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Ernst Knobil - One of the best experts on this subject based on the ideXlab platform.

  • mitigation of the somnolence of insulin induced hypoglycemia by a Vasopressin V1 Receptor antagonist in the rhesus monkey
    Psychoneuroendocrinology, 1998
    Co-Authors: Ming Dao Chen, Tamás Ördög, Ernst Knobil
    Abstract:

    Insulin-induced hypoglycemia causes somnolence in rhesus monkeys, a phenomenon usually considered an aspecific consequence of neuroglycopenia. Previous observations from our laboratory have raised the possibility that arginine Vasopressin (AVP) may also play a role in this decrease in wakefulness. In the present study we tested this hypothesis by inducing hypoglycemia (∼40 mg/dl) in ovariectomized rhesus monkeys by intravenous administration of insulin in the presence of continuous intracerebroventricular infusions of the V1 Receptor antagonist [deamino-Pen1,O-Me-Tyr2,Arg8]-Vasopressin (180 μg/60 μl per h) or of its vehicle alone (artificial cerebrospinal fluid, 60 μl/h). Wakefulness was assessed by a scoring system by observers blinded to the experimental protocol. The AVP antagonist significantly attenuated the decrease in wakefulness observed in response to insulin-induced hypoglycemia (p<.03) without increasing blood glucose levels. These and previous findings suggest that the somnolence induced by a moderate degree of hypoglycemia may not entirely be the direct consequence of neuroglycopenia and that AVP may, directly or indirectly, be involved.

  • MITIGATION OF THE SOMNOLENCE OF INSULIN-INDUCED HYPOGLYCEMIA BY A Vasopressin V1 Receptor ANTAGONIST IN THE RHESUS MONKEY
    Psychoneuroendocrinology, 1998
    Co-Authors: Ming Dao Chen, Tamás Ördög, Ernst Knobil
    Abstract:

    Insulin-induced hypoglycemia causes somnolence in rhesus monkeys, a phenomenon usually considered an aspecific consequence of neuroglycopenia. Previous observations from our laboratory have raised the possibility that arginine Vasopressin (AVP) may also play a role in this decrease in wakefulness. In the present study we tested this hypothesis by inducing hypoglycemia (∼40 mg/dl) in ovariectomized rhesus monkeys by intravenous administration of insulin in the presence of continuous intracerebroventricular infusions of the V1 Receptor antagonist [deamino-Pen1,O-Me-Tyr2,Arg8]-Vasopressin (180 μg/60 μl per h) or of its vehicle alone (artificial cerebrospinal fluid, 60 μl/h). Wakefulness was assessed by a scoring system by observers blinded to the experimental protocol. The AVP antagonist significantly attenuated the decrease in wakefulness observed in response to insulin-induced hypoglycemia (p

Masao Yoshizumi - One of the best experts on this subject based on the ideXlab platform.

  • Prostanoids regulate proliferation of vascular smooth muscle cells induced by arginine Vasopressin.
    European journal of pharmacology, 2000
    Co-Authors: Koichiro Nagano, Kenji Toba, Masahiro Akishita, Tokumitsu Watanabe, Koichi Kozaki, Masato Eto, Masayoshi Hashimoto, Noriko Sudoh, Junya Ako, Masao Yoshizumi
    Abstract:

    Abstract The aim of the present study was to investigate the effect of arginine [Arg8]Vasopressin (Vasopressin) on proliferation of vascular smooth muscle cells and the mechanisms underlying the action of Vasopressin. To clarify these issues, we used two different types of vascular smooth muscle cells, cultured adult rat aortic smooth muscle cells and A10 cells, a cell line derived from fetal rat aorta. Vasopressin (10−8 to 10−6 M) significantly stimulated the proliferation of rat aortic smooth muscle cells in a dose-dependent manner. In contrast, Vasopressin significantly inhibited the proliferation of A10 cells. This inhibition was abolished when A10 cells were treated with indomethacin. Vasopressin stimulated the production of prostanoids several-fold in A10 cells but not in rat aortic smooth muscle cells. These effects were completely blocked by the Vasopressin V1 Receptor antagonist, 1-{1-[4-(3-acetylamino-propoxy)benzoyl]4-piperidyl}-3,4-dihydro-2(1H)-quinolinone (OPC21268), but not by the Vasopressin V2 Receptor antagonist, (±)-5-dimethylamino-1-[4-(2-methylbenzoylamino)benzol]-2,3,4,5-tetrahydro-1H-benzazepine hydrochloride (OPC31260). These results indicate that Vasopressin has diverse effect on proliferation of vascular smooth muscle cells through the Vasopressin V1 Receptor, depending on the production of growth regulatory prostanoids.

Colin I. Johnston - One of the best experts on this subject based on the ideXlab platform.

  • Vascular responses to Vasopressin antagonists in man and rat
    Clinical science (London England : 1979), 1994
    Co-Authors: Louise M. Burrell, P A Phillips, Colin I. Johnston, K A Rolls, Brian F. Buxton, Jianjun Liu
    Abstract:

    1. The effects of the non-peptide arginine Vasopressin V1 Receptor antagonist (OPC-21268) and the non-peptide V2 Receptor antagonist (OPC-31260) on Vasopressin-induced contraction of human internal mammary arteries and rat mesenteric resistance arteries were investigated. 2. In human internal mammary arteries, the non-peptide V1 Receptor antagonist, OPC-21268, failed to antagonize Vasopressin-induced contraction at low concentrations and potentiated the contraction at higher concentrations (300 nmol/l, P < 0.05). A peptide selective V1 Receptor antagonist ([d(CH2)5, sarcosine7]arginine Vasopressin) potently inhibited the Vasopressin-induced contraction, indicating the presence of functionally constrictor V1 Receptors in human internal mammary arteries. Both peptide (desGly-NH29[d(CH2)5, D-Ile2, Ile4]arginine Vasopressin) and non-peptide 'selective' V2 Receptor antagonists (OPC-31260, 3 mumol/l) significantly antagonized Vasopressin-induced contraction (P < 0.01), indicating partial V1 Receptor antagonist activity. 3. The Vasopressin-induced contraction in human internal mammary arteries was reversed by high concentrations of the non-peptide V2 Receptor antagonist, OPC-31260, but not by the non-peptide V1 Receptor antagonist, OPC-21268. 4. The effects of OPC-21268 and OPC-31260 were specific to vascular Vasopressin Receptors as neither compound influenced endothelin- or noradrenaline-induced contraction in human internal mammary arteries. 5. In rat mesenteric resistance arteries, both OPC-21268 (10 nmol/l) and OPC-31260 (1 mumol/l) antagonized Vasopressin-induced contraction (P < 0.01).(ABSTRACT TRUNCATED AT 250 WORDS)

  • Blood pressure-lowering effect of an orally active Vasopressin V1 Receptor antagonist in mineralocorticoid hypertension in the rat.
    Hypertension (Dallas Tex. : 1979), 1994
    Co-Authors: Louise M. Burrell, P A Phillips, John Risvanis, J M Stephenson, K A Rolls, Colin I. Johnston
    Abstract:

    We studied the contribution of Vasopressin to the maintenance of high blood pressure in deoxycorticosterone acetate (DOCA)-salt hypertension in the rat using the nonpeptide orally effective Vasopressin V1 Receptor antagonist OPC-21268. Binding kinetic studies demonstrated that oral OPC-21268 (30 mg/kg) acted as a competitive antagonist at the Vasopressin V1 Receptor in DOCA-salt and salt control rats. Basal mean intra-arterial blood pressure was 140 +/- 4 mm Hg (n = 12) in DOCA-salt rats compared with 111 +/- 2 mm Hg in salt control rats (n = 18). Acute oral OPC-21268 (30 mg/kg) significantly (P < .01) reduced mean intra-arterial pressure in DOCA-salt hypertension, with an average maximal decrease of 24 +/- 3 mm Hg occurring at 2.5 +/- 0.7 hours after dosing. Systolic blood pressure (tail-cuff) in DOCA-salt rats was 178 +/- 2 mm Hg. Chronic oral OPC-21268 (30 mg/kg) twice daily for 7 days significantly (P < .01) reduced systolic blood pressure in DOCA-salt hypertension, with an average maximal decrease of 27 +/- 5 mm Hg. The antihypertensive effect was reversed 5 days after treatment with OPC-21268 was stopped. In water control rats basal systolic pressure (120 +/- 1 mm Hg, n = 20) was unchanged by chronic oral OPC-21268 (30 mg/kg twice daily for 7 days), and this was confirmed by direct measurement of mean intra-arterial pressure. After chronic oral OPC-21268 (30 mg/kg twice daily for 7 days) hepatic V1 Receptor binding was significantly reduced for up to 10 hours (P < .05).(ABSTRACT TRUNCATED AT 250 WORDS)

  • Effects of an orally active Vasopressin V1 Receptor antagonist.
    Clinical and experimental pharmacology & physiology, 1993
    Co-Authors: Louise M. Burrell, P A Phillips, J Stephenson, John Risvanis, Anne Marie Hutchins, Colin I. Johnston
    Abstract:

    SUMMARY 1. This paper reports on the in vitro and in vivo characteristics of a non-peptide Vasopressin V1 Receptor antagonist 1-{1-[4-(3-acetylaminopropoxy)benzoyl]-4-piperidyl}-3,4-dihydro-2(1H)-quinolinone (OPC-21268). 2. OPC-21268 caused a concentration-dependent displacement of the selective V1 Receptor antagonist radioligand, [125I]-[d(CH2)5, sarcosine7]AVP from Vasopressin V1 Receptors in rat liver and kidney membranes, inhibitory concentration of 50% (IC50) 4 ± 10-8, 0.3 mol/L liver and 1.5 ± 10-8, 0.2 mol/L kidney. OPC-21268 had little effect on the selective V2 antagonist radioligand [3H]desGly-NH29-d(CH2)5[d-Ileu2, Ileu4]AVP binding to V2 Receptors in renal membranes (IC50 > 10-4 mol/L). 3. After oral administration to rats, OPC-21268 was an effective V1 antagonist to both liver and kidney V1 Receptors, in a dose-dependent manner. 4. These studies confirm that OPC-21268 is a potent non-peptide, orally effective V1 Vasopressin Receptor antagonist.

  • Characterization of a novel non-peptide Vasopressin V1 Receptor antagonist (OPC-21268) in the rat.
    The Journal of endocrinology, 1993
    Co-Authors: Louise M. Burrell, P A Phillips, J Stephenson, John Risvanis, Anne Marie Hutchins, Colin I. Johnston
    Abstract:

    A non-peptide, orally effective, Vasopressin (AVP) V1 Receptor antagonist 1-(1-[4-(3-acetylaminopropoxy) benzoyl]-4-piperidyl)-3,4-dihydro-2(1H)-quinolinone (OPC-21268) has recently been described. This paper reports the in-vitro and in-vivo characterization of OPC-21268 binding to Vasopressin Receptors in rat liver and kidney. OPC-21268 caused a concentration-dependent displacement of the selective V1 Receptor antagonist radioligand, 125I-labelled [d(CH2)5,sarcosine7]AVP to V1 Receptors in both rat liver and kidney medulla membranes. The concentration of OPC-21268 that displaced 50% of specific AVP binding (IC50) was 40 +/- 3 nmol/l for liver V1 and 15 +/- 2 nmol/l for kidney V1 Receptors (mean +/- S.E.M.; n = 3). OPC-21268 had little effect on the selective V2 antagonist radioligand [3H]desGly-NH2(9)]d(CH2)5,D-Ile2,Ile4] AVP binding to V2 Receptors in renal medulla membranes (IC50 > 0.1 mmol/l). After oral administration to rats, OPC-21268 was an effective V1 antagonist in a time- and dose-dependent manner. Binding kinetic studies showed that OPC-21268 acted as a competitive antagonist at the liver V1 Receptor in vitro and in vivo, in addition to its in-vitro competitive effects at the renal V1 Receptor. OPC-21268 shows promise as an orally active V1 antagonist.

H Gavras - One of the best experts on this subject based on the ideXlab platform.

  • Calcium antagonism abolishes the antipressor action of Vasopressin (V1) Receptor antagonism.
    American journal of hypertension, 1997
    Co-Authors: G L Bakris, S L Kusmirek, A C Smith, I Gavras, H Gavras
    Abstract:

    Previous studies demonstrate that Vasopressin (V1) Receptor antagonism lowers arterial pressure in blacks. This action of V1 Receptor blockade may be mediated through various mechanisms including changes in intracellular calcium fluxes. This study was undertaken to test the hypothesis that inhibition of calcium entry may attenuate the reduction in arterial pressure observed with V1 Receptor blockade. Sixteen hypertensive patients, 8 whites and 8 blacks, were examined. Each had their antihypertensive therapy stopped for 1 week. Following three baseline blood pressure measurements, all patients were given an intravenous bolus injection of a V1 Receptor antagonist. Blood pressure was monitored every 10 min for a period of 3 h. Subjects were then randomized to either 0.2 mg clonidine twice daily or 300 mg diltiazem CD daily for a period of 3 days and the previous experiments repeated. Patients were then crossed over to the other drug for an additional 3 days and the experiments repeated. There was a significant reduction from baseline in the mean arterial pressure among blacks but not whites (-11 +/- 3 delta mm Hg blacks versus -1 +/- 2 delta mm Hg whites, P < .01). In the presence of clonidine, there were similar reductions in arterial pressure in both groups (P = .026) with a further reduction following V1 Receptor blockade only in the blacks (-7 +/- 3 delta mm Hg blacks versus 6 +/- 2 delta mm Hg whites; P < .001). Conversely, in the presence of diltiazem CD, there were no further reductions in arterial pressure in either group following the V1 Receptor antagonist. We conclude that calcium channel blockade abolishes the blood pressure lowering response of V1 Receptor blockade in blacks.

  • Effects of Vasopressin V1-Receptor blockade during acute and sustained hypovolemic hypotension.
    American Journal of Physiology-Regulatory Integrative and Comparative Physiology, 1996
    Co-Authors: Barry M. Wall, H Gavras, Kim Huch, K. R. Runyan, H. H. Williams, C. R. Cooke
    Abstract:

    The response of Vasopressin and its role in the maintenance of arterial pressure during and after development of hypotensive central hypovolemia were studied in tilt table studies in quadriplegic subjects. The studies were performed during acute head-up tilting to a maximally tolerated degree of tilt (8 subjects) and during sustained head-up tilt following a 20% reduction in mean arterial pressure (MAP) (11 subjects). Studies in all subjects were performed on two separate days, once with and once without administration of a selective Vasopressin V1-Receptor antagonist. During acute head-up tilting, plasma Vasopressin concentrations (PAVP) did not increase significantly until MAP decreased to approximately 60 mmHg at maximal tilt. There was no difference in the degree of hypotension produced in the presence compared with the absence of V1-Receptor blockade. There was also no difference in plasma renin activity (PRA) or in plasma cortisol or aldosterone concentrations at maximal tilt. In contrast, during sustained head-up tilt following a 20% reduction in arterial pressures, systolic and mean arterial pressures were significantly lower and PRA was significantly higher in the presence than in the absence of V1-Receptor blockade. PAVP increased and was significantly higher after 30 min of sustained tilt than pretilt PAVP in supine posture. These studies do not provide evidence of a role for Vasopressin in the maintenance of arterial pressure during the acute development of hypotensive hypovolemia in human subjects, but they do provide evidence of a modest role for Vasopressin in the maintenance of arterial pressure when the effect of hypovolemia is more moderate and sustained.

Louise M. Burrell - One of the best experts on this subject based on the ideXlab platform.

  • Vascular responses to Vasopressin antagonists in man and rat
    Clinical science (London England : 1979), 1994
    Co-Authors: Louise M. Burrell, P A Phillips, Colin I. Johnston, K A Rolls, Brian F. Buxton, Jianjun Liu
    Abstract:

    1. The effects of the non-peptide arginine Vasopressin V1 Receptor antagonist (OPC-21268) and the non-peptide V2 Receptor antagonist (OPC-31260) on Vasopressin-induced contraction of human internal mammary arteries and rat mesenteric resistance arteries were investigated. 2. In human internal mammary arteries, the non-peptide V1 Receptor antagonist, OPC-21268, failed to antagonize Vasopressin-induced contraction at low concentrations and potentiated the contraction at higher concentrations (300 nmol/l, P < 0.05). A peptide selective V1 Receptor antagonist ([d(CH2)5, sarcosine7]arginine Vasopressin) potently inhibited the Vasopressin-induced contraction, indicating the presence of functionally constrictor V1 Receptors in human internal mammary arteries. Both peptide (desGly-NH29[d(CH2)5, D-Ile2, Ile4]arginine Vasopressin) and non-peptide 'selective' V2 Receptor antagonists (OPC-31260, 3 mumol/l) significantly antagonized Vasopressin-induced contraction (P < 0.01), indicating partial V1 Receptor antagonist activity. 3. The Vasopressin-induced contraction in human internal mammary arteries was reversed by high concentrations of the non-peptide V2 Receptor antagonist, OPC-31260, but not by the non-peptide V1 Receptor antagonist, OPC-21268. 4. The effects of OPC-21268 and OPC-31260 were specific to vascular Vasopressin Receptors as neither compound influenced endothelin- or noradrenaline-induced contraction in human internal mammary arteries. 5. In rat mesenteric resistance arteries, both OPC-21268 (10 nmol/l) and OPC-31260 (1 mumol/l) antagonized Vasopressin-induced contraction (P < 0.01).(ABSTRACT TRUNCATED AT 250 WORDS)

  • Blood pressure-lowering effect of an orally active Vasopressin V1 Receptor antagonist in mineralocorticoid hypertension in the rat.
    Hypertension (Dallas Tex. : 1979), 1994
    Co-Authors: Louise M. Burrell, P A Phillips, John Risvanis, J M Stephenson, K A Rolls, Colin I. Johnston
    Abstract:

    We studied the contribution of Vasopressin to the maintenance of high blood pressure in deoxycorticosterone acetate (DOCA)-salt hypertension in the rat using the nonpeptide orally effective Vasopressin V1 Receptor antagonist OPC-21268. Binding kinetic studies demonstrated that oral OPC-21268 (30 mg/kg) acted as a competitive antagonist at the Vasopressin V1 Receptor in DOCA-salt and salt control rats. Basal mean intra-arterial blood pressure was 140 +/- 4 mm Hg (n = 12) in DOCA-salt rats compared with 111 +/- 2 mm Hg in salt control rats (n = 18). Acute oral OPC-21268 (30 mg/kg) significantly (P < .01) reduced mean intra-arterial pressure in DOCA-salt hypertension, with an average maximal decrease of 24 +/- 3 mm Hg occurring at 2.5 +/- 0.7 hours after dosing. Systolic blood pressure (tail-cuff) in DOCA-salt rats was 178 +/- 2 mm Hg. Chronic oral OPC-21268 (30 mg/kg) twice daily for 7 days significantly (P < .01) reduced systolic blood pressure in DOCA-salt hypertension, with an average maximal decrease of 27 +/- 5 mm Hg. The antihypertensive effect was reversed 5 days after treatment with OPC-21268 was stopped. In water control rats basal systolic pressure (120 +/- 1 mm Hg, n = 20) was unchanged by chronic oral OPC-21268 (30 mg/kg twice daily for 7 days), and this was confirmed by direct measurement of mean intra-arterial pressure. After chronic oral OPC-21268 (30 mg/kg twice daily for 7 days) hepatic V1 Receptor binding was significantly reduced for up to 10 hours (P < .05).(ABSTRACT TRUNCATED AT 250 WORDS)

  • Effects of an orally active Vasopressin V1 Receptor antagonist.
    Clinical and experimental pharmacology & physiology, 1993
    Co-Authors: Louise M. Burrell, P A Phillips, J Stephenson, John Risvanis, Anne Marie Hutchins, Colin I. Johnston
    Abstract:

    SUMMARY 1. This paper reports on the in vitro and in vivo characteristics of a non-peptide Vasopressin V1 Receptor antagonist 1-{1-[4-(3-acetylaminopropoxy)benzoyl]-4-piperidyl}-3,4-dihydro-2(1H)-quinolinone (OPC-21268). 2. OPC-21268 caused a concentration-dependent displacement of the selective V1 Receptor antagonist radioligand, [125I]-[d(CH2)5, sarcosine7]AVP from Vasopressin V1 Receptors in rat liver and kidney membranes, inhibitory concentration of 50% (IC50) 4 ± 10-8, 0.3 mol/L liver and 1.5 ± 10-8, 0.2 mol/L kidney. OPC-21268 had little effect on the selective V2 antagonist radioligand [3H]desGly-NH29-d(CH2)5[d-Ileu2, Ileu4]AVP binding to V2 Receptors in renal membranes (IC50 > 10-4 mol/L). 3. After oral administration to rats, OPC-21268 was an effective V1 antagonist to both liver and kidney V1 Receptors, in a dose-dependent manner. 4. These studies confirm that OPC-21268 is a potent non-peptide, orally effective V1 Vasopressin Receptor antagonist.

  • Characterization of a novel non-peptide Vasopressin V1 Receptor antagonist (OPC-21268) in the rat.
    The Journal of endocrinology, 1993
    Co-Authors: Louise M. Burrell, P A Phillips, J Stephenson, John Risvanis, Anne Marie Hutchins, Colin I. Johnston
    Abstract:

    A non-peptide, orally effective, Vasopressin (AVP) V1 Receptor antagonist 1-(1-[4-(3-acetylaminopropoxy) benzoyl]-4-piperidyl)-3,4-dihydro-2(1H)-quinolinone (OPC-21268) has recently been described. This paper reports the in-vitro and in-vivo characterization of OPC-21268 binding to Vasopressin Receptors in rat liver and kidney. OPC-21268 caused a concentration-dependent displacement of the selective V1 Receptor antagonist radioligand, 125I-labelled [d(CH2)5,sarcosine7]AVP to V1 Receptors in both rat liver and kidney medulla membranes. The concentration of OPC-21268 that displaced 50% of specific AVP binding (IC50) was 40 +/- 3 nmol/l for liver V1 and 15 +/- 2 nmol/l for kidney V1 Receptors (mean +/- S.E.M.; n = 3). OPC-21268 had little effect on the selective V2 antagonist radioligand [3H]desGly-NH2(9)]d(CH2)5,D-Ile2,Ile4] AVP binding to V2 Receptors in renal medulla membranes (IC50 > 0.1 mmol/l). After oral administration to rats, OPC-21268 was an effective V1 antagonist in a time- and dose-dependent manner. Binding kinetic studies showed that OPC-21268 acted as a competitive antagonist at the liver V1 Receptor in vitro and in vivo, in addition to its in-vitro competitive effects at the renal V1 Receptor. OPC-21268 shows promise as an orally active V1 antagonist.