Negative inotropic effects of phenol on isolated cardiac muscle.

Phenol appears in high concentrations in renal failure with uremia. The effects of this material on contractile activity of isolated cardiac muscle were studied in right ventricular moderator band (MB) of piglets and papillary muscle (PM) of cats and kittens. The muscles were bathed in modified Krebs solution containing 5.6 mM glucose at 30 C and gassed with 95% O2 and 5% CO2. They were paced at 24 contractions per minute, isometrically at Lmax. Over the range 2.5-119.0 mg%, phenol produced dose-related decreases in both developed tension (DT) and maximal rate of tension development (max dT/dt) in MB of piglets. In contrast, the dose-dependent negative inotropic effect of phenol was not detected in feline PM until concentrations in excess of 12.5 mg% were used. Increasing extracellular Ca2+ from 2.5 to 5.0 mM as well as the addition of norepinephrine (3.94 x 10(-7) M) attenuated the phenol-induced cardiac depression in porcine MB. There were no further changes in either DT or max dT/dt when the extracellular Ca2+ was increased to 10 mM. These findings demonstrate that phenol elicits a direct negative inotropic effect on mammalian cardiac muscle that is modified by calcium and norepinephrine. Phenol may participate in the biochemical alterations leading to cardiac failure and death in uremia.     

Negative inotropic influence of hyperosmotic solutions on cardiac muscle.

In cardiac muscle, moderate degrees of hyperosmolality of the type encountered physiologically or clinically (i.e., less than 200 mosM above control) characteristically exert a positive inotropic effect, which presumably is mediated by increased Ca2+ availability for binding to troponin. In contrast, skeletal muscle displays significant contractile depression on exposure to hyperosmotic solutions, even at mild degrees of hypertonicity. To determine whether a similar potential for hyperosmolarity-induced depression also exists in cardiac muscle, right ventricular papillary muscles from cats were exposed to hypertonic solutions of mannitol or sucrose under circumstances in which positive inotropic effects were precluded by prior exposure to a bathing solution of 4.0 mM Ca2+ and paired electrical stimulation to maximize intracellular Ca2+ before addition of the hyperosmotic substances. In contrast to their usual positive inotropic effects, hypertonic solutions under these conditions caused cardiac depression at all osmolarities tested. Developed tension and its maximal rate of development (dT/dt) decreased by 18% at 50 mosM above control, by 30% at 100 mosM, by 36% at 150 mosM, and by 42% at 200 mosM (P less than 0.01 for all). Time to peak tension and resting tension were not changed significantly. When the muscles were returned to control solutions, tension development also returned toward normal. The data are compatible with the hypothesis that, within the range tested, all degrees of hyperosmolarity exert a significant negative inotropic influence on cardiac muscle, as is true in skeletal muscle; manifestation of this effect of increased tonicity normally would be obscured at low degrees of hyperosmolality, however, by an overriding positive influence that is absent in skeletal muscle.     

Length dependent potentiation and inhibition of post-rest twitch tension development in adult cat and kitten papillary muscles

If a rest interval is applied to a regularly stimulated cardiac muscle, the first contraction after this interval (post-rest contraction) has either a greater (post-rest potentiation) or a smaller (post-rest inhibition) developed tension than the regular contraction. Positive inotropic interventions will augment the post-rest potentiation and reduce the post-rest inhibition. We examined the effects of muscle stretching on the post-rest contraction in papillary muscles isolated from adult cats and from kittens and compared the effects with those of two typical inotropic interventions: high frequency stimulation and high calcium concentration. We found that muscle stretching augmented the post-rest potentiation and reduced the post-rest inhibition in a manner similar to the two inotropic interventions in the adult cat papillary muscle, and that these effects were consistently reversed in the kitten papillary muscle. The similarity of the effect of muscle stretching to those of the two typical inotropic interventions in either adult cat or kitten papillary muscle suggests that the effect of muscle stretching is due to an inotropic effect of muscle length change.     

Contractile dysfunction of atrial myocardium from endotoxin-shocked guinea pigs

Atrial muscle isolated from guinea pigs subjected to Escherichia coli endotoxin shock was used to study the myocardial changes associated with this experimental disease state. Isometric contractile tension and its first derivative (dT/dt) consistently were depressed by about 45% in muscle from the shock group (P less than 0.001), but contraction time intervals of the shock tissues were not significantly altered. The inotropic deficit of shock was completely antagonized by high concentrations of Ca2+ (greater than 4.5 mM). However, the maximal positive inotropic response to increased frequency of stimulation (0.1-2.2 Hz) only partially antagonized shock-induced cardiac depression. Heart muscle from shocked animals exhibited increased sensitivity to the negative inotropic effects of Mn2+, low Ca2+, and gentamicin; recovery from the depressant actions of these agents was prolonged 3.6- to 4.8-fold in shock. However, the negative inotropic potency of slow Ca2+ channel blockers, D 600 and nifedipine, was unaffected by shock. Similarly, studies with an isoproterenol-activated slow Ca2+ channel technique demonstrated equivalent inotropic responses of shock and control heart muscle. Present data provide evidence for a disruption of myocardial Ca2+ metabolism associated with endotoxin-induced inotropic depression of the heart but suggest that slow Ca2+ channels of the sarcolemma remain functional in this disease state.     

The nature of the initial positive inotropic effect of K depletion in bullfrog atrial muscle.

In frog atrium, K depletion exerts initial, and late positive inotropic effects. The initial effect on the membrane potential, current and tension components was studied using a double gap method under voltage clamped and unclamped conditions. In both cases, the presence of the initial effect was demonstrated. The effect was clearer in preparations in which a positive inotropic effect to toxic doses of ouabain (10(-6) M) had already been attained. This suggests that the initial phase is independent from Na-pump inhibition. Voltage clamp study revealed that the slow inward calcium current (ICa) was enhanced transiently after K depletion concomitant with an augmentation of ICa-dependent phasic tension. ICa-independent tonic tension was not altered at this initial phase. For the enhancement of ICa, two mechanisms appeared to be involved, one an enhancement of gCa and the other a faster and/or longer opening of the slow channel. These results indicated that an enhancement of ICa together with the well-known prolongation of action potential were the cause of the initial positive inotropic effect of K depletion.     

Effects of insulin on experimental catecholamine cardiomyopathy.

We have recently shown that insulin attenuates norepinephrine (NE) dose-response curves in both isolated cardiac muscle and intact heart preparations. Accordingly, an intact rabbit model was used to determine if insulin would reduce the extent of myocardial damage following a standard NE infusion. Each animal was given pentobarbital, 30 mg/kg, and heart rate, arterial pressure, glucose, blood gases, and pH were measured. NE (2 microgram/min/kg) was given intravenously for 90 minutes. After 48 hours the rabbits were killed and the hearts were examined microscopically and assigned a histologic score. Florid lesions were present in 17 of 24 sections (71%) from 12 animals. They were characterized by myofiber necrosis and an intense cellular reaction. However, only 5 of 40 sections (12.5%) from 20 rabbits given insulin (10 units/kg) 30 minutes before the NE infusion showed advanced lesions (P less than 0.001). The mean histologic score was reduced from 1.7 to 1.0 (P less than 0.001). The frequency of advanced lesions increased to 86% in animals given a higher dose of NE (3 microgram/kg/min) and was reduced to 53% by pretreatment with insulin. A dosage of 5 units/kg was as effective as 10 units/kg, but rabbits given 1 unit/kg manifested cardiomyopathic changes identical to those in rabbits not pretreated with insulin. No differences in heart rate, arterial pressure, PO2, or pH were evident between the groups. It is concluded that large doses of insulin reduce myocardial damage produced by NE in this model. This may be linked with the phenomenon of insulin inhibition of the inotropic action of NE.     

Length-dependent activation of in situ canine skeletal muscle.

This study was designed to assess the contribution of length-dependent activation to the peak isometric twitch tension developed and the maximal rate of tension development (dP/dt) of in situ canine skeletal muscle. Length-developed tension and length-dP/dt relationships were generated for the dog gastrocnemius-plantaris muscle group at three different levels of inotropic state as determined by stimulation frequency. These relationships were then normalized with respect to maximal developed tension and maximal dP/dt and the normalized curves were superimposed for comparison. At progressively shorter muscle lengths the augmentation of tension production by a given increment in inotropic state was greater as measured by either developed tension or dP/dt. Thus, a given change in muscle length produced a greater change in performance in less potentiated muscles. These findings are similar to those from studies of isolated cardiac muscle and illustrate the lack of independence between activational state and muscle length for in situ skeletal muscle.     

Effect of platelet-activating factor (PAF) on human cardiac muscle

The effect of platelet activating factor (PAF) on three mechanical [maximal mechanical tension (Pmax); time to peak tension; maximal rate of rise of tension (+dP/dt)] and four electrical [action potential duration (APD); resting membrane potential; overshoot; maximum rate of depolarization] parameters of cardiac function was studied on fragments of isolated human cardiac papillary muscle. 20 specimens of small tissue fragments excised from the left ventricle by open heart surgery were challenged with various doses of synthetic PAF (10(-10)-10(-6) M). PAF, but not its biologically inactive 2-lyso-derivative (lyso-PAF), induced a biphasic dose-dependent effect, characterized by a transient positive effect on inotropism (increased Pmax, +dP/dt) and of APD, followed by a marked, prolonged negative effect on both inotropism (decreased Pmax, time to peak tension, +dP/dt) and APD. No changes in resting membrane potential, overshoot and maximum rate of depolarization were detected after PAF challenge. Propranolol (2 X 10(-7) M) completely prevented the positive inotropic effect suggesting a stimulation of beta-receptors, possibly exerted by endogenous catecholamines. Indomethacin (1 X 10(-4) M) did not modify the initial positive effect, but markedly reduced the subsequent negative effect induced by PAF on inotropism. These findings are consistent with the interpretation that the effect of PAF on the inotropism is related to liberation of cyclooxygenase-derived metabolites.     

Inotropic responsiveness of atrial myocardium bathed in Tris- or bicarbonate-buffered solutions.

Atrial muscle of guinea pigs was used to study the inotropic influences of substituting a tris(hydroxymethyl)-aminomethane-buffered solution aerated with 100% O2 for a bicarbonate-buffered solution aerated with 95% O2-5% CO2 under otherwise equivalent in vitro conditions. Basal values of isometric contractile tension and its first derivative (dT/dt) were smaller and time to peak tension and time to 90% relaxation were longer in Tris- than in bicarbonate-bathed muscles. Both groups responded similarly to changes in stimulation frequently (0.1--2.2 Hz) and Ca2+ concentration (1.0--7.0 mM); however, maximal inotropic responses to these variables were smaller in the Tris-bathed atria. The negative inotropic effects of D600 and gentamicin were greater in the Tris group. Tris-bathed atria developed pulsus alternans when exposed to Mn2+ or a reduced Ca2+ concentration, whereas pulsus alternans did not occur in the bicarbonate group. A transient increase in contractility occurred in bicarbonate-bathed atria after treatment with 0.125 mM Mn2+, but only a negative response occurred in the Tris group. Thus important, and seemingly Ca2+-dependent, differences exist between the inotropic influences of Tris and bicarbonate solutions that may affect the utility of Tris-buffered (and/or bicarbonate deprived) heart muscle for studying certain inotropic interventions.     

Contractile responses of the basilar artery isolated from rabbits exposed to 8-day head-down tilt

In the present study, the effects of head-down tilt (HDT) on contractile responses of basilar and popliteal arteries were investigated in vitro. The arteries were isolated from rabbits exposed to 8 d of 45 degrees HDT. Isometric tension and intracellular calcium were measured in an organ bath perfused with physiological salt solution. In the HDT rabbits, contractile response to norepinephrine (NE) was attenuated in the basilar artery, but not in the popliteal artery compared with control rabbits. HDT did not change the responses to either KCl or 5-hydroxytryptamine in both arteries. In the response of basilar artery to NE, the difference in both [Ca(2+)](i) transient and Ca sensitivity between control and HDT rabbits were statistically not significant. The response of the basilar artery to phenylephrine, a selective alpha(1)-adrenergic agonist, was also attenuated by HDT. Treatment with propranolol, a beta-adrenergic blockade, did not affect the response to NE in the basilar arteries isolated from control rabbits, but it significantly enhanced the response in the basilar arteries from HDT rabbits. These results suggest that exposure to 8-d HDT decreases a contractile response of the basilar artery to NE in rabbits. The reduction of NE-induced contraction is probably attributable to both decreased Ca transient and decreased Ca sensitivity, and decreased alpha(1)-adrenoceptor activity and increased beta-adrenoceptor activity seem to be involved in the mechanism.     

Papillary muscle dynamics: in situ function and responses of the papillary muscle.

Experiments were designed to 1) study in situ changes in papillary muscle length and force during the cardiac cycle, 2) investigate the relationship between papillary muscle length and maximal ventricular pressure, 3) study the effect of both positive and negative inotropic intervention on this relationship. A mercury gauge transduceror Walton-Brodie strain-gauge arch was sutured to the anterior papillary muscleand used to measure the extent of shortening or lengthening (deltaL) or force (APMF),.respectively. The anterior papillary muscle showed rapid increase of length and forcewhile contracting during isovolumic contraction and reached peak systolic length at end-isovolumic contraction or during the early injection phase. The papillary muscle was observed to shorten during the phases of ejection and isovolumic relaxation. It was concluded that changes in ventricular pressure during the cardiac cycle are associated with changes in papillary muscle length and force such that the resulting "lengthening contraction force" is appropiate for maintenance of normal atrioventricular valve function during isovolumic contraction. There was an inverse relationship between deltaL and maximal ventricular pressure such that for each increment in peak ventricular pressure there was a decrease in deltaL. The deltaL-force relationship was shifted upward and to the right by norepinephrine (NE) and isoproterenol and downward and to the left by occlusion of the posterior vena cava. Phenylephrine had little or no effect on this relationship.     

Inhibition of inotropic effect of hyperosmotic mannitol by lactate in vitro.

Isolated, isometrically contracting cat papillary muscles were used to evaluate the inotropic interactions of lactic acidosis, hypercarbic acidosis, and lactate ion with hypertonic mannitol. These studies have documented that both lactic acidosis (pH less than 7.0) and lactate ion at a normal pH inhibit the inotropic effect of hyperosmotic mannitol in vitro. In contrast, hypercarbic acidosis does not prevent the inotropic effect of mannitol. Inhibition by lactic acid of mannitol's effects on contractility persists in the presence of beta-receptor blockade. The results suggest that inhibition by severe lactic acidosis of the direct inotropic effect of hyperosmolality in isolated cardiac muscle is mediated by lactate ion rather than acidosis per se.     

Aging and glucose transporter plasticity in response to hypobaric hypoxia

In order to gain a better understanding of tissue plasticity with aging, we investigated the adaptive responses of young and adult animals to both 7 and 28 days of hypobaric hypoxia. Senescence is associated with a decreased tolerance to hypoxia that may be related to an age-associated decline in glucose transporter system plasticity. In addition, elucidation of the factors contributing to the decreased hypoxia tolerance with aging may provide insights into ischemia for older individuals. Following 7 days of hypobaric hypoxia, soleus and plantaris muscle Glut-4 contents were increased 23-45% with a greater increase in the soleus muscle for both ages. A parallel decline in insulin receptor content was observed in both the young (soleus 56%; plantaris 74%) and adult (soleus 26%; plantaris 37%) animals over 7 days. Similar responses were observed in cardiac muscle over 7 days, with increases in content for both Glut-4 (young 25%; adult 23%) and Glut-1 (young 33%; adult 44%) and a decline in insulin receptor (young 27%; adult 15%). Following 28 days of hypobaric hypoxia, adult soleus, and both age groups plantaris muscle Glut-4 and insulin receptor contents were similar to control. However, the young soleus muscle Glut-4 and insulin receptor contents were still significantly different from control but only altered about half as much as following 7 days of exposure to hypobaric hypoxia. In contrast to what was observed for skeletal muscle, cardiac Glut-4 content was further elevated in both young (33%) and adult (44%) animals with longer exposure to hypobaric hypoxia. The young animals also showed a further decrease in heart insulin receptor content, while the adult did not. Interestingly, cardiac Glut-1 levels returned to normal values for both young and adult animals with prolonged exposure. An adaptive coregulation of Glut-4 and insulin receptor content appears to optimize the use of glucose during chronic hypobaric hypoxia within these tissues. Differences are apparent in the magnitude and time course of the response between young and adult animals.     

Endothelin has no positive inotropic effect in guinea-pig atria or papillary muscle

Endothelin is a recently discovered, highly potent vasoconstrictor peptide. In isolated atria from rat and guinea-pig, endothelin has been reported to elicit a positive inotropic effect. The purpose of the present study was to compare the effects of endothelin on electromechanical coupling in guinea-pig atrial and ventricular muscle. In isolated, electrically driven specimens of atria and papillary muscle, action potentials and isometric contractions were recorded in the basal state and 30 min following non-cumulative exposure to endothelin (100 nM). In the atria, endothelin reduced action potential overshoot and relaxation velocity, and increased resting tension. In the papillary muscle the peptide slightly shortened the duration of the action potential. Endothelin did not affect peak tension, either in the atria or in the papillary muscle. These data contrast with earlier reports on a positive inotropic effect of endothelin in guinea-pig atria.     

Intracellular mechanism of the negative inotropic effect induced by alpha1-adrenoceptor stimulation in mouse myocardium

Alpha(1)-adrenoceptor stimulation (alpha(1)ARS) shows a positive inotropic effect in most mammalian myocardium. In mouse myocardium, however, alpha(1)ARS showed the negative inotropic effect, of which intracellular mechanisms are not fully clarified. The purpose of this study is to investigate the intracellular mechanism of the negative inotropic effect by alpha(1)ARS in C57BL/6 mouse myocardium. We used isolated ventricular papillary muscles of C57BL/6 strain mouse which is widely used for genetic manipulation. We simultaneously measured isometric tension and intracellular Ca(2+) concentration ([Ca(2+)](i)) using the aequorin method. In twitch contraction, phenylephrine concentration-dependently (1-100 microM) decreased tension without significant changes in the Ca(2+) transient, and these effects were completely blocked by prazosin (3 microM) or calphostin C (a PKC inhibitor, 1 microM). Phorbol 12-myristate 13-acetate (PMA) (a PKC activator, 1 microM) decreased tension as observed in phenylephrine. After PMA application, the negative inotropic effect of phenylephrine disappeared. To estimate the Ca(2+) sensitivity, tetanic contraction was produced, and the relation between [Ca(2+)](i) and tension at a steady state was measured. Phenylephrine (10 microM) decreased the Ca(2+) sensitivity, and PMA showed a similar Ca(2+) desensitizing effect. These results suggest that the negative inotropic effect of phenylephrine in mouse myocardium can be explained by the decrease in the Ca(2+) sensitivity through the activation of PKC. The present result indicates that the effect of alpha(1)ARS differs among species and strains of experiment animals. Thus, we should be careful about using the results of mouse myocardium to understand the functions of the human heart.     

Evidence for a positive inotropic effect of aldadiene (-K, -Na) on the isolated ventricular myocardium

Summary The effect of Aldadiene (-K, -Na) was studied in the isolated cat papillary muscle preparation. At doses of 500–2000 µg/ml, significant increases are observed in the extent of shortening, in the velocity of isotonic shortening and relaxation and in the rate of isometric tension development. Force-velocity relations are shifted upwards and to the right with increases of both the preload velocity and the maximum isometric tension. The maximum increases of cardiac mechanics are observed 3–4 min after Aldadiene incubation. In most of the experiments there is a late decrease of cardiac mechanics compared with the controls, approximately 20 to 30 min after Aldadiene incubation, which is most probably due to the elevation of extracellular potassium concentration associated with Aldadiene-K incubation. Using Aldadiene-Na, this late decrease of cardiac mechanics was largely reduced. The results demonstrate a direct positive inotropic action of Aldadiene (-K, -Na) on the isolated ventricular myocardium.Supported by Deutsche Forschungsgemeinschaft SFB 89 — Kardiologie Göttingen.     

Further characterization of the guinea pig left atrial tension response to histamine by use of selective agonists

1. The responses of guinea pig left atrial tension and right atrial rate to histamine receptor agonists and histamine were compared.
2. Single doses of histamine and another non-selective agonist,N,N-dimethylhistamine, produced biophasic inotropic responses, with an initial increase in tension and a secondary sustained tension increase separated by a negative inotropic component.
3. Selective H₁-receptor agonists — 2-methylhistamine, 3-methylhistamine and 2-pyridylethylamine (2-PEA) — also exhibited biphasic inotropic responses. 2-PEA did so only after blockade with propranolol or in atria from reserpine-pretreated animals, indicating an additional release of endogenous catecholamines which masked the biphasic response.
4. Selective H₂-receptor agonists — 4-methylhistamine and dimaprit — failed to produce biphasic responses except at high concentrations only in the case of 4-methylhistamine.
5. The biphasic responses were converted to monophasic responses by mepyramine. This was a result of antagonism of the initial positive component and the secondary negative component which were therefore mediated via H₁-receptors. The production of a biphasic inotropic response therefore depends upon these two components which were exhibited preferentially by the H₁-receptor-selective agonists.

     

Age-associated alterations in cardiac and skeletal muscle glucose transporters, insulin and IGF-1 receptors, and PI3-kinase protein contents in the C57BL/6 mouse

We investigated potential age-related changes in cardiac and skeletal muscle protein contents of glut-4 and glut-1 transporters, insulin and insulin-like growth factor-1 (IGF-1) receptors, and phosphatidylinositol 3-kinase (PI3-kinase) in the C57B1/6 mouse. Myocardial glut-4 content increased four- to five-fold between mid- to late-adulthood with no further age-related changes. Increases in myocardial glut-1 preceded the increase in glut-4 and was of a much smaller magnitude (25-40%). Skeletal muscle glut-4 was also increased (38-49%) and no further changes were noted between adulthood and old age. Cardiac insulin receptor and the p85 alpha subunit of PI3-kinase both declined by about 40%, whereas the skeletal muscle content of these two proteins were unaffected by aging. Cardiac (-23 to -24%) and skeletal muscle (-40 to -62%) IGF-1 receptor levels were decreased in adult and old animals with senescence being associated with a further decrease in cardiac IGF-1 receptor levels to 20% of controls. A two- to three-fold increase in both basal and maximal in vitro autophosphorylation of the cardiac insulin and IGF-1 receptors by their respective ligands was observed with senescence. It appears that cardiac and skeletal muscle demonstrate differential responses in terms of the magnitude and temporal responses of age-associated alterations in glucose transport related protein contents in the C57B1/6 mouse.     

Left ventricular inotropic and peripheral vasomotor responses from independent changes in pressure in the carotid sinuses and cerebral arteries in anaesthetized dogs

1. The pressure perfusing the isolated carotid sinuses and the pressure perfusing the cerebral circulation were changed independently, and the resulting inotropic responses in the left ventricle and peripheral vasomotor responses were determined.2. Inotropic responses were assessed by measuring changes in the maximum rate of change of left ventricular pressure (dP/dt max) with heart rate and mean aortic pressure held constant. Vascular resistance changes were usually assessed by perfusing the descending thoracic aorta at constant flow and measuring changes in perfusion pressure.3. Decreases in carotid sinus pressure over the baroreceptor sensitivity range resulted in a 45% increase in dP/dt max and a 59% increase in vascular resistance.4. Unless arterial oxygen tension was abnormally low, lowering cerebral perfusion pressure to 50 mm Hg resulted in little or no inotropic and vasomotor responses. In the presence of hypoxaemia (P(a,O2) < 60 mm Hg), lowering cerebral perfusion pressure to below about 80 mm Hg resulted in marked responses.5. These experiments suggest that, unless arterial oxygen tension is abnormally low, the carotid sinus reflex and not cerebral hypotension is important in the control of the inotropic state of the heart and of vasomotor activity. With hypoxaemia, responses from cerebral hypotension may also be important.     

Responses of hypothalamic paraventricular neurons in vitro to norepinephrine and other feeding-relevant agents

To investigate paraventricular hypothalamic neuronal actions responsible for the effects of neurotransmitters on feeding, and to test the notion that a single population of cells there could account for feeding effects, hypothalamic slices containing the paraventricular nucleus (PVN) were prepared from rats. Electrophysiological responses of individual PVN neurons to feeding-inducing agents norepinephrine (NE) and gamma-aminobutyric acid (GABA), and to anorexic agents serotonin (5-HT) and histamine (Hist) were examined. NE inhibited neuronal activity through alpha 2-adrenergic receptors, and excited through alpha 1-receptors. alpha 2-receptors are known to mediate the behavioral effect of NE. NE inhibited most clearly those neurons that otherwise fired continuously in this type of in vitro preparation. GABA affected the activity of 37% of the neurons tested, primarily by inhibition. The inhibitory action of GABA can be related to its feeding-inducing effect. GABA in PVN can also attenuate excitatory responses and enhance inhibitory responses to NE or 5-HT. 5-HT caused excitatory and inhibitory responses with the former action outnumbering the latter by approximately 3 to 1. Since this would result in a net excitation, it appears that 5-HT in PVN inhibits feeding mainly by exciting neuronal activity. Hist excited 72% and inhibited only 2% of PVN neurons. The excitation was blocked by H1-antagonists, which have been shown to mediate Hist effect on feeding. Comparing across neurons, the inhibitory response to NE was correlated with that to GABA, but not with any responses to 5-HT or Hist. The excitatory responses to Hist correlated with 5-HT responses.(ABSTRACT TRUNCATED AT 250 WORDS)