Attenuated defense response and low basal blood pressure in orexin knockout mice

2003 ◽  
Vol 285 (3) ◽  
pp. R581-R593 ◽  
Author(s):  
Yuji Kayaba ◽  
Akira Nakamura ◽  
Yoshitoshi Kasuya ◽  
Takashi Ohuchi ◽  
Masashi Yanagisawa ◽  
...  
Keyword(s):  
Blood Pressure ◽  
Knockout Mice ◽  
Defense Response ◽  
Adrenergic Blockade ◽  
Wild Type ◽  
Gaba A ◽  
Arterial Blood ◽  
Basal Blood Pressure ◽  
The Difference ◽  
Fight Or Flight Response

The perifornical area of the hypothalamus has been known as the center for the defense response, or “fight or flight” response, which is characterized by a concomitant rise in arterial blood pressure (AP), heart rate (HR), and respiratory frequency (Rf). We examined whether orexin, a recently identified hypothalamic neuropeptide, contributes to the defense response and basal cardiovascular regulation using orexin knockout mice. Microinjection of a GABA-A receptor antagonist, bicuculline methiodide (0.1-1 mM in 20 nl), to the perifornical area in urethane-anesthetized wild-type mice elicited dose-dependent increases in AP, HR, and Rf. Although similar changes were observed in orexin knockout mice, intensities were smaller and duration was shorter than those in wild-type mice. Moreover, in an awake and freely moving condition, telemeter-indwelling orexin knockout mice showed diminished cardiovascular and behavioral responses to emotional stress in the resident-intruder test. We also found that basal AP in orexin knockout mice was significantly lower in both anesthetized (117 ± 8 mmHg in wild type and 92 ± 3 in knockout) and conscious (125 ± 6 mmHg in wild type and 109 ± 2 in knockout) conditions. α-Adrenergic blockade with prazosin or ganglion blockade with hexamethonium canceled the difference in basal AP. HR and cardiac contractile parameters by echocardiography did not differ between the two strains of mice. These results indicate lower sympathetic vasoconstrictor tone in knockout mice. The present study suggests that orexin-containing neurons in the perifornical area play a role as one of the efferent pathways of defense response and also operate as a regulator of AP at basal condition by activating sympathetic outflow.

scholarly journals Larger Anastomoses in Angiotensinogen-Knockout Mice Attenuate Early Metabolic Disturbances after Middle Cerebral Artery Occlusion

1999 ◽  
Vol 19 (10) ◽  
pp. 1092-1098 ◽  
Author(s):  
Keiichiro Maeda ◽  
Ryuji Hata ◽  
Michael Bader ◽  
Thomas Walther ◽  
Konstantin-Alexander Hossmann
Keyword(s):  
Blood Pressure ◽  
Middle Cerebral Artery ◽  
Arterial Blood Pressure ◽  
Cerebral Artery ◽  
Mean Arterial Blood Pressure ◽  
Knockout Mice ◽  
Therapeutic Window ◽  
Wild Type ◽  
Arterial Blood ◽  
Mca Occlusion

Abnormalities in the homeostasis of the renin-angiotensin system have been implicated in the pathogenesis of vascular disorders, including stroke. The authors investigated whether angiotensinogen (AGN) knockout mice exhibit differences in brain susceptibility to focal ischemia, and whether such differences can be related to special features of the collateral circulation. Wild-type and AGN-knockout mice were submitted to permanent suture occlusion of the middle cerebral artery (MCA). The collateral vascular system was visualized by systemic latex infusion, and the ischemic lesions were identified by cresyl-violet staining. The core and penumbra of the evolving infarct were differentiated by bioluminescence and autoradiographic imaging of A TP and protein biosynthesis, respectively. In wild-type mice, mean arterial blood pressure was 95.0 ± 8.6 mm Hg, and the diameter of fully relaxed anastomotic vessels between the peripheral branches of the anterior and middle cerebral arteries 26.6 ± 4.0 μm In AGN knockouts, mean arterial blood pressure was significantly lower, 71.5 ± 8.5 mm Hg ( P <,01), and the anastomotic vessels were significantly larger, 29.4 ± 4.6 μm ( P < .01). One hour after MCA occlusion, AGN-knockout mice exhibited a smaller ischemic core (defined as the region of ATP depletion) but a larger penumbra (the area of disturbed protein synthesis with preserved ATP). At 24 hours after MCA occlusion, this difference disappeared, and histologically visible lesions were of similar size in both strains. The observations show that in AGN-knockout mice the more efficient collateral blood supply delays ischemic injury despite the lower blood pressure. Pharmacologic suppression of angiotensin formation may prolong the therapeutic window for treatment of infarcts.

Increased central AT1-receptor activation, not systemic vasopressin, sustains hypertension in ANP knockout mice

2000 ◽  
Vol 278 (6) ◽  
pp. R1441-R1445 ◽  
Author(s):  
Uwe Ackermann ◽  
Newsha Azizi
Keyword(s):  
Blood Pressure ◽  
Angiotensin Ii ◽  
Receptor Antagonist ◽  
Knockout Mice ◽  
Blood Pressure Measurement ◽  
Receptor Activation ◽  
Wild Type ◽  
Vasopressin Release ◽  
Arterial Blood ◽  
Left Lateral Ventricle

We tested the hypothesis that hypertension in atrial natriuretic peptide (ANP) knockout mice is caused in part by disinhibition of angiotensin II-mediated vasopressin release. Inactin-anesthetized F2 homozygous ANP gene-disrupted mice (−/−) and wild-type (+/+) littermates were surgically prepared for carotid arterial blood pressure measurement (ABP) and background intravenous injection of physiological saline or vasopressin V1-receptor antagonist (Manning compound, 10 ng/g body wt) and subsequent intracerebroventricular (left lateral ventricle) injection of saline (5 μl) or ANP (0.5 μg) or angiotensin II AT1-receptor antagonist losartan (10 μg). Only (−/−) showed significant decrease in ABP after intracerebroventricular ANP or losartan. Both showed significant hypotension after intravenous V1 antagonist, but there was no difference between their responses. We conclude that 1) vasopressin contributes equally to ABP maintenance in ANP-disrupted mice and wild-type controls; 2) permanently elevated ABP in ANP knockouts is associated with increased central nervous angiotensin II AT1-receptor activation; 3) disinhibition of central nervous angiotensin II AT1receptors in ANP-deficient animals does not lead to a significant increase in the importance of vasopressin as a mechanism for blood pressure maintenance.

scholarly journals Novel Role of GPR35 (G-Protein–Coupled Receptor 35) in the Regulation of Endothelial Cell Function and Blood Pressure

Hypertension ◽  
2021 ◽  
Author(s):  
Hainan Li ◽  
Huong Nguyen ◽  
Sai Pranathi Meda Venkata ◽  
Jia Yi Koh ◽  
Anjaneyulu Kowluru ◽  
...  
Keyword(s):  
Blood Pressure ◽  
Endothelial Cell ◽  
G Protein ◽  
Arterial Blood Pressure ◽  
Knockout Mice ◽  
Wild Type ◽  
G Protein Coupled Receptor ◽  
Arterial Blood ◽  
G Protein Coupled ◽  
Wild Type Control

GPR35 (G-protein–coupled receptor 35) is a poorly characterized receptor that has garnered increased interest as a therapeutic target through its implications in a range of inflammatory and cardiovascular diseases, but its biological functions stay largely unknown. The current study evaluated the effect of GPR35 on endothelial cell (EC) functions and hemodynamic homeostasis. In primary human aortic ECs, the expression of GPR35 was manipulated by transfections of adenovirus carrying either GPR35 cDNA or shRNA against GPR35, using adenovirus carrying β-gal as control. Mouse aortic ECs were isolated and cultured from GPR35 knockout and wild-type control mice. Our results indicated that genetic inhibition of GPR35 in human and mouse ECs significantly promoted cell proliferation, migration, and tube formation in vitro. The GCH1 (guanosine triphosphate cyclohydrolase I)-mediated biosynthesis of tetrahydrobiopterin was enhanced, reducing intracellular superoxide. Knocking down GCH1 or eNOS (endothelial nitric oxide synthase) significantly blunted the robust angiogenesis induced by GPR35 suppression. Male GPR35 knockout mice demonstrated reduced basal arterial blood pressure and an attenuated onset of hypertension in deoxycorticosterone acetate-salt induced hypertensive model compared with male GPR35 wild-type control mice in vivo, with concomitant improved endothelium-dependent vasodilation and decreased superoxide in isolated aortas. The difference in arterial blood pressure was absent between female GPR35 wild-type control and female GPR35 knockout mice. Our study provides novel insights into the roles of GPR35 in endothelial function and vascular tone modulation that critically contribute to the pathophysiology of blood pressure elevation. Antagonizing GPR35 activity might represent a potentially effective therapeutic approach to restore EC function and hemodynamic homeostasis.

Orexin neuron-mediated skeletal muscle vasodilation and shift of baroreflex during defense response in mice

2006 ◽  
Vol 290 (6) ◽  
pp. R1654-R1663 ◽  
Author(s):  
Wei Zhang ◽  
Takeshi Sakurai ◽  
Yasuichiro Fukuda ◽  
Tomoyuki Kuwaki
Keyword(s):  
Skeletal Muscle ◽  
Defense Response ◽  
Wild Type ◽  
Air Jet ◽  
Arterial Blood ◽  
Orexin Neuron ◽  
Efferent Pathways ◽  
Β Blocker ◽  
The Difference ◽  
Stimulation Of

We have previously shown that some features of the defense response, such as increases in arterial blood pressure (AP), heart rate (HR), and ventilation were attenuated in prepro-orexin knockout (ORX-KO) mice. Here, we examined whether the same was true in orexin neuron-ablated [orexin/ataxin-3 transgenic mice (ORX/ATX-Tg)] mice. In addition, we examined other features of the defense response: skeletal muscular vasodilation and shift of baroreceptor reflex. In both anesthetized and conscious conditions, basal AP in ORX/ATX-Tg mice was significantly lower by ∼20 mmHg than in wild-type (WT) controls, as was the case in ORX-KO mice. The difference in AP disappeared after treatment with an α-blocker but not with a β-blocker, indicating lower sympathetic vasoconstrictor outflow. Stimulation of the perifornical area (PFA) in urethane-anesthetized ORX/ATX-Tg mice elicited smaller and shorter-lasting increases in AP, HR, and ventilation, and skeletal muscle vasodilation than in WT controls. In addition, air jet stress-induced elevations of AP and HR were attenuated in conscious ORX/ATX-Tg mice. After pretreatment with a β-blocker, atenolol, stimulation of PFA suppressed phenylephrine (50 μg/kg iv)-induced bradycardia (ΔHR = −360 ± 29 beats/min without PFA stimulation vs. −166 ± 26 during stimulation) in WT. This demonstrated the resetting of the baroreflex. In ORX/ATX-Tg mice, however, no significant suppression was observed (−355 ± 16 without stimulation vs. −300 ± 30 during stimulation). The present study provided further support for our hypothesis that orexin-containing neurons in PFA play a role as a master switch to activate multiple efferent pathways of the defense response and also operate as a regulator of basal AP.

Enhancement of the Antihypertensive Effect of Hydrochlorothiazide in Dogs after Suppression of Renin Release by Beta-Adrenergic Blockade

1975 ◽  
Vol 48 (2) ◽  
pp. 147-151
Author(s):  
C. S. Sweet ◽  
M. Mandradjieff
Keyword(s):  
Blood Pressure ◽  
Plasma Renin Activity ◽  
Arterial Blood Pressure ◽  
Antihypertensive Effect ◽  
Plasma Renin ◽  
Renin Activity ◽  
Renin Release ◽  
Antihypertensive Activity ◽  
Adrenergic Blockade ◽  
Arterial Blood

1. Renal hypertensive dogs were treated with hydrochlorothiazide (8−2 μmol/kg or 33 μmol/kg daily for 7 days), or timolol (4.6 μmol/kg daily for 4 days), a potent β-adrenergic blocking agent, or combinations of these drugs). Changes in mean arterial blood pressure and plasma renin activity were measured over the treatment period. 2. Neither drug significantly lowered arterial blood pressure when administered alone. Plasma renin activity, which did not change during treatment with timolol, was substantially elevated during treatment with hydrochlorothiazide. 3. When timolol was administered concomitantly with hydrochlorothiazide, plasma renin activity was suppressed and blood pressure was significantly lowered. 4. These observations suggest that compensatory activation of the renin-angiotensin system limits the antihypertensive activity of hydrochlorothiazide in renal hypertensive dogs and suppression of diuretic-induced renin release by timolol unmasks the antihypertensive effect of the diuretic.

scholarly journals Salt sensitivity of blood pressure in NKCC1-deficient mice

2008 ◽  
Vol 295 (4) ◽  
pp. F1230-F1238 ◽  
Author(s):  
Soo Mi Kim ◽  
Christoph Eisner ◽  
Robert Faulhaber-Walter ◽  
Diane Mizel ◽  
Susan M. Wall ◽  
...  
Keyword(s):  
Blood Pressure ◽  
Heart Rate ◽  
Wheel Running ◽  
Plasma Renin ◽  
Pressure Change ◽  
Standard Diet ◽  
Wild Type ◽  
Vascular Effects ◽  
Arterial Blood ◽  
Deficient Mice

NKCC1 is a widely expressed isoform of the Na-2Cl-K cotransporter that mediates several direct and indirect vascular effects and regulates expression and release of renin. In this study, we used NKCC1-deficient (NKCC1−/−) and wild-type (WT) mice to assess day/night differences of blood pressure (BP), locomotor activity, and renin release and to study the effects of high (8%) or low (0.03%) dietary NaCl intake on BP, activity, and the renin/aldosterone system. On a standard diet, 24-h mean arterial blood pressure (MAP) and heart rate determined by radiotelemetry, and their day/night differences, were not different in NKCC1−/− and WT mice. Spontaneous and wheel-running activities in the active night phase were lower in NKCC1−/− than WT mice. In NKCC1−/− mice on a high-NaCl diet, MAP increased by 10 mmHg in the night without changes in heart rate. In contrast, there was no salt-dependent blood pressure change in WT mice. MAP reductions by hydralazine (1 mg/kg) or isoproterenol (10 μg/mouse) were significantly greater in NKCC1−/− than WT mice. Plasma renin (PRC; ng ANG I·ml−1·h−1) and aldosterone (aldo; pg/ml) concentrations were higher in NKCC1−/− than WT mice (PRC: 3,745 ± 377 vs. 1,245 ± 364; aldo: 763 ± 136 vs. 327 ± 98). Hyperreninism and hyperaldosteronism were found in NKCC1−/− mice during both day and night. High Na suppressed PRC and aldosterone in both NKCC1−/− and WT mice, whereas a low-Na diet increased PRC and aldosterone in WT but not NKCC1−/− mice. We conclude that 24-h MAP and MAP circadian rhythms do not differ between NKCC1−/− and WT mice on a standard diet, probably reflecting a balance between anti- and prohypertensive factors, but that blood pressure of NKCC1−/− mice is more sensitive to increases and decreases of Na intake.

Umbilical venous pressure and other cardiovascular responses of fetal lambs to epinephrine

1962 ◽  
Vol 203 (5) ◽  
pp. 955-960 ◽  
Author(s):  
S. R. M. Reynolds ◽  
John D. Mackie
Keyword(s):  
Blood Pressure ◽  
Umbilical Vein ◽  
Venous Pressure ◽  
Cardiovascular Responses ◽  
Ductus Venosus ◽  
Arterial Blood ◽  
Femoral Route ◽  
The Difference ◽  
Pregnant Ewe

Large fetuses in utero are more sensitive to infused epinephrine than smaller ones. The quality of response is the same. Increased arterial blood pressure and heart rate are associated with an increase in umbilical vein pressure. The large fetus is as sensitive as the pregnant ewe and the latter is more sensitive than the nonpregnant ewe. Single injections of epinephrine into umbilical or femoral veins have similar effects, except for the difference that the latent period is about twice as long when epinephrine is given by the femoral route as by the umbilical route. The sphincter of the ductus venosus is believed to constrict in response to epinephrine. It is shown to be adrenergically controlled. The import of the sphincter for maintenance of umbilical vein pressure is considered.

Changes in angiotensin type 1 receptor binding and angiotensin-induced pressor responses in the rostral ventrolateral medulla of angiotensinogen knockout mice

2010 ◽  
Vol 298 (2) ◽  
pp. R411-R418 ◽  
Author(s):  
Daian Chen ◽  
Lisa Hazelwood ◽  
Lesley L. Walker ◽  
Brian J. Oldfield ◽  
Michael J. McKinley ◽  
...  
Keyword(s):  
Blood Pressure ◽  
Receptor Binding ◽  
Knockout Mice ◽  
Pressor Response ◽  
Ventrolateral Medulla ◽  
Ang Ii ◽  
Wild Type ◽  
Intravenous Injections ◽  
Angiotensin Type

ANG II, the main circulating effector hormone of the renin-angiotensin system, is produced by enzymatic cleavage of angiotensinogen. The present study aimed to examine whether targeted deletion of the angiotensinogen gene ( Agt) altered brain ANG II receptor density or responsiveness to ANG II. In vitro autoradiography was used to examine the distribution and density of angiotensin type 1 (AT1) and type 2 receptors. In most brain regions, the distribution and density of angiotensin receptors were similar in brains of Agt knockout mice ( Agt −/− ) and wild-type mice. In Agt −/− mice, a small increase in AT1 receptor binding was observed in the rostral ventrolateral medulla (RVLM), a region that plays a critical role in blood pressure regulation. To examine whether Agt −/− mice showed altered responses to ANG II, blood pressure responses to intravenous injection (0.01–0.1 μg/kg) or RVLM microinjection (50 pmol in 50 nl) of ANG II were recorded in anesthetized Agt −/− and wild-type mice. Intravenous injections of phenylephrine (4 μg/kg and 2 μg/kg) were also made in both groups. The magnitude of the pressor response to intravenous injections of ANG II or phenylephrine was not different between Agt −/− and wild-type mice. Microinjection of ANG II into the RVLM induced a pressor response, which was significantly smaller in Agt −/− compared with wild-type mice (+10 ± 1 vs. +23 ± 4 mmHg, respectively, P = 0.004). Microinjection of glutamate into the RVLM (100 pmol in 10 nl) produced a robust pressor response, which was not different between Agt −/− and wild-type mice. A diminished response to ANG II microinjection in the RVLM of Agt −/− mice, despite an increased density of AT1 receptors suggests that signal transduction pathways may be altered in RVLM neurons of Agt −/− mice, resulting in attenuated cellular excitation.

scholarly journals Arterial Blood Pressure and Renal Sodium Excretion in Dopamine D3 Receptor Knockout Mice

2007 ◽  
Vol 30 (1) ◽  
pp. 93-101 ◽  
Author(s):  
Torsten STAUDACHER ◽  
Bärbel PECH ◽  
Michael TAPPE ◽  
Gerhard GROSS ◽  
Bernd MÜHLBAUER ◽  
...  
Keyword(s):  
Blood Pressure ◽  
Arterial Blood Pressure ◽  
Knockout Mice ◽  
Sodium Excretion ◽  
Dopamine D3 Receptor ◽  
D3 Receptor ◽  
Arterial Blood ◽  
Renal Sodium Excretion ◽  
Dopamine D3
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