scholarly journals Pharmacological Targeting of KCa Channels to Improve Endothelial Function in the Spontaneously Hypertensive Rat

2019 ◽  
Vol 20 (14) ◽  
pp. 3481 ◽  
Author(s):  
Rayan Khaddaj Mallat ◽  
Cini Mathew John ◽  
Ramesh C Mishra ◽  
Dylan J Kendrick ◽  
Andrew P Braun
Keyword(s):  
Endothelial Dysfunction ◽  
Spontaneously Hypertensive Rat ◽  
Receptor Expression ◽  
Mesenteric Arteries ◽  
Vascular Pathology ◽  
Systemic Hypertension ◽  
Bolus Administration ◽  
Spontaneously Hypertensive ◽  
Kca Channels

Systemic hypertension is a major risk factor for the development of cardiovascular disease and is often associated with endothelial dysfunction. KCa2.3 and KCa3.1 channels are expressed in the vascular endothelium and contribute to stimulus-evoked vasodilation. We hypothesized that acute treatment with SKA-31, a selective activator of KCa2.x and KCa3.1 channels, would improve endothelium-dependent vasodilation and transiently lower mean arterial pressure (MAP) in male, spontaneously hypertensive rats (SHRs). Isolated vascular preparations exhibited impaired vasodilation in response to bradykinin (i.e., endothelial dysfunction) compared with Wistar controls, which was associated with decreased bradykinin receptor expression in mesenteric arteries. In contrast, similar levels of endothelial KCa channel expression were observed, and SKA-31 evoked vasodilation was comparable in vascular preparations from both strains. Addition of a low concentration of SKA-31 (i.e., 0.2–0.3 μM) failed to augment bradykinin-induced vasodilation in arteries from SHRs. However, responses to acetylcholine were enhanced. Surprisingly, acute bolus administration of SKA-31 in vivo (30 mg/kg, i.p. injection) modestly elevated MAP compared with vehicle injection. In summary, pharmacological targeting of endothelial KCa channels in SHRs did not readily reverse endothelial dysfunction in situ, or lower MAP in vivo. SHRs thus appear to be less responsive to endothelial KCa channel activators, which may be related to their vascular pathology.

Mesenteric arteries from stroke-prone spontaneously hypertensive rats exhibit an increase in nitric-oxide-dependent vasorelaxation

2018 ◽  
Vol 96 (8) ◽  
pp. 719-727 ◽  
Author(s):  
Brandi M. Wynne ◽  
Hicham Labazi ◽  
Victor V. Lima ◽  
Fernando S. Carneiro ◽  
R. Clinton Webb ◽  
...  
Keyword(s):  
Nitric Oxide ◽  
Endothelial Dysfunction ◽  
Vascular Reactivity ◽  
Spontaneously Hypertensive Rat ◽  
No Synthase ◽  
Mesenteric Arteries ◽  
Maximum Effect ◽  
No Production ◽  
Primary Role ◽  
Spontaneously Hypertensive

The endothelium is crucial for the maintenance of vascular tone by releasing several vasoactive substances, including nitric oxide (NO). Systemic mean arterial pressure is primarily regulated by the resistance vasculature, which has been shown to exhibit increased vascular reactivity, and decreased vasorelaxation during hypertension. Here, we aimed to determine the mechanism for mesenteric artery vasorelaxation of the stroke-prone spontaneously hypertensive rat (SHRSP). We hypothesized that endothelial NO synthase (eNOS) is upregulated in SHRSP vessels, increasing NO production to compensate for the endothelial dysfunction. Concentration–response curves to acetylcholine (ACh) were performed in second-order mesenteric arteries; we observed decreased relaxation responses to ACh (maximum effect elicited by the agonist) as compared with Wistar-Kyoto (WKY) controls. Vessels from SHRSP incubated with Nω-nitro-l-arginine methyl ester and (or) indomethacin exhibited decreased ACh-mediated relaxation, suggesting a primary role for NO-dependent relaxation. Vessels from SHRSP exhibited a significantly decreased relaxation response with inducible NO synthase (iNOS) inhibition, as compared with WKY vessels. Western blot analysis showed increased total phosphorylated NF-κB, and phosphorylated and total eNOS in SHRSP vessels. Overall, these data suggest a compensatory role for NO by increased eNOS activation. Moreover, we believe that iNOS, although increasing NO bioavailability to compensate for decreased relaxation, leads to a cycle of further endothelial dysfunction in SHRSP mesenteric arteries.

Role of adenosine in noradrenergic neurotransmission in spontaneously hypertensive rats

1987 ◽  
Vol 253 (4) ◽  
pp. H909-H918 ◽  
Author(s):  
E. K. Jackson
Keyword(s):  
Plasma Levels ◽  
Spontaneously Hypertensive Rat ◽  
Base Line ◽  
Inhibitory Effects ◽  
Spontaneously Hypertensive ◽  
Vascular Responses ◽  
Rat Mesentery ◽  
Wistar Kyoto

The purpose of this study was to compare the in vivo role of adenosine as a modulator of noradrenergic neurotransmission in the spontaneously hypertensive rat (SHR) and Wistar-Kyoto control rat (WKY). In the in situ blood-perfused rat mesentery, vascular responses to periarterial (sympathetic) nerve stimulation (PNS) and to exogenous norepinephrine (NE) were enhanced in SHR compared with WKY. In both SHR and WKY, vascular responses to PNS were more sensitive to inhibition by adenosine than were responses to NE. At matched base-line vascular responses, compared with WKY, SHR were less sensitive to the inhibitory effects of adenosine on vascular responses to PNS, but SHR and WKY were equally sensitive with respect to adenosine-induced inhibition of responses to NE. Antagonism of adenosine receptors with 1,3-dipropyl-8-p-sulfophenylxanthine shifted the dose-response curve to exogenous adenosine sixfold to the right yet did not influence vascular responses to PNS or NE in either SHR or WKY. Furthermore, PNS did not alter either arterial or mesenteric venous plasma levels of adenosine in SHR or WKY, and plasma levels of adenosine in both strains were always lower than the calculated threshold level required to attenuate neurotransmission. It is concluded that in vivo 1) exogenous adenosine interferes with noradrenergic neurotransmission in both SHR and WKY; 2) SHR are less sensitive to the inhibitory effects of exogenous adenosine on noradrenergic neurotransmission than are WKY; 3) endogenous adenosine does not play a role in modulating neurotransmission in either strain under the conditions of this study; and 4) enhanced noradrenergic neurotransmission in the SHR is not due to defective modulation of neurotransmission by adenosine.

Hypoxic moderation of systemic hypertension in the spontaneously hypertensive rat

1987 ◽  
Vol 252 (3) ◽  
pp. R554-R561 ◽  
Author(s):  
W. N. Henley ◽  
A. Tucker
Keyword(s):  
Blood Pressure ◽  
Spontaneously Hypertensive Rat ◽  
Metabolic Adaptation ◽  
Systemic Hypertension ◽  
Thyroid Status ◽  
Blood Pressure Elevation ◽  
Spontaneously Hypertensive ◽  
Moderate Hypobaric Hypoxia ◽  
Hypertensive Rat ◽  
Wistar Kyoto

The mechanism by which chronic, moderate, hypobaric hypoxia attenuates systemic systolic blood pressure (SBP) in the spontaneously hypertensive rat (SHR) was investigated in a three-part study. In experiment 1, 10 wk of hypoxia (3,658 m altitude) commencing in 7-wk-old rats was partially effective in preventing the rise in SBP [hypoxic SHR (SHR-H) 154 mmHg vs. normoxic SHR (SHR-N) 180 mmHg; P less than 0.01]. When hypoxia was initiated in 5-wk-old SHR (experiments 2 and 3), protection against hypertension was nearly complete (experiment 2: SHR-H 122 mmHg vs. SHR-N 175 mmHg; P less than 0.001; experiment 3: 135 vs. 152 mmHg, respectively; P less than 0.05). Elevations in O2 consumption (VO2) and rectal temperature (Tre) in SHR vs. normotensive [Wistar-Kyoto (WKY)] rats provided evidence that the SHR is a hypermetabolic animal. Thyroid hormonal indices suggested that SHR changed from a low to high thyroid status at a time that rapid blood pressure elevation occurred; however, hypoxia did not influence thyroid status. Acute, significant decrements in VO2 and Tre in SHR-H (experiments 2 and 3) accompanied the attenuation of SBP by hypoxia, whereas large decrements in VO2 and SBP did not occur in hypoxic WKY. Timely administration of moderate hypoxia protects against the development of hypertension in the SHR. This protection may relate to a metabolic adaptation made by the hypoxic SHR.

Voiding behavior in awake unrestrained untethered spontaneously hypertensive and Wistar control rats

2021 ◽  
Author(s):  
Christopher L Langdale ◽  
Danielle J Degoski ◽  
Philip H Milliken ◽  
Warren M. Grill
Keyword(s):  
Body Weight ◽  
Water Consumption ◽  
Genetic Model ◽  
Spontaneously Hypertensive Rat ◽  
Infusion Pump ◽  
Bladder Capacity ◽  
In Vivo Studies ◽  
Spontaneously Hypertensive ◽  
Voided Volume

The spontaneously hypertensive rat (SHR), a genetic model of high blood pressure, has also been studied as a potential model of overactive bladder (OAB). In vivo studies confirmed the presence of surrogate markers of OAB, including detrusor overactivity (DO), increased urinary frequency, decreased bladder capacity and voided volume, and afferent hypersensitivity to bladder irritation. However, these observations were during awake cystometry (CMG) using implanted bladder catheters tethered to an infusion pump and artificially filled. We conducted studies in awake unrestrained untethered age-matched female SHR and Wistar rats to quantify naïve consumption and voiding behavior and the effect of capsaicin desensitization on consumption and voiding behavior. Food and water consumption, body weight, voiding frequency (VF), and voided volume (VV) were recorded. Rats were placed in metabolism cages for 24 h, up to twice a week, from 17 to 37 weeks of age. In SHRs, body weight, food, and water consumption were decreased compared to Wistars. However, after normalizing for body weight, only water consumption was reduced. Wistars exhibited a diurnal pattern of voiding behavior. Compared to Wistars, SHRs showed smaller VV and lacked a diurnal voiding pattern such that VV was similar during both light cycles. No difference in VF was observed after normalizing for water consumption. We observed no change in SHR voiding behavior following capsaicin desensitization, which was in contrast to a prior awake in vivo cystometry study describing increased VV and micturition interval in SHRs, and suggests that C-fiber activity may not contribute to bladder hypersensitivity in SHRs.

Nerve Growth Factor Enhances Calcitonin Gene-Related Peptide Expression in the Spontaneously Hypertensive Rat

Hypertension ◽  
2000 ◽  
Vol 36 (suppl_1) ◽  
pp. 701-701
Author(s):  
M Huawei Zhao ◽  
M Scott C Supowit ◽  
M Donald J DiPette
Keyword(s):  
Spontaneously Hypertensive Rat ◽  
Day Treatment ◽  
Fold Increase ◽  
Spontaneously Hypertensive ◽  
Treatment Groups ◽  
Continuous Map ◽  
Potent Vasodilator ◽  
Peptide Expression ◽  
Cgrp Receptor Antagonist

P45 We previously reported that there is a marked decrease in neuronal (dorsal root ganglia [DRG] sensory neurons) CGRP expression in the SHR compared to WKY controls. This reduction in such a potent vasodilator could contribute to the elevated BP. We hypothesize that administration of NGF, a potent in vivo stimulator of CGRP expression, to SHR would decrease the BP. NGF (10 nM/kg/day, i.p.) was given to 12 week SHR (n=8-11/group) once a day for 1, 3, and 7 days. Control SHR received vehicle only. All rats were instrumented for CGRP receptor antagonist (CGRP 8-37 ) administration (i.v.) and continuous MAP (arterial) recording and were studied in a concious and unrestrained state. Both the 1 and 3 day NGF treatments lowered the MAP (147±5 and 147±3 mmHg; respectively, p<0.05) compared to the controls (166±3 mmHg). However, by day 7 the MAP had returned to control levels (169±5 mmHg). To determine whether CGRP was involved in the BP lowering response to NGF, saline or CGRP 8-37 (bolus dose of 200 μg) were administered i.v. to all rats. Saline was without effect in any of the groups studied. In contrast, CGRP 8-37 administration produced a significant increase in MAP in both the 1 (13±1 mmHg) and 3 (10±1 mmHg) day NGF treatment groups. Surprisingly, in the 7 day treatment group, CGRP 8-37 also increased the MAP (13±2 mmHg) despite the baseline BP being back up to control levels. Quantification of CGRP mRNA and peptide levels in DRG revealed a significant (p<0.05) 1.5-fold increase on days 1 and 3 and a 1.75-fold increase on day 7. These data demonstrate that NGF treatment of SHR can significantly increase neuronal CGRP expression. At days 1 and 3, NGF produces a marked depressor response that is primarily due to CGRP as evidenced by the pressor effect of CGRP 8-37 . In the day 7 group, CGRP also plays a counterregulatory role even though the MAP has returned to control levels. This may result from an NGF-mediated upregulation of a pressor system that counteracts the hypotensive actions of CGRP. These results, therefore, suggest that the decreased production of CGRP in the SHR could contribute to the elevated BP observed in this hypertensive model.

Pathogenesis of systemic hypertension and glomerular injury in the spontaneously hypertensive rat

1987 ◽  
Vol 60 (17) ◽  
pp. 47-52 ◽  
Author(s):  
Manuel Martinez-Maldonado ◽  
Carmen Rodríguez-Sargent ◽  
JoséL. Cangiano ◽  
Lance D. Dworkin
Keyword(s):  
Spontaneously Hypertensive Rat ◽  
Systemic Hypertension ◽  
Glomerular Injury ◽  
Spontaneously Hypertensive ◽  
Hypertensive Rat

CYP4A1 antisense oligonucleotide reduces mesenteric vascular reactivity and blood pressure in SHR

2001 ◽  
Vol 280 (1) ◽  
pp. R255-R261 ◽  
Author(s):  
Mong-Heng Wang ◽  
Fan Zhang ◽  
Jackleen Marji ◽  
Barbara A. Zand ◽  
Alberto Nasjletti ◽  
...  
Keyword(s):  
Blood Pressure ◽  
Arachidonic Acid ◽  
Antisense Oligonucleotide ◽  
Vascular Reactivity ◽  
Spontaneously Hypertensive Rat ◽  
Mesenteric Arteries ◽  
Arachidonic Acid Metabolite ◽  
Spontaneously Hypertensive ◽  
Arterial Blood ◽  
Renal Tubular

The cytochrome P-450 4A (CYP4A)-derived arachidonic acid metabolite 20-hydroxyeicosatetraenoic acid (20-HETE) affects renal tubular and vascular functions and has been implicated in the control of arterial pressure. We examined the effect of antisense oligonucleotide (ODN) to CYP4A1, the low K m arachidonic acid ω-hydroxylating isoform, on vascular 20-HETE synthesis, vascular reactivity, and blood pressure in the spontaneously hypertensive rat (SHR). Administration of CYP4A1 antisense ODN decreased mean arterial blood pressure from 137 ± 3 to 121 ± 4 mmHg ( P < 0.05) after 5 days of treatment, whereas treatment with scrambled antisense ODN had no effect. Treatment with CYP4A1 antisense ODN reduced the level of CYP4A-immunoreactive proteins along with 20-HETE synthesis in mesenteric arterial vessels. Mesenteric arteries from rats treated with antisense ODN exhibited decreased sensitivity to the constrictor action of phenylephrine (EC50 0.69 ± 0.17 vs. 1.77 ± 0.40 μM). Likewise, mesenteric arterioles from antisense ODN-treated rats revealed attenuation of myogenic constrictor responses to increases of transmural pressure. The decreased vascular reactivity and myogenic responses were reversible with the addition of 20-HETE. These data suggest that CYP4A1-derived 20-HETE facilitates myogenic constrictor responses in the mesenteric microcirculation and contributes to pressor mechanisms in SHR.

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