Ischemia Changes the Contribution of KATP-Channels to Basal Tone and Dilation of Rat Pial Arteries

Coronary blood flow in the subendocardium is preferentially increased by adenosine but is redistributed to the subepicardium during ischemia in association with coronary pressure reduction. The mechanism for this flow redistribution remains unclear. Since adenosine is released during ischemia, it is possible that the coronary microcirculation exhibits a transmural difference in vasomotor responsiveness to adenosine at various intraluminal pressures. Although the ATP-sensitive K+ (KATP) channel has been shown to be involved in coronary arteriolar dilation to adenosine, its role in the transmural adenosine response remains elusive. To address these issues, pig subepicardial and subendocardial arterioles (60–120 μm) were isolated, cannulated, and pressurized to 20, 40, 60, or 80 cmH2O without flow for in vitro study. At each of these pressures, vessels developed basal tone and dilated concentration dependently to adenosine and the KATP channel opener pinacidil. Subepicardial and subendocardial arterioles dilated equally to adenosine and pinacidil at 60 and 80 cmH2O luminal pressure. At lower luminal pressures (i.e., 20 and 40 cmH2O), vasodilation in both vessel types was enhanced. Enhanced vasodilatory responses were not affected by removal of endothelium but were abolished by the KATP channel inhibitor glibenclamide. In a manner similar to reducing pressure, a subthreshold dose of pinacidil potentiated vasodilation to adenosine. In contrast to adenosine, dilation of coronary arterioles to sodium nitroprusside was independent of pressure changes. These results indicate that coronary microvascular dilation to adenosine is enhanced at lower intraluminal pressures by selective activation of smooth muscle KATP channels. Since microvascular pressure has been shown to be consistently lower in the subendocardium than in the subepicardium, it is likely that the inherent pressure gradient in the coronary microcirculation across the ventricular wall may be an important determinant of transmural flow in vivo during resting conditions or under metabolic stress with adenosine release.

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Role of KATP Channels in the Regulation of Rat Dura and Pia Artery Diameter

Cephalalgia ◽

10.1111/j.1468-2982.2004.00848.x ◽

2005 ◽

Vol 25 (4) ◽

pp. 249-260 ◽

Cited By ~ 16

Author(s):

A Gozalov ◽

KA Petersen ◽

C Mortensen ◽

I Jansen-Olesen ◽

D Klaerke ◽

...

Keyword(s):

Intravenous Infusion ◽

Katp Channels ◽

Organ Bath ◽

Pial Arteries ◽

Cranial Window ◽

Pial Artery ◽

Isolated Arteries

The aim of the present study was to examine the effect of KATP channel openers pinacidil and levcromakalim on rat dural and pial arteries as well as their inhibition by glibenclamide. We used an in-vivo genuine closed cranial window model and an in-vitro organ bath. Glibenclamide alone reduced the dural but not the pial artery diameter compared with controls. Intravenous pinacidil and levcro-makalim induced dural and pial artery dilation that was significantly attenuated by glibenclamide. In the organ bath pinacidil and levcromakalim induced dural and middle cerebral artery relaxation that was significantly attenuated by glibenclamide. In conclusion, KATP channel openers induce increasing diameter/relaxation of dural and pial arteries after intravenous infusion in vivo and on isolated arteries in vitro. Furthermore, dural arteries were more sensitive to KATP channel openers than pial arteries.

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Amine-Induced Responses of Pial and Penetrating Cerebral Arteries: Evidence for Heterogeneous Responses

Journal of Cerebral Blood Flow & Metabolism ◽

10.1038/jcbfm.1990.137 ◽

1990 ◽

Vol 10 (6) ◽

pp. 808-818 ◽

Cited By ~ 20

Author(s):

R. Sercombe ◽

J. E. Hardebo ◽

J. Kåhrström ◽

J. Seylaz

Keyword(s):

Cerebral Arteries ◽

Isometric Tension ◽

Outer Diameter ◽

Perfusion Technique ◽

Pial Arteries ◽

Contractile Responses ◽

Low Concentrations ◽

Basal Tone ◽

Middle Cerebral Arteries ◽

Different Types

Middle cerebral arteries (MCAs) of rabbits were compared with two types of small branches (<100-µm outer diameter), penetrating arteries (PAs) and surface arteries (SAs), by determining their mechanical reactivity to several amines and standard contractile agents. Two techniques were employed: (a) measurement of isometric tension of 1-mm rings (MCA, PA, or SA); (b) measurement of perfusion pressure of segments consisting of essentially MCA or essentially PA. Both techniques revealed similar reactivity of the different types of vessel to acetylcholine, i.e., relaxations to a maximum of 52–78%, and similar strong contractile responses to histamine, although the MCA was more sensitive. Under H1 blockade, histamine dilated the PA (both techniques) and the MCA (perfusion technique), but not the SA. Relatively weak contractile responses to serotonin were observed in the MCA (both techniques) and the PA (perfusion technique), but not the SA (isometric tension only); no dilative responses could be elicited. Responses to noradrenaline varied with the vessel considered: The MCA contracted only, whereas the PA weakly contracted or relaxed at basal tone, and many preparations relaxed after precontraction with uridine triphosphate; the SA did not react. Relaxation of precontracted PA by noradrenaline occurred at relatively low concentrations and was antagonized by propranolol at 3 × 10− 7 or 3 × 10− 6 M. These results reveal very significant differences in the segmental reactivity to amines and suggest that noradrenaline released from sympathetic fibers might have opposing actions in the major pial arteries and the smaller penetrating branches.

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Microvascular features that suggest effectors of blood-flow regulation in the brain: Evidence by SEM of corrosion casts of intracerebral vessels

Proceedings, annual meeting, Electron Microscopy Society of America ◽

10.1017/s0424820100158923 ◽

1990 ◽

Vol 48 (3) ◽

pp. 274-275

Author(s):

Enrico D.F. Motti ◽

Hans-Georg Imhof ◽

Gazi M. Yasargil

Keyword(s):

Blood Flow ◽

Perfusion Pressure ◽

Corrosion Casts ◽

Cerebral Microcirculation ◽

Pial Arteries ◽

Random Occurrence ◽

Brain Arteries ◽

Homogeneous Network ◽

The Brain

Physiologists have devoted most attention in the cerebrovascular tree to the arterial side of the circulation which has been subdivided in three levels: 1) major brain arteries which keep microcirculation constant despite changes in perfusion pressure; 2) pial arteries supposed to be effectors regulating microcirculation; 3) intracerebral arteries supposed to be deprived of active cerebral blood flow regulating devices.The morphological search for microvascular effectors in the cerebrovascular bed has been elusive. The opaque substance of the brain confines in vivo investigation to the superficial pial arteries. Most morphologists had to limit their observation to the random occurrence of a favorable site in the practically two-dimensional thickness of diaphanized histological sections. It is then not surprising most investigators of the cerebral microcirculation refer to an homogeneous network of microvessels interposed between arterioles and venules.We have taken advantage of the excellent depth of focus afforded by the scanning electron microscope (SEM) to investigate corrosion casts obtained injecting a range of experimental animals with a modified Batson's acrylic mixture.

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Central KATP channels modulate glucose effectiveness in humans and rodents

10.2337/db20-4567/suppl.12023250 ◽

2020 ◽

Author(s):

Ada Admin ◽

Michelle Carey ◽

Eric Lontchi-Yimagou ◽

William Mitchell ◽

Sarah Reda ◽

...

Keyword(s):

Katp Channel ◽

Glucose Production ◽

Katp Channels ◽

Endogenous Glucose Production ◽

Elevated Plasma ◽

Sprague Dawley ◽

Glucose Effectiveness ◽

Sprague Dawley Rats ◽

The Central Nervous System

Hyperglycemia is a potent regulator of endogenous glucose production (EGP). Loss of this ‘glucose effectiveness’ is a major contributor to elevated plasma glucose concentrations in type 2 diabetes (T2D). ATP-sensitive potassium channels (KATP channels) in the central nervous system (CNS) have been shown to regulate EGP in humans and rodents. We examined the contribution of central KATP channels to glucose effectiveness. Under fixed hormonal conditions (‘pancreatic clamp’ studies), hyperglycemia suppressed EGP by ~50% in both non-diabetic humans and normal Sprague Dawley rats. By contrast, antagonism of KATP channels with glyburide significantly reduced the EGP-lowering effect of hyperglycemia in both humans and rats. Furthermore, the effects of glyburide on EGP and gluconeogenic enzymes in rats were abolished by intracerebroventricular (ICV) administration of the KATP channel agonist diazoxide. These findings indicate that about half of EGP suppression by hyperglycemia is mediated by central KATP channels. These central mechanisms may offer a novel therapeutic target for improving glycemic control in T2D.

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Faculty Opinions recommendation of Adaptation of airway smooth muscle to basal tone: relevance to airway hyperresponsiveness.

Faculty Opinions – Post-Publication Peer Review of the Biomedical Literature ◽

10.3410/f.1145050.602177 ◽

2009 ◽

Author(s):

Jason HT Bates

Keyword(s):

Smooth Muscle ◽

Airway Smooth Muscle ◽

Airway Hyperresponsiveness ◽

Basal Tone

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Postjunctional Alpha(2)-Adrenoceptors in Pial Arteries of Anesthetized Newborn Pigs

Developmental Pharmacology and Therapeutics ◽

10.1159/000457726 ◽

1987 ◽

Vol 10 (1) ◽

pp. 36-46 ◽

Cited By ~ 24

Author(s):

David W. Busija ◽

Charles W. Leffler

Keyword(s):

Pial Arteries ◽

Newborn Pigs

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Molecular Mechanisms of the Inhibitory Effects of Bupivacaine, Levobupivacaine, and Ropivacaine on Sarcolemmal Adenosine Triphosphate–sensitive Potassium Channels in the Cardiovascular System

Anesthesiology ◽

10.1097/00000542-200408000-00020 ◽

2004 ◽

Vol 101 (2) ◽

pp. 390-398 ◽

Cited By ~ 24

Author(s):

Takashi Kawano ◽

Shuzo Oshita ◽

Akira Takahashi ◽

Yasuo Tsutsumi ◽

Yoshinobu Tomiyama ◽

...

Keyword(s):

Cardiovascular System ◽

Adenosine Triphosphate ◽

Local Anesthetics ◽

Molecular Mechanisms ◽

Transmembrane Domain ◽

Katp Channels ◽

Inhibitory Effect ◽

Amino Acid Residues ◽

Sulfonylurea Receptor ◽

Inhibitory Effects

Background Sarcolemmal adenosine triphosphate-sensitive potassium (KATP) channels in the cardiovascular system may be involved in bupivacaine-induced cardiovascular toxicity. The authors investigated the effects of local anesthetics on the activity of reconstituted KATP channels encoded by inwardly rectifying potassium channel (Kir6.0) and sulfonylurea receptor (SUR) subunits. Methods The authors used an inside-out patch clamp configuration to investigate the effects of bupivacaine, levobupivacaine, and ropivacaine on the activity of reconstituted KATP channels expressed in COS-7 cells and containing wild-type, mutant, or chimeric SURs. Results Bupivacaine inhibited the activities of cardiac KATP channels (IC50 = 52 microm) stereoselectively (levobupivacaine, IC50 = 168 microm; ropivacaine, IC50 = 249 microm). Local anesthetics also inhibited the activities of channels formed by the truncated isoform of Kir6.2 (Kir6.2 delta C36) stereoselectively. Mutations in the cytosolic end of the second transmembrane domain of Kir6.2 markedly decreased both the local anesthetics' affinity and stereoselectivity. The local anesthetics blocked cardiac KATP channels with approximately eightfold higher potency than vascular KATP channels; the potency depended on the SUR subtype. The 42 amino acid residues at the C-terminal tail of SUR2A, but not SUR1 or SUR2B, enhanced the inhibitory effect of bupivacaine on the Kir6.0 subunit. Conclusions Inhibitory effects of local anesthetics on KATP channels in the cardiovascular system are (1) stereoselective: bupivacaine was more potent than levobupivacaine and ropivacaine; and (2) tissue specific: local anesthetics blocked cardiac KATP channels more potently than vascular KATP channels, via the intracellular pore mouth of the Kir6.0 subunit and the 42 amino acids at the C-terminal tail of the SUR2A subunit, respectively.

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