R. Clinton Webb

University of South Carolina

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David F. Bohr

University of Michigan–Ann Arbor

Rita C. Tostes

Universidade de São Paulo

Camilla F. Wenceslau

University of South Carolina

Fernanda Priviero

University of South Carolina

Stephanie W. Watts

Michigan State University

Fernanda R. Giachini

Universidade Federal de Mato Grosso

Cameron G. McCarthy

University of South Carolina

Douglas G. Johns

Merck & Co., Inc., Rahway, NJ, USA (United States)

Rômulo Leite

Universidade Federal de Ouro Preto

Fred S. Lamb

Vanderbilt University Medical Center

Cooperative Institutions

University of Michigan–Ann Arbor

125

Augusta University

108

Augusta University Health

University of South Carolina

Universidade de São Paulo

Georgia Regents Medical Center

Michigan State University

University of Virginia

National Institutes of Health

University of Iowa

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Effect of felodipine on blood pressure and vascular reactivity in stroke-prone spontaneously hypertensive rats

Journal of Hypertension (1989)

Cathy A. Bruner R. Clinton Webb

Isolated tail arteries from stroke-prone spontaneously hypertensive rats (SHRSP), but not from normotensive Wistar-Kyoto rats (WKY), exhibit oscillatory contractions in response to norepinephrine. Previous studies indicate that the mechanism for these oscillations involves altered membrane calcium and/or potassium handling, and that this vascular change is a genetic defect associated with hypertension in SHRSP. The purpose of this experiment was to determine whether treatment of SHRSP with the calcium entry blocker felodipine would alter oscillatory activity. Adult SHRSP and WKY rats were treated orally with felodipine for 8 weeks. Felodipine treatment produced a significant decrease in blood pressure in SHRSP (control SHRSP: 240 ± 7 mmHg, n=6; felodipine-treated SHRSP: 164 ± 8 mmHg, n=5, P < 0.05; tail-cuff method). Helically-cut tail artery strips from all rats were mounted in tissue baths for isometric force recording and exposed to norepinephrine (6 x 10-9 to 6 x 10-6mol/l) for 20min at each concentration. Oscillatory activity was defined as the sum of the magnitudes of all phasic contractions occurring during the final 10min of norepinephrine incubation. Oscillatory activity was markedly reduced in tail arteries from felodipine-treated SHRSP when compared with control SHRSP. Felodipine also inhibited oscillatory activity when added directly to the tissue bath. It seems, therefore, that felodipine may lower blood pressure in SHRSP, at least in part, by correcting the genetic defect responsible for oscillatory activity

Felodipine

Stroke

10.1097/00004872-198901000-00005

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Citations (7)

Abstract 027: Chronic Unpredictable Stress Affects Mitochondrial Function In The Hypothalamic-Pituitary-Adrenal Axis And Impairs Vascular Reactivity In Male And Female Mice

Hypertension (2023)

Rinaldo Rodrigues dos Passos Fernanda Priviero Raiana dos Anjos Moraes Olufunke Arishe Stephanie Wilczynski

Chronic stress is associated with hypertension but the underlying mechanisms linking the interplay between the changes in the hypothalamic-pituitary-adrenal axis and vascular dysfunction remain unclear. We hypothesize that chronic unpredictable stress (CUS) induces mitochondrial dysfunction in the HPA axis and in the vasculature, associated with GasderminD pore formation in the mitochondrial membrane. Adult male and female C57Bl6/J mice were exposed to 28 consecutive days of CUS or handling (CTL). Anxiety-like behavior, coping behavior, and systolic blood pressure (SBP) were assessed. Mitochondrial function was assessed using high-resolution respirometry in the hypothalamus, amygdala, and adrenal tissues. The vascular reactivity of mesenteric resistance arteries (MRA), pudendal arteries (PA), and aorta were assessed in response to phenylephrine or acetylcholine. GasderminD protein expression was measured in the MRA. Data are presented as mean ± S.E.M and significance was set at p<0.05. In both sexes, CUS increased SBP by 12.1±4.9%. CUS decreased body weight gain by 53% (p=0.04) and increased anxiety-like behavior (p=0.01) in males (vs CTL) but did not affect females. CUS decreased latency to immobility in the forced swim test by 46% (p=0.0001) in both sexes. Sex-dependent decreases in mitochondrial respiration were observed as follows: in the amygdala of males (20%, p=0.05) and the hypothalamus (20%, p=0.004) and adrenal glands (17%, p=0.06) of females. In the vasculature, CUS led to endothelial dysfunction observed by reduced potency of ACh in the MRA (pEC 50 CUS 6.17±0.09 vs CTL 6.81±0.11; p=0.003) and PA (pEC 50 CUS 6.31 ±0.07 vs CTL 6.65±0.09; p=0.008) of male mice, as well as in the MRA of females (pEC 50 CUS 5.94±0.30 vs CTL 6.98±0.15; p=0.041). Contractile responses to PE were significantly reduced in the aorta of CUS males only (E MAX CTL: 4.70±0.48 mN vs CUS 3.01± 0.23 mN; p=0.007). The expression of gasderminD was increased in the MRA of female mice only. CUS increased SBP in males and females, induced sex-specific changes in the mitochondrial function in key areas of the brain, and caused vascular dysfunction, suggesting that behavioral, brain, and vascular adaptations to CUS are sex-dependent.

Mesenteric arteries

Hypothalamic–pituitary–adrenal axis

10.1161/hyp.80.suppl_1.027

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Insulin-like growth factor inhibits vascular contraction to 5-hydroxytryptamine

General Pharmacology The Vascular System (2000)

Alessandra Melis Stephanie W. Watts Jennifer A. Florian Susan A. Klarr R. Clinton Webb

Sodium orthovanadate

10.1016/s0306-3623(00)00055-0

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Citations (2)

Lowering of Activator Calcium Concentration in the Relaxation of Vascular Smooth Muscle1

S. Karger AG eBooks (2015)

David F. Bohr R. Clinton Webb

10.1159/000401668

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Citations (11)

Decreased sensitivity to vasoconstrictors in aortic rings after acute exposure to nitric oxide

AJP Heart and Circulatory Physiology (1996)

Nancy L. Kanagy John R. Charpie J. Dananberg R. Clinton Webb

Nitric oxide (NO) has been postulated as a regulator of vascular reactivity, and the current study tested the hypothesis that NO-induced decreased sensitivity to vasoconstrictors persists following removal of NO. Endothelium-denuded segments of rat aorta were incubated 2-4 h at 37 degrees C with the NO donor S-nitroso-N-acetylpenicillamine (SNAP). Incubation produced rightward shifts in concentration response curves for phenylephrine [i.e., half-maximum effective concentration (EC50; in microM): control = 0.016, NO = 0.14], aluminum fluoride (i.e., EC50 in mM: control = 1.66, NO = 2.29), and KCl (i.e., EC50 in mM: control = 5.9, NO = 23.9). Similar shifts were seen for two other NO donors. The SNAP-induced shift was not attenuated by a guanylyl cyclase inhibitor, LY-83583 (10 microM) and was not mimicked by 8-bromoguanosine 3',5'-cyclic monophosphate (100 microM). It was attenuated by 1,4-naphthoquinone (50 microM), an inhibitor of endogenous mono-ADP ribosyltransferases. NO incubation increased cGMP content (4.6 +/- 0.8 vs. 1.5 +/- 0.15 pmol/mg protein), an increase unaffected by 1,4-naphthoquinone (3.3 +/- 1.0 pmol/mg protein) but prevented by LY-83583 (1.6 +/- 0.36 pmol/mg protein). ADP ribosylation of three proteins was observed in membranes from HEK 293 cells: 88,66, and 38 kDa. ADP ribosylation of the 38-kDa protein was stimulated in a concentration-dependent manner by NO but was not decreased by 1,4-naphthoquinone. In conclusion, NO produces a long-lasting inhibition of vascular contractility by both a cGMP-dependent and -independent mechanism. Based on the observations of 1,4-naphthoquinone, we conclude that the cGMP-independent mechanism is not stimulation of endogenous ADP ribosylation but some other covalent modification in the pathway that mediates contraction.

Snap

Phenylephrine

Soluble guanylyl cyclase

EC50

Phosphodiesterase inhibitor

10.1152/ajpheart.1996.271.1.h253

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Citations (27)

Chronic Toll‐like receptor 9 activation mediates heightened vascular contractility via attenuated NOS activity in isolated aortic segments

The FASEB Journal (2013)

Cameron G. McCarthy Styliani Goulopoulou Camilla F. Wenceslau Takayuki Matsumoto R. Clinton Webb

Toll‐like receptor 9 (TLR 9) is a pattern recognition receptor of the innate immune system. Activation of TLR 9 in immune cells leads to the release of pro‐inflammatory cytokines. TLR 9 is also expressed in the vasculature; however, its role in vascular function remains to be clarified. We hypothesized that chronic administration (three i.p. injections within five days) of TLR 9 agonist [synthetic oligonucleotide (ODN 2395); 0.1 μg/i.p.], would augment aortic contractility in female, 13–15 weeks old, Sprague Dawley rats. Concentration response curves were performed ex vivo using the myograph to norepinephrine (NE; 10 −9 –3×10 −5 M), in the presence of either nitric oxide synthase (NOS) inhibitor L‐NNA (10 −4 M; 30 min), or cyclooxygenase inhibitor indomethacin (10 −5 M; 30 min). ODN 2395 amplified the contractile response to NE [E max (% max KCl), ODN 2395: 108±4 vs. Veh: 94±5]. This difference was normalized in the presence of L‐NNA [E max (% max KCl), ODN 2395: 141±6 vs. Veh: 134±10], but not indomethacin [E max (% max KCl), ODN 2395: 105±8 vs. Veh: 89±8]. These data illustrate that NOS activity was decreased in the ODN 2395 treated animals, as NOS inhibition normalized the potentiated contractile response to ODN 2395. Therefore, attenuation of NOS activity by TLR 9 activation could subsequently contribute to the development and progression of vascular diseases such as hypertension. Research Support: Society for Women's Health Research (SWHR)

Contractility

Myograph

10.1096/fasebj.27.1_supplement.878.6

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Citations (1)

Increased Responsiveness and Decreased Expression of G Proteins in Deoxycorticosterone Hypertension

Hypertension (1996)

Nancy L. Kanagy R. Clinton Webb

Abstract Deoxycorticosterone-salt (DOCA-salt) hypertension is characterized by elevated vasoconstriction to agonists that stimulate G protein–mediated activation of phospholipase C. However, the mechanisms responsible for the augmented responsiveness are unknown. This study tested the hypothesis that this augmented vascular responsiveness is due to elevated content of Gα q , the G protein α-subunit that activates phospholipase C. Thoracic aortae from DOCA-salt hypertensive rats (systolic blood pressure 183±7 mm Hg) and normotensive controls (systolic blood pressure 115±2 mm Hg) were homogenized and G protein content determined. Western analysis revealed that Gα i content was decreased in DOCA compared with control rats (1364±196 versus 2343±188 densitometry units, P ≤.05) with no differences observed for Gα q or Gα s . In addition, contractile responses in denuded femoral artery strips revealed a significant decrease in EC 50 values in DOCA arteries to all of the agonists examined: aluminum fluoride (DOCA=1.42, control=2.34 mmol/L), mastoparan (DOCA=0.51, control=35 μmol/L), phenylephrine (DOCA=0.08, control=0.53 μmol/L), and serotonin (DOCA=0.014, control=0.04 μmol/L, EC 20 values). Finally, arteries from DOCA rats contracted with aluminum fluoride had increased sensitivity to G protein antagonists but not to a phospholipase C inhibitor. The enhanced contractile responsiveness in the DOCA arteries may be mediated in part through decreased Gα i levels. However, it is not caused by increased concentrations of Gα q in the cell membrane or by increased phospholipase C sensitivity, and the increased constrictor response to G protein stimulators of phospholipase C appears to depend primarily on increased G protein sensitivity.

Phenylephrine

Phentolamine

10.1161/01.hyp.27.3.740

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Citations (20)

Microtubule disruption potentiates receptor-mediated vasoconstriction

The FASEB Journal (1998)

Alessandra Melis Douglas G. Johns J. L. Park R. Clinton Webb

Source

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Increased incidence and severity of polyarteritis nodosa in reproductive senescent female spontaneously hypertensive stroke-prone rats (SHRSP)