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Biomedical subjects

R Couture

Publications and source records attributed to R Couture.

At least 91 records · Page 5Linked to original sources
PubMed1989

Capillary permeability induced by intravenous neurokinins. Receptor characterization and mechanism of action.

The effects on plasma extravasation of three increasing doses from 6.5 pmol to 650 nmol/kg of substance P (SP), SP fragments, neurokinin A (NKA), neurokinin B (NKB) and selective agonists for neurokinin receptors were assessed in three cutaneous tissues (skin of hind paws, dorsal skin and ears) by intravenous (i.v.) administration in the pentobarbitone anaesthetized rat. Dose-dependent increases in plasma extravasation were observed with the following rank orders of potency (SP greater than NKA greater than NKB) for neurokinins and (SP greater than [p-Glu6]SP(6-11) greater than SP(4-11) greater than [p-Glu5]SP(5-11) greater than SP(7-11] for C-terminal SP fragments. The metabolically stable SP analogue [p-Glu5, MePhe8, Sar9]SP(5-11) was slightly more potent than [p-Glu5]SP(5-11). The N-terminal fragments SP(1-4), SP(1-7) and SP(1-9) were inactive up to 650 nmol/kg. The NK-1 receptor selective agonists [Sar9, Met(O2)11]SP and [beta-Ala4, Sar9, Met (O2)11]SP(4-11) were more potent than the NK-2 [( Nle10]NKA(4-10] and NK-3 [( MePhe7]NKB and [beta-Asp4, MePhe7]NKB(4-10] receptor selective agonists. Plasma extravasation induced by SP (6.5 nmol/kg) was unchanged in the presence of atropine, methysergide, diphenhydramine or during the i.v. and intra-arterial (i.a.) infusion of D-Arg0[Hyp3.D-Phe7]BK, an antagonist of bradykinin. Plasma extravasation induced by SP and [Sar9, Met(O2)11]SP was significantly reduced by indomethacin while that induced by NKA, NKB, [beta-Ala4, Sar9, Met(O2)11]SP(4-11), SP(4-11) and [p-Glu6]SP(6-11) was unaffected by the cyclooxygenase inhibitor. Compound 48/80 (0.75 mg/kg), histamine (10 mg/kg) and 5-HT (10 mg/kg) caused an increase in plasma extravasation, only the effect of compound 48/80 was abolished by indomethacin. Pretreatment with compound 48/80 prevented its own action on plasma extravasation and significantly reduced that induced by 6.5 nmol/kg of SP. These results rule out the involvement of acetylcholine (muscarinic receptors), 5-HT (5-HT1 and 5-HT2 receptors), histamine (H1 receptors) and kinins (B2 receptors) in the response to SP and indicate that the two positively charged amino acids (Arg, Lys) at the N-terminal end of the SP molecule are essential to trigger the release of prostaglandins from mast cells. This mechanism is responsible for the indirect effect of SP and related peptides on capillary permeability and does not appear to be mediated by a selective SP receptor. In addition, neurokinins may increase capillary permeability by direct activation of a NK-1 receptor type on the vascular endothelium.

Animals↗
PubMed1989

Characterization of the peripheral action of neurokinins and neurokinin receptor selective agonists on the rat cardiovascular system.

The effects on mean arterial pressure (MAP) and heart rate (HR) of increasing doses (0.65-65 nmol/kg) of substance P (SP), neurokinin A (NKA), neurokinin B (NKB) and selective agonists for neurokinin receptors were measured after intravenous (i.v.) injection in urethane anaesthetized rats. Neurokinins (NKs) elicited a vasodepressor effect with the following rank order of potency: SP (100%) greater than NKB (17.5%) greater than NKA (10%). The two undecapeptide NK-1 selective agonists, [Pro9, Met(O2)11]SP (787%) and [Sar9, Met(O2)11]SP (697%), evoked a significantly (P less than 0.05) greater vasodepressor response than SP, while the potency of the octapeptide NK-1 selective agonist [beta-Ala4, Sar9, Met(O2)11]SP (4-11) (316%) was not significantly different from SP. Conversely, the NK-2 selective agonist NKA (4-10) (less than 2%) caused only a small effect. The vasodepressor effect elicited by [MePhe7]NKB (112%) and [beta-Asp4, MePhe7]NKB (4-10) (92%), two NK-3 selective agonists, were not significantly different from that of SP. Senktide (1,095%) is the most potent NK-3 agonist, and is significantly (P less than 0.01) more potent than SP. No cross-desensitization, of the vasodepressor response, was observed between NK-1 and NK-3 selective agonists. I.V. injection of 32.5 nmol/kg of NKA, NKA (4-10) and [beta-Ala4, Sar9, Met(O2)11]SP (4-11) raised HR, while NKB and the NK-3 selective agonists produced a rapid and marked bradycardia. SP and the two undecapeptide, NK-1 selective agonists, produced an initial increase in HR and a latent long-lasting bradycardia. The bradycardia elicited by [Sar9, Met(O2)11]SP (32.5 nmol/kg) was blocked by methylatropine, hexamethonium, indomethacin and by treatment with capsaicin or compound 48/80. Although the bradycardia elicited by [beta-Asp4, MePhe7]NKB (4-10) (32.5 nmol/kg) was also blocked by hexamethonium, methylatropine, and by bilateral vagotomy, it remained unaffected after indomethacin, or in rats pretreated with either capsaicin or compound 48/80. The drop in MAP produced by the NK-1 and NK-3 agonists were reduced by hexamethonium, methylatropine and bilateral vagotomy (NK-3 agonist), but remained unaffected by indomethacin, capsaicin, and compound 48/80. The tachycardia to NKA (4-10) (65 nmol/kg) was blocked entirely by sotalol or metoprolol and potentiated by hexamethonium. Guanethidine and bilateral adrenalectomy (48 h) failed to affect the tachycardia induced by the agonist, whereas the combination of both treatments abolished the response. Rats sympathectomized with 6-hydroxydopamine (48 h) reduced the increase in HR to NKA (4-10) only at 1 min post-administration.(ABSTRACT TRUNCATED AT 400 WORDS)

Animals↗
PubMed1989

Prostacyclin release induced by neurokinins in cultured human endothelial cells.

The effects of neurokinins (NK) and related peptides on the secretion of 6-keto-prostaglandin F1 alpha, a stable metabolite of prostacyclin, were measured. These peptides enhanced three- to five-fold the basal secretion rate with the following rank order of potency (based on threshold concentrations for a significant output): substance P (SP) greater than or equal to NKA greater than SP 4-11 greater than or equal to [pGlu6]SP 6-11 = SP 7-11.NKB and SP 1-9 were inactive. Ac[Arg6, Sar9, Met(O2)11]SP, a NK1 receptor selective agonist, was more potent than other selective agonists for the NK2 and NK3 receptor subtypes. These results suggest that the NK receptors, which mediate the release of prostacyclin from human endothelial cells, belong to the NK1 subtype.

6-Ketoprostaglandin F1 alpha↗
PubMed1989

Intrinsic origin of atrioventricular nodal functional properties in rabbits.

The goal of the present study was to document the intrinsic origin of atrioventricular nodal functional properties (recovery time, facilitation, and fatigue) in two groups of six superfused isolated rabbit heart preparations. These properties were determined from recovery curves (A2H2 versus H1A2 intervals) obtained with previously defined periodic premature stimulation sequences performed before and after autonomic blockade demonstrated effective with the injection of agonists. In group 1 preparations, the muscarinic cholinergic and beta-adrenergic receptors were blocked with atropine (1 mg/L) and propranolol (1 mg/L), respectively. The blockade reduced the facilitation and increased the fatigue by the direct membranous effect of propranolol. To avoid this effect in group 2 preparations, propranolol was replaced by sotalol (5 mg/L), which in combination with atropine altered neither the presence nor the magnitude of the functional properties. These results show that the origin of the three nodal functional properties is independent from the autonomic nervous system.

Animals↗
PubMed1989

Cardiovascular responses induced by intrathecal substance P in the conscious freely moving rat.

In conscious freely moving rats, administration of 0.65 to 32.5-nmol doses of substance P (SP) into the intrathecal (i.th.) space at the T8-T10 level of the spinal cord increased both mean arterial pressure (MAP) and heart rate (HR) in a dose-related manner. Concomitant with these cardiovascular effects, behavioral responses were observed. Injection of the peptide produced agitation of the rat for approximately 1 min as well as intermittent reciprocal hindlimb scratching which lasted for 3-6 min. The cardiovascular responses elicited by SP (6.5 nmol) were not blocked by systemic pretreatment with morphine (3-6 mg/kg), and the effect of SP on HR was potentiated by an i.th. dose of morphine (10 micrograms) given prior to the injection of SP. A systemic dose of phentolamine (1 mg/kg) blocked the pressor response and a depressor effect appeared, whereas propranolol (1 mg/kg) blocked the HR response. Although catecholamines mediate the spinal action of SP on MAP and HR, bilateral adrenalectomy of the rat 48 h prior to experimentation failed to affect the cardiovascular responses to SP. After transection of the spinal cord at the C3-C4 level, the hindlimb scratching behavior and the pressor response to SP were unaffected but the peak HR response was significantly reduced. These results demonstrate that the rise in MAP and HR evoked by SP is not secondary to perception of a noxious stimulus by the rat and that adrenal medullary catecholamines are not essential for these cardiovascular effects.(ABSTRACT TRUNCATED AT 250 WORDS)

Adrenalectomy↗
PubMed1988

Spinal action of neurokinins producing cardiovascular responses in the conscious freely moving rat: evidence for a NK-1 receptor mechanism.

This study was initiated to characterize the receptors which mediate the cardiovascular responses elicited by the intrathecal (i.th.) administration of neurokinins (NK) in the conscious freely moving rat. The dose response profile for substance P (SP), neurokinin A (NKA) and neurokinin B (NKB) was determined over 0.065-65 nmol doses of the peptides. After i.th. administration at the T8-T10 thoracic level, only SP elicited a dose dependent pressor response. However, all NK elicited a dose dependent increase in heart rate (HR), and the following rank order of potency was observed: SP greater than NKA greater than NKB. SP (6.5 nmol) produced cardiovascular responses markedly greater than an equimolar dose of any of the seven SP fragments which were studied. The C-terminal sequences SP (4-11), [pGlu5]SP (5-11), [pGlu6]SP (6-11), and SP (7-11), as a group were slightly more potent than the N-terminal fragments, SP (1-4), SP (1-7) and SP (1-9) which were almost inactive. The NK-1 receptor selective agonists [Pro9, Met(O2)11]SP and [beta-Ala4, Sar9, Met(O2)11]SP (4-11), produced pressor and positive chronotropic responses equal to or greater in intensity than SP. With up to 6.5 nmol of the NK-2 receptor selective agonist [Nle10]NKA (4-10), no dose dependent cardiovascular response was produced and the NK-3 receptor selective agonist senktide (succinyl-[Asp6, MePhe8]SP (6-11], produced neither a cardiac nor pressor response when 6.5 nmol was administered. These results are consistent with the hypothesis that, receptors of the NK-1 subtype mediate the cardiovascular responses evoked by the spinal action of NK.

Animals↗
PubMed1988

Characterization of the effects produced by neurokinins and three agonists selective for neurokinin receptor subtypes in a spinal nociceptive reflex of the rat.

In the awake restrained rat the intrathecal (i.th.) administration of 6.5 pmol-40 nmol of substance P (SP), neurokinin A (NKA) or one of two selective NK-1 receptor agonists [Pro9, Met(O2)11]SP, denoted ana1 and [beta-Ala4, Sar9, Met(O2)11]SP , denoted ana2 decreased reaction time (RT) to a noxious radiant heat stimulus in a dose-related manner. The following rank order of potency was observed in relation to this response: ana1 = ana2 greater than SP much greater than NKA. The decrement of tail-flick latency was greatest at 1 min and RT returned to the basal level within 6-11 min post-administration. However, in some rats SP produced a small increase in RT (anti-nociception) at 6-11 min post-administration. The i.th. administration of neurokinin B (NKB) or a selective NK-3 receptor agonist [beta-Asp4, MePhe7]NKB), denoted ana3 induced an antinociceptive effect which was greatest at 1 min and lasted less than 11 min after NKB or more than 30 min after ana3 administration. The magnitude of the increase in RT produced by 65 pmol-40 nmol doses of these peptides is ana3 much greater than NKB much greater than SP. The effect of NKB (8.0 nmol) was significantly blocked (P less than 0.005) by prior i.th. administration of naloxone (opioid antagonist) but not by idazoxan (alpha 2-adrenoceptor antagonist), [Thi5,8, D-Phe7]BK (kinin antagonist), or following bilateral adrenalectomy. From these results, we conclude that NKB-induced antinociception is mediated by the spinal release of an opioid and not through a BK or NA mechanism. The results also suggest that the nociceptive and antinociceptive effects of neuro-kinins are mediated by the activation of NK-1 and NK-3 receptor subtypes respectively, in the rat spinal cord.

Adrenalectomy↗
PubMed1988

Studies on the cardiovascular effects produced by the spinal action of substance P in the rat.

Administration of 6.5-pmol-6.5-nmol doses of substance P (SP) into the spinal subarachnoid space at T-8-T-10 in urethane-anesthetized rats increases both mean arterial pressure (MAP) and heart rate (HR) in a dose-related manner. However, in rats anesthetized with sodium pentobarbital, an increase in MAP is seen only at low doses of SP (6.5-65 pmol), while a biphasic response is obtained at 650 pmol and only a depressor response at 6.5 nmol SP. These responses also are accompanied by a tachycardia. Depending on the spinal cord level, cardiovascular responses of different time course and magnitude are elicited by SP. The amplitude of the increases in MAP and HR produced by SP (6.5 nmol) are: T-8-T-10 greater than T-1-T-3 greater than L-2-L-4 in rats anesthetized with urethane. In rats anesthetized with sodium pentobarbital, the decrease in MAP levels is greatest at T-1-T-3, while it is similar at T-8-T-10 and L-2-L-4 levels. The effects of SP on HR are more complex. The different cardiovascular responses obtained with the two anesthetics are not attributed to the relative depth of anesthesia but may be due to differential effects of the anesthetics on sympathetic nervous activity. The effect of SP on HR can be blocked by propranolol, but it remains unaffected by the surgical removal of the adrenal glands. We conclude that this cardiovascular response is most likely mediated by the postganglionic noradrenergic fibres and that adrenal medullary catecholamines are not essential. Using several inhibitors of endogenous mediators, two components to the spinal action of SP on MAP are made evident. The pressor response can be explained solely by the activation of sympathetic preganglionic fibres in the intermediolateral nucleus of the spinal cord, while the depressor response, in addition, may involve the release of a vasodilatatory substance in the periphery, the action of which persists in the presence of cholinergic, histaminergic, serotonergic, or opioid antagonists. Moreover, the adrenal glands are excluded as a possible source of this substance.

Adrenalectomy↗
PubMed1987

Bradykinin analogue blocks bradykinin-induced inhibition of a spinal nociceptive reflex in the rat.

In the awake restrained rat the intrathecal (i.th.) administration of 81 pmol to 8.1 nmol of bradykinin (BK) increased reaction time to a noxious radiant heat stimulus. The enhancement of tail-flick latency peaked at 1 min and returned to the basal level 11-16 min after BK administration. Behavioural responses were observed as early as 5 s following peptide administration and lasted for 30-45 s. When BK was given after prior i.th. administration of 6.1 nmol of [Thi5,8, D-Phe7]BK, an antagonist of BK at the B2-receptor, the increase in latency was significantly attenuated. The analogue [Leu8]BK-(1-8) (10.3 nmol), an antagonist of BK at the B1-receptor, failed to modify the BK-induced antinociception. The two analogues alone and the fragment BK-(1-8), a potent stimulant of B1-receptors for BK, failed to alter reaction time and only the B2-receptor antagonist reduced BK-induced behavioural responses. These results suggest that BK may play a role through the activation of a B2-receptor type in a spinal sensory pathway subserving pain.

Animals↗
PubMed1987

Studies on the cardiovascular effects produced by the spinal action of two substance P analogues in the rat: evidence for a central catecholaminergic mechanism.

The effects of two substance P (SP) analogues, [D-Trp7,9,10]SP (ana1) and [D-Pro4,Lys6,D-Trp7,9,10,Phe11]SP-(4-11) (ana2) on mean arterial pressure (MAP) and heart rate (HR) were measured following intrathecal administration at one of three spinal cord levels in rats anaesthetized with sodium pentobarbital. Following an initial increase, a profound and long-lasting fall in MAP and HR occurred when 6.5 nmol of either ana1 or ana2 was injected at T1-T3 or T8-T10. Only transient changes in MAP and a slight increase in HR was observed after injection of either peptide at L2-L4. The profound and long-lasting hypotension and bradycardia induced by ana1 were not significantly altered after intravenous injection of hexamethonium, phentolamine, propranolol, atropine, diphenhydramine, cimetidine, methysergide, naloxone or morphine. However, the biphasic effect of ana1 on MAP was prevented by the intrathecal administration of prazosin and yohimbine, suggesting that a central catecholaminergic mechanism including alpha 1- and alpha 2-adrenergic receptors is involved. The latter treatment did not prevent the tachycardia which occurred when the bradycardia was blocked, indicating that different mechanisms mediate the spinal action of ana1 on MAP and HR. Finally, cervical transection of the spinal cord eliminated the profound and long-lasting depressor effect of ana2, suggesting that a supraspinal mechanism is involved in this cardiovascular response.

Animals↗
PubMed1987

Effects of substance P analogues in the rat tail-flick test.

Five substance P (SP) analogues which antagonize tachykinins on isolated organs were studied using the tail-flick test. None antagonized the nociceptive effect of 1.9 nmol of physalaemin when studied at the concentrations of 6.5 and 65.0 nmol. [D-alpha Npa7,9,10]SP (65.0 nmol) produced a flaccid paralysis of the hindlimbs and the tail in 2 out of 9 rats; however, [D-Pro4,Lys6,D-Trp7,9,10,Phe11]SP-(4-11) (6.5 nmol) produced this type of paralysis in 4 out of 6 rats so treated. The [D-Trp]SP analogue appears to be the most toxic. The results also suggest that the receptor for physalaemin in the spinal cord is different from that in peripheral tissues.

Animals↗
PubMed1987

Intrathecal administration of substance P enhances cutaneous plasma protein extravasation in pentobarbital anaesthetized rats.

In pentobarbital-anaesthetized rats, the intrathecal administration of substance P (SP) at T9 spinal cord level enhances plasma protein extravasation (PE) in cutaneous tissues of the back, the hind paws and the ears. This vascular response is maximum at 15 min after administration of SP (6.5 nmol), and the most striking in the skin of the hind paws. Contrary to SP, neurotensin (NT) administered intrathecally failed to enhance PE. Both peptides are however potent enhancers of PE following intravenous injection. PE elicited by intrathecal administration of SP is significantly reduced in both spinal rats and in capsaicin treated animals. These results suggest that SP but not NT may play a role as a spinal chemical mediator in peripheral vascular permeability through a supraspinal reflex mechanism involving sensory afferents.

Animals↗
PubMed1987

Plasma protein extravasation induced by mammalian tachykinins in rat skin: influence of anaesthetic agents and an acetylcholine antagonist.

The effect of mammalian tachykinins on plasma protein extravasation was assessed in the rat dorsal skin. Substance P (SP), neurokinin A (NKA) and neurokinin B (NKB) increased vascular permeability in a dose-related manner with a threshold dose of about 0.07 pmol in sodium pentobarbitone-anaesthetized animals. Plasma protein extravasation induced by the tachykinins was 100-500 times less in magnitude in animals anaesthetized with urethane. Plasma protein extravasation induced by SP (66 pmol) was significantly reduced (63%; P less than 0.001) by atropine (a muscarinic inhibitor) while that induced by NKA or NKB was unaffected by the inhibitor suggesting that a cholinergic component might only be involved in the vascular permeability elicited by SP. The rank order of potency for the tachykinins on plasma protein extravasation was: NKB greater than SP greater than NKA (in absence of atropine) and NKB greater than NKA greater than SP (in presence of atropine), suggesting that this vascular response is mediated by a SP-E receptor type. The amplitudes of the plasma protein extravasation induced by NKB and its hydrophilic analogue [Arg degrees]NKB were similar, indicating that the lipophilic features of the native peptide cannot account for its potent biological activity. Plasma protein extravasation was enhanced by the SP analogue [D-Pro4,Lys6,D-Trp7,9,10,Phe11]SP (4-11), thus showing the limitation of such SP analogues (antagonists) for characterizing the tachykinin receptors involved in vascular permeability.

Anesthetics↗
PubMed1987

Spinal actions of substance P analogues on cardiovascular responses in the rat: a structure-activity analysis.

Ten substance P (SP) analogues were tested for their effects on mean arterial pressure and heart rate following intrathecal administration in the pentobarbital anaesthetized rat. The 10 analogues are [D-Pro4,D-alpha Npa7,9,10]SP(4-11) (A-I), (D-alpha Npa7,9,10]SP (A-II), [D-Trp7,9,10]SP (A-III), [D-Pro4,D-Npa7,9,Phe11]SP(4-11) (A-IV), [D-Pro4,D-beta Npa7,D-alpha Npa9,D-Phe11]SP(4-11) (A-V), [D-Pro4,Lys6,D-Trp7,9,10,Phe11]SP(4-11) (A-VI), [D-Pro4,D-Trp7,9,10,Phe11]SP(4-11) (A-VII), [D-Pro4,D-Trp7,9,10,Trp11]SP(4-11) (A-VIII), [D-Trp7,9,10,Trp11]SP (A-IX), and [D-Pro4,D-Phe7,9,10,Phe11]SP(4-11) (A-X). At 6.5 nmol, the analogues containing the amino acid D-Npa (A-I, A-II, A-IV, and A-V) or D-Phe (A-X) in positions 7, 9, or 10 of SP or its C-terminal octapeptide are devoid of the long-lasting cardio- and vaso-depressor effects, which are otherwise seen with analogues containing the amino acid D-Trp (A-III, A-VI, A-VII, A-VIII, and A-IX) in the same positions. Some of the analogues containing D-Npa maintain the initial hypotensive effect seen with SP while the analogue containing D-Phe produces only a small hypertensive response. The 10 analogues when tested at a dose that failed to alter basal mean arterial pressure and heart rate did not block the cardiovascular responses elicited by SP and no cross desensitization was observed between SP and these analogues. It appears that these SP analogues exert cardiovascular effects in the rat spinal cord probably without interacting with SP receptors.

Animals↗
PubMed1987

Spinal action of neurokinins in the rat: effects on mean arterial pressure, heart rate, and vascular permeability.

In urethane-anaesthetized rats, the intrathecal administration of 6.5 nmol of substance P (SP), neurokinin A (NKA), or neurokinin B (NKB) at the T8-T10 level of the spinal cord enhances mean arterial pressure and heart rate. However, in the pentobarbital-anaesthetized rat, while NKB produces no effect on mean arterial pressure, NKA produces a biphasic change and SP, a depressor response. All three neurokinins elicit a tachycardia. The following rank order of potency SP greater than or equal to NKA greater than NKB is observed in relation to these cardiovascular responses when either one of the two anaesthetics is used. The low cardiovascular activity of NKB cannot be attributed to its hydrophobicity, as the water soluble analogue of NKB, [Arg0]NKB, elicits a response as weak as the native peptide. In pentobarbital-anaesthetized rats, the intrathecal administration of 6.5 nmol of SP, also enhances plasma protein extravasation in cutaneous tissues of the back, the hind paws, and the ears. In this response NKA and NKB are either inactive (skin of hind paws) or less potent than SP (ears and dorsal skin). These findings agree with the hypothesis that in the rat spinal cord, the neurokinin receptor producing changes in mean arterial pressure, heart rate, and vascular permeability is of the NK-1 subtype.

Animals↗
PubMed1985

Trigeminal antidromic vasodilatation and plasma extravasation in the rat: effects of sensory, autonomic and motor denervation.

The cutaneous vasodilatation and plasma extravasation observed following antidromic stimulation of trigeminal sensory branches in the rat are reduced by atropine. The atropine-sensitive component does not originate from the seventh cranial nerve (facial nerve) or from the mental nerve, because after chronic section of these nerves an atropine-sensitive component persists. The cholinergic component of the plasma extravasation is abolished by chronic bilateral extirpation of the superior cervical ganglia but this is not the case for the vasodilatation. Our data suggest that trigeminal sensory fibres are not the only fibres involved in these vascular responses seen in the lower lip of the rat after electrical stimulation of the mental nerve.

Animals↗
PubMed1985

Characterization of spinal actions of four substance P analogues.

Four substance P (SP) analogues were tested on reaction time (RT) in the tail flick test and on the decrease in RT produced by the SP homologue physalaemin. The four analogues were [D-Trp7,9,10]SP, denoted A, [D-Pro4,D-Trp7,9,Nle11]SP-(4-11), denoted B, [D-Pro2,D-Trp7,9,10]SP, denoted C and [D-Pro4,D-Trp7,9,10,Phe11]SP-(4-11), denoted D. Physalaemin alone (1.89 nmol) reduced RT. The analogue A, at 3.25 nmol, blocked the effects of physalaemin without altering basal RT. The analogues B and D, which block the action of physalaemin in peripheral tissues, had neither agonistic nor antagonistic effects in doses up to 6.5 nmol. The replacement of L-Pro2 by D-Pro2 in the analogue A yielded the analogue C, which had no antagonistic activity. All analogues produced a flaccid paralysis of the hindlimbs and the tail; this effect was inconsistent, though, occurring only in some rats, and appearing in some cases after the first administration of the analogue yet in other cases only after a subsequent administration. Because B and D are inactive in the spinal cord, our results suggest that physalaemin activates receptors in the spinal cord different from those it activates in peripheral tissues. Furthermore, because all four analogues produced a flaccid paralysis none is suitable for use as an SP antagonist in vivo in the CNS.

Animals↗