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Article: Exogenous detection of

Verlande, Amandine / Chun, Sung Kook / Song, Wei A / Oettler, Daniela / Knot, Harm J / Masri, Selma

2022 Volume 13, Page(s) 1023614

Abstract: Metabolic rewiring is a hallmark feature prevalent in cancer cells as well as insulin resistance (IR) associated with diet-induced obesity (DIO). For instance, tumor metabolism shifts towards an enhanced glycolytic state even under aerobic conditions. In ...

Abstract	Metabolic rewiring is a hallmark feature prevalent in cancer cells as well as insulin resistance (IR) associated with diet-induced obesity (DIO). For instance, tumor metabolism shifts towards an enhanced glycolytic state even under aerobic conditions. In contrast, DIO triggers lipid-induced IR by impairing insulin signaling and reducing insulin-stimulated glucose uptake. Based on physiological differences in systemic metabolism, we used a breath analysis approach to discriminate between different pathological states using glucose oxidation as a readout. We assessed glucose utilization in lung cancer-induced cachexia and DIO mouse models using a U-
Language	English
Publishing date	2022-10-05
Publishing country	Switzerland
Document type	Journal Article
ZDB-ID	2564217-0
ISSN	1664-042X
ISSN	1664-042X
DOI	10.3389/fphys.2022.1023614
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Article ; Online: Nitrate tolerance in hypertension: new insight into a century-old problem.

Knot, Harm J

Circulation research

2003 Volume 93, Issue 9, Page(s) 799–801

MeSH term(s)	Animals ; Blood Vessels/drug effects ; Blood Vessels/physiopathology ; Calcium Signaling/drug effects ; Drug Tolerance ; Humans ; Hypertension/drug therapy ; Hypertension/physiopathology ; Nitrates/therapeutic use ; Nitroglycerin/therapeutic use ; Potassium Channels, Calcium-Activated/metabolism ; Signal Transduction/drug effects ; Vasodilation/drug effects
Chemical Substances	Nitrates ; Potassium Channels, Calcium-Activated ; Nitroglycerin (G59M7S0WS3)
Language	English
Publishing date	2003-10-31
Publishing country	United States
Document type	Comment ; Editorial ; Research Support, Non-U.S. Gov't
ZDB-ID	80100-8
ISSN	1524-4571 ; 0009-7330 ; 0931-6876
ISSN (online)	1524-4571
ISSN	0009-7330 ; 0931-6876
DOI	10.1161/01.RES.0000100846.76792.C2
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Ui IV Zs.70: Show issues			Location: Je nach Verfügbarkeit (siehe Angabe bei Bestand) bis Jg. 2021: Bestellungen von Artikeln über das Online-Bestellformular ab Jg. 2022: Lesesaal (EG)
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Article: Relative contribution of Rho kinase and protein kinase C to myogenic tone in rat cerebral arteries in hypertension.

Jarajapu, Yagna P R / Knot, Harm J

American journal of physiology. Heart and circulatory physiology

2005 Volume 289, Issue 5, Page(s) H1917–22

Abstract: Arterial smooth muscle constriction in response to pressure, i.e., myogenic tone, may involve calcium-dependent and calcium-sensitization mechanisms. Calcium sensitization in vascular smooth muscle is regulated by kinases such as PKC and Rho kinase, and ... ...

Abstract	Arterial smooth muscle constriction in response to pressure, i.e., myogenic tone, may involve calcium-dependent and calcium-sensitization mechanisms. Calcium sensitization in vascular smooth muscle is regulated by kinases such as PKC and Rho kinase, and activity of these kinases is known to be altered in cardiovascular disorders. In the present study, we evaluated the relative contribution of PKC and Rho kinase to myogenic tone in cerebral arteries in hypertension. Myogenic tone and arterial wall calcium in Wistar-Kyoto (WKY) rats and spontaneously hypertensive rats (SHR) were measured simultaneously, and the effect of PKC and Rho kinase inhibitors on myogenic tone was evaluated. SHR arteries showed significantly greater myogenic tone than WKY arteries. Pressure/wall tension-arterial wall calcium curves showed a hyperbolic relation in WKY rats, but the curves for SHR arteries were parabolic. Myogenic tone was decreased by the Rho kinase inhibitors Y-27632 and HA-1077, with a significantly greater effect in SHR than in WKY arteries. Reduction in myogenic tone produced by the PKC inhibitor bisindolylmaleimide I in WKY and SHR arteries was significantly less than that produced by Rho kinase inhibition. The pressure-dependent increase in myogenic tone was significantly decreased by Y-27632, and the decrease was markedly greater than that produced by bisindolylmaleimide I in SHR arteries. In WKY arteries, the pressure-dependent increase in myogenic tone was decreased to a similar extent by Y-27632 and bisindolylmaleimide I. These results suggest greater myogenic tone with increased calcium sensitization in SHR arteries, largely because of Rho kinase activation, with a minor contribution of PKC activation.
MeSH term(s)	1-(5-Isoquinolinesulfonyl)-2-Methylpiperazine/analogs & derivatives ; 1-(5-Isoquinolinesulfonyl)-2-Methylpiperazine/pharmacology ; Alkaloids ; Amides/pharmacology ; Animals ; Benzophenanthridines ; Blood Pressure/drug effects ; Calcium/metabolism ; Calcium Signaling/drug effects ; Calcium Signaling/physiology ; Cerebral Arteries/drug effects ; Cerebral Arteries/metabolism ; Cerebral Arteries/physiopathology ; Enzyme Inhibitors/pharmacology ; Hypertension/physiopathology ; Indoles/pharmacology ; Intracellular Signaling Peptides and Proteins ; Maleimides/pharmacology ; Muscle Tonus/drug effects ; Muscle Tonus/physiology ; Muscle, Smooth, Vascular/drug effects ; Muscle, Smooth, Vascular/metabolism ; Muscle, Smooth, Vascular/physiology ; Phenanthridines/pharmacology ; Protein Kinase C/antagonists & inhibitors ; Protein Kinase C/physiology ; Protein-Serine-Threonine Kinases/antagonists & inhibitors ; Protein-Serine-Threonine Kinases/physiology ; Pyridines/pharmacology ; Rats ; Rats, Inbred SHR ; Rats, Inbred WKY ; rho-Associated Kinases
Chemical Substances	Alkaloids ; Amides ; Benzophenanthridines ; Enzyme Inhibitors ; Indoles ; Intracellular Signaling Peptides and Proteins ; Maleimides ; Phenanthridines ; Pyridines ; Y 27632 (138381-45-0) ; 1-(5-Isoquinolinesulfonyl)-2-Methylpiperazine (84477-87-2) ; chelerythrine (E3B045W6X0) ; Protein-Serine-Threonine Kinases (EC 2.7.11.1) ; rho-Associated Kinases (EC 2.7.11.1) ; Protein Kinase C (EC 2.7.11.13) ; bisindolylmaleimide I (L79H6N0V6C) ; fasudil (Q0CH43PGXS) ; Calcium (SY7Q814VUP)
Language	English
Publishing date	2005-06-24
Publishing country	United States
Document type	Journal Article
ZDB-ID	603838-4
ISSN	1522-1539 ; 0363-6135
ISSN (online)	1522-1539
ISSN	0363-6135
DOI	10.1152/ajpheart.01012.2004
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Article: Characteristics of myogenic tone in the rat ophthalmic artery.

Ito, Isamu / Jarajapu, Yagna P R / Grant, Maria B / Knot, Harm J

American journal of physiology. Heart and circulatory physiology

2006 Volume 292, Issue 1, Page(s) H360–8

Abstract: The pressure-induced constriction in the rat ophthalmic artery was characterized. Ophthalmic arteries were isolated, cannulated in an arteriograph, and pressurized. Arteries developed 25% constriction at 70 mmHg of intraluminal pressure. Arteries ... ...

Abstract	The pressure-induced constriction in the rat ophthalmic artery was characterized. Ophthalmic arteries were isolated, cannulated in an arteriograph, and pressurized. Arteries developed 25% constriction at 70 mmHg of intraluminal pressure. Arteries maintained almost similar diameter over the range of pressures 50-210 mmHg, and forced dilatation was observed at pressures >210 mmHg. Denudation of endothelium increased the sensitivity of arteries to pressure-induced constriction, and significantly higher myogenic tone was observed in the pressure range of 10-100 mmHg. Indomethacin and cyclooxygenase-2 inhibition by SC-236 decreased myogenic tone, whereas cyclooxygenase-1 inhibition by SC-560 potentiated myogenic tone in a lower concentration range and decreased at a higher concentration. Pressure-induced constriction was completely blocked by 1 microM nifedipine. Phospholipase C inhibition by 6 microM U-73122 decreased myogenic tone by 39%, whereas PKC inhibitor GF-109203X (3 microM) had no effect. Constriction to phenylephrine was significantly decreased by U-73122 (1 microM) and GF-109203X (3 microM) at an intraluminal pressure of 10 mmHg. Rho-kinase inhibition by Y-27632 (30 microM) and HA-1077 (30 microM) decreased myogenic tone by 75% and 73%, respectively, and 1 microM Y-27632 significantly decreased myogenic tone developed in response to graded increases in pressure. These results suggest that rat ophthalmic artery has an efficient pressure-dependent autoregulatory function that is modulated by endothelium. Contribution of phospholipase C-activation to myogenic tone is minimal, whereas Rho-kinase activation plays a predominant role in the myogenic reactivity in this artery.
MeSH term(s)	Animals ; Blood Flow Velocity/physiology ; Blood Pressure/physiology ; Hemostasis/physiology ; In Vitro Techniques ; Muscle Contraction/physiology ; Muscle, Smooth, Vascular/physiology ; Ophthalmic Artery/physiology ; Rats ; Rats, Sprague-Dawley ; Vasoconstriction/physiology
Language	English
Publishing date	2006-08-18
Publishing country	United States
Document type	Journal Article ; Research Support, N.I.H., Extramural ; Research Support, Non-U.S. Gov't
ZDB-ID	603838-4
ISSN	1522-1539 ; 0363-6135
ISSN (online)	1522-1539
ISSN	0363-6135
DOI	10.1152/ajpheart.00630.2006
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Article: Myogenic tone and reactivity of the rat ophthalmic artery.

Jarajapu, Yagna P R / Grant, Maria B / Knot, Harm J

Investigative ophthalmology & visual science

2003 Volume 45, Issue 1, Page(s) 253–259

Abstract: Purpose: To study and quantify myogenic behavior and reactivity of the rat ophthalmic artery to pressure and different vasoactive substances in vitro.: Methods: Rat ophthalmic arteries (diameter of 217 +/- 6 microm, n = 22) were isolated, cannulated ... ...

Abstract	Purpose: To study and quantify myogenic behavior and reactivity of the rat ophthalmic artery to pressure and different vasoactive substances in vitro. Methods: Rat ophthalmic arteries (diameter of 217 +/- 6 microm, n = 22) were isolated, cannulated with glass pipettes in an arteriograph and pressurized in a physiological buffer. Internal diameter was continuously monitored. The effect of intraluminal pressure on the diameter was assessed and concentration-response curves to different constrictor and dilator agonists were obtained at an intraluminal pressure of 70 mm Hg. Results: Myogenic tone developed at an intraluminal pressure of 30 to 40 mm Hg, continued to increase, and was maintained up to a pressure of 199 mm Hg in these arteries. Arteries dilated and constricted in response to 16 and 60 mM potassium, respectively. Endothelin-1 was the most potent and efficacious constrictor, with a biphasic concentration-response curve, followed by vasopressin, serotonin, U-46619 and phenylephrine. Carbachol was the most efficacious dilator, followed by isoprenaline. The peptide dilators calcitonin gene-related peptide (CGRP) and vasoactive intestinal peptide (VIP) were potent but less efficacious than carbachol and isoprenaline. Histamine and adenosine were even less potent and less efficacious dilators. NG-nitro-L-arginine methyl ester (L-NAME) constricted and indomethacin dilated the arteries. Conclusions: This study provides the first direct evidence for myogenic autoregulatory properties and pharmacological heterogeneity in the rat ophthalmic artery.
MeSH term(s)	Animals ; Dose-Response Relationship, Drug ; Enzyme Inhibitors/pharmacology ; Homeostasis ; Indomethacin/pharmacology ; Male ; Muscle Contraction/physiology ; Muscle Relaxation/physiology ; Muscle Tonus/physiology ; Muscle, Smooth, Vascular/physiology ; NG-Nitroarginine Methyl Ester/pharmacology ; Ophthalmic Artery/physiology ; Pressure ; Rats ; Rats, Sprague-Dawley ; Vasoconstrictor Agents/pharmacology ; Vasodilation/drug effects ; Vasodilator Agents/pharmacology
Chemical Substances	Enzyme Inhibitors ; Vasoconstrictor Agents ; Vasodilator Agents ; NG-Nitroarginine Methyl Ester (V55S2QJN2X) ; Indomethacin (XXE1CET956)
Language	English
Publishing date	2003-12-15
Publishing country	United States
Document type	Journal Article ; Research Support, Non-U.S. Gov't ; Research Support, U.S. Gov't, P.H.S.
ZDB-ID	391794-0
ISSN	1552-5783 ; 0146-0404
ISSN (online)	1552-5783
ISSN	0146-0404
DOI	10.1167/iovs.03-0546
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Article ; Online: INSPIRE: A European training network to foster research and training in cardiovascular safety pharmacology.

Guns, Pieter-Jan D / Guth, Brian D / Braam, Stefan / Kosmidis, Georgios / Matsa, Elena / Delaunois, Annie / Gryshkova, Vitalina / Bernasconi, Sylvain / Knot, Harm J / Shemesh, Yair / Chen, Alon / Markert, Michael / Fernández, Miguel A / Lombardi, Damiano / Grandmont, Céline / Cillero-Pastor, Berta / Heeren, Ron M A / Martinet, Wim / Woolard, Jeanette /

Skinner, Matt / Segers, Vincent F M / Franssen, Constantijn / Van Craenenbroeck, Emeline M / Volders, Paul G A / Pauwelyn, Thomas / Braeken, Dries / Yanez, Paz / Correll, Krystle / Yang, Xi / Prior, Helen / Kismihók, Gábor / De Meyer, Guido R Y / Valentin, Jean-Pierre

Journal of pharmacological and toxicological methods

2020 Volume 105, Page(s) 106889

Abstract: Safety pharmacology is an essential part of drug development aiming to identify, evaluate and investigate undesirable pharmacodynamic properties of a drug primarily prior to clinical trials. In particular, cardiovascular adverse drug reactions (ADR) have ...

Abstract	Safety pharmacology is an essential part of drug development aiming to identify, evaluate and investigate undesirable pharmacodynamic properties of a drug primarily prior to clinical trials. In particular, cardiovascular adverse drug reactions (ADR) have halted many drug development programs. Safety pharmacology has successfully implemented a screening strategy to detect cardiovascular liabilities, but there is room for further refinement. In this setting, we present the INSPIRE project, a European Training Network in safety pharmacology for Early Stage Researchers (ESRs), funded by the European Commission's H2020-MSCA-ITN programme. INSPIRE has recruited 15 ESR fellows that will conduct an individual PhD-research project for a period of 36 months. INSPIRE aims to be complementary to ongoing research initiatives. With this as a goal, an inventory of collaborative research initiatives in safety pharmacology was created and the ESR projects have been designed to be complementary to this roadmap. Overall, INSPIRE aims to improve cardiovascular safety evaluation, either by investigating technological innovations or by adding mechanistic insight in emerging safety concerns, as observed in the field of cardio-oncology. Finally, in addition to its hands-on research pillar, INSPIRE will organize a number of summer schools and workshops that will be open to the wider community as well. In summary, INSPIRE aims to foster both research and training in safety pharmacology and hopes to inspire the future generation of safety scientists.
MeSH term(s)	Cardiovascular System/drug effects ; Drug Development/methods ; Drug-Related Side Effects and Adverse Reactions/prevention & control ; Humans ; Pharmacology/methods ; Safety
Language	English
Publishing date	2020-06-18
Publishing country	United States
Document type	Journal Article
ZDB-ID	1105919-9
ISSN	1873-488X ; 1056-8719
ISSN (online)	1873-488X
ISSN	1056-8719
DOI	10.1016/j.vascn.2020.106889
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Article: Histamine decreases myogenic tone in rat cerebral arteries by H2-receptor-mediated KV channel activation, independent of endothelium and cyclic AMP.

Jarajapu, Yagna P R / Oomen, Charlotte / Uteshev, Victor V / Knot, Harm J

European journal of pharmacology

2006 Volume 547, Issue 1-3, Page(s) 116–124

Abstract: The effect of histamine on the pressure-induced constriction was characterized in rat cerebral arteries and mechanisms were investigated. Rat cerebral arteries were pressurized to 70 mm Hg in an arteriograph and the effect of histamine on myogenic tone ... ...

Abstract	The effect of histamine on the pressure-induced constriction was characterized in rat cerebral arteries and mechanisms were investigated. Rat cerebral arteries were pressurized to 70 mm Hg in an arteriograph and the effect of histamine on myogenic tone was studied. Histamine and amthamine, a selective histamine H(2)-receptor agonist, concentration-dependently decreased myogenic tone, which was unchanged in the absence of endothelium. 2-(2-aminoethyl) pyridine, a selective histamine H(1)-receptor agonist, produced concentration-dependent constriction of arteries that was significantly increased in the absence of endothelium. Imetit, a selective histamine H(3)-receptor agonist, has no effect on myogenic tone. The dilation to histamine was antagonized by tiotidine, a selective antagonist of histamine H(2)-receptor subtype, giving a pK(B) of 7.86 that was not altered in the absence of endothelium. The histamine-mediated dilation was significantly antagonized by NF 449, a reversible inhibitor of Gs-protein activation but was not affected by ODQ and SQ 22536. Dilations to histamine and amthamine were accompanied by a decrease in arterial wall calcium measured by fura-2 ratios. The dilation to histamine was significantly reduced by partial depolarization of smooth muscle by 25 mM KCl (control 91+/-5%, 25 mM KCl 53+/-5%, P<0.002) and was not observed in the presence of strongly depolarizing 60 mM KCl. The histamine dilation was not affected by iberiotoxin, barium chloride and glibenclamide but was strongly antagonized by 4-aminopyridine (0.3 mM) and tetraethylammonium chloride (10 mM) (pEC(50): control: 5.6+/-0.1, 4-aminopyridine: 4.1+/-0.1 (P<0.001); tetraethylammonium chloride: 3.2+/-0.2 (P<0.0001)). These results suggest that histamine-mediated reversal of myogenic tone in rat cerebral arteries is endothelium-independent, mediated by histamine H(2)-receptor subtype with no involvement of guanylyl cyclase or adenylyl cyclase activation and most likely involves activation of K(V) potassium channels.
MeSH term(s)	Adenine/analogs & derivatives ; Adenine/pharmacology ; Adenylyl Cyclase Inhibitors ; Animals ; Benzenesulfonates/pharmacology ; Calcium/metabolism ; Cerebral Arteries/drug effects ; Cerebral Arteries/metabolism ; Cerebral Arteries/physiology ; Cyclic AMP/metabolism ; Dose-Response Relationship, Drug ; Endothelium, Vascular/physiology ; Enzyme Inhibitors/pharmacology ; Guanylate Cyclase/antagonists & inhibitors ; Histamine/pharmacology ; Histamine Agonists/pharmacology ; Histamine Antagonists/pharmacology ; In Vitro Techniques ; Male ; Muscle, Smooth, Vascular/drug effects ; Muscle, Smooth, Vascular/physiology ; Oxadiazoles/pharmacology ; Potassium Channel Blockers/pharmacology ; Potassium Channels, Voltage-Gated/antagonists & inhibitors ; Potassium Channels, Voltage-Gated/physiology ; Potassium Chloride/pharmacology ; Quinoxalines/pharmacology ; Rats ; Rats, Sprague-Dawley ; Thiazoles/pharmacology ; Vasoconstriction/drug effects ; Vasodilation/drug effects
Chemical Substances	1H-(1,2,4)oxadiazolo(4,3-a)quinoxalin-1-one ; 4,4,',4'',4'''-(carbonylbis(imino-5,1,3-benzenetriylbis(carbonylimino)))tetrakis(benzene-1,3-disulfonate) ; Adenylyl Cyclase Inhibitors ; Benzenesulfonates ; Enzyme Inhibitors ; Histamine Agonists ; Histamine Antagonists ; Oxadiazoles ; Potassium Channel Blockers ; Potassium Channels, Voltage-Gated ; Quinoxalines ; Thiazoles ; amthamine (142437-67-0) ; 9-(tetrahydro-2-furyl)-adenine (17318-31-9) ; Potassium Chloride (660YQ98I10) ; Histamine (820484N8I3) ; Cyclic AMP (E0399OZS9N) ; Guanylate Cyclase (EC 4.6.1.2) ; Adenine (JAC85A2161) ; Calcium (SY7Q814VUP)
Language	English
Publishing date	2006-10-10
Publishing country	Netherlands
Document type	Journal Article
ZDB-ID	80121-5
ISSN	1879-0712 ; 0014-2999
ISSN (online)	1879-0712
ISSN	0014-2999
DOI	10.1016/j.ejphar.2006.07.036
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Article: Role of phospholipase C in development of myogenic tone in rat posterior cerebral arteries.

Jarajapu, Yagna P R / Knot, Harm J

American journal of physiology. Heart and circulatory physiology

2002 Volume 283, Issue 6, Page(s) H2234–8

Abstract: Earlier studies have implicated phospholipase C (PLC) in the development of myogenic tone (MT) based on pharmacological studies in larger arteries. In the present study, we further investigated the cellular effects of PLC inhibition using pharmacological ...

Abstract	Earlier studies have implicated phospholipase C (PLC) in the development of myogenic tone (MT) based on pharmacological studies in larger arteries. In the present study, we further investigated the cellular effects of PLC inhibition using pharmacological and electrophysiological approaches to provide more quantitative functional evidence for the involvement of PLC in the genesis of MT in small cerebral arteries. The phosphatidylinositol-selective PLC (PI-PLC) inhibitor U-73122 decreased MT by 87% in posterior cerebral arteries from Sprague-Dawley rats with pIC(50) of 6.2 +/- 0.09 (n = 5). Similar potency (pIC(50) of 6.2 +/- 0.04, n = 5) was observed in arteries with MT that were further constricted with 30 nM serotonin. The phosphatidylcholine-specific (PC-PLC) inhibitor D609 had no effect on MT. U-73343, the inactive analog of U-73122, did not show any relaxant effect, but at higher concentrations (>1 microM) it reduced MT. In the presence of 125-500 nM U-73122, the pressure-diameter curves shifted toward that obtained in Ca-free conditions. U-73122-mediated decrease in MT was accompanied by a decrease in mean arterial wall calcium (maximum effect: 77 +/- 3% of 16 mM KCl-mediated decrease, n = 4). This was due to a simultaneous membrane potential hyperpolarization of approximately 9 mV or from -44 +/- 1 to -53 +/- 2 mV (10 microM, P < 0.001, n = 8). In summary, this study provides the first quantitative data suggesting a critical importance of PI-PLC in the genesis of pressure-induced MT in rat cerebral arteries via membrane potential depolarization and increased calcium influx.
MeSH term(s)	Animals ; Blood Pressure/physiology ; Calcium/metabolism ; Dose-Response Relationship, Drug ; Enzyme Inhibitors/pharmacology ; In Vitro Techniques ; Male ; Membrane Potentials/drug effects ; Membrane Potentials/physiology ; Muscle Tonus/drug effects ; Muscle Tonus/physiology ; Muscle, Smooth, Vascular/drug effects ; Muscle, Smooth, Vascular/metabolism ; Posterior Cerebral Artery/drug effects ; Posterior Cerebral Artery/enzymology ; Posterior Cerebral Artery/physiology ; Rats ; Serotonin/pharmacology ; Type C Phospholipases/antagonists & inhibitors ; Type C Phospholipases/metabolism ; Vasoconstriction/drug effects ; Vasoconstriction/physiology
Chemical Substances	Enzyme Inhibitors ; Serotonin (333DO1RDJY) ; Type C Phospholipases (EC 3.1.4.-) ; Calcium (SY7Q814VUP)
Language	English
Publishing date	2002-08-29
Publishing country	United States
Document type	Journal Article ; Research Support, Non-U.S. Gov't ; Research Support, U.S. Gov't, P.H.S.
ZDB-ID	603838-4
ISSN	1522-1539 ; 0363-6135
ISSN (online)	1522-1539
ISSN	0363-6135
DOI	10.1152/ajpheart.00624.2002
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Article: Myogenic tone and reactivity of cerebral arteries in type II diabetic BBZDR/Wor rat.

Jarajapu, Yagna P R / Guberski, Dennis L / Grant, Maria B / Knot, Harm J

European journal of pharmacology

2007 Volume 579, Issue 1-3, Page(s) 298–307

Abstract: BBZDR/Wor rat is a new model of type II diabetes with spontaneous obesity and clinical characteristics close to human diabetes. In this study the time-course of cerebroarterial dysfunction was characterized. Posterior cerebral arteries from BBZDR/Wor ... ...

Abstract	BBZDR/Wor rat is a new model of type II diabetes with spontaneous obesity and clinical characteristics close to human diabetes. In this study the time-course of cerebroarterial dysfunction was characterized. Posterior cerebral arteries from BBZDR/Wor rats and their age-matched lean controls were pressurized to 70 mm Hg in an arteriograph. Effects of intraluminal pressure and different pharmacological agents on myogenic tone were evaluated. Pressure-myogenic tone curves in diabetic arteries were similar to that in non-diabetic arteries at pre-diabetic age, showed leftward shift at 4 weeks and were significantly different with higher myogenic tone at 5 and 8 months of diabetes. Age-dependent decrease in myogenic tone was observed in non-diabetic arteries. Dilation to histamine was similar to that in non-diabetic arteries at pre-diabetic and at 4 weeks but significantly reduced at 5 and 8 months of diabetes. Bradykinin-mediated dilation was significantly reduced in early and chronic diabetes, whereas (+/-)-S-nitroso-N-acetylpenicillamine (SNAP)-mediated dilation was decreased modestly at 8 months of diabetes. Sensitivity and constriction to 5-hydroxytryptamine were increased in early and chronic diabetes. Responses to bradykinin and 5-hydroxytryptamine were decreased and increased, respectively. Myogenic tone was significantly less sensitive to (lower pIC(50)) U-73122 than normal arteries at 4 weeks and 8 months of diabetes suggesting an increased activation of phospholipase C (PLC). This study shows that pressure-mediated autoregulation of cerebral arteries in type II diabetes operates at higher resistance. Endothelium-dependent dilation was decreased with chronic diabetes with increased sensitivity to constrictor agonist. Endothelium-independent dilation was modestly affected. Arterial hyper-reactivity to pressure and constrictor agonist were likely due to increased PLC activation.
MeSH term(s)	Age Factors ; Animals ; Blood Pressure/physiology ; Bradykinin/pharmacology ; Diabetes Mellitus, Type 2/physiopathology ; Disease Models, Animal ; Endothelium, Vascular/physiopathology ; Male ; Posterior Cerebral Artery/physiopathology ; Rats ; Rats, Inbred BB ; Rats, Zucker ; S-Nitroso-N-Acetylpenicillamine/pharmacology ; Serotonin/pharmacology ; Time Factors ; Type C Phospholipases/metabolism ; Vasodilation/physiology
Chemical Substances	Serotonin (333DO1RDJY) ; S-Nitroso-N-Acetylpenicillamine (79032-48-7) ; Type C Phospholipases (EC 3.1.4.-) ; Bradykinin (S8TIM42R2W)
Language	English
Publishing date	2007-10-25
Publishing country	Netherlands
Document type	Journal Article ; Research Support, N.I.H., Extramural ; Research Support, Non-U.S. Gov't
ZDB-ID	80121-5
ISSN	1879-0712 ; 0014-2999
ISSN (online)	1879-0712
ISSN	0014-2999
DOI	10.1016/j.ejphar.2007.10.028
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Article: Muscarinic acetylcholine type-3 receptor desensitization due to chronic exposure to Sjögren's syndrome-associated autoantibodies.

Cha, Seunghee / Singson, Eric / Cornelius, Janet / Yagna, Jarajapu P / Knot, Harm J / Peck, Ammon B

The Journal of rheumatology

2006 Volume 33, Issue 2, Page(s) 296–306

Abstract: Objective: Anti-muscarinic acetylcholine type-3 receptor (anti-M3R) autoantibodies have been shown to inhibit M3R-mediated responses by both in vitro contractility and fura-2 microfluorimetry analyses of intracellular calcium mobilization, suggesting an ...

Abstract	Objective: Anti-muscarinic acetylcholine type-3 receptor (anti-M3R) autoantibodies have been shown to inhibit M3R-mediated responses by both in vitro contractility and fura-2 microfluorimetry analyses of intracellular calcium mobilization, suggesting an important role for anti-M3R autoantibody in secretory dysfunction. We investigated whether chronic stimulation of M3R by anti-M3R autoantibodies and/or the agonist pilocarpine results in a general M3R desensitization. Methods: Carbachol-evoked responses of mouse-bladder smooth muscle strips were measured following exposure to anti-M3R-positive and/or anti-M3R-negative sera from either NOD/Lt mice, a model of SS-like disease, or human patients with primary SS. Results: Bladder smooth muscle strips isolated from NOD/Lt mice with circulating anti-M3R autoantibodies exhibited lower carbachol-evoked responses than smooth muscle strips from anti-M3R autoantibody-negative NOD/Lt mice and control C57BL/6 mice. Repeated pilocarpine injections of NOD mice for 6 days also revealed M3R desensitization in the agonist-evoked contractile assay, whereas age and sex matched C57BL/6 mice injected with pilocarpine for the same period showed a 2-fold higher response. Incubation of smooth muscle strips with sera obtained from patients with primary SS resulted in both stimulated and inhibited responses. Conclusion: These results support the hypothesis that chronic stimulation of membrane-bound M3R can result in receptor desensitization, and raise questions about repeated use of pilocarpine by patients positive for anti-M3R autoantibodies.
MeSH term(s)	Animals ; Antibodies, Blocking/blood ; Antibodies, Blocking/immunology ; Antibodies, Blocking/pharmacology ; Autoantibodies/blood ; Autoantibodies/immunology ; Autoantibodies/pharmacology ; Carbachol/pharmacology ; Disease Models, Animal ; Dose-Response Relationship, Drug ; Humans ; Male ; Mice ; Mice, Inbred C57BL ; Mice, Inbred NOD ; Muscarinic Antagonists/blood ; Muscarinic Antagonists/immunology ; Muscarinic Antagonists/pharmacology ; Muscle Contraction/drug effects ; Muscle Contraction/physiology ; Muscle, Smooth/drug effects ; Pilocarpine/pharmacology ; Receptors, Muscarinic/drug effects ; Receptors, Muscarinic/immunology ; Sjogren's Syndrome/blood ; Sjogren's Syndrome/immunology ; Sjogren's Syndrome/pathology ; Urinary Bladder/drug effects ; Urinary Bladder/physiology
Chemical Substances	Antibodies, Blocking ; Autoantibodies ; Muscarinic Antagonists ; Receptors, Muscarinic ; Pilocarpine (01MI4Q9DI3) ; Carbachol (8Y164V895Y)
Language	English
Publishing date	2006-02
Publishing country	Canada
Document type	Journal Article ; Research Support, N.I.H., Extramural ; Research Support, Non-U.S. Gov't
ZDB-ID	194928-7
ISSN	1499-2752 ; 0315-162X
ISSN (online)	1499-2752
ISSN	0315-162X
Database	MEDical Literature Analysis and Retrieval System OnLINE

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