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Both dopamine D3 receptor (D3R) partial agonists and antagonists have been implicated as potential medications for substance use disorders. In contrast to antagonists, partial agonists may cause fewer side effects since they maintain some dopaminergic tone and may be less disruptive to normal neuronal functions. Here, we report three sets of 4-phenylpiperazine stereoisomers that differ considerably in efficacy: the (R)-enantiomers are antagonists/weak partial agonists, whereas the (S)-enantiomers are much more efficacious. To investigate the structural basis of partial agonism, we performed comparative microsecond-scale molecular dynamics simulations starting from the inactive state of D3R in complex with these enantiomers. Analysis of the simulation results reveals common structural rearrangements near the ligand binding site induced by the bound (S)-enantiomers, but not by the (R)-enantiomers, that are features of partially activated receptor conformations. These receptor models bound with partial agoni...

Background and Purpose A ligand is believed to produce either positive or negative responses, or to block both of them. However, an indole compound was found to promote both positive and negative effects at the 5-HT3AB receptor, which displays a low level of spontaneous activity. The present study attempted to delineate the mechanisms underlying this phenomenon. Experimental Approach The spontaneously active V291S 5-HT3A receptor was used to explore the properties of 5-hydroxyindole (5-HoI) and 5-methoxyindole (5-MoI), structural analogues of 5-HT, either alone or in combination with orthosteric probes. Key Results Two types of efficacy switching were initiated by altering ligand structure and concentration. At lower concentrations, a subtle structural change at position 5 of the indole molecule resulted in opposite effects. 5-HoI apparently elicited partial allosteric inverse agonism, whereas 5-MoI induced allosteric agonism. Interestingly, at a higher concentration, these indoles produced distinct auto-inhibition, manifested as a switch from positive to negative effects. 5-HoI induced a transition from orthosteric agonism to allosteric inverse agonism, whereas 5-MoI produced a shift from allosteric agonism to orthosteric inverse agonism. The auto-inhibition appears to involve communication between orthosteric and allosteric sites of the active receptor conformation and/or between inactive and active conformations. An additive effect of orthosteric and allosteric inverse agonism and insensitivity of allosteric agonism to orthosteric antagonism were also demonstrated. Conclusions and Implications Together, the results suggest that the moiety at position 5 of the indole structure is a critical determinant of a ligand's properties at the 5-HT3A receptor, providing new insights into understanding ligand–receptor interactions.

Drug discovery strives for selective ligands to achieve targeted modulation of tissue function. Here we introduce engineered context-sensitive agonism as a postreceptor mechanism for tissue-selective drug action through a G protein-coupled receptor. Acetylcholine M2-receptor activation is known to mediate, among other actions, potentially dangerous slowing of the heart rate. This unwanted side effect is one of the main reasons that limit clinical application of muscarinic agonists. Herein we show that dualsteric (orthosteric/allosteric) agonists induce less cardiac depression ex vivo and in vivo than conventional full agonists. Exploration of the underlying mechanism in living cells employing cellular dynamic mass redistribution identified context-sensitive agonism of these dualsteric agonists. They translate elevation of intracellular cAMP into a switch from full to partial agonism. Designed context-sensitive agonism opens an avenue toward postreceptor pharmacologic selectivity, which even works in target tissues operated by the same subtype of pharmacologic receptor.

A great deal is known about the evolutionary significance of body size and development time. They are determined by the nonlinear interaction of three physiological traits: two hormonal events and growth rate (GR). In this study we investigate how the genetic architecture of the underlying three physiological traits affects the simultaneous response to selection on the two life-history traits in the hawkmoth Manduca sexta. The genetic architecture suggests that when the two life-history traits are both selected in the same direction (to increase or decrease) the response to selection is primarily determined by the hormonal mechanism. When the life-history traits are selected in opposite directions (one to increase and one to decrease) the response to selection is primarily determined by factors that affect the GR. To determine how the physiological traits affect the response to selection of the life-history traits, we simulated the predicted response to 10 generations of selection. A total of 83% of our predictions were supported by the simulation. The main components of this physiological framework also exist in unicellular organisms, vertebrates, and plants and can thus provide a robust framework for understanding how underlying physiology can determine the simultaneous evolution of life-history traits.

It is generally accepted that seven-transmembrane receptors have the capacity to regulate cellular signaling systems in the absence of occupancy by a ligand (i.e. the receptors display constitutive activity). Drugs can increase (agonists), decrease (inverse agonists) or not change (antagonists) receptor activity towards a cellular effector. Moreover, some drugs (protean ligands) have multiple pharmacological properties (e.g. agonism towards one response and inverse agonism towards another response coupled to the same receptor and measured from the same cells, simultaneously). In this article, we describe response-dependent constitutive activity and ligand pharmacology for 5-HT2A and 5-HT2C receptors in vitro. Moreover, we provide evidence that 5-HT2A and 5-HT2C receptor constitutive activity is physiologically relevant in vivo and suggest that strong consideration should be given to the impact of constitutive receptor activity on disease and the therapeutic potential of inverse agonism.

Endothelins (ETs) act through two receptors, namely ET(A) and ET(B). In the cardiovascular system, the activation of both receptors leads to vasoconstriction. However, ET(B) receptors also mediate endothelium-dependent vasodilatation and clearance of plasma ET-1. With regard to these latter properties, we wanted to assess the contribution of ET(B) receptors and the effects of selective and mixed ET receptor blockade on vascular tone in control Syrian Golden hamsters and in Bio 14.6 cardiomyopathic hamsters after bolus injection of ET-1 and IRL-1620, a selective ET(B) agonist. In 12-week-old anaesthetized control hamsters, ET-1 (0.5 nmol/kg) induced a sustained pressor response which was only partly reduced by the selective ET(A) receptor antagonist BQ-123, suggesting a contribution of ET(B) receptor activation to the vasoconstrictive effects of ET-1. This was confirmed by injection of the selective ET(B) receptor agonist IRL-1620 (1 nmol/kg). However, the pressor response to this agonist was always preceded by a transient vasodilatation, indicating activation of endothelium-located ET(B) receptors. When the selective ET(B) receptor antagonist BQ-788 was administered, the hypotensive phase following IRL-1620 injection was abolished. Interestingly, BQ-788 or a mixture of BQ-788 and BQ-123 significantly potentiated the pressor responses to ET-1. In 12-week-old Bio 14.6 cardiomyopathic hamsters, ET-1 and IRL-1620 induced haemodynamic responses similar to those observed in control hamsters, although the IRL-1620-induced pressor increase was lower. No difference in cardiac prepro ET-1 mRNA expression was observed between the two strains of hamsters. In conclusion, we suggest that endothelium-located ET(B) receptors are involved in the physiological antagonism of ET-dependent protracted pressor effects, and thus may play a protective role in both normal hamsters and those with cardiomyopathy.

5-HT2B/2C receptors might be involved on memory formation probably mediating a suppressive or constraining action; certainly, whether the drug-induced memory impairments in the above study are explained by simple agonism, antagonism, or inverse agonism at 5-HT2 receptors, and evidence suggests interesting new horizons.

Pharmacology is the study of the chemical control of physiology. Drugs have two primary properties that enable them to change the behavior of physiological systems. These are affinity (this enables drugs to selectively bind to pharmacological targets in the body) and efficacy (a fundamental property of the drug molecule that causes the target to change its behavior toward the cell and modify physiology). This article will discuss the chemical nature of drug affinity and efficacy, as well as the application of these concepts to drug agonism (whereby a molecule actively produces a physiological response), drug antagonism (where the drug prevents the action of an endogenous molecule that produces an active physiological response), allosteric modulation (where no direct response may be seen, but the response to an endogenous agonist or another drug is enhanced or reduced), as well as biased agonism (where the drug changes the conformation of its target receptor in such a way that only some of the signaling cascades are activated). All these phenomena have important therapeutic implications.

If one drug, B, antagonizes another, A, by producing the opposite physiological effect, the antagonist concentration-effect curves should be affected by the recording system, which limits the range of agonist responses. With pieces of isolated guinea-pig ileum taken from adjacent parts of the same animal, one recorded isotonically, the other isometrically with the same load, the isotonic IC50 values for (−)isoprenaline opposing carbachol or histamine were lower than the isometric values (P

The ability of four endogenous vasodilators, nitric oxide (NO; 0.01 - 30 microM), atrial (ANP), brain (BNP) and C-type (CNP) natriuretic peptide (0.1 - 300 nM), to reverse endothelin-1 (ET-1; 10 nM) constrictions in human resistance and conductance coronary arteries (CA) in vitro was investigated. ET-1 (0.1 - 300 nM) constricted resistance CA more potently than conductance CA (P

Toluene is an abused solvent widely used in several commercial products. Recent evidence indicates that this solvent is a non-competitive inhibitor of NMDA receptors. Since NMDA receptors have been implicated in pain, this paper describes studies of the effects of increasing concentrations of inhaled toluene on nociception. Swiss Webster mice were exposed to toluene (500-8000 ppm) in static exposure chambers for 30 min. After completing the exposure period, animals were tested for nociception using the hot plate test. Toluene dose-dependently increased nociception as reflected by shorter latencies for the reflex, paw-lick and escape responses in toluene-treated mice with respect to their controls (animals exposed to air). In order to determine the possible role of opioids in this response, morphine (1-10 mg/kg) was injected before toluene inhalation. Toluene was not able to block morphine-induced antinocieption, however, it produced a shift of the morphine dose-response curve to lower effects, suggesting a physiological antagonism. No potentiation was seen when toluene was administered in combination with naloxone. Present results suggest that toluene increases nociception via neurotransmitter systems others than the glutamatergic.

Bombesin along with several closely related neuropeptides elicit scratching behavior when administered centrally. The first part of the study was designed to determine the antagonistic effects of a novel phyllolitorin analogue [desTrp3,Leu8]phyllolitorin (DTP) on scratching induced by three peptides (bombesin, neuromedin-C, and [Leu8]phyllolitorin). In addition, the binding affinity of each peptide for the bombesin receptor site was determined. DTP (30 μg) inhibited scratching induced by these peptides, but unlike the peptides, DTP had no affinity for the bombesin site, thereby suggesting that DTP is displaying physiological antagonism through an unknown mechanism.

Abstract —Previous biochemical experiments have revealed two antisense peptide antagonists to human angiotensin II (Ang II), one encoded in the cDNA in the antiparallel reading, the other in the parallel reading. Neither peptide’s ability to produce physiological antagonism has been demonstrated previously. Both peptides were tested for their ability to antagonize Ang II–induced contractions on rabbit aorta smooth muscle. Neither peptide had any direct contractile activity. The antiparallel Ang II peptide had physiological antagonism to Ang II contractions at a lower sensitivity than reported in biochemical studies, and its antagonist activity was partially blocked by Ang II antiserum, suggesting that it is not an antipeptide but an Ang II homologue. The parallel Ang II antipeptide also required high concentrations for physiological inhibition. Its contractile inhibition was not affected by Ang II antiserum and diminished the Ang II contraction at high micromolar concentrations, findings consistent with physicochemical data showing that it is an Ang II complement. The concentration of either peptide required to produce an antagonistic physiological effect was too high to predict any pharmacological usefulness. The parallel antipeptide, however, significantly increased the force of muscle contractions at high nanomolar concentrations, thus displaying a unique dual augmentation/antagonist activity. This antipeptide seems to have highly sequence-specific activity because other similar parallel antipeptides had no activity. The parallel antipeptide augmentation mimics the shift in the Ang II dose-response curve produced in hypertension studies of the slow pressor effect of Ang II and may be useful in deducing the currently unknown cause of the slow pressor effect. It may also have some uses in migraine studies.

We used mu-opioid receptor-deficient (MOR-/-) mice to determine the effects of the CB1 cannabinoid receptor inverse agonist AM251 on feeding in the absence of MOR signaling. A single dose of AM251 at 0.6, 2 or 6 mg/kg caused similar dose-dependent suppression of food intake in wild-type and MOR-/- mice. Administration of AM251 at 3 mg/kg/day for 9 consecutive days also led to a similar reduction ( approximately 8%) in body weight in wild-type and MOR-/- mice. Our results suggest that MOR signaling is not necessary for cannabinoid-mediated effects on feeding and that physiological antagonism of opioid receptor tone might be required for the observed synergistic effects of a CB1 inverse agonist and an opioid receptor antagonist on feeding.

The effects of two interventions, high ambient temperature, a sympathetic activator, and clonidine, a centrally acting sympatholytic drug, were compared on a number of autonomic functions. Eight healthy male volunteers participated in four weekly sessions. Each session was associated with one of the following treatments: placebo (physiological saline infused intravenously over 10 min) at 20 degrees C; clonidine hydrochloride (1.5 micrograms kg-1 in 10 ml infused intravenously over 10 min) at 20 degrees C; placebo at 40 degrees C; clonidine at 40 degrees C. Subjects were allocated to treatments and sessions according to a double-blind (for drug condition) balanced design. In each session, the following indices of autonomic function were recorded: systolic and diastolic blood pressure, heart rate, salivation, body temperature, plasma noradrenaline and adrenaline concentrations, baseline and carbachol-evoked sweating, physiological finger tremor. Raised ambient temperature (40 degrees C) caused increases in heart rate, body temperature, carbachol-evoked sweating and physiological finger tremor. Clonidine (at 20 degrees C) reduced systolic blood pressure, body temperature, salivation and plasma noradrenaline concentration, but did not affect any of the other measures. Clonidine (at 40 degrees C) counteracted the increase in heart rate, but not the increases in carbachol-evoked sweating and finger tremor, evoked by high ambient temperature. The high ambient temperature condition abolished the body-temperature-lowering effect of clonidine, but did not modify the effects of clonidine on systolic blood pressure, salivation and plasma noradrenaline concentration. These result indicate that while the effects of the heat stressor are consistent with an increase in sympathetic activity, and most of the effects of clonidine are consistent with a decrease in sympathetic activity, only two functions (body temperature and heart rate) were affected in opposite directions by the two interventions. Indeed physiological antagonism between the two interventions could be demonstrated on body temperature and heart rate only, and there was no evidence for an interaction between the effects of the two variables on any of the other indices of autonomic activity. The failure of clonidine to affect two sympathetically mediated functions, carbachol-evoked sweating and physiological finger tremor, under either temperature condition, indicates that central alpha 2-adrenoceptors cannot be involved in the regulation of these functions.

1. In the present study, we have pharmacologically characterized two novel mixed endothelin ETA/ETB receptor antagonists, namely BQ-928 and BQ-238, in ETA and ETB preparations, the rabbit carotid artery (RbCA) and the rabbit pulmonary artery (RbPA), respectively. These two antagonists were compared to established ETA (BQ-123 and BMS 182874), ETB (BQ-788) and mixed ETA/ETB (SB 209670) receptor antagonists. 2. In the RbCA, the ETA monoreceptor preparation, BQ-238 and BQ-928 had apparent affinities (pA2) of 7.42 +/- 0.22 and 7.22 +/- 0.18, respectively, BQ-788 being inactive in this preparation. In the ETB monoreceptor preparation, the RbPA (when IRL-1620 was used as an ETB receptor agonist), the pA2 for BQ-238 was 7.05 +/- 0.14 and for BQ-928 was 8.43 +/- 0.04. BQ-123 and BMS 182874 were inactive in this preparation. Similar to SB 209670, BQ-238 but not BQ-928 had a higher affinity for the ETA than the ETB receptor. 3. All of the antagonists were tested for their ability to block and reverse endothelin-l-induced vasoconstrictions in the rabbit perfused kidney. In this preparation endothelin-1-induced increases in vascular resistance have been shown to be mediated solely by ETA receptors. All compounds (except BQ-788) blocked the pressor effects of endothelin within the kidney; the calculated IC50 values for BQ-123, BMS 182874, SB 209670, BQ-928 and BQ-238 were 0.4 microM, 2 microM, 0.01 microM, 0.4 microM and 0.09 microM, respectively. 4. In all experiments in the rabbit perfused kidney, endothelin-1 was readministered for a third time, 60 min following cessation of infusion of the above-mentioned antagonists. The response to the third infusion of endothelin-1 following cessation of infusion of BQ-123, BMS 182874 and SB 209670 was not significantly different from that to the third infusion of endothelin in control conditions. However, the response to endothelin-1 was significantly higher than control in tissues pre-infused with BQ-788 or BQ-928 (56 +/- 9 and 41.6 +/- 15%, respectively, n = 8 each, P < 0.05). 5. Our results suggest that in a system where ETA receptor activation is responsible for vasoconstriction and ETB-receptor activation for vasodilatation. ETA receptor selective antagonists or mixed ETA/ETB receptor antagonists which possess high affinity for ETA receptors do not induce hyperresponsiveness to endothelin-1. In contrast, ETB selective antagonists or mixed antagonists possessing a high affinity for ETB receptors (such as BQ-928) interfere with the ETB-receptor-dependent physiological antagonism of endothelin-1-induced pressor responses in these same tissues.

Endothelin-1 causes long-lasting contraction via endothelin type A receptor (ETAR) in isolated rat mesenteric arteries (RMA) that cannot be readily terminated by removing the agonist, or by adding the ETAR antagonist BQ123 or the NO donor sodium nitroprusside. It could be terminated by adding calcitonin-gene related peptide (CGRP), most likely because CGRP causes ET-/ETAR dissociation. Here we investigated this phenomenon in human coronary microarteries (HCMA). We simultaneously verified the effects of CGRP in RMA and HCMA towards other vasoconstrictors, i.e., the alpha(1)-adrenoceptor agonist phenylephrine, the thromboxane A(2) analog U46619 (9,11-dideoxy-11 alpha,9 alpha-epoxy-methano-prostaglandin F-2 alpha) and KG. Long-lasting contraction (remaining after washing away the agonist) was observed for ET-1 in RMA, but not HCMA. Constrictions to phenylephrine, U46619 or KCl did not last upon washing. When added on Lop of ET-1-initiatecl contraction in RMA, CGRP effectively counteracted vasoconstriction, i.e., it caused full relaxation. Inhibitory effects of CGRP were also observed when briefly exposing RMA and HCMA to CGRP 1 h before the addition of ET 1, Similar inhibitory effects of transient CGRP pre-incubation were seen towards phenylephrine. U46619 or KCl in RMA and HCMA. In conclusion, our data imply that CGRP, like ET-1, causes long-lasting effects that remain apparent up to 1 h after its removal horn the organ bath. Thus, in addition to the reported dissociation of ET-1/ETAR complexes, CGRP causes long-lasting non-selective arterial smooth muscle relaxation that may add to the neuropeptide being a physiological antagonist of arterial effects of ET-1. Long-lasting, washout-resistant ET-1/ETAR interaction does not occur in HCMAs. (C) 2013 Elsevier B.V. All rights reserved.

See related article, pp 753–758 As noted by Romo et al,1 the past decade has witnessed an increased incidence, in the general population, of intrauterine growth retardation (IUGR), currently averaged at 5.13% of all newborns. An elegant survey by Hutter et al2 subsequently highlighted the major causes of intrauterine hypoxia often associated with IUGR. Those authors additionally argued in favor of an important role for intrauterine hypoxia-induced alteration of gene expression in the increased incidence of risk factors in premature cardiovascular diseases at later life stages.2 In the present study, Bourque et al3 provide experimental evidence toward a role for the precursor of endothelin-1 (ET-1), big-ET-1, as a new stressor in aged male rats that experienced prenatal hypoxia-induced IUGR. Interestingly, the authors demonstrated a vascular hyper-responsiveness to big-ET-1 and a 2-fold reduction in nitric oxide (NO)–dependent physiological antagonism of the precursor’s contractile properties in vessels derived from aged male but not female rats. Furthermore, an orally available mixed ETA/ETB antagonist, tezosentan,4 attenuated the hypertensive state of aged IUGR …

The effects of aconitine, higenamine and coryneine derived from processed aconite, a Sino-Japanese medicine on pulse rate were examined in unanaesthetized mice. The intraperitoneal (i.p.) administration of the water extract (3 mg/kg) of processed aconite produced a bradycardia, like bigeminy, within 15 min which was prolonged for 30 min. Aconitine (30 μg/kg, i.p.) produced a similar bradycardia. Higenamine induced tachycardia at doses of 30 and 100 μg/kg, i.p. The aconitine-induced bradycardia was antagonized completely by higenamine (10 μg/kg, i.p.), isoproterenol (1 μg/kg. s.c.), or scopolamine (10 μg/kg. s.c.). The anti-aconitine effect of higenamine was prevented by propranolol (1 mg/kg, i.p.). Centrally administered aconitine (1 and 3μg) also induced bradycardia. The aconitine (i.c.v.)-induced bradycardia was prevented by centrally administered atropine (1 μg, i.c.v.). These results demonstrated that aconitine (i.p.)-induced bradycardia is mainly due to a central muscarinic action. As higenamine has a peripheral β1-adrenergic action, like isoproterenol, the inhibition by higenamine of aconitine-induced bradycardia is due to physiological antagonism.

The family of angiotensin peptides has been steadily growing in recent years. Most are fragments of angiotensin II (Ang II) with different affinities to the known angiotensin receptors. Here, we describe a novel endogenous Ang II-like octapeptide in plasma from healthy humans and patients with end-stage renal failure, which acts as a stronger agonist at Mas receptors than Ang 1-7. Chromatographic purification and structural analysis by matrix-assisted laser desorption/ionization time-of-flight/time-of-flight (MALDI-TOF/TOF) revealed an Ang II-like octapeptide, angioprotectin, with the sequence Pro-Glu-Val-Tyr-Ile-His-Pro-Phe, which differs from Ang II in Pro¹ and Glu² instead of Asp¹ and Arg². Pro-Glu-Val-Tyr-Ile-His-Pro-Phe in angioprotectin is most likely generated enzymatically from Ang II. Angioprotectin antagonized the contractile actions of Ang II on rat aortic rings. The physiological antagonism of vasoconstrictor actions of Ang II by angioprotectin is mediated by the Mas receptor. Angioprotectin has a stronger affinity to the Mas receptor than Ang-1-7. Plasma concentrations were ~15% of plasma Ang II concentrations in healthy volunteers and up to 50% in patients with renal failure. A commercially available Ang II antibody did not discriminate between angioprotectin and Ang II; thus, angioprotectin can contribute to Ang II concentrations measured by antibody-based assays. This novel peptide is likely to be a relevant component of the human renin-angiotensin-system.

TRPV1 has emerged as a promising therapeutic target for pain as well as a broad range of other conditions such as asthma or urge incontinence. The identification of resiniferatoxin as an ultrapotent ligand partially able to dissect the acute activation of TRPV1 from subsequent desensitization and the subsequent intense efforts in medicinal chemistry have revealed that TRPV1 affords a dramatic landscape of opportunities for pharmacological manipulation. While agonism and antagonism have represented the primary directions for drug development, the pharmacological complexity of TRPV1 affords additional opportunities. Partial agonism/partial antagonism, its modulation by signaling pathways, variable desensitization, and slow kinetics of action can all be exploited through drug design.

Contemporary receptor theory was developed to account for the existence of constitutive activity, as defined by the presence of receptor signaling in the absence of any ligand. In vitro studies with a variety of cell types have revealed the existence of constitutive activity and inverse agonism at a large number of receptors and also additional complexities of ligand-receptor interactions. Thus, ligands acting at a constitutively active receptor can act as agonists, antagonists, and/or inverse agonists, and these pharmacological characteristics can differ for an individual ligand depending upon the receptor response measured and the physiological state of the system under study. Studies with a variety of cell types have established that the serotonin 5-HT(2A) and 5-HT(2C) receptors and the cannabinoid CB1 receptor demonstrate constitutive activity and inverse agonism in vitro. Serotonin and cannabinoid receptors are involved in a large number of physiological and behavioral functions. The possible existence of constitutive activity and inverse agonism at these receptors in vivo would provide new avenues for drug development. Recent studies have provided compelling evidence that both the serotonin 5-HT(2A) and 5-HT(2C) receptors and cannabinoid CB1 receptor demonstrate inverse agonism and constitutive activity also in vivo. This chapter describes our current knowledge of constitutive activity in vitro and then examines the evidence for constitutive activity in vivo.

This article describes functional selectivity of agonists and antagonists and distinguishes conventional cell-based functional selectivity, where the strength of signal produces selective signaling in various organs, from true receptor active-state based selectivity, also alternatively referred to in the literature as “stimulus trafficking,” “biased agonism,” and “collateral efficacy.” This latter mechanism of selectivity depends on the ligand-related conformation of the receptor and is not compatible with the parsimonious view that agonists produce a single receptor active state. In addition, protean agonism is described, whereby a ligand produces positive agonism in quiescent systems and inverse agonism in constitutively active systems. This is a special case of active state-based selectivity in which the ligand produces an active state that is of lower efficacy than the natural constitutively active state. It is postulated that receptor active-state based selectivity, unlike cell-based functional selectivity, is controllable through the chemical structure of the ligand and is therefore more likely to be a viable avenue for therapeutic selectivity in the clinic. Reasons are given for differentiating receptor active-state based selectivity from conventional functional organ selectivity.

OBJECTIVE: Recent evidence challenges the 'low-fibre/high-colonic intraluminal pressure' hypothesis of diverticular disease (DD) and raises the possibility that other mechanisms are involved. Although bowel wall smooth muscle is known to be hypercontractile in DD, the nature of its relaxation is unknown. The present study investigated colonic smooth muscle responses to nitric oxide, as well as the smooth muscle contents of neural nitric oxide and elastin associated with the disease. METHOD: Immunohistochemical/image analysis of antibodies to nitric oxide synthase (NOS1), co-localized with protein gene product (PGP) and to elastin, was performed on three histological sections of sigmoid colons from 20 patients (10 DD, 10 controls) following resections for rectal tumours. Organ bath experiments examined smooth muscle responsiveness to nitroprusside, a nitric oxide donor. RESULTS: Uncomplicated diverticular longitudinal muscle showed lower nitric oxide immunoreactivity compared with controls: median percentage surface area of NOS1 over PGP was 26.0% (range 0.5-58.3), controls 45.0% (35.0-70.1; P = 0.018). Median percentage surface area of elastin was elevated, 21.3% (10.6-45.6), controls 8.2% (1.7-13.5; P = 0.0002), together with a low sensitivity to nitroprusside [mean - log EC(50) 5.3 (SD 0.5), controls 6.6 (SD 0.5), difference 1.3, 95% CI 0.8-1.7; P < 0.0001] and there were lower maximum relaxation responses to nitroprusside compared with controls: median percentage (relaxation induced by nitroprussside/contraction induced by bethanecol) was 52.0%, range (20.0-92.0), controls 100.0% (71.0-125.0), P < 0.0001. No statistically significant differences were found in circular muscle, at the sample size studied. CONCLUSION: This study established, for the first time, specific abnormalities in longitudinal muscle relaxation and contents of neural nitric oxide and elastin in uncomplicated DD. These findings may have important implications for both colon structure and function in the disease.

Many drugs with important therapeutic actions that had been assumed to be antagonists at G-protein-coupled receptors (GPCRs) have been shown to be inverse agonists. For both basic pharmacology and drug design it is important to understand the mechanisms whereby these drugs achieve their effects. It had been assumed that these drugs achieved their effects by stabilizing an inactive state of the receptor (R) at the expense of a partially activated state (R*). In this article, I consider this and other mechanisms that could explain inverse agonist actions, and conclude that more than one mechanism can apply to inverse agonism at GPCRs.

Publisher Summary Over the past decade, it has become accepted that G protein-coupled receptors (GPCRs) can activate G proteins and thus initiate signaling in the absence of agonist; this spontaneous receptor activity can be inhibited to varying degrees by antagonists, a phenomenon termed “inverse agonism.” Inverse agonism has been observed in a wide variety of systems, with both endogenously and heterologously expressed GPCRs. The contribution of inverse agonism to the overall therapeutic effects of antagonists is difficult to determine because of the continual presence of endogenous agonists under normal physiological conditions. An emerging concept related to inverse agonism is that of protean agonism, in which some ligands display both agonist and inverse agonist properties at a single GPCR. Although this phenomenon has only been observed at a handful of GPCRs and is poorly understood at present, it may ultimately provide a key to understanding the way by which all ligands modulate GPCR behavior. Because agonists and inverse agonists appear to bind to different receptor conformations, it may be possible to design improved therapeutics by targeting them to specific receptor states. The sensitivity of inverse agonists and protean agonists to receptor desensitization implies an additional level of complexity in structure–activity relationships.

Recent studies have demonstrated that the renin-angiotensin system (RAS) participates in the processes of inflammation. An active component of this system, angiotensin II (Ang II), differentially regulates the production of oxyradicals, nitric oxide, prostaglandins, platelet-activating factors and bradykinins by acting through AT1 or AT2 receptor subtypes. Many of the physiological actions of Ang II mediated through AT1 and AT2 receptors are opposite and thereby show physiological antagonism to each other. In the present study, we evaluated the effect of locally administered Ang II, the ACE inhibitor captopril and the AT1 receptor antagonist losartan in the carrageenan model of acute inflammation. Local administration of losartan (10-50 micrograms/paw) or Ang II (0.2-1 microgram/paw) alone did not induce inflammation, but significantly enhanced the carrageenan-induced edema in a dose-dependent manner. Coadministration of subeffective doses of losartan (10 micrograms/paw) and Ang II (0.2 microgram/paw) significantly potentiated the carrageenan-induced inflammation. In conclusion, the present study predicts that Ang II might be formed locally during carrageenan-induced acute inflammation. Potentiation of the Ang II effect in carrageenan-induced inflammation by losartan may be mediated through over-stimulation of unblocked AT2 receptors or due to stimulation of inflammatory pathways by unknown mechanisms.

This study assesses the importance of metabolites formed following exogenous administration of glucagon-like peptide-1-(7-36) amide (GLP-1). After subcutaneous (s.c.) administration of GLP-1 to dogs the plasma immunoreactivity of GLP-1 measured by two different radioimmunoassays (RIAs) were higher than that measured by a sandwich enzyme-linked immunosorbent assay (ELISA). This discrepancy was due to the formation of the metabolites GLP-1-(9-36) amide, GLP-1-(7-35) and GLP-1-(7-34). Receptor binding studies using baby hamster kidney cells expressing the human pancreatic GLP-1 receptor showed that the affinity of GLP-1-(9-36) amide, GLP-1-(7-35) and GLP-1-(7-34) was 0.95%, 12% and 2.8%, respectively, of the affinity of GLP-1-(7-36) amide. Furthermore, GLP-1-(9-36) amide was shown to be an antagonist to adenylyl cyclase activity, whereas GLP-1-(7-35) and GLP-1-(7-34) were shown to be agonists. GLP-1-(9-36) amide was shown to be present in vivo in amounts up to 10-fold that of GLP-1-(7-36) amide. Due to its low binding affinity, this antagonistic metabolite does not seem to be able to cause physiological antagonism upon s.c. administration of the peptide.

+/- -Higenamine (demethylcoclaurine), a cardiotonic principle from aconite root, chronotropic and inotropic actions mediated through beta 1-adrenergic receptors. We have investigated the influence of cholera toxin (CTX), a Gs-protein activator, and pertussis toxin (PTX), a Gi-protein inhibitor on the chronotropic interaction between higenamine and a muscarinic agonist, acetylcholine (ACh) in the isolated right atria of mice. CTX (100nm, 1h) pretreatment accentuated the inhibitory responses to cumulative applications of ACh (30nM--30 microns for the positive chronotropic effects induced by higenamine (100nM), isoproterenol (3 and 10 nM) or dobutamine (100nM). In normal atria (CTX-untreated), ACh physiologically antagonized the positive chronotropic effects of these beta-adrenergic agonists. Pretreatment with PTX (150 microgram/kg, i.p., 3d) abolished the CTX (100nm, 1 h)-induced accentuation in the inhibitory effect of ACh against higenamine. PTX pretreatment also attenuated the physiological antagonism by ACh against higenamine in normal atria. The negative chronotropic effect of ACh was not affected by a submaximal concentration of forskolin (1 micron). The These results suggest an accentuated antagonism between higenamine and ACH in CTX-treated, but not in untreated, isolated right atria of mice, which may occur through a functional interaction between the beta1-adrenergic-Gs and muscarinic-Gi systems.

Nitroglycerin (NTG) has been demonstrated to provide uterine relaxation in the management of various obstetric complications. A 32-yr-old woman presented 40 min postpartum for manual removal of a retained placenta. Repeated, alternating doses of NTG 250 micrograms and syntocinon (SYN) 10U iv were used over 15 min to produce periods of uterine relaxation and contraction respectively for uterine exploration. Multiple attempts to extract the placenta failed and a diagnosis of placenta accreta was made. There were no major side effects from this combination of drugs apart from a transient 20% decrease in blood pressure after NTG, which responded to ephedrine 10-15 mg iv. The rapid change in uterine tone was believed to be due not only to the short duration of action of NTG and SYN, but also to the possible physiological antagonism between the two drugs. The mechanism of interaction may involve calcium mobilization and myosin light chain phosphorylation. We conclude that NTG and SYN can be used to produce alternating periods of uterine relaxation and contraction rapidly and consistently with little sustained effects from either agents.

International audience; Interactions between CCKergic and enkephalinergic systems were studied in mice using behavioral responses measured in Animex. The hyperlocomotion induced by 5 mg/kg of RB 101, a mixed inhibitor of enkephalin-degrading enzymes able to cross the blood-brain barrier, was previously shown to be mediated by delta-opioid receptor stimulation. The IP administration of a CCKA agonist, Boc-Tyr-Lys-(CONH-o-tolyl)-Asp-Phe-NH2 (0.1, 1, 10 micrograms/kg), suppressed the hyperlocomotion produced by IV injection of 5 mg/kg of RB 101. The effect of the CCKA agonist was suppressed by a selective CCKA antagonist, devazepide, injected IP at doses of 20 and 200 micrograms/kg and was potentiated by the selective delta-opioid antagonist naltrindole at the doses of 0.03 mg/kg. IP injection of the selective CCKB agonist BC 264 (0.1-1 mg/kg) did not modify the RB 101-induced hyperlocomotor effect. These results reinforce the observed physiological antagonism between the endogenous CCK and opioid systems but are at variance with the responses measured in stressful conditions. It is concluded that CCKA, but not CCKB, receptor activation counteracts the opioid-related hyperlocomotion.

Despite much debate as to the validity of different models of agonism, there is apparently very little to choose between them in practice. However, most experiments to test the various models have used classical isolated tissue systems. In these systems, the response that is measured is far removed from receptor activation, and it is likely that the properties of the events at the receptor may be masked by more distal processes. In this article, Mary Keen examines the effects of agonists on responses that follow, very closely, activation of G protein-coupled receptors. The data appear to be inconsistent with any of the current models of agonism.

Substance P (SP) in the dose range 0.75–1.5 nmol exerts a potent stimulatory effect on ventilation after microinjection into the rat ventrolateral medulla oblongata (VLM; n. reticularis lateralis, n. paragigantocellularis lateralis). A significant but less pronounced effect is also seen in the dorsal medulla (DM; n. tractus solitarius). Somatostatin (0.6–1.8 nmol) inhibited ventilation and induced apnoea after microinjection into the VLM but not the DM. Serial microinjections of the two peptides showed a reciprocal antagonistic action in the VLM but not in the DM. The apnoea-inducing effect of SOM was blunted by SP while SOM reduced the ventilatory stimulation induced by SP. Extracellular single unit recordings were performed following the microiontophoretic application of SP and/or SOM to respiratory-related and non-respiratory-related neurons in the VLM and DM. Although a heterogeneous population of neurons were recorded from, the majority of respiratory-related units in the VLM responded with excitation to SP and inhibitory to SOM. A direct interaction between the peptides was seen in some respiratory-related units. The neurons not responding to either of the peptides were usually non-respiratory. Dorsal to the VLM, the type of response to the two peptides was less likely to be antagonistic and a wider distribution of response types were recorded. The results indicate a direct physiological antagonism between SP and SOM regarding their effects on respiratory regulation elicited in the VLM.

It is well-known that flavonoids including rutin exert a wide range of pharmacological effects. This study was carried out for further characterization of the pharmacological effect of rutin. A significant rise in the serum 5-HT levels was found 2 h after the administration of rutin (25 mg kg-1 i.p.). The same dose of rutin caused no significant change in the serum 5-hydroxytryptomine levels after 8 and 72 h when compared to controls. In the in vivo experiments, rutin (25 mg kg-1 i.p.) was ineffective on the blood pressure and respiratory tract of the guinea-pigs in spite of its smooth muscle relaxant effects in the in vitro preparations. These findings strongly suggest a physiological antagonism in the effects of rutin in intact animals. Copyright © 1991 John Wiley & Sons, Ltd.

In rats, morphine may either raise or lower body temperature depending on the dose. A morphine dose of 50 mg/kg, i.p., consistently produced a nearly maximal hypothermic response in non tolerant rats, whereas this dosage induced an elevation of body temperature in tolerant rats. In rats pretreated with alpha-fluoromethylhistidine (alpha-FMH), an irreversible inhibitor of histidine decarboxylase which induces a reduction in brain histamine synthesis, this morphine dose of 50 mg/kg, i.p. produced an elevation of rectal temperature resembling that observed in morphine-tolerant rats. To confirm the suggestion that hyperthermic effects of the higher dose of morphine in morphine-tolerant rats or in alpha-FMH-pretreated rats could be related to a possible involvement of mediators of fever, e.g. prostaglandins, animals were pretreated with acetylsalicylic acid (aspirin, Bayer) 30 mg/kg, i.p., 60 min before morphine. Results showed that acetylsalicylic acid prevented the hyperthermic response of morphine, resulting in a fall in body temperature. Since morphine releases histamine and alpha-FMH inhibits histamine synthesis, our data demonstrating that an inhibitor of prostaglandin-synthetase showed efficacy only in animals responding with fever to the higher dose of the opiate, suggests a physiological antagonism between histamine and prostaglandins on mechanisms underlying hyper/hypothermic responses to morphine.

Numerous mediators are involved in both the control and the transmission of nociceptive messages, and several lines of research have been developed in the management of pain. Complete enkephalin- degrading enzyme inhibitors, which produce naloxone-reversible analgesia in all tests where morphine has been found to be active, remains the most promising way. CCK compounds, especially the CCKB antagonists also may be interesting drugs. Indeed, they are able to strongly potentiate the antinociceptive effects of the opioids. [dickenson, wiesenfeld-hallin et al.]

The peptide cholecystokinin (CCK) has been shown to counteract the analgesic effects of morphine suggesting a physiological antagonism between opioid and CCK neural systems. The implications that could result from the management of this antiopioid system are very important since it might be possible to modify opioid analgesia and/or to prevent the development of opioid tolerance. In this work we have studied the effects of selective antagonists of CCK-A and CCK-B receptors on the antinociception induced by RB 101, a new systemically active full inhibitor of the enkephalin-catabolizing enzimes (1). The naloxone reversible antinociceptive effects induced by RB101 in rat tail-flick test were strongly increased by low doses of the CCK-B antagonists L-365,260 and PD-134,308

Penile erection is regulated by two opposing systems: noradrenergic (anti-erectile) and nitrergic (pro-erectile) neurotransmission. Noradrenaline released from sympathetic nerves causes contraction of the blood vessels and smooth muscle of the penile corpus cavernosum, thus leading to detumescence of the penis. Nitric oxide (NO) released from nitrergic nerves causes relaxation of the smooth muscle of the corpus cavernosum, thus allowing engorgement of blood into the cavernous space and leading to erection. Nitrergic neurotransmission is known to modulate noradrenergic responses. We have recently shown that the degree of this modulation varies among species. In the human corpus cavernosum, noradrenergic responses are under nitrergic control, such that even pharmacological concentrations of noradrenaline fail to show an effect when nitrergic neurotransmission is operating. This situation is similar in the monkey and rabbit, where nitrergic neurotransmission does not merely modulate but actually controls the sympathetic responses; however it differs in the rat, mouse and dog where the sympathetic system is predominant. Our recent work has demonstrated that the interaction between the two systems occurs in the smooth muscle, suggesting a physiological antagonism. Our observations suggest that the key element in this interaction is intracellular calcium in the smooth muscle. The nitrergic pathway causes a decrease in intracellular calcium concentrations thus leading to relaxation of the smooth muscle. Noradrenergic stimulation, in contrast, elicits an increase in the intracellular calcium concentrations thus leading to a contraction. The neuronal pathway which controls the concentrations of intracellular calcium in the smooth muscle determines the dominance of that pathway over the other. Nitrergic dominance over noradrenergic system in the human corpus cavernosum also suggests a key role for this interaction in the pathophysiology of erectile dysfunction. Indeed, a nitrergic-noradrenergic imbalance in favor of the noradrenergic system has been implicated in penile tissues from patients with erectile dysfunction. However, the mechanism of this imbalance is not fully understood. In addition, since the present study has demonstrated that phosphodiesterase type V inhibitors can enhance and prolong the nitrergic control of noradrenergic responses, such compounds may have therapeutic potential in impotence, where defective nitrergic transmission is accompanied by increased noradrenergic activity.

1 The incorporation of [3H]-thymidine into guinea-pig lymphocytes stimulated by a plant lectin (concanavalin A), soluble antigen (tuberculin (P.P.D.)) and syngeneic hepatoma cells, was partially inhibited (50%) by histamine in vitro. 2 The effect of histamine on both mitogen and antigen dose-response curves suggests a non-competitive, probably physiological antagonism. 3 The inhibitory dose range of histamine lay between 10 nM and 30 microM with an ID50 of approximately 400 nM. 4 The potency order for histamine analogues for the inhibition of lymphocyte activation was histamine greater than or equal to 4-methylhistamine greater than 2-methylhistamine greater than 3-methylhistamine. This is in accord with the mediation of the response through an H2-receptor. 5 H2-receptor antagonists reversed the inhibitory effect of histamine in a dose-related manner, but both metiamide and burimamide, in high concentrations, augmented lymphocyte activation in their own right. This precluded the determination of affinity constants and made it impossible to state with certainty that the inhibition of lymphocyte activation by histamine was mediated by an H2-receptor.

In the few years since its identification, a clear role for ANP in the regulation of water and electrolyte balance has emerged (Figure 3). The peptide is released in response to blood volume expansion, both acutely and gradually during changes in dietary sodium intake. Similarly, plasma levels are elevated in pathophysiological conditions such as cardiac and renal failure. It has become apparent that ANP has natriuretic, diuretic and vasorelaxant properties. Many of the original studies employed what we now know to be pharmacological doses of the peptide. However, recent reports have confirmed that small, sustained elevations in plasma ANP within or marginally above the 'normal' physiological range produce similar effects. A number of recent studies have tried to specifically address the physiological relevance of ANP. Although undoubtedly release by atrial distension and effective when infused to similar concentrations, atrial distension also has other effects via neural pathways. Thus, the demonstration that excretion of saline is impaired by atrial appendectomy (Benjamin et al, 1988) does not imply that this is only due to the absence of an atrial hormone. Goetz et al (1986) demonstrated that in the denervated heart, although ANP is still released, the excretion of a saline load is impaired. Similarly, in man, Richards et al (1988a) needed to infuse ANP to much higher plasma levels than those achieved by a saline load in order to reproduce the natriuresis. Although these experiments can be criticized, they confirm that ANP is not the sole mechanism for excreting a volume load, or for the natriuresis following atrial distension, but that these effects are likely to reflect the balance between ANP, AVP, the renin-angiotensin and autonomic nervous systems. In rats immunized against ANP (Greenwald et al, 1988), although the ability to excrete an acute saline load was impaired, long-term sodium balance was normal, suggesting that the rats were able to compensate for the absence of ANP. Many of the actions of ANP can be explained by antagonism of the renin-angiotensin-aldosterone system. Teleologically, it seems appropriate that a natriuretic hormone should counterbalance the major pressor and antinatriuretic hormones within the body. There is good evidence for cellular interactions between angiotensin, AVP, aldosterone and ANP at a number of discrete sites which are additional to the straightforward physiological antagonism of systems with opposing actions. ANP inhibits aldosterone secretion directly and may also reduce renal renin release. In the vascular tree there is evidence that ANP specifically blocks the vasoconstrictor actions of angiotensin II and possibly AVP.(ABSTRACT TRUNCATED AT 400 WORDS)

The occurrence, molecular characteristics and biological function of neuropeptide Y (NPY) has been studied in the female genital tract of non-pregnant rabbits. NPY immunoreactivity was demonstrated throughout the genital tract. Maximum concentrations were found in the salpinx (fallopian tube), 570 pmol/g (median) lower within the uterine body (1.5 pmol/g), cervix (2.8 pmol/g) and vagina (3.6 pmol/g). In vitro, NPY had a dose-dependent stimulatory effect on non-vascular smooth muscle (ED50 10(-9) mol/l) as studied by myometrial tension recordings. In vivo, NPY (50 pmol/min.kg) induced a dose-related, non-adrenergic and non-cholinergic decrease in myometrial blood flow. Small C-terminal (NPY31-36) or N-terminal (NPY1-16) fragments of NPY had no effect on myometrial blood flow. NPY was found to interact with the smooth muscle effect of VIP; the presence of VIP (10(-8) mol/l) counteracted the contraction elicited by NPY (10(-8) mol/l) returning the response to control value. VIP and NPY displayed a similar physiological antagonism on myometrial blood flow. There was a clear difference in the response to VIP and NPY as the effect of NPY on myometrial blood flow first appeared after a lag period of 2 minutes whereas the effect of VIP was almost instantaneous. It is concluded that NPY and VIP may interact in the local nervous control of genital functions.

1. Propranolol administered intravenously in the dose-range of 1.2–3.6 mg/kg reduced the electromyographic (EMG) activity of the breast muscles in the pigeon under exposure to cold. Concomitantly the body temperature (T b ) decreased. 2. Isoprenaline in the dose-range of 0.3–2.7 mg/kg evoked positive chrono-and inotrophic effects. EMG activity was slightly reduced with a moderate fall in T b and elevation in T f . 3. No physiological antagonism was seen between the agonist isoprenaline and antagonist propranolol. The induced tachycardia has been correlated with more intense hypothermia after isoprenaline-propranolol administration than after propranolol alone. 4. It is suggested that the hypothermia produced by propanolol is triggered either directly or indirectly by the inhibitory effect on heat production in the skeletal muscles and that the inhibition of β-adrenoceptors cannot be regarded as evidence for the presence of regulated non-shivering thermogenesis in birds.

1. The effects of porcine endothelin were examined in rat thoracic aortic rings. 2. Endothelin was a potent contractile agonist (EC50 4.0 +/- 0.6 nmol/L). 3. Endothelin (1 nmol/L) did not affect contractile responses to cumulative concentrations of the thromboxane analogue, U46619. 4. In the presence of U46619, but not phenylephrine, endothelin (1 nmol/L) and endothelium abrogated the vasodilator response to cumulative concentrations of sodium nitroprusside. 5. The inhibitory effect of endothelin on vasodilator responses to nitroprusside in the presence of U46619 was abolished by nifedipine (0.1 mumol/L) but unaffected by indomethacin (3 mumol/L) or haemoglobin (10 mumol/L). 6. These data suggest that endothelin generated by native endothelium exerts a physiological antagonism of sodium nitroprusside in the presence of thromboxane.

The present investigation reports on the accumulation and damage caused by copper in the liver and kidney of albino rats. Simultaneous treatment with copper and molybdenum shows that no traces of copper are retained in these tissues. Thus these observations lead to the conclusion that copper is ineffective in the presence of molybdenum exhibiting physiological antagonism. Several hypothesises have been considered for their antagonistic behaviour. Present authors suggest that molybdenum may act on copper as a chelating agent binding with it and forming either cupric molybdate or copper thiomolybdate which is ultimately excreted. Intake of molybdenum with the diet has also been suggested for the occupational victims of copper.

SUMMARY 1. The influence of intra-arterial infusion of rat atrial natriuretic factor (ANF 8–33) and/or ouabain on the vascular responses to noradrenaline was investigated in the denervated and flow-controlled hindlimb preparations in pentobarbital anaesthetized dogs. 2. During the continuous infusions of ANF (30–40 min) vascular responses to noradrenaline were significantly depressed. Subsequent infusion of ouabain together with ANF (50–60 min) reversed and restored the vascular reactivity to the control levels. Hypotension produced by ANF infusion was partially reversed during the simultaneous infusions of both the agents. 3. In a separate series of experiments, in which ouabain was first infused (50–60 min) vascular responses to noradrenaline were significantly enhanced. Subsequent infusions of ANF (plus ouabain) even up to 60 min or longer failed to alter the enhanced vascular responsiveness facilitated by ouabain. 4. The present studies demonstrate a physiological antagonism between ANF and ouabain and such a phenomenon could account for the previous observation that vascular reactivity to noradrenaline was progressively enhanced after acute blood volume expansion. Whereas plasma levels of both ANF and ouabain-like inhibitor(s) of the sodium pump are elevated after volume expansion, inhibitory effects of ANF on the vascular smooth muscle may be compromised in the presence of an Na+ pump inhibitor(s).

1 Pressor responses to bolus injections of noradrenaline (NA) were studied, in the isolated perfused rat mesenteric arterial bed, in the presence of β-adrenoreceptor agonists and antagonists, in an attempt to identify a possible β-adrenoreceptor mediated modulation of catecholamine-induced vasoconstrictor effects. 2 NA-induced responses were potentiated in the presence of timolol and (-)propranolol and suppressed in the presence of (-)isoprenaline; (+)isoprenaline was less effective against the NA-induced responses. 3 Timolol attenuated the effects of (-)isoprenaline on NA-induced responses but not those of the stereoisomer (+)isoprenaline. 4 It is concluded that the NA-induced pressor effect in the rat mesenteric vasculature is the net result of vasoconstrictor α- and vasodilator β-adrenoreceptor activation and that the interaction of the two opposing adrenoreceptor-mediated effects represents a ‘physiological antagonism’.

To summarize the report briefly, the Eppinger and Hess hypothesis has been slightly reworded as follows: A. The differential chemical reactivity and the physiological antagonism of of the adrenergic and cholinergic branches of the autonomic nervous system permit of a situation in which the action of one branch may predominate over that of the other. This predominance, or autonomic imbalance, may be phasic or chronic, and may obtain for either the adrenergic or the cholinergic system. B. Autonomic imbalance, when measured in an unselected population, will be distributed continuously about a central tendency which shall be defined as autonomic balance. The hypothesis has been tested by measuring the physiological status of 62 children 6 to 11 years of age, for twenty physiological variables, twelve of them supposedly mediated at least in part by the autonomic nervous system; and by intercorrelating the resulting data. Positive intercorrelation among most of the appropriately reflected autonomic functions, and further evidence of their communality from a factor analysis, lends support to the first portion of the hypothesis. For 48 of these children, scores for the autonomic factor are shown to be quite consistent over periods of at least a year, and best measured in terms of a multiple regression equation derived from the factor analysis. These regression scores are regarded as measures of autonomic balance and are found to distribute themselves symmetrically about a central tendency. Support is thus afforded the second portion of the hypothesis which defines the central tendency of the distribution as autonomic balance. The seven-test and its regression equation is offered as the first, though tentative, quantitative, weighted scale for the measurement of individual differences in the autonomic nervous system.