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P M Pilowsky

Publications and source records attributed to P M Pilowsky.

At least 19 recordsLinked to original sources
PubMed2005

Pre-protachykinin A mRNA is colocalized with tyrosine hydroxylase-immunoreactivity in bulbospinal neurons.

Previous studies have generated controversy about the extent of co-localization between substance P- and catecholamine-containing neurons that project to the spinal cord. In earlier studies, estimates using immunofluorescence after colchicine have ranged from almost all, to almost none. We sought to resolve this issue by combining in situ hybridization and immunofluorescence. Catecholamine (A1 to A7, C1 to C3; tyrosine hydroxylase immunoreactive) neurons in the rat brainstem were examined to determine their content of mRNA for the preprotachykinin-A gene. In the A1 to A7 and the C1 to C3 cell groups, preprotachykinin-A mRNA was found only in substantial amounts in the C1-C3 cell groups. On average 20.9+/-0.9% (234/1120, n=3) of rostral C1 neurons contained preprotachykinin-A mRNA. Co-localization was also observed in C2 and C3 neurons to a similar extent. Retrograde tract-tracing with cholera toxin B subunit was used to identify bulbospinal neurons and 17.9+/-2.7% (96/529 cells) of the bulbospinal tyrosine hydroxylase-containing neurons of the rostral C1 cell group were found to contain preprotachykinin-A mRNA. In addition a new population of non-catecholaminergic bulbospinal preprotachykinin-A neurons is described in an area corresponding to the recently described caudal pressor area. To confirm that the preprotachykinin-A mRNA observed in cells in the medulla was converted to protein, dual immunofluorescence for fiber labeling at the confocal level was carried out. This confirmed colocalization of substance P and tyrosine hydroxylase in the intermediolateral cell column, but nowhere else, in a small number of cases. The results provide evidence for a much larger population of substance P/neurokinin A containing neurons in the brainstem than was previously suspected. Furthermore, many of these neurons are catecholaminergic and spinally projecting. The specific sympathetic outflow that these neurons influence remains to be determined.

Animals↗
PubMed2005

Phosphorylated extracellular signal-regulated kinase 1/2 immunoreactivity identifies a novel subpopulation of sympathetic preganglionic neurons.

Distinct chemical codes are thought to reflect functional specificity in sympathetic preganglionic neurons (SPN). Although a number of chemical candidates have been identified including neurotransmitter-related, calcium-binding and other proteins, signal transduction proteins have been largely neglected. Not only might these chemicals allow discrimination of functionally unique chemical signatures, but they may also identify activated neurons. Immunoreactivity (ir) to phosphorylated extracellular signal-regulated kinase 1/2 (p-ERK1/2) was differentially located within the thoracic spinal cord depending upon which of three forms of killing was used: the only exception to this was the intermediolateral cell column (IML) which was consistently, densely labeled. The presence or absence of p-ERK1/2 in SPN (n=17,541) within the IML of the thoraco-lumbar spinal cord was determined in seven rats. SPN were identified on the basis of their location, size and that they contained choline acetyltransferase ir. On average, 58% of SPN contained p-ERK1/2, however, more SPN in both the upper (72%; C8-T4) and lower (78%; T11-L3) thoraco-lumbar spinal cord contained p-ERK1/2-ir than the middle thoracic region (47%; T4-T10). p-ERK1/2-ir was also examined in SPN (n=1895) innervating the adrenal medulla (identified by retrograde tracing using cholera toxin B subunit) combined with localization of neuronal nitric oxide synthase (nNOS) in three rats. On average, 64% of adrenal SPN contain p-ERK1/2-ir, and it was confirmed that all adrenal SPN contain nNOS-ir. It appears that p-ERK1/2-ir SPN, described in this study, have tonically activated receptors that are coupled to intracellular signal transduction pathways that lead to the phosphorylation of ERK1/2.

Animals↗
PubMed2003

Maintenance of sympathetic tone by a nickel chloride-sensitive mechanism in the rostral ventrolateral medulla of the adult rat.

In urethane-anaesthetised artificially ventilated Sprague-Dawley rats, bilateral microinjection of the divalent cation nickel chloride (Ni(2+); 50 mM, 50 nl) into the rostral ventrolateral medulla elicited a dramatic inhibition of splanchnic sympathetic nerve activity (-44+/-6%) and a marked depressor response (-35+/-7 mmHg). Selective blockade of high-voltage activated Ca(2+) channels with omega-agatoxin IVA (P/Q-type), omega-conotoxin GVIA (N-type) and nifedipine (L-type) did not decrease arterial pressure or splanchnic sympathetic nerve activity when injected separately into the rostral ventrolateral medulla, or combined with kynurenate. Injection of caesium chloride or ZD 7288, a blocker of the hyperpolarization-activated cation current, into the rostral ventrolateral medulla had no effect on arterial pressure or splanchnic sympathetic nerve activity. Bilateral microinjection of nickel chloride into the caudal ventrolateral medulla/pre-Bötzinger complex elicited small increases in splanchnic sympathetic nerve activity (+17+/-13%) and arterial pressure (+12+/-4 mmHg). These were substantially smaller than those evoked by blockade of glutamatergic receptors or high-voltage activated Ca(2+) channels in this area. Injection of kynurenate or high-voltage activated Ca(2+) channel blocker, but not Ni(2+), in this area evoked respiratory termination. The results indicate the existence of a distinct mechanism maintaining the tonic activity of rostral ventrolateral medulla presympathetic neurons that is different from that maintaining the tonic activity in the caudal ventrolateral medulla/pre-Bötzinger region. We conclude that ion channels that are sensitive to Ni(2+), but are insensitive to high-voltage activated (L, P/Q, N) Ca(2+) channel blockers, and are located postsynaptically on the presympathetic rostral ventrolateral medulla neurons are responsible for the tonic activity of the presympathetic neurons in rostral ventrolateral medulla. These channels could well be the low-voltage-activated (or T-type) Ca(2+) channels although other conductances cannot be conclusively excluded.

Age Factors↗
PubMed2003

Presynaptic delta opioid receptors differentially modulate rhythm and pattern generation in the ventral respiratory group of the rat.

The specific role of the Delta opioid receptor (DOR), in opioid-induced respiratory depression in the ventral respiratory group (VRG) is largely unknown. Here, we sought to determine (1) the relationship between DOR-immunoreactive (ir) boutons, bulbospinal and functionally identified respiratory neurons in the VRG and (2) the effects of microinjection of the selective DOR agonist, D-Pen 2,5-enkephalin (DPDPE), into different subdivisions of the VRG, on phrenic nerve discharge and mean arterial pressure. Following injections of retrograde tracer into the spinal cord or intracellular labelling of respiratory neurons, in Sprague-Dawley rats, brainstem sections were processed for retrograde or intracellular labelling and DOR-ir. Bulbospinal neurons were apposed by DOR-ir boutons regardless of whether they projected to single (cervical or thoracic ventral horn) or multiple (cervical and thoracic ventral horn) targets in the spinal cord. In the VRG, a total of 24 +/- 5% (67 +/- 13/223 +/- 49) of neurons projecting to the cervical ventral horn, and 37 +/- 3% (96 +/- 22/255 +/- 37) of neurons projecting to the thoracic ventral horn, received close appositions from DOR-ir boutons. Furthermore, DOR-ir boutons closely apposed six of seven intracellularly labelled neurons, whilst the remaining neuron itself possessed boutons that were DOR-ir. DPDPE was microinjected (10 mM, 60 nl, unilateral) into regions of respiratory field activity in the VRG of anaesthetised, vagotomised rats, and the effects on phrenic nerve discharge and mean arterial pressure were recorded. DPDPE depressed phrenic nerve amplitude, with little effect on phrenic nerve frequency in the Bötzinger complex, pre-Bötzinger complex and rVRG, the greatest effects occurring in the Bötzinger complex. The results indicate that the DOR is located on afferent inputs to respiratory neurons in the VRG. Activation of the DOR in the VRG is likely to inhibit the release of neurotransmitters from afferent inputs that modulate the pattern of activity of VRG neurons.

Action Potentials↗
PubMed2002

Activation of mu-opioid receptors in rat ventrolateral medulla selectively blocks baroreceptor reflexes while activation of delta opioid receptors blocks somato-sympathetic reflexes.

The effects of activation of mu and delta-opioid receptors in the rostral ventrolateral medulla (RVLM) on somato-sympathetic, baroreceptor and chemoreceptor reflexes, as well as respiratory rhythmicity in sympathetic nerves, were examined in urethane anaesthetized (1.1-1.2 g/kg) and artificially ventilated Sprague-Dawley rats. Microinjection of the delta-opioid receptor agonist [D-Pen(2,5)]-enkephalin (DPDPE; 8 mM, 50 nl) bilaterally into the RVLM potently inhibited the post-inspiratory-related burst discharges of lumbar sympathetic nerve activity (LSNA) but had only limited effects on splanchnic sympathetic nerve activity (SSNA) and phrenic nerve discharge. Injection of DPDPE into the RVLM strongly attenuated the somato-sympathetic reflex (approximately 50-80%) evoked in the lumbar sympathetic nerve and splanchnic sympathetic nerve by tibial nerve stimulation but had no effect on baroreceptor reflexes and chemoreceptor reflexes evoked by aortic nerve stimulation and brief hypoxia, respectively. Injection of the mu-opioid receptor agonist, [D-Ala(2),N-Me-Phe(4),Gly-ol(5)]-enkephalin (DAMGO; 4 mM, 50 nl), also elicited a greater inhibition of LSNA than SSNA accompanied by an abolition of phrenic nerve discharge. Injection of DAMGO inhibited the baroreceptor reflex without significant effect on either the somato-sympathetic or the chemoreceptor reflexes. We propose that opioid peptides diminish specific excitatory and inhibitory inputs to the presympathetic neurons in RVLM via distinct presynaptic receptor subclasses.

Action Potentials↗
PubMed2001

NK1 receptor and the ventral medulla of the rat: bulbospinal and catecholaminergic neurons.

Bulbospinal C1 neurons are sympathoexcitatory and excited by substance P. However the substance P receptor (NK1 receptor), has been reported to be absent from the somata of C1 neurons. In this study, using double and triple labelling immunofluorescence and retrograde tracing, we provide evidence that the NK1 receptor is present on 5.3% of C1 neurons, and that 4.7% of C1 neurons receive close oppositions from NK1 receptor immunoreactive terminals, indicating a pre-synaptic and post-synaptic site for the action of substance P. These results provide support for the sympathoexcitatory actions of substance P on C1 neurons. We also demonstrate the NK1 receptor on bulbospinal neurons of the ventral respiratory group, in a region overlapping the pre-Bötzinger Complex.

Animals↗
PubMed2001

Differential expression of catecholamine synthetic enzymes in the caudal ventral pons.

The analysis of colocalization of multiple catecholamine biosynthetic enzymes within the ventrolateral part of the medulla oblongata of the rat revealed distinct subpopulations of neurons within the C1 region (Phillips et al., J Comp Neurol 2001, 432:20-34). In extending this study to include the caudal pons, it was shown for the first time that the A5 cell group could be distinguished by the presence of immunoreactivity to tyrosine hydroxylase (TH), aromatic l-amino acid decarboxylase (AADC), and dopamine beta hydroxylase (DBH). A novel cell group was also identified. The cells within this new group were immunoreactive to DBH but not TH, AADC, or phenylethanolamine N-methyltransferase (PNMT) and will be referred to as the TH-, DBH+ cell group. The TH-, DBH+ neurons were not immunoreactive for either the dopamine or noradrenaline transporters, suggesting that these neurons do not take up these transmitters. A5 neurons were immunoreactive for the noradrenaline transporter but not the dopamine transporter (as previously shown). Retrograde tracing with cholera toxin B revealed that the TH-, DBH+ neurons do not project to the thoracic spinal cord or to the rostral ventrolateral medulla, but A5 neurons do. A calbindin immunoreactive cell group is located in a region overlapping TH-, DBH+ cell group. However, only a few neurons were immunoreactive for both markers. The physiological role of the TH-, DBH+ cell group remains to be determined.

Animals↗
PubMed2001

Firing patterns of pre-Bötzinger and Bötzinger neurons during hypocapnia in the adult rat.

Controversy exists about how a coordinated respiratory rhythm is generated in the brainstem. Some authors suggest that neurons in the pre-Bötzinger complex are key to initiation of all types of breathing. While, on the other hand, it has been reported that some pre-Bötzinger neurons fail to maintain a rhythmic discharge in phase with phrenic nerve discharge during mechanical hyperventilation. Extracellular recordings were made from respiratory units in the pre-Bötzinger and Bötzinger complexes of 13 anaesthetised, paralysed and vagotomised rats. Central respiratory activity was monitored from the C5 phrenic nerve. During mechanical hyperventilation, several changes were observed in the phrenic neurogram. Firstly, the frequency and amplitude of integrated phrenic nerve discharge were reduced and reversibly stopped. Secondly, the patterned discharges changed from an augmenting to a variety of non-augmenting patterns in 53 of 60 cases. In some cases (n=9) we observed that the pattern appeared to have two components, an early short duration discharge followed by a longer duration discharge. Respiratory units also started to show different firing patterns during mechanical hyperventilation. In general, they were divided into those units that fired tonically (n=28) and units that became silent (n=32), before phrenic nerve discharge ceased coincidently with complete apnoea. Of particular interest were those expiratory-inspiratory units in the pre-Bötzinger complex (n=8) that narrowed their firing period towards late expiration and early inspiration during mechanical hyperventilation. Given their firing features, it is possible that these expiratory-inspiratory units may participate in generation of the early inspiratory component of phrenic nerve discharge.

Age Factors↗
PubMed2001

Differential expression of catecholamine biosynthetic enzymes in the rat ventrolateral medulla.

Adrenergic (C1) neurons located in the rostral ventrolateral medulla are considered a key component in the control of arterial blood pressure. Classically, C1 cells have been identified by their immunoreactivity for the catecholamine biosynthetic enzymes tyrosine hydroxylase (TH) and/or phenylethanolamine N-methyltransferase (PNMT). However, no studies have simultaneously demonstrated the expression of aromatic L-amino acid decarboxylase (AADC) and dopamine beta-hydroxylase (DBH) in these neurons. We examined the expression and colocalization of all four enzymes in the rat ventrolateral medulla using immunohistochemistry and reverse transcription-polymerase chain reaction (RT-PCR) analysis. Retrograde tracer injected into thoracic spinal segments T2-T4 was used to identify bulbospinal neurons. Using fluorescence and confocal microscopy, most cells of the C1 group were shown to be double or triple labeled with TH, DBH, and PNMT, whereas only 65-78% were immunoreactive for AADC. Cells that lacked detectable immunoreactivity for AADC were located in the rostral C1 region, and approximately 50% were spinally projecting. Some cells in this area lacked DBH immunoreactivity (6.5-8.3%) but were positive for TH and/or PNMT. Small numbers of cells were immunoreactive for only one of the four enzymes. Numerous fibres that were immunoreactive for DBH but not for TH or PNMT were noted in the rostral C1 region. Single-cell RT-PCR analysis conducted on spinally projecting C1 neurons indicated that only 76.5% of cells that contained mRNA for TH, DBH, and PNMT contained detectable message for AADC. These experiments suggest that a proportion of C1 cells may not express all of the enzymes necessary for adrenaline synthesis.

Animals↗
PubMed2001

Rostral ventral medulla 5-HT1A receptors selectively inhibit the somatosympathetic reflex.

The role of the 5-hydroxytryptamine (5-HT1A) receptors in the rostral ventrolateral medulla (RVLM) on somatosympathetic, baroreceptor, and chemoreceptor reflexes was examined in anesthetized rats. Microinjection of the selective 5-HT1A agonist 8-hydroxy-di-n-propylamino tetralin (8-OH-DPAT) decreased arterial blood pressure and splanchnic sympathetic nerve activity (SNA). Electrical stimulation of the hindlimb evoked early and late excitatory sympathetic responses. Bilateral microinjection in the RVLM of 8-OH-DPAT markedly attenuated both the early and late responses. This potent inhibition of the somatosympathetic reflex persisted even after SNA and arterial blood pressure returned to preinjection levels. Preinjection of the selective 5-HT1A antagonist NAN-190 in the RVLM blocked the sympathoinhibitory effect of 8-OH-DPAT and attenuated the inhibitory effect on the somatosympathetic reflex. 8-OH-DPAT injected in the RVLM did not affect baroreceptor or chemoreceptor reflexes. Our findings suggest that activation of 5-HT1A receptors in the RVLM exerts a potent, selective inhibition on the somatosympathetic reflex.

8-Hydroxy-2-(di-n-propylamino)tetralin↗
PubMed2001

Differential role of kinases in brain stem of hypertensive and normotensive rats.

Spontaneously hypertensive rats (SHR) are characterized by extreme elevations of blood pressure. The genetic factors underlying this are yet to be identified. Here we demonstrate, in vivo, that in SHR and normotensive Wistar-Kyoto rats (WKY), injection of the mitogen-activated protein kinase inhibitor PD 098,059 bilaterally into the rostral ventrolateral medulla (RVLM) dramatically lowers arterial pressure. PD 098,059 does not alter the responses evoked by microinjection of glutamate into the RVLM or brief apnea. Wortmannin (phosphatidylinositol-3 kinase inhibitor) bilaterally into the RVLM causes a 35+/-4% fall in arterial pressure in SHR but has no effect in WKY. Furthermore, wortmannin reduces the pressor response evoked by microinjection of angiotensin (Ang) II in the RVLM of SHR compared with WKY. The response to Ang II microinjection into the RVLM of WKY was unaffected by wortmannin. Simultaneous bilateral injections of PD 098,059 and wortmannin into the RVLM abolished the response to exogenous Ang II in the RVLM but did not affect the response evoked by glutamate in either SHR or WKY. Thus, it appears that PD 098,059- and/or wortmannin-sensitive mechanisms are not involved in the responses evoked by glutamate in the RVLM and that these kinase inhibitors are not neurotoxic. We conclude that a PD 098,059-sensitive pathway in the RVLM of SHR and WKY tonically regulates arterial pressure and that a wortmannin-sensitive pathway in the RVLM is important in the maintenance of hypertension in SHR. This may be related to a phosphatidylinositol-3 kinase-dependent mechanism involved in the action of Ang II on the Ang II type 1 receptor.

Androstadienes↗
PubMed2000

Calbindin-immunoreactive neurons in the reticular formation of the rat brainstem: catecholamine content and spinal projections.

Calbindin-D28k (calbindin) is a calcium-binding protein that is distributed widely in the rat brain. The localisation of calbindin immunoreactivity in the medulla oblongata and its colocalisation with adrenaline-synthesising neurons [phenylethanolamine-N-methyltransferase-immunoreactive (PNMT-IR)] was examined (Granata and Chang [1994] Brain Res. 645:265-277). However, detailed information about the distribution of calbindin-IR neurons in the reticular formation of the medulla oblongata in particular is lacking. In this report, the authors address this issue with an emphasis on the quantitation of calbindin-IR neurons, catecholamine neurons [tyrosine hydroxylase (TH)-IR, or PNMT-IR], and spinally projecting neurons in the ventral brainstem. Rats received injections of the retrograde tracing agent cholera toxin B (CTB) into the thoracic spinal cord or into the superior cervical ganglion. Immunocytochemistry was used to reveal calbindin, TH, PNMT, and CTB immunoreactivity. Ten calbindin-IR cell groups were identified within the pontomedullary reticular formation. Seven previously undescribed but distinct clusters of calbindin-IR neurons were found. Within the ventral pons, a population of calbindin-IR neurons occurred dorsal but adjacent to the A5 cell group. These calbindin-IR neurons did not contain either TH or PNMT immunoreactivity, and few if any of these neurons projected to the spinal cord. A distinct group of calbindin-IR neurons was present in the ventral medulla. Seventy-five percent of these calbindin-IR neurons contained TH immunoreactivity, 45% contained PNMT immunoreactivity, and 21% were spinally projecting neurons. Spinally projecting, calbindin-IR neurons were a subpopulation of PNMT-IR cells. In the caudal ventral medulla, no TH-IR or PNMT-IR cells were calbindin-IR. In the intermediolateral cell column, close appositions of calbindin-IR terminals on identified sympathetic preganglionic neurons as well as calbindin-IR synapses indicated that these neurons may affect directly the sympathetic outflow. The results demonstrate for the first time the existence of a new subpopulation of spinally projecting, PNMT-IR neurons in the rostral ventrolateral medulla.

Animals↗
PubMed2000

Delta opioid receptor immunoreactive boutons appose bulbospinal CI neurons in the rat.

Bulbospinal sympathoexcitatory neurons in the rostral ventrolateral medulla are inhibited by activation of delta opioid receptors. However, it is not known whether this opioidergic effect is pre- or post- synaptic. Here, using retrograde tracing and immunocytochemistry in adult rats, we provide evidence that the delta opioid receptor is located on boutons that are presynaptic to both catecholaminergic and non-catecholaminergic neurons that project to the spinal cord. We suggest that the sympathoinhibitory action of delta opioid receptor activation in the rostral ventrolateral medulla is mediated presynaptically, resulting in a reduction of excitatory neurotransmitter release from boutons that oppose sympathoexcitatory bulbospinal neurons.

Adrenergic Fibers↗
PubMed2000

Spinal GABA(A) receptors do not mediate the sympathetic baroreceptor reflex in the rat.

Activation of baroreceptors causes efferent sympathetic nerve activity (SNA) to fall. Two mechanisms could account for this sympathoinhibition: disfacilitation of sympathetic preganglionic neurons (SPN) and/or direct inhibition of SPN. The roles that spinal GABA and glycine receptors play in the baroreceptor reflex were examined in anesthetized, paralyzed, and artificially ventilated rats. Spinal GABA(A) receptors were blocked by an intrathecal injection of bicuculline methiodide, whereas glycine receptors were blocked with strychnine. Baroreceptors were activated by stimulation of the aortic depressor nerve (ADN), and a somatosympathetic reflex was used as control. After an intrathecal injection of vehicle, there was no effect on any measured variable or evoked reflex. In contrast, bicuculline caused a dose-dependent increase in arterial pressure, SNA, phrenic nerve discharge, and it significantly facilitated the somatosympathetic reflex. However, bicuculline did not attenuate either the depressor response or sympathoinhibition evoked after ADN stimulation. Similarly, strychnine did not affect the baroreceptor-induced depressor response. Thus GABA(A) and glycine receptors in the spinal cord have no significant role in baroreceptor-mediated sympathoinhibition.

Adrenergic Fibers↗
PubMed1999

Neurokinin-1 receptors and spinal cord control of blood pressure in spontaneously hypertensive rats.

In this study we examined blood pressure and heart rate responses to intrathecal administration of a synthetic NK1-receptor agonist, H2N-(CH2)4-CO-Phe-Phe-Pro-NmeLeu-Met-NH2 (GR 73,632), in spontaneously hypertensive rats (SHR) and their progenitor strain, the Wistar-Kyoto rat (WKY). Sodium pentobarbitone anaesthetised rats with implanted intrathecal catheters were paralysed (pancuronium dibromide) and artificially ventilated. Injection of GR 73,632 at the T9 spinal level evoked dose-dependent increases in mean arterial pressure (MAP) in WKY and SHR. SHR had a lower MAP response threshold than WKY but increase in response with increasing dose was less in SHR than WKY. Biphasic blood pressure responses at high doses were observed in both strains. Prior administration of the NK1-receptor antagonist (3 aR,7aR)-7,7-diphenyl-2-[1-imino-2(methoxyphenyl)ethyl] perhydroisoindol-4-one (RP 67,580) significantly reduced the pressor response in WKY but not SHR. The depressor response was not attenuated in either strain.

Analgesics↗
PubMed1999

Activation of spinal opioid receptors contributes to hypotension after hemorrhage in conscious rats.

Opioid receptors are activated during severe hemorrhage, resulting in sympathoinhibition and a profound fall in blood pressure. This study examined the location and subtypes of opioid receptors that might contribute to hypotension after hemorrhage. Intrathecal naloxone methiodide (100 nmol) abolished the fall in blood pressure after hemorrhage (1.5% of body wt; mean arterial pressure 122 +/- 8 mmHg after naloxone methiodide vs. 46 +/- 5 mmHg in controls, P < 0. 001). Intracisternal naloxone methiodide was less effective than intrathecal naloxone methiodide, whereas intravenous naloxone methiodide, which does not cross the blood-brain barrier, did not alter the fall in blood pressure after hemorrhage. These results demonstrate that spinal opioid receptors contribute to hypotension after hemorrhage but do not exclude supraspinal effects. In separate experiments, the subtype-specific opioid antagonists ICI-174864 (delta-antagonist), norbinaltorphimine (nor-BNI; kappa-antagonist), and H-D-Phe-Cys-Tyr-D-Trp-Orn-Thr-Pen-Thr-NH2 (CTOP; mu-antagonist) were each administered intrathecally to determine the minimum dose that would attenuate hypotension during severe hemorrhage. These antagonists were effective at similar doses (3 nmol for CTOP, 6 nmol for ICI-174864, and 10 nmol for nor-BNI), although the binding affinities of these three different agents for their target receptors varied >1600-fold. Comparisons of the minimum effective doses of these antagonists in relation to their binding affinities provides strong evidence for the participation of delta-receptors in mediating hypotension after hemorrhage. In contrast, the dose at which nor-BNI was effective suggests an effect at delta-receptors but not kappa-receptors. The efficacy of CTOP, albeit at a high dose, also suggests an effect at mu-receptors.

Animals↗