Biomedical subjects

R Couture

Publications and source records attributed to R Couture.

At least 37 records · Page 2Linked to original sources

PubMed1997

Renal effects of intracerebroventricularly injected tachykinins in the conscious saline-loaded rat: receptor characterization.

1. The effects of intracerebroventricularly (i.c.v.) injected substance P (SP), neurokinin A (NKA) and [MePhe7]neurokinin B (NKB) were investigated on renal excretion of water, sodium and potassium in the conscious saline-loaded rat. The central effects of [MePhe7]NKB were characterized with selective tachykinin antagonists for NK1 (RP 67580), NK2 (SR 48968) and NK3 (R 820) receptors. 2. Whereas SP or NKA (65 or 650 pmol) failed to modify the renal responses, [MePhe7]NKB (65-6500 pmol) produced dose-dependent and long-lasting (30-45 min) decreases in renal excretion of water (maximal reduction at 65 pmol: from 66.14 +/- 7.62 to 21.07 +/- 3.79 microliters min-1), sodium (maximal reduction at 65 pmol: from 10.19 +/- 2.0 to 1.75 +/- 0.48 mumol min-1) and potassium (maximal reduction at 65 pmol: from 4.31 +/- 1.38 to 0.71 +/- 0.27 mumol min-1). While 650 pmol [MePhe7]NKB elevated urinary osmolality, neither 65 pmol nor 6.5 nmol [MePhe7]NKB altered this parameter. 3. Both the antidiuresis and antinatriuresis induced by [MePhe7]NKB (65 pmol) were significantly blocked by the prior i.c.v. injection of R 820 (1.3 nmol, 5 min earlier), although the potassium excretion was only partially reduced. However, R 820 did not affect the antidiuresis and antinatriuresis elicited by endothelin-1 (1 pmol, i.c.v.). On its own, R 820 decreased renal potassium excretion with no effect on urinary osmolality and renal excretion of water and sodium. The i.c.v. co-injection of RP 67580 and SR 48968 (6.5 nmol each, 5 min earlier) failed to modify the renal responses to [MePhe7]NKB in a similar study. 4. The central effects of [MePhe7]NKB (65 pmol) on renal excretion were blocked by the prior i.v. administration of a linear peptide vasopressin V2 receptor antagonist (50 micrograms kg-1, 5 min earlier). 5. These results suggest that the central NK3 receptor, probably located in the hypothalamus, is implicated in the renal control of water and electrolyte homeostasis through the release of vasopressin in the conscious saline-loaded rat.

Animals↗

PubMed1997

Renal effects of intrathecally injected tachykinins in the conscious saline-loaded rat: receptor and mechanism of action.

1. The effects of intrathecally (i.t.) injected substance P (SP), neurokinin A (NKA), [beta-Ala8]NKA (4-10) and [MePhe7]neurokinin B (NKB) at T13 thoracic spinal cord level were investigated on renal excretion of water, sodium and potassium in the conscious saline-loaded rat. Antagonists selective for NK1 (RP 67580), NK2 (SR 48968) and NK3 (R 820; 3-indolylcarbonyl-Hyp-Phg-N(Me)-Bzl) receptors were used to characterize the spinal effect of SP on renal function. 2. Saline gavage (4.5% of the body weight) enhanced renal excretion of water, sodium and potassium over the subsequent hour of measurement. Whereas these renal responses were not affected by 0.65 nmol SP, the dose of 6.5 nmol SP blocked the natriuretic response (aCSF value 3.9 +/- 0.8; SP value 0.7 +/- 0.3 micromol min(-1), P<0.01) as well as the renal excretion of water (aCSF value 48.9 +/- 5.8; SP value 14.5 +/- 4.0 microl min(-1), P<0.01) and potassium (aCSF value 4.8 +/- 0.6; SP value 1.5 +/- 0.6 micromol min(-1), P<0.01) at 30 min post-injection. SP had no significant effect on urinary osmolality. The SP-induced renal inhibitory effects during the first 30 min were abolished in rats subjected to bilateral renal denervation 1 week earlier or in rats injected i.t. 5 min earlier with 6.5 nmol RP 67580. In contrast, the co-injection of SR 48968 and R 820 (6.5 nmol each) did not affect the inhibitory responses to SP. On their own, these antagonists had no direct effect on renal excretion function. Since SP induced only transient changes in mean arterial blood pressure (-18.8 +/- 3.8 mmHg at 1 min and +6.3 +/- 2.4 mmHg at 5 min post-injection), it is unlikely that the renal effects of SP are due to systemic haemodynamic changes. 3. NKA (6.5 nmol but not 0.65 nmol) produced a transient drop in renal excretion of water (aCSF value 31.2 +/- 5.1; NKA value 11.3 +/- 4.2 microl min(-1), P<0.05), sodium (aCSF value 1.7 +/- 0.8; NKA value 0.4 +/- 0.2 micromol min(-1), P<0.05) and potassium (aCSF value 4.1 +/- 0.7; NKA value 1.5 +/- 0.4 micromol min(-1), P<0.05) at 15 min post-injection. However, the same doses (6.5 nmol) of selective agonists for tachykinin NK2 ([beta-Ala8]NKA(4-10)) and NK3 ([MePhe7]NKB) receptors were devoid of renal effects. 4. This study provided functional evidence that tachykinins may be involved in the renal control of water and electrolyte excretion at the level of the rat spinal cord through the activation of NK1 receptors and the sympathetic renal nerve.

Animals↗

PubMed1997

Cardiovascular and behavioural effects of intracerebroventricularly administered tachykinin NK3 receptor antagonists in the conscious rat.

1. In the conscious rat, three tachykinin NK3 receptor antagonists, namely SR142801 ((S)-(N)-(1-(3-(1-benzoyl-3-(3,4-dichlorophenyl)piperidin-3-yl)pro pyl)-4-phenylpiperidin-4-yl)-N-methylacetamide), R820 (3-indolylcarbonyl-Hyp-Phg-N(Me)-Bzl) and R486 (H-Asp-Ser-Phe-Trp-beta-Ala-Leu-Met-NH2) were assessed against the intracerebroventricular (i.c.v.) effects induced by senktide, a selective NK3 receptor agonist, on mean arterial blood pressure (MAP), heart rate (HR) and motor behaviour. 2. Senktide (10-650 pmol per animal; i.c.v; n = 4-16) at the lowest dose caused a significant fall in MAP (-10 +/- 6 mmHg), while at the highest doses (100 and 650 pmol), senktide caused a rise in MAP (9 +/- 3 and 12 +/- 1 mmHg, respectively) when compared to vehicle. The intermediate doses (25 and 65 pmol) had no effect on MAP. The highest two doses caused a tachycardia of 62 +/- 15 and 88 +/- 8 beats min(-1), respectively. The dose of 65 pmol had a biphasic effect on HR, an initial bradycardia of 47 +/- 12 beats min(-1) followed by a tachycardia of 46 +/- 14 beats min(-1). The lowest doses caused either a rise of 52 +/- 10 beats min(-1) (25 pmol) or no effect (10 pmol) on HR. All doses of senktide caused similar increases in face washing, sniffing and wet dog shakes except at the dose of 100 pmol, when wet dog shakes were more than double those observed with the other doses. 3. The antagonist SR142801 (100 pmol -65 nmol per animal; i.c.v.; n = 6-8) caused increases in MAP at the highest two doses (6.5 and 65 nmol) while HR, dose-dependently, increased (23 +/- 6 to 118 +/- 26 beats min[-1]) and the onset dose-dependently decreased. The (R)-enantiomer, SR142806 (100 pmol - 65 nmol per animal; i.c.v.; n = 6-8) only caused rises in MAP (13 +/- 2 mmHg) and HR (69 +/- 11 beats min[-1]) at the highest dose. These drugs had no apparent effect on behaviour, except for the highest dose of SR142801 which increased sniffing. The antagonist R820 (650 pmol - 6.5 nmol per animal; i.c.v.; n = 6) had no effect on MAP or HR and only increased sniffing behaviour at 6.5 nmol. At 650 pmol (n = 6), R486 had no effect on any variable, but at 3.25 nmol, i.c.v. (n = 4) a delayed tachycardia and a significant increase in all behavioural variables were observed. 4. The cardiovascular responses induced by 6.5 nmol SR142801 and 25 pmol senktide were inhibited by R820 (6.5 nmol, 5 min earlier i.c.v.). In contrast, R820 failed to affect the central cardiovascular and behavioural responses induced by 10 pmol [Sar9, Met(O2)11]substance P, a NK1 receptor selective agonist. The senktide-induced behavioural changes were not inhibited by R820 (6.5 nmol, i.c.v.) while R486 (650 pmol, i.c.v.) blocked both the cardiovascular and behavioural responses to 25 pmol senktide. A mixture of antagonists for NK1 (RP67580; 6.5 nmol) and NK2 (SR48968; 6.5 nmol) receptors injected i.c.v. did not affect the cardiovascular response to SR142801. Cross-desensitization was shown between the central responses to SR142801 and senktide, but not between SR142801 and [Sar9, Met(O2)11]substance P. 5. The antagonists SR142801 and SR142806 (6.5-650 nmol kg(-1); n = 5-7), given i.v., did not evoke any cardiovascular or behavioural changes, except a delayed bradycardia for SR142806 (650 nmol kg[-1]), and also failed to inhibit the increase in MAP evoked by senktide (4 nmol kg(-1), i.v.). However, at the highest dose, both drugs slightly reduced the senktide-induced tachycardia. 6. Although the present data are consistent with the in vitro pharmacological bioassays and binding data, showing that SR142801 is a poor antagonist at rat peripheral NK3 receptors, they suggest that SR142801 has a partial agonist action at these receptors centrally. A separation of the cardiovascular and behavioural effects mediated by central NK3 receptor activation was achieved with SR142801 and R820 but not with R486. These results could be explained by the existence of NK3 receptor subtypes in the rat or by the differential activation and inhibition of the same receptor protein linked to the production of different second messengers. Differences in the pharmacokinetic or pharmacodynamic properties of the antagonists cannot be excluded at this time.

Animals↗

PubMed1997

LY303870, a centrally active neurokinin-1 antagonist with a long duration of action.

The selective neurokinin (NK)-1 antagonist LY303870 has high affinity and specificity for human and guinea pig brain NK-1 receptors labeled with 125I-substance P. It has approximately 15- to 30-fold lower affinity for rat and mouse brain NK-1 receptors, consistent with previously reported species differences in the affinities of nonpeptide antagonists for NK-1 receptors. In vivo, LY303870 blocked the characteristic, caudally directed, biting and scratching response elicited by intrathecal administration of the selective NK-1 agonist Ac-[Arg6,Sar9,Met(O2)11]substance P6-11 in conscious mice. The potentiation of the tail-flick response elicited by intrathecal administration of the NK-1 agonist [Sar9,Met(O2)11]substance P in rats was also selectively blocked by LY303870. When tested in a model of persistent nociceptive activation induced by tissue injury (the formalin test), LY303870 blocked licking behavior in the late phase of the formalin test, in a dose-dependent manner. After oral administration of 10 mg/kg, the blockade of the late-phase licking behavior was evident for at least 24 hr. Ex vivo binding studies in guinea pigs showed that orally administered LY303870 potently inhibited binding to central and peripheral NK-1 receptors labeled with 125I-substance P. This inhibition was long-lasting, consistent with other in vivo activities. LY306155, the opposite enantiomer of LY303870, was less active in all of the functional assays. In rodents, LY303870 did not exhibit any neurological, motor, cardiovascular, gastrointestinal or autonomic side effects at doses of < or = 50 mg/kg p.o. Thus, LY303870 is a potent, centrally active, NK-1 antagonist in vivo, with long-lasting oral activity.

Animals↗

PubMed1997

Modulation of noradrenaline release by B1 and B2 kinin receptors during metabolic anoxia in the rat isolated atria.

A model of metabolic anoxia was used to investigate the modulatory effect of bradykinin (BK) on the release of noradrenaline (NA) in isolated rat atria. Atria were isolated from Wistar rats and inserted into a perfusion system. After an equilibration period of 20 min, the perfusate was collected every 5 min for a period of 85 min, during which the atria were field stimulated (5 Hz, 2 ms, 50 mA, 60 s) at 10 (S1) and 75 (S2) min. The metabolic anoxia was started 40 min before S2 by replacing O2 with N2 and by removing glucose. The drugs were added 20 min before S2, and their effects on NA release were assessed by the ratio S2/S1. The spontaneous and electrically stimulated induced (S-I) releases of NA were significantly increased by the anoxic procedure. BK (30 nM) significantly increased the S-I release of NA under normoxic conditions. However, under anoxia, BK had no effect on the S-I release of NA but inhibited its spontaneous release. BK coadministered with HOE-140 (100 nM), a B2 receptor antagonist, significantly increased the S-I release of NA during anoxia, whereas the coadministration of BK with Leu3-des-Arg9-BK (100 nM), a B1 receptor antagonist, significantly inhibited that release. Administration of des-Arg9-BK (100 nM) had no effect on the S-I outflow of NA following anoxia, although its coadministration with a B1 antagonist resulted in a significant inhibition of the S-I outflow of NA. The present results suggest that BK inhibits NA release through the activation of a B2 receptor following a 40-min period of metabolic anoxia. Because this inhibition can be observed only in the presence of a B1 receptor antagonist, this could imply that B1 receptor activation, revealed by the anoxia, is involved in the facilitation of NA release.

Animals↗

PubMed1997

Paradoxical action of desipramine on the modulatory effect of bradykinin on noradrenaline release in a model of metabolic anoxia in rat isolated atria.

We have previously shown that bradykinin (BK) can modulate the release of noradrenaline (NA) in a model of metabolic anoxia in the rat isolated atria. In this study, we tested the effect of an inhibitor of NA reuptake, desipramine, on the modulatory action of BK on NA release in this experimental model. Atria were isolated from Wistar rats and inserted into a perfusion system. After an equilibration period of 20 min, the perfusate was collected every 5 min for a period of 85 min, during which the atria were field stimulated (5 Hz, 2 ms, 50 mA, 60 s) at 10 (S1) and 75 (S2) min. Desipramine (1 microM) was present throughout the experimental procedures. The metabolic anoxia was started 40 min before S2 by replacing O2 with N2 and by removing glucose. The drugs were added 20 min before S2, and their effects were assessed by the ratio S2/S1. The spontaneous release of NA was not changed by the anoxic procedure, which significantly increased the electrically stimulated induced (S-I) release of NA. BK (30 nM) significantly increased the S-I release of norepinephrine under normoxic conditions. However, following anoxia, both BK and the B1 receptor agonist des-Arg9-BK (100 nM) significantly inhibited the S-I release of NA. The inhibition induced by BK was prevented by selective antagonists for B1 and B2 receptors. These observations contrast with the results obtained without desipramine, where BK, but not des-Arg(9)-BK, inhibited the S-I release of NA during anoxia. Therefore, blockade of NA reuptake during metabolic anoxia appears to alter the modulatory effect of kinins on NA release via the B1 receptor in the rat isolated atria.

Adrenergic Uptake Inhibitors↗

PubMed1996

Peripheral effects of three novel non-peptide tachykinin NK1 receptor antagonists in the anaesthetized rat.

Three novel non-peptide tachykinin NK1 receptor antagonists were assessed on the transient fall in mean arterial blood pressure and the salivation induced by i.v. substance P (0.65 nmol/kg) in the urethane-anaesthetized rat. LY303241 ((R)-1-[N-(2-methoxybenzyl)acetylamino]-3-(1H-indol-3-yl)-2-[N-(2-(4- phenylpiperazin-1-yl)acetyl)amino]propane), LY303870 ((R)-1-[N-(2-methoxybenzyl)acetylamino]-3-(1H-indol-3-yl)-2-[N-(2-(4-(++ +piperidin-1 -yl)piperidin-1-yl)acetyl)amino]propane) and LY306740 ((R)-1-[N-(2-methoxybenzyl)acetylamino]-3-(1H-indol-3-yl)-2-[N-(2-(4 -cyclohexylpiperazin-1-yl)acetyl)amino]propane) (65 nmol-9 micromol/kg i.v.; 5 min earlier) inhibited both the vasodepressor and salivary responses to substance P in a dose-dependent manner. LY303241 and LY306740 were more potent in inhibiting the vascular response to substance P while LY303870 was more potent in inhibiting the salivary response. LY303870 and LY306740 were devoid of direct effects while LY303241 decreased blood pressure and heart rate for 1 and 10 min, respectively. The antagonists act in a stereoselective and specific manner since the opposite (S) enantiomers of LY303870 (LY306155) and LY306740 (LY307679) failed to block the effects of substance P. In addition, LY303241, LY303870 and LY306740 neither affected the hypotension and the salivation induced by carbachol nor the increases in mean arterial pressure and heart rate induced by the tachykinin NK2 receptor agonist [beta-Ala8]neurokinin A-(4-10). Only LY303241 attenuated the decreases in mean arterial pressure and heart rate evoked by the tachykinin NK3 receptor agonist senktide. LY303870 and LY306740 appear to be the most interesting antagonists since they act in a specific and selective manner at the tachykinin NK1 receptor. The difference in the order of potency of the three antagonists to inhibit the hypotension and salivation elicited by substance P could be ascribed to their pharmacodynamic features or to the existence of different signal transduction mechanisms or receptor subtypes.

Anesthesia↗

PubMed1996

Receptor and mechanism that mediate endothelin- and big endothelin-1-induced phosphoinositide hydrolysis in the rat spinal cord.

In rat spinal cord slices, endothelin-1 and endothelin-3 enhanced [3H]inositol phosphate production between 1 nM and 10 microM (endothelin-1 > endothelin-3) while sarafotoxin 6c and the endothelin ETB receptor agonist IRL-1620 (Suc-[Glu9,Ala11,15]endothelin-1-(8-21)) were almost ineffective. BQ-123 (cyclo(D-Trp,D-Asp,L-Pro,D-Val,L-Leu), a selective endothelin ETA receptor antagonist, reduced the endothelin-1- and endothelin-3-induced [3H]inositol phosphate production, with similar inhibition constants (IC50: 16.7 +/- 3.4 and 8.0 +/- 1.6 microM, respectively). The inhibition of endothelin-1 was enhanced when BQ-123 was preincubated for 30 min instead of 15 min. BQ-788 (N-cis-2,6-dimethylpiperidinocarbonyl-L-gamma-methylleucyl-D -1-methoxy- carbonyltryptophanyl-D-Nle), a selective ETB receptor antagonist, did not modify the endothelin-1-induced [3H]inositol phosphate production. Big endothelin-1 (1 nM to 1 microM) was slightly less potent than endothelin-1 in enhancing [3H]inositol phosphate production. This response was sensitive to phosphoramidon and [Phe22]big endothelin-1-(19-37), two inhibitors of endothelin-converting enzyme. Pretreatment of slices with pertussis toxin, indomethacin or PN 200-110 ((-)-isradipine, a dual inhibitor of L- and R-type Ca2+ channels) did not alter the response to 1 microM endothelin-1 while this response was abolished by tetrodotoxin. Finally, endothelin-1 enhanced [3H]inositol phosphate production with an identical EC50 (2.1 nM) in spinal cord slices of Wistar-Kyoto rats (WKY) and spontaneously hypertensive rats (SHR) although the maximal response was reduced in SHR. These data indicate that endothelins stimulated [3H]inositol phosphate production in the rat spinal cord through the activation of an endothelin ETA receptor that trigger the release of an unidentified neurotransmitter. This effect does not appear to be associated to activation of a Gi/G(o)-type of G-protein, dihydropyridine-sensitive L-type Ca2+ channels or to the production of prostaglandins. Furthermore, the findings support the presence of a phosphoramidon-sensitive endothelin-converting enzyme in the spinal cord.

Animals↗

PubMed1996

Effects of captopril and Icatibant on bradykinin (BK) and des [Arg9] BK in carrageenan-induced edema.

The effects of captopril, an angiotensin-converting enzyme inhibitor (ACEI), and a selective B2 kinin receptor antagonist (Icatibant) were examined on the paw edema and tissue contents of bradykinin (BK) and des[Arg9]BK following the intraplantar injection of carrageenan in rats. To this end, BK-like immunoreactivity (BK-LI) and des[Arg9]BK-LI were measured with highly sensitive and specific chemiluminescent enzyme immunoassays. Because pentobarbital significantly reduced the carrageenan-induced edema between 3 and 8 h, experiments were conducted in conscious rats. Icatibant (32.5 nmol/paw; intraplantar) significantly reduced carrageenan-induced paw edema between 3 and 8 h in captopril-untreated rats and at 1 and 3 h in captopril-treated rats (0.2 mg/kg x 5 days, per os). The paw content of BK-LI was increased 10-fold in captopril-untreated and 29-fold in captopril-treated rats 1 h after carrageenan injection. In parallel, des[Arg9]BK-LI was increased 8-fold in captopril-untreated and 24-fold in captopril-treated rats. Icatibant prevented the maximal increases in BK-LI and des[Arg9]BK-LI induced by carrageenan. It is concluded that inhibition of ACE by captopril enhanced the early production of endogenous BK and the edema formation induced by carrageenan through a B2 receptor-mediated mechanism. However, the B2 receptor does not appear to be involved in the late phase of the inflammatory response (from 5 to 24 h) to carrageenan in rats pretreated with ACEI. Although the concentrations of des[Arg9]BK were greater than those of BK, it is unlikely that B1 receptors play a significant role in this model of carrageenan-induced edema.

Angiotensin-Converting Enzyme Inhibitors↗

PubMed1996

The selection of needs indicators for regional resource allocation in the fields of health and social services in Québec.

In Québec, recent political statements have strengthened the necessity to allocate resources according to regional population needs. A regional-provincial working group was set up to propose needs indicators in 8 different fields-or client-oriented programs-which subdivide the entire spectrum of health and social services in Québec. These programs include physical health, mental health, public health, functionally impaired elderly people, physical deficiency, intellectual deficiency, alcoholism and drug abuse and problems (abuse, neglect, delinquency) among young people and their families. The following paper summarizes the main proposals of the working group. Some comments are made on the definition of client-oriented programs, basic concepts, research questions and methodological approaches. Concrete examples are given in order to illustrate the type of data and methods used. Furthermore, the indicators selected for resource allocation (in each of the 8 client-oriented programs) are presented on a regional basis (n = 18) and introduced in a principal component analysis. Their variations are discussed and recommendations to facilitate their use and promote their development are made. Finally, the actual utilization of these indicators is reported.

Adolescent↗

PubMed1996

A role for B1 and B2 kinin receptors in the modulation of T-kininogen during the acute phase response of inflammation.

Kinin antagonists at B1 and B2 receptors were examined on liver and serum concentrations of immunoreactive T-kininogen and its gene expression in a rat model of carrageenan-induced hindpaw edema. Whereas the B2 antagonist, HOE140, dose-dependently inhibited the paw edema induced by intraplantar injection of carrageenan, the B1 receptor agonist [Sar(D-Phe8)des-Arg9]BK and antagonist [Lys(Leu8)des-Arg9]BK were ineffective. On its own, HOE140 (3.25 x 10(-7) mol/ paw, intraplantar) had no effect on liver and serum T-kininogen levels but it significantly enhanced liver T-kininogen concentrations in rats pretreated with carrageenan at 8 and 24 h postinjection. In the liver, the most pronounced effect was seen at 24 h (treated 248 +/- 7 micrograms/g vs. untreated 113 +/- 9 micrograms/g). The same dose of HOE140 increased serum T-kininogen from 1255 +/- 57 to 1696 +/- 83 micrograms/ml at 24 h. HOE140 did not affect tissue albumin content during the same period. Transcript measurements revealed that the steady-state level of liver T2-kininogen mRNA was specifically increased by HOE140 during inflammation. In carrageenan-treated rats, the B1 antagonist [Lys(Leu8)des-Arg9]BK also significantly increased liver T-kininogen at 24 h. The present results support a role for B2 kinin receptors in the early phase of acute phase protein synthesis and of both B2 and B1 receptors in the late phase (24 h). Hence, systemic effects of kinins should be taken into account in the pharmacology and physiopathology of B1 and B2 kinin receptors in inflammation.

Acute-Phase Reaction↗

PubMed1996

Mechanisms of kinin B1-receptor-induced hypotension in the anesthetized dog.

Our study was performed to investigate the mechanism underlying the phypotensive effect of kinin B1-receptor activation with des-Arg9-bradykinin (des-Arg9-BK), in comparison with B2-receptor activation with bradykinin (BK), in anesthetized dogs. Bolus intravenous and intraarterial injections of both kinins were compared. BK (0.6 microgram/kg) produced a transient hypotension of the same magnitude, regardless of the route of administration (from 110 +/- 6 mm Hg to 66 +/- 6 mm Hg, or -41 +/- 5%). In contrast, intraarterial injection of des-Arg9-BK (0.6 microgram/kg) induced a weaker hypotension compared with its intravenous injection (-27 +/- 2% vs. -39 +/- 3%, p < 0.05). The hypotension induced by both kinins was accompanied by increases in heart rate, maximum left ventricular dP/dt, and aortic blood flow, suggesting a reduction in peripheral resistance. The positive inotropic and chronotropic effects of BK and des-Arg9-BK were found to be mediated by the sympathetic nervous system, because they were abolished by propranolol. The hypotension induced by intravenous and intraarterial injections of BK and intravenous injections of des-Arg9-BK was only slightly reduced after nitric oxide (NO) synthase inhibition with NG-nitro-L-arginine (L-NNA). In contrast, the hypotensive effect of intraarterial injection of des-Arg9-BK was reduced by half after treatment with L-NNA (p < 0.05). Neither bilateral vagotomy nor ganglionic blockade with pentolinium reduced the hypotension induced by both kinins. In conclusion, the hypotensive effect of des-Arg9-BK and BK results from a peripheral vasodilation. The contribution of NO in this vasodilation is substantial for des-Arg9-BK when administered intraarterial but limited for BK and intravenous des-Arg9-BK.

Animals↗

PubMed1996

Intracerebroventricular responses to neuropeptide gamma in the conscious rat: characterization of its receptor with selective antagonists.

1. The cardiovascular and behavioural effects elicited by the intracerebroventricular (i.c.v.) administration of neuropeptide gamma (NP gamma) in the conscious rat were assessed before and 5 min after i.c.v. pretreatment with antagonists selective for NK1 (RP 67,580), NK2 (SR 48,968) and NK3 (R 820) receptors. In addition, the central effects of NP gamma before and after desensitization of the NK1 and NK2 receptors with high doses of substance P (SP) and neurokinin A (NKA) were compared. 2. Intracerebroventricular injection of NP gamma (10-780 pmol) evoked dose- and time-dependent increases in mean arterial blood pressure (MAP), heart rate (HR), face washing, head scratching, grooming and wet-dog shake behaviours. Similar injection of vehicle or 1 pmol NP gamma had no significant effect on those parameters. 3. The cardiovascular and behavioural responses elicited by NP gamma (25 pmol) were significantly and dose-dependently reduced by pretreatment with 650 pmol and 6.5 nmol of SR 48,968. No inhibition of NP gamma responses was observed when 6.5 nmol of RP 67,580 was used in a similar study. Moreover, the prior co-administration of SR 48,968 (6.5 nmol) and RP 67,580 (6.5 nmol) with or without R 820 (6.5 nmol) did not reduce further the central effects of NP gamma and significant residual responses (30-50%) remained. 4. No tachyphylaxis to NP gamma-induced cardiovascular and behavioural changes was observed when two consecutive injections of 25 pmol NP gamma were given 24 h apart. 5. Simultaneous NK1 and NK2 receptor desensitization reduced significantly central effects mediated by 25 pmol NP gamma. However, significant residual responses persisted as seen after pretreatment with SR 48,968. 6. The results suggest that the central effects of NP gamma are mediated partly by NK2 receptors and by another putative tachykinin receptor subtype (NP gamma receptor?) that appears to be different from NK1 and NK3 receptors.

Animals↗

PubMed1996

Cardiovascular responses to intrathecal neuropeptide gamma in conscious rats: receptor characterization and mechanism of action.

1. In the conscious rat, cardiovascular responses to intrathecally (i.t.) administered neuropeptide gamma (NP gamma) were studied prior to and after the i.t. pretreatment with selective antagonists at NK1 ((+/-)-CP 96345 and RP 67580), NK2 (SR 48968) and NK3 (R 486) receptors. Pretreatment with a mixture of peptidase inhibitors (phosphoramidon, captopril, bacitracin, phenanthroline) was also tested to ascertain whether or not the effect of NP gamma was mediated by a metabolite. The involvement of peripheral catecholamines was examined with intravenous injection of alpha-adrenoceptor (phentolamine) and beta-adrenoceptor (propranolol) antagonists. 2. NP gamma (0.078-78 nmol) induced dose-dependent increases in heart rate (HR) and mean arterial blood pressure (MAP). The highest dose of 78 nmol did not induce an increase of MAP greater than that with 7.8 nmol but was preceded by a transient decrease of MAP (1-3 min). No desensitization was observed when three injections of 7.8 nmol NP gamma were given at 90 min intervals. 3. Cardiovascular and behavioural (biting/scratching) effects evoked by 0.78 nmol NP gamma were significantly reduced by the NK1 antagonists, (+/-)-CP 96345 (65 nmol) or RP 67580 (7.8 and 78 nmol). However, cardiovascular responses to NP gamma were not affected by (+/-)-CP 96345 (6.5 nmol), SR 48968 (7.8 and 78 nmol) or R 486 (25 nmol). Pretreatment with peptidase inhibitors significantly enhanced the cardiovascular and behavioural responses to NP gamma. 4. The pressor response to 7.8 nmol NP gamma was converted to a vasodepressor response by pretreatment with phentolamine (2 mg kg-1, i.v.) while the chronotropic response was markedly reduced by propranolol (2 mg kg-1, i.v.). 5. These results suggest that the cardiovascular responses to i.t. NP gamma are mediated by NK1 receptors in the spinal cord leading to the peripheral release of catecholamines from sympathetic fibres or the adrenal medulla. It is unlikely that the spinal action of NP gamma results from its metabolic conversion into neurokinin A or another major metabolite.

Animals↗

PubMed1996

Serum interspecies differences in metabolic pathways of bradykinin and [des-Arg9]BK: influence of enalaprilat.

Among the different enzymes responsible for the metabolism of bradykinin (BK), three peptidases look relevant in vivo: kininase I (KI), which transforms BK into its active metabolite, [des-Arg9]BK; kininase II (KII); and neutral endopeptidase, which inactivate BK and [des-Arg9]BK. The in vitro incubation of BK and [des-Arg9]BK in the serum of four species with or without enalaprilat and the quantification of the immunoreactivity of both peptides at different time intervals allowed the measurement of the kinetic parameters characterizing their metabolic pathways. Highly sensitive chemiluminescent enzyme immunoassays were used to measure the residual concentrations of BK and [des-Arg9]BK. Half-life (t1/2) of BK showed significant difference among species: rats (10 +/- 1 s) = dogs (13 +/- 1 s) < rabbits (31 +/- 1 s) < humans (49 +/- 2 s). t1/2 values of [des-Arg9]BK were also species dependent: rats (96 +/- 6 s) < < rabbits (314 +/- 6 s) = dogs (323 +/- 11 s) = humans (325 +/- 12 s). Enalaprilat significantly prevented the rapid BK and [des-Arg9]BK degradation in all species except that of [des-Arg9]BK in rat serum. Relative amount of BK hydrolyzed by serum KII was given as follows: rabbits (93.7 +/- 14.8%) = rats (83.6 +/- 6.7%) = humans (76.0 +/- 7.5%) > dogs (50.0 +/- 3.9%). Its importance in the hydrolysis of [des-Arg9]BK was 5.2 +/- 0.5% in rats < < 33.9 +/- 1.5% in humans < 52.0 +/- 1.1% in rabbits < 65.1 +/- 3.4% in dogs. The participation of serum KI in the transformation of BK into [des-Arg9]BK was dogs (67.2 +/- 5.3%) > > humans (3.4 +/- 1.2%) = rabbits (1.8 +/- 0.2%) = rats (1.4 +/- 0.3%). Finally, no significant difference on t1/2 values for BK and [des-Arg9]BK could be demonstrated between serum and plasma treated with either sodium citrate or a thrombin inhibitor. These results revealed striking species differences in the serum metabolism of kinins that could address at least partially some of the controversial data related to the cardioprotective role of kinins.

Angiotensin-Converting Enzyme Inhibitors↗

PubMed1996

Apolipoprotein E polymorphism in a French Canadian population of northeastern Quebec: allele frequencies and effects on blood lipid and lipoprotein levels.

Apolipoprotein E phenotypes and plasma lipid and lipoprotein levels were determined in 435 individuals (233 men, 202 women) of French Canadian descent living in northeastern Quebec. This region is known for its high frequency of mutant genes responsible for rare genetic disorders. Total cholesterol, low-density lipoprotein (LDL) cholesterol, high-density lipoprotein (HDL) cholesterol, and triglyceride levels were adjusted for age, height, weight, body mass index (BMI), and waist circumference using regressions performed separately in men and in premenopausal and postmenopausal women. The APOE allele frequencies in this population-based sample were 0.137, 0.749, and 0.114 for the *2, *3, and *4 alleles, respectively. APOE2 (APOE 2,2 and APOE 3,2) subjects had lower total and LDL cholesterol levels than APOE3 (APOE 3,3) subjects. In APOE4 (APOE 4,3 and APOE 4,4) men and postmenopausal women levels of total and LDL cholesterol and triglycerides were significantly higher than in the corresponding APOE3 subjects. The *2 allele was also found to be associated with higher triglyceride levels in men and postmenopausal women. Men of the APOE4 group also presented lower HDL cholesterol levels. Although the impact of APOE polymorphism on blood lipid and lipoprotein levels in this French Canadian population is similar to what has been reported in other white populations, the frequency of the *2 allele is among the highest ever reported. This finding is discussed in terms of the founder effect characterizing the Quebec population.

Abnormalities, Multiple↗

PubMed1995

Quantitative autoradiographic localization of [125I-Tyr8]bradykinin receptor binding sites in the rat spinal cord: effects of neonatal capsaicin, noradrenergic deafferentation, dorsal rhizotomy and peripheral axotomy.

In vitro receptor autoradiography was used to localize, quantify and characterize [125I-Tyr8]bradykinin binding sites in all major spinal cord segments of normal rats and animals subjected to various chemical treatments and surgical lesions. [125I-Tyr8]bradykinin specific binding sites were predominantly located to superficial laminae of the rat dorsal horn, with the substantia gelatinosa showing the highest density of labelling (values ranging from 3.1 fmol/mg tissue in cervical to 4.5 fmol/mg tissue in lumbar segments). A moderate density (1.8-3.0 fmol/mg tissue) of specific binding was observed in lamina III, whereas in other areas, i.e. laminae I and IV-X, lower amounts of labelling were detected. Within the superficial laminae of the dorsal horn, [125I-Tyr8]bradykinin binding was largely distributed over the neurophil with some perikarya showing concentrations of labelling. In contrast, the ventral horn showed a rather homogeneous distribution of [125I-Tyr8]bradykinin binding over the neuropil, with silver grain alignments surrounding motoneuron perikaryas and proximal processes. Bradykinin, [Tyr8]bradykinin and B2 receptor antagonists (D-Arg[Hyp3,Thi5,D-Tic7,Oic8]bradykinin (Hoe 140), D-Arg[Tyr3,D-Phe7,Leu8]bradykinin, D-Arg[Hyp3, Leu8]bradykinin, D-Arg[Hyp2, Thi5,8,-Phe7]bradykinin D-Arg[Hyp3, D-Phe7, Leu8]bradykinin, Tyr0, D-Arg[Hyp3, D-Phe7, Leu8]bradykinin inhibited [125I-Tyr8]-bradykinin binding with very high subnanomolar affinities, while the B1 receptor agonist (Tyr0,des-Arg10-kallidin) and antagonist ([Leu8]-des-Arg9-bradykinin) did not significantly affect [125I-Tyr8]bradykinin binding at up to micromolar concentrations. Two weeks after unilateral lumbar dorsal rhizotomy (L1-L6) or peripheral lesions of the sciatic nerve, significant decreases ( +/- 50%) in [125I-Tyr8]bradykinin binding sites were found in ipsilateral laminae I-III of lumbar spinal cord.(ABSTRACT TRUNCATED AT 250 WORDS)

Amino Acid Sequence↗

PubMed1995

Functional interaction between losartan and central tachykinin NK3 receptors in the conscious rat.

1. The cardiovascular and behavioural effects elicted by the intracerebroventricular (i.c.v.) injection of substance P (SP), neurokinin A (NKA), [MePhe7]neurokinin B ([MePhe7]NKB) or angiotensin II (AII) in the conscious rat were assessed before and 5 min after i.c.v. pretreatment with antagonists selective for angiotensin AT1 (losartan and its active metabolite EXP 3174), angiotensin AT2 (PD 123,319) or tachykinin NK3 (R 486) receptors. 2. I.c.v. administration of 25 pmol AII evoked an increase in mean arterial blood pressure (MAP) and water intake behaviour, accompanied by a transient bradycardia, whereas 25 pmol [MePhe7]NKB caused a transient increase in MAP and heart rate (HR) concurrently with marked wet dog shake behaviour. At the same dose, SP and NKA were more potent than [MePhe7]NKB in increasing MAP and HR, but did not produce water intake or wet dog shake behaviours. 3. Losartan (650 pmol, i.c.v.) reduced significantly the cardiovascular and behavioural responses to AII or [MePhe7]NKB, but not to SP or NKA. While 65 pmol losartan was inactive, 260 pmol inhibited selectively the central effects of AII. Whereas EXP 3174 (6.5 nmol) blocked both AII and [MePhe7]NKB-mediated responses, the dose of 650 pmol blocked only the responses to AII. 4. The central responses to AII and [MePhe7]NKB were not affected by PD 123,319 (650 pmol). On the other hand, the [MePhe7]NKB-induced central effects were significantly reduced by R 486 (650 pmol). The NK3-selective antagonist had no effect against AII. 5. This study provides functional evidence, to support earlier binding data, that losartan (and to some extent its active metabolite EXP 3174) interact with the tachykinin NK3 receptor in rat brain. However,the cardiovascular and behavioural responses induced by central tachykinin agonists (SP, NKA and[MePhe7]NKB) and All are mediated by unrelated mechanisms.

Angiotensin II↗