Potassium channels modulate cerebral autoregulation during acute hypertension

2000 ◽  
Vol 278 (6) ◽  
pp. H2003-H2007 ◽  
Author(s):  
Roberto Paternò ◽  
Donald D. Heistad ◽  
Frank M. Faraci ◽  
Keyword(s):  
Blood Pressure ◽  
Arterial Pressure ◽  
Cerebral Autoregulation ◽  
Acute Hypertension ◽  
Calcium Dependent ◽  
Control Value ◽  
Cranial Window ◽  
Cerebral Arterioles ◽  
Arteriolar Diameter ◽  
Baseline Diameter

We tested the hypothesis that constriction of cerebral arterioles during acute increases in blood pressure is attenuated by activation of potassium (K+) channels. We tested the effects of inhibitors of calcium-dependent K+ channels [iberiotoxin (50 nM) and tetraethylammonium (TEA, 1 mM)] on changes in arteriolar diameter during acute hypertension. Diameter of cerebral arterioles (baseline diameter = 46 ± 2 μm, mean ± SE) was measured using a cranial window in anesthetized rats. Arterial pressure was increased from a control value of 96 ± 1 mmHg to 130, 150, 170, and 200 mmHg by intravenous infusion of phenylephrine. Increases in arterial pressure from baseline to 130 and 150 mmHg decreased the diameter of cerebral arterioles by 5–10%. Greater increases in arterial pressure produced large increases in arteriolar diameter (i.e., “breakthrough of autoregulation”). Iberiotoxin or TEA inhibited increases in arteriolar diameter when arterial pressure was increased to 170 and 200 mmHg. The change in arteriolar diameter at 200 mmHg was 20 ± 3% and −1 ± 4% in the absence and presence of iberiotoxin, respectively. These findings suggest that calcium-dependent K+ channels attenuate cerebral microvascular constriction during acute increases in arterial pressure, and that increases in arteriolar diameter at high levels of arterial pressure are not simply a passive phenomenon.

Nitric oxide contributes to dilatation of cerebral arterioles during seizures

1993 ◽  
Vol 265 (6) ◽  
pp. H2209-H2212 ◽  
Author(s):  
F. M. Faraci ◽  
K. R. Breese ◽  
D. D. Heistad
Keyword(s):  
Nitric Oxide ◽  
Amino Acids ◽  
Arterial Pressure ◽  
Excitatory Amino Acids ◽  
No Synthase ◽  
Cerebral Microcirculation ◽  
Cranial Window ◽  
Cerebral Arterioles ◽  
Endogenous Release ◽  
Arteriolar Diameter

Endogenous release of excitatory amino acids during seizures produces marked increases in neuronal activity and guanosine 3',5'-cyclic monophosphate levels in brain tissue, which are mediated by nitric oxide (NO). We tested the hypothesis that dilatation of the cerebral microcirculation during seizures is mediated by NO. Diameters of cerebral arterioles were measured using a closed cranial window in anesthetized rabbits. Three, five, nine, and eleven minutes after the onset of pentylenetetrazole-induced seizure (which releases endogenous excitatory amino acids), arteriolar diameter increased by 42 +/- 6, 30 +/- 3, 20 +/- 2, and 16 +/- 2% (means +/- SE), respectively, from a control diameter of 86 +/- 6 microns. Arterial pressure was maintained at control levels during seizures. In the presence of NG-nitro-L-arginine (L-NNA, 300 microM), an inhibitor of NO synthase, vasodilatation during seizures was not affected at 3 min (40 +/- 8%) but was significantly reduced at 5, 9, and 11 min (17 +/- 5, 6 +/- 3, and 1 +/- 3%, respectively, P < 0.05 vs. control). Vasodilatation in response to topical application of acetylcholine (1 microM) was also inhibited by L-NNA (33 +/- 5 vs. 3 +/- 2%, P < 0.05). Dilatation of cerebral arterioles in response to nitroprusside (1 and 10 microM) was not inhibited by L-NNA. Thus sustained, but not initial, dilatation of cerebral arterioles during seizures appears to be mediated in part by NO.

scholarly journals Arachidonate dilates basilar artery by lipoxygenase-dependent mechanism and activation of K+channels

2001 ◽  
Vol 281 (1) ◽  
pp. R246-R253 ◽  
Author(s):  
Frank M. Faraci ◽  
Christopher G. Sobey ◽  
Sophocles Chrissobolis ◽  
Donald D. Lund ◽  
Donald D. Heistad ◽  
...  
Keyword(s):  
Arachidonic Acid ◽  
Potassium Channels ◽  
Basilar Artery ◽  
Nordihydroguaiaretic Acid ◽  
Chiral Hplc ◽  
Lipoxygenase Pathway ◽  
Calcium Dependent ◽  
Cranial Window ◽  
Cerebral Arterioles ◽  
Baseline Diameter

Dilatation of cerebral arterioles in response to arachidonic acid is dependent on activity of cyclooxygenase. In this study, we examined mechanisms that mediate dilatation of the basilar artery in response to arachidonate. Diameter of the basilar artery (baseline diameter = 216 ± 7 μm) (means ± SE) was measured using a cranial window in anesthetized rats. Arachidonic acid (10 and 100 μM) produced concentration-dependent vasodilatation that was not inhibited by indomethacin (10 mg/kg iv) or N G-nitro-l-arginine (100 μM) but was inhibited markedly by baicalein (10 μM) or nordihydroguaiaretic acid (NDGA; 10 μM), inhibitors of the lipoxygenase pathway. Dilatation of the basilar artery was also inhibited markedly by tetraethylammonium ion (TEA; 1 mM) or iberiotoxin (50 nM), inhibitors of calcium-dependent potassium channels. For example, 10 μM arachidonate dilated the basilar artery by 19 ± 7 and 1 ± 1% in the absence and presence of iberiotoxin, respectively. Measurements of membrane potential indicated that arachidonate produced hyperpolarization of the basilar artery that was blocked completely by TEA. Incubation with [3H]arachidonic acid followed by reverse-phase and chiral HPLC indicated that the basilar artery produces relatively small quantities of prostanoids but large quantities of 12(S)-hydroxyeicosatetraenoic acid (12-S-HETE), a lipoxygenase product. Moreover, the production of 12-HETE was inhibited by baicalein or NDGA. These findings suggest that dilatation of the basilar artery in response to arachidonate is mediated by a product(s) of the lipoxygenase pathway, with activation of calcium-dependent potassium channels and hyperpolarization of vascular muscle.

Indomethacin-sensitive CO2 reactivity of cerebral arterioles is restored by vasodilator prostaglandin

1994 ◽  
Vol 266 (4) ◽  
pp. H1332-H1338 ◽  
Author(s):  
L. C. Wagerle ◽  
P. A. Degiulio
Keyword(s):  
Sodium Nitroprusside ◽  
Intracellular Signaling ◽  
Receptor Activation ◽  
Cyclooxygenase Inhibitors ◽  
Relaxation Response ◽  
Cyclic Monophosphate ◽  
Cranial Window ◽  
Vasodilator Response ◽  
Cerebral Arterioles ◽  
Arteriolar Diameter

To investigate the role of vasodilator prostanoids in the CO2-induced relaxation of cerebral arterioles, the present study examined the effect of exogenous prostaglandin (PG) E2 and nonprostanoid vasodilators, adenosine and sodium nitroprusside, on the indomethacin-impaired pial arteriolar response to CO2 in newborn piglets. Reactivity of pial arterioles (52-131 microns diam) was determined using a closed cranial window with intravital microscopy. Cortical prostanoid synthesis was assessed by analyzing for select prostanoids in cerebrospinal fluid sampled from under the cranial window. Inhalation of 7% CO2 caused an elevation of cortical 6-keto-PGF1 alpha and thromboxane (Tx) B2 and increased pial arteriolar diameter by 34 +/- 5%. Two cyclooxygenase inhibitors, indomethacin (5 mg/kg i.v.) and ibuprofen (30 mg/kg i.v.), abolished the CO2-induced elevation of cortical prostanoids. Indomethacin, but not ibuprofen, blocked the CO2-induced increase in pial arteriolar diameter. The indomethacin-impaired vasodilator response to CO2 was restored when PGE2 (0.1-1 microM) was applied topically to the cortical surface. Adenosine (1-100 microM) and sodium nitroprusside (0.5 microM) only partially restored the vasodilator response to CO2. The data suggest that vasodilator prostanoids facilitate cerebrovascular relaxation to CO2 and may play a permissive role in the relaxation response of vascular smooth muscle. The fact that adenosine (adenosine 3',5'-cyclic monophosphate-mediated dilator) and sodium nitroprusside (guanosine 3',5'-cyclic monophosphate-mediated dilator), were partially effective suggests a role for those intracellular signaling pathways. We speculate that receptor activation of intracellular pathways may alter Ca2+ sensitivity of the contractile apparatus in such a way that the relaxation response to CO2 can occur.(ABSTRACT TRUNCATED AT 250 WORDS)

Hypertension Induced by Prolonged Intracoronary Administration of Dobutamine in Conscious Dogs

1978 ◽  
Vol 54 (2) ◽  
pp. 153-160 ◽  
Author(s):  
J.-F. Liard
Keyword(s):  
Blood Pressure ◽  
Cardiac Output ◽  
Arterial Pressure ◽  
Peripheral Resistance ◽  
Extracellular Fluid ◽  
Electromagnetic Flowmeter ◽  
Plasma Renin ◽  
Conscious Dogs ◽  
Control Value ◽  
A Value

1. In order to determine if a sustained increase in cardiac output can lead to hypertension, seven conscious dogs were given a continuous infusion of dobutamine, a powerful stimulant of cardiac inotropism, into the left coronary artery for a 7 day period while arterial pressure, cardiac output (electromagnetic flowmeter) and heart rate were measured. 2. The infusion technique (1·5 × 10−8 mol min−1 kg−1, intracoronary) was selected after short-term experiments showed that it increased cardiac output more effectively than intravenous infusion at the same rate. 3. The rise in cardiac output elicited by intracoronary infusion of dobutamine was largest during the first 6 h of the 7 days administration, at which time calculated peripheral resistance was decreased. Subsequently, cardiac output returned progressively toward its control value whereas mean arterial pressure remained elevated (by an average of 20–25 mmHg) and peripheral resistance increased significantly. 4. Measurements of blood and extracellular fluid volumes as well as plasma renin activity indicated that these factors were not involved in the blood pressure increase. 5. When the infusion was ended, arterial pressure fell rapidly but peripheral resistance remained elevated during the first 6 h. Cardiac output fell after 2 and 6 h to a value below that of the pre-infusion control. After 1 day and subsequently, blood pressure became normal, as did the peripheral resistance and cardiac output. 6. Both at the onset and offset transients of this model of hypertension, changes in cardiac output preceded changes in peripheral resistance. These experiments may give experimental support to the concept of cardiogenic hypertension.

Ouabain prevents loss of autoregulation in rat pial arterioles caused by reoxygenation after a brief hypoxic episode

1989 ◽  
Vol 67 (5) ◽  
pp. 423-427 ◽  
Author(s):  
J. Kettler ◽  
B. Y. Ong ◽  
D. Bose
Keyword(s):  
Blood Pressure ◽  
Arterial Blood Pressure ◽  
Protective Effects ◽  
Cranial Window ◽  
Arterial Blood ◽  
Hypoxic Episode ◽  
Electrogenic Sodium Pump ◽  
Before And After ◽  
Pressure Changes ◽  
Arteriolar Diameter

Pial arteriolar diameter changes inversely with changes in systemic arterial blood pressure. Such changes are consistent with autoregulatory functions. These responses are reduced by a brief period of hypoxia followed by reoxygenation. By using an open cranial window preparation we assessed the changes in pial arteriolar diameters during blood pressure changes in rats induced by hemorrhage and reinfusion of blood, before and after a brief period of hypoxia. The slopes of the changes in pial arteriolar diameter as a function of mean arterial blood pressure were −0.47 ± 0.26 μm/mmHg (mean ± SD; 1 mmHg = 133.3 Pa) before hypoxia and −0.11 ± 0.23 μm/mmHg after hypoxia in the untreated rats. In ouabain-treated rats, corresponding slopes were −0.42 ± 0.24 and −0.46 ± 0.22 μm/mmHg. The observed protective effects of ouabain might be a blockade of the Na–K pump in the sarcolemma of the vascular smooth muscle.Key words: vascular smooth muscle, electrogenic sodium pump, metabolic inhibition.

Mechanisms of endotoxin-induced dilatation of cerebral arterioles

1995 ◽  
Vol 269 (3) ◽  
pp. H783-H788 ◽  
Author(s):  
J. E. Brian ◽  
D. D. Heistad ◽  
F. M. Faraci
Keyword(s):  
No Synthase ◽  
Vascular Responses ◽  
Time Points ◽  
Cranial Window ◽  
Inducible No Synthase ◽  
Calcitonin Gene ◽  
Cerebral Arterioles ◽  
Arteriolar Diameter ◽  
Inducible Nitric Oxide

Lipopolysaccharide (LPS; endotoxin) produces dilatation of cerebral arterioles in vivo which may be due, in part, to expression of inducible nitric oxide (NO) synthase. We tested the hypothesis that aminoguanidine, an inhibitor of inducible NO synthase, would reduce endotoxin-induced dilatation of cerebral arterioles. Because mechanisms other than expression of inducible NO synthase may contribute to endotoxin-induced dilatation of cerebral arterioles, we also tested the hypothesis that calcitonin gene-related peptide (CGRP) contributes to vascular responses to endotoxin. Cerebral arteriolar diameter was measured using a closed cranial window in anesthetized rabbits under control conditions [77 +/- 3 (SE) microns] and during topical application of endotoxin (100 micrograms/ml). After 4 h, diameter of cerebral arterioles increased by 41 +/- 5%. Coapplication of aminoguanidine (0.3 mM) with endotoxin reduced vasodilatation at all time points (30 min to 4 h). Relative to control values, endotoxin treatment increased guanosine 3',5'-cyclic monophosphate (cGMP) concentration in cerebrospinal fluid (CSF) by approximately 20 fold at 4 h. Aminoguanidine attenuated the endotoxin-induced increased in CSF cGMP concentration. Aminoguanidine (0.3 mM) did not alter acetylcholine-mediated dilatation of cerebral arterioles. Coapplication of CGRP-(8-37) (0.5 microM), a specific blocker of CGRP receptors, with endotoxin significantly reduced vasodilatation in response to endotoxin at 2, 3, and 4 h. Thus 1) aminoguanidine inhibits endotoxin- but not acetylcholine-mediated dilatation of cerebral arterioles, and 2) activation of CGRP receptors mediates a portion of endotoxin-induced dilation of cerebral arterioles.

Altered cerebrovascular responsiveness to N-methyl-D-aspartate after asphyxia in piglets

1993 ◽  
Vol 265 (1) ◽  
pp. H389-H394 ◽  
Author(s):  
D. W. Busija ◽  
M. Wei
Keyword(s):  
Topical Application ◽  
Intravital Microscopy ◽  
Cranial Window ◽  
Time Control ◽  
Pial Arterioles ◽  
Newborn Pigs ◽  
Arteriolar Diameter ◽  
Baseline Diameter ◽  
H 30

We examined effects of prior asphyxia and reventilation on pial arteriolar responses to arterial hypercapnia, topical application of forskolin, and topical application of N-methyl-D-aspartate (NMDA) in newborn pigs. Piglets were anesthetized and ventilated with a respirator. Pial arteriolar diameter was determined using a closed cranial window and intravital microscopy. After baseline diameter was determined, the respirator was turned off for 10 min. Then the respirator was turned on, and the piglet was ventilated for 4 h. At 1, 2, and 4 h after asphyxia, arteriolar diameter was determined during control conditions and during arterial hypercapnia (inspiration of 10% CO2 in air; n = 4), topical application of 2.4 x 10(-8) M forskolin (n = 6), and topical application of 10(-5) M NMDA (n = 6). At 1 h after asphyxia, arterial hypercapnia dilated pial arterioles by 39 +/- 3%, topical forskolin dilated pial arterioles by 24 +/- 3%, and NMDA dilated pial arterioles by 10 +/- 1%. For arterial hypercapnia and forskolin application, arteriolar responses were not different from 1 h at 2 and 4 h postasphyxia. In contrast, for NMDA, arteriolar responses were greater at 2 h (23 +/- 6%) and 4 h (30 +/- 5%) than at 1 h. In time-control animals, NMDA dilated arterioles by 20 +/- 5% at 1 h, by 24 +/- 8% at 2 h, and by 21 +/- 4% at 4 h (n = 5). Indomethacin administration (5 mg/kg iv) before asphyxia resulted in a 23 +/- 3% arteriolar dilation in response to NMDA at 1 h (n = 7).(ABSTRACT TRUNCATED AT 250 WORDS)

Lipoxins A4 and B4 dilate cerebral arterioles of newborn pigs

1989 ◽  
Vol 256 (2) ◽  
pp. H468-H471 ◽  
Author(s):  
D. W. Busija ◽  
W. Armstead ◽  
C. W. Leffler ◽  
R. Mirro
Keyword(s):  
Cerebrospinal Fluid ◽  
Topical Application ◽  
Cerebral Microcirculation ◽  
Lipoxin A4 ◽  
Vascular Responses ◽  
Neonatal Pigs ◽  
Cranial Window ◽  
Cerebral Arterioles ◽  
Newborn Pigs ◽  
Arteriolar Diameter

We determined the effects of lipoxins A4 and B4 on the cerebral microcirculation of neonatal pigs and whether vascular responses were modulated by prostanoids. Pial arteriolar diameters were determined using a closed cranial window and intravital microscopy. Before lipoxin A4 application, arteriolar diameter was 143 +/- 6 microns (means +/- SE). Topical application of lipoxin A4 increased the diameter to 160 +/- 7 microns at 0.1 ng/ml, 167 +/- 7 microns at 1 ng/ml, and 173 +/- 7 microns at 10 ng/ml (n = 9). Before application of lipoxin B4, arteriolar diameter was 146 +/- 7 microns. Topical application of lipoxin B4 increased the diameter to 165 +/- 7, 169 +/- 6, and 175 +/- 6 microns at 0.1, 1, and 10 ng/ml (n = 9), respectively. Intravenous injection of indomethacin (5 mg/kg) or vehicle did not affect these responses. Levels of prostaglandins E2 and F2 alpha in cerebrospinal fluid (measured by radioimmunoassay) did not increase in response to lipoxins. We conclude that lipoxins are dilator stimuli in the cerebral circulation and that prostanoids do not mediate these responses.

scholarly journals Calcium-Activated K+ Channels in Cerebral Arterioles in Piglets are Resistant to Ischemia

1997 ◽  
Vol 17 (11) ◽  
pp. 1152-1156 ◽  
Author(s):  
Ferenc Bari ◽  
Thomas M. Louis ◽  
David W. Busija
Keyword(s):  
Intravital Microscopy ◽  
Global Ischemia ◽  
Dibutyryl Camp ◽  
K Channels ◽  
Calcium Dependent ◽  
Cranial Window ◽  
Cerebral Arterioles ◽  
Pharmacologic Agents ◽  
Ischemic Stress

Our previous studies indicate that function of ATP-dependent K+ channels (KATP) in cerebral arterioles is suppressed after ischemia. In the current study, we examined pial arteriolar responses to forskolin, dibutyryl-cAMP, NS-1619, and methionine (met)-enkephalin, activators of calcium-dependent K+ channels (KCa) before and 1 hour after 10 minutes of total, global ischemia in anesthetized piglets. Arteriolar diameters were measured using a closed cranial window and intravital microscopy. All pharmacologic agents were given topically. Baseline diameters were approximately 100 μm, and diameters had returned to normal by 1 hour after ischemia. Forskolin dilated arterioles by 9 ± 3%, 18 ± 4%, and 31 ± 12% at 5 × 10−8, 5 × 10−7, and 10−6 mol/L, respectively ( P < 0.05, n = 10). In addition, dibutyryl-cAMP dilated arterioles by 8 ± 2% at 10−4 mol/L and 14 ± 2% at 3 × 10−4 mol/L ( P < 0.05, n = 6). Also, NS-1619 increased diameter of arterioles by 9 ± 2% at 10−7 mol/L and 17 ± 9% at 10−5 mol/L ( P < 0.05, n = 5). Finally, met-enkephalin dilated arterioles by 9 ± 2% at 10−8 mol/L and 16 ± 3% at 10−6 mol/L ( P < 0.05, n = 5). At 1 hour after ischemia, arteriolar dilator effects to forskolin, dibutyryl-cAMP and NS-1619, and met-enkephalin were intact. Thus, in contrast to KATP, KCa in cerebral arterioles are resistant to ischemic stress.

Influence of endothelin on piglet cerebral microcirculation

1989 ◽  
Vol 257 (2) ◽  
pp. H707-H710 ◽  
Author(s):  
W. M. Armstead ◽  
R. Mirro ◽  
C. W. Leffler ◽  
D. W. Busija
Keyword(s):  
Endothelial Cells ◽  
Cerebrospinal Fluid ◽  
Cerebral Microcirculation ◽  
Cranial Window ◽  
Pial Arterioles ◽  
Cerebral Arterioles ◽  
Newborn Pigs ◽  
Fluid Levels ◽  
Porcine Endothelial Cells ◽  
Arteriolar Diameter

The purpose of this study was to determine responses of the newborn pig cerebral microcirculation to endothelin. Pial arterioles were observed directly using a closed cranial window in chloralose-anesthetized piglets. Topical application of endothelin derived from porcine endothelial cells produced increases in pial arteriolar diameter at the lowest concentration (0.1 ng/ml) (159 +/- 6 to 180 +/- 8 microns) and concentration-dependent decreases in pial arteriolar diameter at higher concentrations (141 +/- 6, 127 +/- 5, and 110 +/- 4 microns at 1, 10, and 100 ng/ml, respectively). Indomethacin (5 mg/kg iv) and aspirin (50 mg/kg iv) blocked dilator responses to endothelin and attenuated constrictor responses. Endothelin produced concentration-dependent increases in cortical periarachnoid cerebrospinal fluid levels of 6-ketoprostaglandin (6-keto-PG) F1 alpha, PGE2, PGF2 alpha, and thromboxane B2. Thus endothelin can produce either dilation or constriction of cerebral arterioles in newborn pigs, depending on concentration. Furthermore, prostanoids appear to mediate vasodilation induced by the lowest concentration of endothelin and contribute to constriction induced by higher concentrations of endothelin.

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