Postexercise hypotension is not explained by a prostaglandin-dependent peripheral vasodilation.

In normally active individuals, postexercise hypotension after a single bout of aerobic exercise occurs due to an unexplained peripheral vasodilation. Prostaglandin production has been suggested to contribute to the increases in blood flow during and after exercise; however, its potential contribution to postexercise hypotension has not been assessed. The purpose of this study was to determine the potential contribution of a prostaglandin-dependent vasodilation to changes in systemic vascular conductance underlying postexercise hypotension; this was done by inhibiting production of prostaglandins with the cyclooxygenase inhibitor ibuprofen. We studied 11 healthy normotensive men (aged 23.7 +/- 4.2 yr) before and during the 90 min after a 60-min bout of cycling at 60% peak O(2) uptake on a control and a cyclooxygenase inhibition day (randomized). Subjects received 10 mg/kg of oral ibuprofen on the cyclooxygenase inhibition day. On both study days, arterial blood pressure (automated auscultation) and cardiac output (acetylene uptake) were measured, and systemic vascular conductance was calculated. Inhibition of cyclooxygenase had no effect on baseline values of mean arterial pressure or systemic vascular conductance (P > 0.2). After exercise on both days, mean arterial pressure was reduced (-2.2 +/- 1.0 mmHg change with the control condition and -3.8 +/- 1.5 mmHg change with the ibuprofen condition, both P < 0.05 vs. preexercise) and systemic vascular conductance was increased (5.2 +/- 5.0% change with the control condition and 8.7 +/- 4.1% change with the ibuprofen condition, both P < 0.05 vs. preexercise). There were no differences between study days (P > 0.6). These data suggest that prostaglandin-dependent vasodilation does not contribute to the increased systemic vascular conductance underlying postexercise hypotension.     

Post-suspension hypotension is attenuated in Sprague-Dawley rats by prostacyclin synthase inhibition

Cardiovascular deconditioning, sometimes manifested in astronauts during standing postflight, may be related to the impairment of autonomic function and/or excessive production of endothelium-dependent relaxing factors. In the present study, we examined the cardiovascular responses to 7-day 30 degrees tail-suspension and a subsequent 6-h post-suspension period in conscious male Sprague-Dawley rats to determine the role of prostacyclin in the observed post-suspension reduction in mean arterial pressure (MAP). The specific prostacyclin synthase inhibitor U-51605 (0.3 mg/kg), or saline, was administered intravenously prior to release from suspension and at 2 and 4 h post-suspension. During 7 days of suspension, MAP did not change, however, there was a post-suspension reduction in MAP which was associated with significant increases in plasma prostacyclin and nitric oxide. U-51605 attenuated the observed post-suspension hypotension and reduced plasma prostacyclin levels, but not nitric oxide levels. The baroreflex sensitivity for heart rate was modified by U-51605: increased MAP threshold and effective MAP range. Thus, the post-suspension reduction in mean arterial pressure may be due to overproduction of prostacyclin and/or other endothelium-dependent relaxing factors and alteration in baroreflex activity.     

Autoradiographic localization of substance P receptors using I substance P

This paper describes a method for localization of substance P receptors in the rat central nervous system using ¹²⁵I labeled substance P in an autoradiographic procedure. Particularly high densities of substance P receptors were observed in the olfactory bulb, dentate gyrus, amygdala, superior colliculus, and locus coeruleus. Surprisingly low densities of substance P receptors were found in the substantia nigra pars reticulata, a region which contains high concentrations of substance P.     

Sympathetic and parasympathetic component of bradycardia triggered by stimulation of NTS P2X receptors

We have previously shown that activation of P2X purinoceptors in the subpostremal nucleus tractus solitarius (NTS) produces a rapid bradycardia and hypotension. This bradycardia could occur via sympathetic withdrawal, parasympathetic activation, or a combination of both mechanisms. Thus we investigated the relative roles of parasympathetic activation and sympathetic withdrawal in mediating this bradycardia in chloralose-urethane anesthetized male Sprague-Dawley rats. Microinjections of the selective P2X purinoceptor agonist alpha,beta-methylene ATP (25 pmol/50 nl and 100 pmol/50 nl) were made into the subpostremal NTS in control animals, after atenolol (2 mg/kg i.v.), a beta1-selective antagonist, and after atropine methyl bromide (2 mg/kg i.v.), a muscarinic receptor antagonist. The bradycardia observed with activation of P2X receptors at the low dose of the agonist is mediated almost entirely by sympathetic withdrawal. After beta1-adrenergic blockade, the bradycardia was reduced to just -5.1 +/- 0.5 versus -28.8 +/- 5.1 beats/min in intact animals. Muscarinic blockade did not produce any significant change in the bradycardic response at the low dose. At the high dose, both beta1-adrenergic blockade and muscarinic blockade attenuated the bradycardia similarly, -37.4 +/- 6.4 and -40.6 +/- 3.7 beats/min, respectively, compared with -88.0 +/- 11 beats/min in control animals. Double blockade of both beta1-adrenergic and muscarinic receptors virtually abolished the response (-2.5 +/- 0.8 beats/min). We conclude that the relative contributions of parasympathetic activation and sympathetic withdrawal are dependent on the extent of P2X receptor activation.     

Use of substance P fragments to differentiate substance P receptors of different tissues

The C- and N-terminal fragments of substance P were compared to the parent molecule with respect to their ability to: (a) contract the isolated guinea pig ileum, (b) induce salivation in the rat, (c) excite single cat dorsal horn neurones, and (d) induce scratching by intracranial injections in mice. C-terminal fragments as small as the heptapeptide were potent SP agonists on all assay systems. C-terminal fragments containing five amino acids or less were, at most, only weakly active. The C-terminal hexapeptide was a potent SP receptor stimulant on the isolated guinea pig ileum and, when directly applied by microiontophoresis, on cat dorsal horn neurons. However, the same compound was only 2-5% as potent as substance P in eliciting salivation and scratching in vivo, an indication that this fragment may be especially labile to enzymatic degradation. N-terminal fragments were totally inactive on the isolated guinea pig ileum. On the rat salivation and central nervous system assays, however, N-terminal fragments were capable of weak SP-like activity. It is concluded that SP receptors exist in multiple forms which we have labelled SP1 and SP2 receptors for those insensitive or sensitive to N-terminal fragments, respectively.     

Opposite modulation of capsaicin-evoked substance P release by glutamate receptors

Substance P and glutamate are present in primary afferent C-fibers and play important roles in persistent inflammatory and neuropathic pain. In the present study, we have examined whether activation of different glutamate receptor subtypes modulates the release of substance P evoked by the C-fiber selective stimulant capsaicin (1 μM) from rat trigeminal nucleus slices. The selective NMDA glutamate receptor agonist L-CCG-IV (1–10 μM) enhanced capsaicin-evoked substance P release about 100%. This facilitatory effect was blocked by 0.3 μM MK-801, a selective NMDA receptor antagonist. The metabotropic glutamate receptor agonists L-AP4 (group III) and DHPG (group I) (30–100 μM) inhibited capsaicin-evoked substance P release by approximately 60%. These inhibitory effects were blocked by the selective metabotropic glutamate receptor antagonist (±)-MCPG (5 μM). On the other hand, AMPA and kainate (0.1–10 μM), did not significantly affect capsaicin-evoked substance P release. Thus, substance P release from non-myelinated primary afferents, and possibly nociception, may be under the functional antagonistic control of some metabotropic and ionotropic glutamate receptor subtypes.     

Interaction of substance P antagonists with substance P receptors on dispersed pancreatic acini

In the present study we examined the abilities of three analogs of substance P, [D-Pro2-, D-Phe7-, D-Trp9]-substance P, [D-Pro2-, D- Trp7 ,9]-substance P and [D-Arg1-, D-Pro2-, D- Trp7 ,9-, Leu11 ]-substance P to alter substance P-induced changes in pancreatic acinar cell function and to occupy substance P receptors. At 30 microM, each analog of substance P lacked agonist activity and inhibited amylase secretion stimulated by substance P receptor agonists. The inhibition was reversible and specific for peptides that interact with substance P receptors (physalaemin, substance P, eledoisin, kassinin ). The analogs of substance P did not inhibit the actions of cholecystokinin, caerulein, gastrin, carbamylcholine, secretin, vasoactive intestinal peptide, PHI, ionophore A23187 or 8Br -cAMP. At high concentrations, [D-Arg1-, D-Pro2-, D- Trp7 ,9-, Leu11 ]-substance P, but not [D-Pro2-, D- Trp7 ,9]-substance P or [D-Pro2-, D-Phe7-, D-Trp9]-substance P, caused a small but significant inhibition of bombesin-stimulated amylase release. For each analog of substance P, the inhibition was competitive in nature in that there was a rightward shift of the dose-response curve for physalaemin-stimulated amylase secretion with no change in efficacy. From Schild plots of the ability of [D-Arg1-, D-Pro2-, D- Trp7 ,9-, Leu11 ]-substance P to inhibit either substance p- or physalaemin-stimulated amylase release, the slopes were not different from unity. For each analog of substance P, there was a close correlation between its ability to inhibit substance P- or physalaemin-stimulated amylase release and its ability to inhibit binding of 125I-labeled substance P or 125I-labeled physalaemin. [D-Arg1-, D-Pro2-, D- Trp7 ,9-, Leu11 ]-substance P was 2-fold more potent than [D-Pro2-, D- Trp7 ,9]-substance P which was 4-fold more potent than [D-Pro2-, D-Phe7-, D-Trp9]-substance P, (i.e., pA2 6.1, 5.9, and 5.2, respectively). For each analog, the dose-response curve for its ability to inhibit physalaemin-stimulated amylase release was superimpossible on the dose-response curve for its ability to inhibit binding of 125I-labeled physalaemin. These results indicate that each of these analogs of substance P is a specific competitive inhibitor of the action of the substance P on dispersed acini from guinea-pig pancreas, and that their abilities to inhibit substance P-induced changes in acinar cell function can be accounted for by their abilities to occupy the substance P receptor.     

Cardiovascular mechanisms activated by microinjection of baclofen into NTS of conscious rats

The peripheral mechanisms responsible for pressor response produced by microinjections of baclofen (GABA(B) agonist) into the nucleus tractus solitarii (NTS) of conscious rats were studied. Bilateral microinjections of baclofen (10-1,000 pmol/100 nl) produced a dose-related increase in mean arterial pressure (MAP) and heart rate. The maximal response was observed after 15 min. Intravenous injection of prazosin decreased MAP to control levels. Subsequent treatment with Manning compound (vasopressin receptor antagonist; iv) produced an additional decrease in MAP. In a different group of rats, vasopressin antagonist was injected first and MAP was significantly decreased; however, it remained elevated compared with prebaclofen injection levels. Subsequent treatment with prazosin abolished the baclofen-induced pressor response. Reductions in baclofen-induced pressor response with prazosin treatment were followed by a reflex tachycardia in animals that received a 100 pmol/100 nl dose of baclofen. The tachycardia was not observed with a dose of 1,000 pmol/100 nl. The pressor response induced by microinjection of baclofen into the NTS of conscious rats may be produced by both increases in sympathetic tonus and vasopressin release.     

Renal mitochondrial impairment is attenuated by AT1 blockade in experimental Type I diabetes

To investigate whether ANG II type 1 (AT(1)) receptor blockade could protect kidney mitochondria in streptozotocin-induced Type 1 diabetes, we treated 8-wk-old male Sprague-Dawley rats with a single streptozotocin injection (65 mg/kg ip; STZ group), streptozotocin and drinking water containing either losartan (30 mg.kg(-1).day(-1); STZ+Los group) or amlodipine (3 mg.kg(-1).day(-1); STZ+Amlo group), or saline (intraperitoneally) and pure water (control group). Four-month-long losartan or amlodipine treatments started 30 days before streptozotocin injection to improve the antioxidant defenses. The number of renal lesions, plasma glucose and lipid levels, and proteinuria were higher and creatinine clearance was lower in STZ and STZ+Amlo compared with STZ+Los and control groups. Glycemia was higher in STZ+Los compared with control. Blood pressure, basal mitochondrial membrane potential and mitochondrial pyruvate content, and renal oxidized glutathione levels were higher and NADH/cytochrome c oxidoreductase activity was lower in STZ compared with the other groups. In STZ and STZ+Amlo groups, mitochondrial H(2)O(2) production rate was higher and uncoupling protein-2 content, cytochrome c oxidase activity, and renal glutathione level were lower than in STZ+Los and control groups. Mitochondrial nitric oxide synthase activity was higher in STZ+Amlo compared with the other groups. Mitochondrial pyruvate content and H(2)O(2) production rate negatively contributed to electron transfer capacity and positively contributed to renal lesions. Uncoupling protein-2 content negatively contributed to mitochondrial H(2)O(2) production rate and renal lesions. Renal glutathione reduction potential positively contributed to mitochondria electron transfer capacity. In conclusion, AT(1) blockade protects kidney mitochondria and kidney structure in streptozotocin-induced diabetes independently of blood pressure and glycemia.     

Cardiovascular interactions between methionine-enkephalin and substance P in the conscious dog

Interactions between the undecapeptide Substance P (SP) and the pentapeptide methionine-enkephalin (Met5-ENK) have been described in isolated organ systems and in baroreceptor reflex mechanisms. Previous studies in our laboratory have demonstrated that systemically injected Met5-ENK simultaneously increases mean systemic arterial pressure (MAP) and heart rate (HR) in the conscious, chronically instrumented dog. We have now evaluated cardiovascular interactions between SP and Met5-ENK. In this model, SP injected intravenously produces a rapid and transient decrease in MAP and increase in HR over the dose range from 1.0 to 10.0 ng/kg. SP does not appear to appreciably alter subsequent responses to Met5-ENK. At SP doses of 1.0 ng/kg, the peak hemodynamic response to SP and Met5-ENK (35 micrograms/kg) given together appears to represent a simple summation effect of both drugs on HR and MAP. However, at higher SP doses (5.0 ng/kg), the SP response predominates and is little altered by the presence of Met5-ENK. Thus, Met5-ENK does appear capable of modulating the hemodynamic responses to SP over certain dose ranges.     

Hemodynamic effects elicited by microinjection of glutamatergic agonists into NTS of conscious rats

In this study, we characterized the arterial pressure, heart rate, and regional vascular conductance responses elicited by unilateral microinjection of ionotropic glutamatergic agonists N-methyl-D-aspartic acid (NMDA and non-NMDA) into the nucleus of tractus solitarius (NTS) of conscious rats. Microinjections of NMDA and S-alpha-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA) caused changes in mean arterial pressure (MAP). Lower doses elicited decreases in MAP, whereas higher doses elicited biphasic responses (decreases followed by increases). Both agonists induced bradycardia and elicited dose-dependent vasoconstriction in the renal, mesenteric, and hindquarter beds. AMPA elicited delayed vasodilation in the hindquarter bed but NMDA did not. Bradycardia and initial hypotension produced by each agonist were abolished by systemic administration of the muscarinic antagonist methylatropine. However, methylatropine did not affect either the vasoconstriction or the vasodilatation. The contrasting hemodynamic effects produced by NMDA and AMPA could be caused by activation of differential subsets of NTS neurons. Preferential activation of one subset could produce the NMDA-related responses, whereas activation of another subset would elicit AMPA-related responses.     

Hypertension induced by blockade of ET(B) receptors in conscious nonhuman primates: role of ET(A) receptors

The role of endothelin-B (ET(B)) receptors in circulatory homeostasis is ambiguous, reflecting vasodilator and constrictor effects ascribed to the receptor and diuretic and natriuretic responses that could oppose the hypertensive effects of ET excess. With the use of conscious, telemetry-instrumented cynomolgus monkeys, we characterized the hypertension produced by ET(B) blockade and the role of ET(A) receptors in mediating this response. Mean arterial pressure (MAP) and heart rate (HR) were measured 24 h/day for 24 days under control conditions and during administration of the ET(B)-selective antagonist A-192621 (0.1, 1.0, and 10 mg/kg bid, 4 days/dose) followed by coadministration of the ET(A) antagonist atrasentan (5 mg/kg bid) + A-192621 (10 mg/kg bid) for another 4 days. High-dose ET(B) blockade increased MAP from 79 +/- 3 (control) to 87 +/- 3 and 89 +/- 3 mmHg on the first and fourth day, respectively; HR was unchanged, and plasma ET-1 concentration increased from 2.1 +/- 0.3 pg/ml (control) to 7.24 +/- 0.99 and 11.03 +/- 2.37 pg/ml. Atrasentan + A-192621 (10 mg/kg) decreased MAP from hypertensive levels (89 +/- 3) to 75 +/- 2 and 71 +/- 4 mmHg on the first and fourth day, respectively; plasma ET-1 and HR increased to 26.64 +/- 3.72 and 28.65 +/- 2.89 pg/ml and 113 +/- 5 (control) to 132 +/- 5 and 133 +/- 7 beats/min. Thus systemic ET(B) blockade produces a sustained hypertension in conscious nonhuman primates, which is mediated by ET(A) receptors. These data suggest an importance clearance function for ET(B) receptors, one that influences arterial pressure homeostasis indirectly by reducing plasma ET-1 levels and minimizing ET(A) activation.     

Mechanisms of modulation of neuronal nicotinic receptors by substance P and OAG

Substance P is known to modulate neuronal nicotinicacetylcholine receptors (nAChRs) in the sympathetic nervous system.There are two conflicting proposals for the mechanism of this effect, an indirect action mediated by protein kinase C (PKC) and a direct interaction with receptor subunits. We studied the mechanisms of thiseffect in PC-12 cells. Substance P enhanced the decay of thenicotine-induced whole cell current. This effect was fast in its onsetand was not antagonized by guanosine5'-O-(2-thiodiphosphate), a G protein blocker, orstaurosporine, a nonselective PKC blocker. Staurosporine failed toreverse the inhibition by 1-oleoyl-2-acetyl-sn-glycerol (OAG), a synthetic diacylglycerol analog known to activate PKC. Theinhibitory effects of the peptide and OAG were preserved in excisedpatches, but substance P applied to the extra patch membrane wasineffective in the cell-attached patch configuration. We conclude thatsubstance P modulates neuronal nAChRs most likely by direct interactions with the receptors but independently from activation ofPKC or G proteins and that PKC does not participate in modulation by OAG.

     

Gastrointestinal dysfunction induced by early weaning is attenuated by delayed weaning and mast cell blockade in pigs

Our previous work has demonstrated that weaning at 19 days of age has deleterious effects on mucosal barrier function in piglet intestine that are mediated through peripheral CRF receptor signaling pathways. The objectives of the present study were to assess the impact of piglet age on weaning-associated intestinal dysfunction and to determine the role that mast cells play in weaning-induced breakdown of mucosal barrier function. Nursing Yorkshire-cross piglets were either weaned at 19 days of age (early-weaned, n = 8) or 28 days of age (late-weaned, n = 8) and housed in nursery pens. Twenty-four hours postweaning, segments of midjejunum and ascending colon from piglets within each weaning age group were harvested and mounted on Ussing chambers for measurements of transepithelial electrical resistance and serosal-to-mucosal [(3)H]mannitol fluxes. Early weaning resulted in reductions in transepithelial electrical resistance and increases in mucosal permeability to [(3)H]mannitol in the jejunum and colon (P < 0.01). In contrast, postweaning reductions in intestinal barrier function were not observed in piglets weaned at 28 days of age. Early-weaned piglet intestinal mucosa had increased expression of CRF receptor 1 protein, increased mucosal mast cell tryptase levels, and evidence of enhanced mast cell degranulation compared with late-weaned intestinal mucosa. Pretreatment of piglets with the mast cell stabilizer drug cromolyn, injected intraperitoneally 30 min prior to weaning, abolished the early-weaning-induced intestinal barrier disturbances. Our results indicate that early-weaning stress induces mucosal dysfunction mediated by intestinal mast cell activation and can be prevented by delaying weaning.     

Distinct classes of substance P receptors revealed by a comparison of the activities of substance P and some of its segments

The contracting potency of Substance P and of its C-terminal fragments was studied using four isolated preparations of smooth muscle. The Substance P receptors in the four muscles studied can be differentiated on the basis of their interactions with Substance P and its C-terminal fragments. On the guinea pig ileum, the potency of Substance P is equal to that of the C-terminal octa- and heptapeptide segments and in the rat ileum the potency of Substance P is equal to that of the C-terminal octapeptide and even higher than that of the heptapeptide. In contrast, on the cow pupillary sphincter and guinea pig urinary bladder, Substance P is markedly less potent that the C-terminal octa-, hepta- and hexapeptides. These results suggest the existence of different classes of Substance P receptors and indicate that the N-terminal sequence may be important in regulating Substance P activity.     

Impaired substance P release from renal sensory nerves in SHR involves a pertussis toxin-sensitive mechanism

Stretching the renal pelvic wall activates renal mechanosensory nerves by a PGE2-mediated release of substance P via activation of the cAMP-PKA pathway. Renal pelvic ANG II modulates the responsiveness of renal sensory nerves by suppressing the PGE2-mediated activation of adenylyl cyclase via a pertussis toxin (PTX)-sensitive mechanism. In SHR, activation of renal mechanosensory nerves is impaired. This is due to suppressed release of substance P in response to increased pelvic pressure. The present study was performed to investigate whether the PGE2-mediated release of substance P was suppressed in SHR vs. WKY and, if so, whether the impaired PGE2-mediated release of substance P was due to ANG II activating a PTX-sensitive mechanism. In an isolated renal pelvic wall preparation, PGE2, 0.14 microM, increased substance P release from 9 +/- 3 to 22 +/- 3 pg/min (P < 0.01) in Wistar-Kyoto rats (WKY), but had no effect in spontaneously hypertensive rats (SHR). A tenfold higher concentration of PGE2, 1.4 microM, was required to increase substance P release in SHR, from 7 +/- 1 to 22 +/- 3 pg/min (P < 0.01). In SHR, treating renal pelvises with losartan enhanced the release of substance P produced by subthreshold concentration of PGE2, 0.3 microM, from 16 +/- 2 to 26 +/- 3 pg/min (P < 0.01). Likewise, treating renal pelvises with PTX enhanced the PGE2-mediated release of substance P from 10 +/- 1 to 33 +/- 3 pg/min (P < 0.01) in SHR. In WKY, neither losartan nor PTX had an effect on the release of substance P produced by subthreshold concentrations of PGE2, 0.03 microM. In conclusion, the impaired responsiveness of renal sensory nerves in SHR involves endogenous ANG II suppressing the PGE2-mediated release of substance P via a PTX-sensitive mechanism.     

Regional vasodilator actions of calcitonin gene-related peptide in conscious SHR

In the present study the regional hemodynamic effects of CGRP were examined in conscious unrestrained spontaneously hypertensive rats (SHR). The animals were chronically instrumented with miniaturized pulsed Doppler flow probes to allow continuous measurement of renal, mesenteric and hindquarter blood flow. Bolus intravenous injection of CGRP (0.1-5 micrograms/kg) produced a dose-dependent fall in mean arterial pressure (maximal change = -48 +/- 5 mmHg) which was accompanied by a marked tachycardia (maximal change = 143 +/- 16 b/min). Depressor responses to CGRP were sustained for approximately 3-5 min. CGRP markedly reduced regional vascular resistance in all three vascular beds. No regional-selective vasodilator response was observed. These data indicate that CGRP is a potent vasodilator peptide in conscious SHR. The study suggests further that CGRP may contribute to the physiologic regulation of cardiovascular function.     

A comparison of the anatomical distribution of substance P and substance P receptors in the rat central nervous system

A comparison of anatomical distributions of substance P (SP) and substance P receptors in the rat central nervous system was performed. SP was localized by microdissection and radioimmunoassay and SP fibers and cell bodies by immunohistochemistry. Receptors for ¹²⁵I-Bolton Hunter labelled SP (¹²⁵I-BH-SP) were characterized pharmacologically by a slice binding technique in sections that contained primarily striatum. The receptor was saturable and had an equilibrium dissociation constant (K_D) of 0.30 nM and maximum number of binding sites (B_max) of 37.8 fmol/mg protein. Pharmacological characterization using C terminal fragments and naturally occurring analogues of SP reflected characteristics of the receptor which had been shown previously in bioassays and biochemical assays. Comparison of distribution of SP fibers and cell bodies and SP receptors indicated that there is no consistent relationship between the amount of SP receptor and density of SP fibers or cell bodies in a given region of the brain.     

Concomitant regulation of hippocampal calcium antagonist receptors and calcium uptake by substance P

The interaction of various neuropeptides with calcium antagonist binding was investigated in rat hippocampus. Among the peptides examined Substance P selectively increased the binding of phenylalkylamine and dihydropyridine calcium antagonists; this action was receptor mediated. No effect was observed with Substance P in other brain areas and with neurotensin and met-enkephalin in all the areas examined. The modification in calcium antagonist binding is functionally paralleled by an area specific increase in voltage-dependent calcium uptake. These data suggest that in hippocampus Substance P may be an endogenous regulator of voltage sensitive calcium channels.     

Sustained pharmacological blockade of NK1 substance P receptors causes functional desensitization of dorsal raphe 5-HT 1A autoreceptors in mice

Antagonists at NK1 substance P receptors have demonstrated similar antidepressant properties in both animal paradigms and in human as selective serotonin reuptake inhibitors (SSRIs) that induce desensitization of 5-HT 1A autoreceptors within the dorsal raphe nucleus (DRN). We investigated whether this receptor adaptation also occurs upon NK1 receptor blockade. C57B/L6J mice were treated for 21 days with the selective NK1 receptor antagonist GR 205171 (10 mg/kg daily) through subcutaneously implanted osmotic mini pumps, and DRN 5-HT 1A autoreceptor functioning was assessed using various approaches. Recording of DRN serotonergic neurons in brainstem slices showed that GR 205171 treatment reduced (by approximately 1.5 fold) the potency of the 5-HT 1A receptor agonist, ipsapirone, to inhibit cell firing. In parallel, the 5-HT 1A autoreceptor-mediated [35S]GTP-gamma-S binding induced by 5-carboxamidotryptamine onto the DRN in brainstem sections was significantly decreased in GR 205171-treated mice. In vivo microdialysis showed that the cortical 5-HT overflow caused by acute injection of the SSRI paroxetine (1 mg/kg) was twice as high in GR 205171-treated as in vehicle-treated controls. In the DRN, basal 5-HT outflow was significantly enhanced by GR 205171 treatment. These data supported the hypothesis that chronic NK1 receptor blockade induces a functional desensitization of 5-HT 1A autoreceptors similar to that observed with SSRIs.