SHAM (16.8 +/- 0.6 ml/kg). In nine rabbits, OSC prevented hypotension even after a blood loss of 27 ml/kg. Thus a stressful stimulus that resulted in cardiovascular changes similar to those seen during freezing behavior enhanced defense of arterial pressure during hemorrhage.     

Varying temporal placement during CS of an added stimulus correlated with non-delivery of UCS.

This experiment extends Pavlov's method of contrasts for training a stimulus discrimination to the case of the cardiac conditional response in the rhesus monkey. It explores the parameter of temporal placement of an additional stimulus ("CS2") within a 10-sec CS (or "CS1"), with the appearance of the former stimulus on any trial signalling the absence of UCS (electric shock) on that trial. This experimental paradigm is a parallel to that of the "intruded stimulus" studies in operant conditioning. In both cases, several ways of describing the function of the added stimulus are possible, but all seem reducible to the same operational terms. Data were taken in the present study with respect to the form and latency of the cardiac rate changes produced by intrusion of CS2 (light), across a range of placements varying from simultaneity with CS1 (a different light) onset to two sec before UCS would have been delivered. The control of CS2 over the cardiac rate CR was occasionally exhibited with a latency as short as three beats after stimulus onset. The order of CS2 temporal placements to which a subject was exposed was a factor in determining the form of the conditioned cardiac rate response to CS1.     

Classical conditioning of human systolic pressure: replication and extension using three stimulus durations

Recent efforts have demonstrated classical conditioning of human systolic pressure (De Leon, 1972). The present research attempted a replication with longer sessions and to maximize the CS+, CS- differentiation by varying CS+ durations. Student volunteers (N = 64) underwent four, 50 minute sessions, three conditioning and one extinction, distributed over two weeks. Shock (UCS) occurred intermittently in light-on (CS+) and never in light-off (CS-). Results closely replicated the earlier work, revealing a characteristic UCR, a significant CS+, CS- differential and, conditioned elevations failed to adapt within and across sessions. The pressure differential was inversely related to CS+ duration. Clarification of conditioning influences requires follow-up research on these clients outside of the laboratory. Nevertheless, these studies provide firm experimental evidence for implicating stimulus variables in the origins of certain hypertensive states.     

NG-monomethyl-l-arginine (NMA) restores arterial blood pressure but reduces cardiac output in a canine model of endotoxic shock

Previous studies have suggested that NMA or similar inhibitors of nitric oxide synthesis from L-arginine reverses or prevents the hypotension associated with endotoxin administration. We wanted to determine if vascular and cardiac responses to NMA support the idea that inhibitors of nitric oxide synthesis might be useful in the treatment of septic shock. Pentobarbital-anesthetized beagle dogs were administered endotoxin for 2 hours at a dose of 250 ng/kg/min. This resulted in reductions in systemic vascular resistance (34% decrease) and mean arterial pressure (25% decrease). Administration of NMA (30 mg/kg, IV) caused large and sustained increases in mean arterial pressure and systemic vascular resistance, and a large decrease in cardiac output and femoral arterial blood flow. Although NMA restored arterial pressure, the large and sustained fall in cardiac output suggests that the cardiovascular action of NMA is detrimental to dogs treated with endotoxin.