scholarly journals Genetic basis of the impaired renal myogenic response in FHH rats

2013 ◽  
Vol 304 (5) ◽  
pp. F565-F577 ◽  
Author(s):  
Marilyn Burke ◽  
Malikarjuna Pabbidi ◽  
Fan Fan ◽  
Ying Ge ◽  
Ruisheng Liu ◽  
...  
Keyword(s):  
Renal Injury ◽  
Chromosome 1 ◽  
Brown Norway ◽  
Myogenic Response ◽  
Renal Vasculature ◽  
Congenic Strains ◽  
Channel Current ◽  
Protein Excretion ◽  
Afferent Arterioles ◽  
Renal Vascular

This study examined the effect of substitution of a 2.4-megabase pair (Mbp) region of Brown Norway (BN) rat chromosome 1 (RNO1) between 258.8 and 261.2 Mbp onto the genetic background of fawn-hooded hypertensive (FHH) rats on autoregulation of renal blood flow (RBF), myogenic response of renal afferent arterioles (AF-art), K+ channel activity in renal vascular smooth muscle cells (VSMCs), and development of proteinuria and renal injury. FHH rats exhibited poor autoregulation of RBF, while FHH.1BN congenic strains with the 2.4-Mbp BN region exhibited nearly perfect autoregulation of RBF. The diameter of AF-art from FHH rats increased in response to pressure but decreased in congenic strains containing the 2.4-Mbp BN region. Protein excretion and glomerular and interstitial damage were significantly higher in FHH rats than in congenic strains containing the 2.4-Mbp BN region. K+ channel current was fivefold greater in VSMCs from renal arterioles of FHH rats than cells obtained from congenic strains containing the 2.4-Mbp region. Sequence analysis of the known and predicted genes in the 2.4-Mbp region of FHH rats revealed amino acid-altering variants in the exons of three genes: Add3, Rbm20, and Soc-2. Quantitative PCR studies indicated that Mxi1 and Rbm20 were differentially expressed in the renal vasculature of FHH and FHH.1BN congenic strain F. These data indicate that transfer of this 2.4-Mbp region from BN to FHH rats restores the myogenic response of AF-art and autoregulation of RBF, decreases K+ current, and slows the progression of proteinuria and renal injury.

scholarly journals Temporal characterization of the development of renal injury in FHH rats and FHH.1BN congenic strains

2011 ◽  
Vol 300 (2) ◽  
pp. F330-F338 ◽  
Author(s):  
Jan Michael Williams ◽  
Marilyn Burke ◽  
Jozef Lazar ◽  
Howard J. Jacob ◽  
Richard J. Roman
Keyword(s):  
Renal Injury ◽  
Transforming Growth Factor ◽  
Renal Perfusion ◽  
Chromosome 1 ◽  
Brown Norway ◽  
Glomerular Permeability ◽  
Congenic Strains ◽  
Protein Excretion ◽  
And Control ◽  
Progression Of Renal Disease

The present study examined the effect of transfer of portions of chromosome 1 that includes (FHH.1BN AR+ strain) or excludes (control FHH.1BN AR− strain) a 4.3-Mb region from the Brown Norway (BN) rat that restores the autoregulation (AR) of renal blood flow (RBF) on the development of hypertension and renal injury in congenic strains of Fawn Hooded Hypertensive (FHH) rats. FHH and control AR− rats exhibited poor autoregulation of RBF, and glomerular capillary pressure (Pgc) rose by 19 ± 2 mmHg in FHH rats when renal perfusion pressure (RPP) was increased from 100 to 150 mmHg. In contrast, RBF was well autoregulated in the AR+ strain, and Pgc only increased by 3 ± 1 mmHg when RPP was increased over this range. Baseline mean arterial pressure (MAP) at 12 wk of age was similar in all strains and averaged 122 mmHg. MAP increased significantly in FHH rats and was significantly higher by 12 mmHg in 21-wk-old FHH rats than in the FHH.1BN congenic strains. Protein excretion rose from 5 ± 1 to 397 ± 29 mg/day in 6- vs. 21-wk-old FHH rats. In contrast, protein excretion only increased to 139 ± 21 mg/day in the control AR− strain, and it did not increase significantly in the AR+ strain. Glomerular permeability to albumin was similar in all strains at 6 wk of age. It increased significantly in 9-wk-old FHH and control AR− rats, but not in the AR+ strain. The levels of matrix metalloproteinase (MMP)-2 and transforming growth factor (TGF)-β2 protein were significantly higher in the renal cortex of 9-wk-old FHH rats compared with the levels seen in the AR+ strain. These data indicate that transfer of a 4.3-Mb region of BN chromosome 1 into the FHH genetic background improves autoregulation of RBF, normalizes Pgc, and slows the progression of renal disease.

Abstract 127: Identification of a Region of Rat Chromosome 1 That Impairs the Myogenic Response and Cerebral Blood Flow Autoregulation in Fawn Hooded Hypertensive Rats.

Hypertension ◽  
2012 ◽  
Vol 60 (suppl_1) ◽  
Author(s):  
Mallikarjuna R Pabbidi ◽  
Julio Juncos ◽  
Marija Renic ◽  
Hurtis J. Tullos ◽  
Jozeph Lazar ◽  
...  
Keyword(s):  
Blood Flow ◽  
Cerebral Blood Flow ◽  
Infarct Size ◽  
Congenic Strain ◽  
Bk Channel ◽  
Chromosome 1 ◽  
Brown Norway ◽  
Myogenic Response ◽  
Congenic Strains ◽  
Channel Current

This study examined the effect of transfer of a 2.4 Mbp region of Brown Norway (BN) rat Chr 1 into the Fawn Hooded Hypertensive (FHH) genetic background on autoregulation (AR) of cerebral blood flow (CBF) and the myogenic response of isolated middle cerebral arteries (MCA). Autoregulation of CBF measured by laser Doppler flowmetry was poor in FHH rats (AR index (AI), 0.8±0.1) and in FHH.1BN congenic strains which excluded the critical region (AR-: AI, 0.9± 0.1). In contrast, autoregulation of CBF was completely restored by transfer of the region of BN Chr 1 between 258.8 to 261.2 Mbp in AR+ FHH.1BN congenic strains (AI, 0.3 ± 0.1). The diameter of MCA of FHH rats and AR- congenic strains increased by ∼10% (140 ± 1 to 157± 2 μm), when transmural pressure was increased from 40 to 140 mmHg. In contrast, the diameter of the MCA in AR+ congenic strain fell from 127 ± 2 to 65 ± 1 μm. Whole-cell patch-clamp of cerebral VSM cells revealed a 4.3-fold increase in BK channel current densities at depolarized potentials in FHH versus AR+ rats (105 ± 2 versus 24 ± 4 pA/pF at +80mV). Using single channel analysis we found that the increase in BK channel current was largely due to a marked increase in the NPo of BK channel in FHH as compared to AR+ rats (0.9 ± 0.1 and 0.2 ± 0.1 at +80mV). To explore the significance of the impaired myogenic response, we compared changes in CBF and infarct size following transient occlusion and reperfusion of the MCA in FHH rats and the AR- and AR+ congenic strains. Occlusion of MCA reduced CBF similarly in all the strains. However, the hyperemic response following reperfusion in FHH and AR- strains was significantly greater and more prolonged than that seen in AR+ rats (AR-: 173 ± 1%, 45 min versus AR+: 124 ± 5%, 15 min). Moreover, infarct size and edema formation was significantly greater in the AR- congenic strain (39 ± 3 % and 12 ± 2 %) in comparison to that seen in the AR+ strain (28 ± 2 %; 7 ± 1%). These results indicate that there is a gene that plays a critical role in the regulation of the myogenic response of the cerebral vasculature by altering BK channel activity in the critical 2.4 Mb region of Chr 1 containing just 15 genes and that transfer of this region from BN to FHH rats restores autoregulation of CBF, vascular reactivity and reduces infarct size following ischemia/reperfusion injury.

Identification of a QTL on chromosome 1 for impaired autoregulation of RBF in fawn-hooded hypertensive rats

2006 ◽  
Vol 290 (5) ◽  
pp. F1213-F1221 ◽  
Author(s):  
Bernardo López ◽  
Robert P. Ryan ◽  
Carol Moreno ◽  
Albert Sarkis ◽  
Jozef Lazar ◽  
...  
Keyword(s):  
Genetic Background ◽  
Significant Quantitative Trait Locus ◽  
Chromosome 1 ◽  
Brown Norway ◽  
Genetic Linkage Analysis ◽  
Hypertensive Rats ◽  
Congenic Strains ◽  
Protein Excretion ◽  
Trait Locus ◽  
Consomic Strain

The present study evaluated whether the impairment in autoregulation of renal blood flow (RBF) in the fawn-hooded Hypertensive (FHH) rat colocalizes with the Rf-1 region on chromosome 1 that has been previously linked to the development of proteinuria in this strain. Autoregulation of RBF was measured in FHH and a consomic strain (FHH.1BN) in which chromosome 1 from the Brown-Norway (BN) rat was introgressed into the FHH genetic background. The autoregulation indexes (AI) averaged 0.80 ± 0.08 in the FHH and 0.19 ± 0.05 in the FHH.1BN rats. We next performed a genetic linkage analysis for autoregulation of RBF in 85 F2 rats generated from a backcross of FHH.1BN consomic and FHH rats. The results revealed a significant quantitative trait locus (QTL) with a peak logarithm of the odds score of 6.3 near marker D1Rat376. To confirm the existence of this QTL, five overlapping congenic strains were created that spanned the region from markers D1Rat234 to D1Mit14. Transfer of a region of BN chromosome 1 from markers D1Mgh13 to D1Rat89 into the FHH genetic background improved autoregulation of RBF (AI = 0.23 ± 0.04) and reduced protein excretion. In contrast, RBF was poorly autoregulated and the rats were not protected from proteinuria in congenic strains in which other regions of chromosome 1 that exclude the D1Rat376 marker were transferred. These results indicate that there is a gene(s) that influences autoregulation of RBF and proteinuria between markers D1Mgh13 and D1Rat89 on chromosome 1 that lies within the confidence interval of the Rf-1 QTL previously linked to the development of proteinuria in FHH rats.

scholarly journals Identification of a region of rat chromosome 1 that impairs the myogenic response and autoregulation of cerebral blood flow in fawn-hooded hypertensive rats

2013 ◽  
Vol 304 (2) ◽  
pp. H311-H317 ◽  
Author(s):  
Mallikarjuna R. Pabbidi ◽  
Julio Juncos ◽  
Luis Juncos ◽  
Marija Renic ◽  
Hurtis J. Tullos ◽  
...  
Keyword(s):  
Blood Flow ◽  
Cerebral Blood Flow ◽  
Vascular Reactivity ◽  
Cerebral Arteries ◽  
Cerebral Injury ◽  
Chromosome 1 ◽  
Brown Norway ◽  
Myogenic Response ◽  
Edema Formation ◽  
Congenic Strains

This study examined the effects of transfer of a 2.4-Mbp region of rat chromosome 1 (RNO1) from Brown Norway (BN) into fawn-hooded hypertensive (FHH) rats on autoregulation (AR) of cerebral blood flow (CBF) and the myogenic response of middle cerebral arteries (MCAs). AR of CBF was poor in FHH and FHH.1BN AR− congenic strains that excluded the critical 2.4-Mbp region. In contrast, AR was restored in FHH.1BN AR+ congenic strains that included this region. The diameter of MCAs of FHH rats increased from 140 ± 14 to 157 ± 18 μm when transmural pressure was increased from 40 to 140 mmHg, but it decreased from 137 ± 5 to 94 ± 7 μm in FHH.1BN AR+ congenic strains. Transient occlusion of MCAs reduced CBF by 80% in all strains. However, the hyperemic response following ischemia was significantly greater in FHH and AR− rats than that seen in AR+ congenic strains (AR−, 173 ± 11% vs. AR+, 124 ± 5%). Infarct size and edema formation were also significantly greater in an AR− strain (38.6 ± 2.6 and 12.1 ± 2%) than in AR+ congenic strains (27.6 ± 1.8 and 6.5 ± 0.9%). These results indicate that there is a gene in the 2.4-Mbp region of RNO1 that alters the development of myogenic tone in cerebral arteries. Transfer of this region from BN to FHH rats restores AR of CBF and vascular reactivity and reduces cerebral injury after transient occlusion and reperfusion of the MCA.

scholarly journals Knockdown of Add3 impairs the myogenic response of renal afferent arterioles and middle cerebral arteries

2017 ◽  
Vol 312 (6) ◽  
pp. F971-F981 ◽  
Author(s):  
Fan Fan ◽  
Mallikarjuna R. Pabbidi ◽  
Ying Ge ◽  
Longyang Li ◽  
Shaoxun Wang ◽  
...  
Keyword(s):  
Vascular Reactivity ◽  
Vascular Dysfunction ◽  
Cerebral Arteries ◽  
Chromosome 1 ◽  
Brown Norway ◽  
Myogenic Response ◽  
Norway Rat ◽  
Vasoconstrictor Response ◽  
Brown Norway Rat ◽  
Interfering Rna

We have reported that the myogenic response of the renal afferent arteriole (Af-art) and middle cerebral artery (MCA) and autoregulation of renal and cerebral blood flow are impaired in Fawn-Hooded Hypertensive (FHH) rats. Transfer of a region of chromosome 1 containing γ-adducin (Add3) from the Brown Norway rat rescued the vascular dysfunction and the development of renal disease. To examine whether Add3 is a viable candidate gene altering renal and cerebral hemodynamics in FHH rats, we knocked down the expression of Add3 in rat Af-arts and MCAs cultured for 36-h using a 27-mer Dicer-substrate short interfering RNA (DsiRNA). Control Af-arts constricted by 10 ± 1% in response to an elevation in pressure from 60 to 120 mmHg but dilated by 4 ± 3% when treated with Add3 DsiRNA. Add3 DsiRNA had no effect on the vasoconstrictor response of the Af-art to norepinephrine (10−7 M). Add3 DsiRNA had a similar effect on the attenuation of the myogenic response in the MCA. Peak potassium currents were threefold higher in smooth muscle cells isolated from Af-arts or MCAs transfected with Add3 DsiRNA than in nontransfected cells isolated from the same vessels. This is the first study demonstrating that Add3 plays a role in the regulation of potassium channel function and vascular reactivity. It supports the hypothesis that sequence variants in Add3, which we previously identified in FHH rats, may play a causal role in the impaired myogenic response and autoregulation in the renal and cerebral circulation.

Abstract 36: Deficiency in the Production of 20-HETE Contributes to Impaired Myogenic and TGF Responses in the Afferent Arteriole of Dahl S Rats

Hypertension ◽  
2012 ◽  
Vol 60 (suppl_1) ◽  
Author(s):  
Ying Ge ◽  
Fan Fan ◽  
Sydney R Murphy ◽  
Jan Michael Williams ◽  
Ruisheng Liu ◽  
...  
Keyword(s):  
Renal Injury ◽  
Tubuloglomerular Feedback ◽  
Brown Norway ◽  
Sodium Reabsorption ◽  
Thick Ascending Limb ◽  
Afferent Arteriole ◽  
Synthesis Inhibitor ◽  
Renal Vasculature ◽  
Luminal Diameter ◽  
Consomic Strain

Previous studies have indicated that a deficiency in the formation of 20-HETE in the proximal tubule and thick ascending limb of Henle in Dahl S rats increases sodium reabsorption and contributes to the development of hypertension. The present study examined whether the lack of 20-HETE production in the renal vasculature contributes to the progression of renal injury by altering the myogenic or tubuloglomerular feedback (TGF) response of the afferent arteriole (Af-Art). The production of 20-HETE was significantly lower by 54% in renal microvessels isolated from the kidneys of Dahl S rats versus that seen than in SS.5BN consomic strain in which chromosome 5 from the Brown Norway (BN) rat containing the CYP4A genes responsible for the formation of 20-HETE was transferred into the Dahl S genetic background. The luminal diameter of the Af-Art decreased by 14.7± 1.5% (from 20.5 ± 0.7 to 17.5 ± 0.8 μm, n=6) in SS.5BN rats whereas the diameter of the Af-Art remained unaltered in Dahl S rats (from 20.1 ± 0.6 to 21.7 ± 0.6 μm, n=7) when the perfusion pressure was increased from 60 mmHg to 120 mmHg. In other experiments, adenosine (1 μM) reduced the diameter of the Af-Art in the SS.5BN rats by 15±0.7% (from 20.1 ±0.4 to 17.1 ± 0.9 μm, n=3) whereas the Af-Art of Dahl S rats was unaltered. However, administration of a 20-HETE synthesis inhibitor, HET0016 (1 μM, n=6), or a selective 20-HETE antagonist, 6, 15-20-HEDE (10 μM, n=6) completely blocked the myogenic and adenosine responses in the Af-Art of SS.5BN rats but it had no effect in Dahl S rats. Administration of a 20-HETE agonist, 5, 14-20-HEDE (1 μM) restored the myogenic response (from 20.7 ± 0.7 to 17.6 ± 0.6 μm, n=7) and vasoconstrictor response to adenosine in the Af-Art of Dahl S rats. These studies confirm the key role of 20-HETE in modulating the responsiveness of the Af-Art and indicate that a deficiency in the formation of 20-HETE in renal microvessels contributes to the marked susceptibility of Dahl S rats to develop hypertension induced renal injury.

Renal vascular dysfunction precedes the development of renal damage in the hypertensive Fawn-Hooded rat

2010 ◽  
Vol 298 (3) ◽  
pp. F625-F633 ◽  
Author(s):  
Peter Ochodnický ◽  
Robert H. Henning ◽  
Hendrik J. Buikema ◽  
Dick de Zeeuw ◽  
Abraham P. Provoost ◽  
...  
Keyword(s):  
Renal Damage ◽  
Vascular Dysfunction ◽  
Organ Damage ◽  
Mesenteric Arteries ◽  
Myogenic Tone ◽  
Myogenic Response ◽  
Resistance Arteries ◽  
Renal Vasculature ◽  
End Organ Damage ◽  
Renal Vascular

It is unknown whether generalized vascular dysfunction precedes the development of kidney disease. Therefore, we studied myogenic constriction and endothelium-mediated dilatory responses in two inbred Fawn-Hooded (FH) rat strains, one of which spontaneously develops hypertension, proteinuria, and glomerulosclerosis (FHH), whereas the other (FHL) does not. Small renal, mesenteric resistance arteries and thoracic aorta isolated from FH rats before (7 wk old) and after the development of mild proteinuria (12 wks old) were mounted in perfused and isometric set-ups, respectively. Myogenic response, endothelium-dependent relaxation, and the contribution of endothelium-mediated dilatory compounds were studied using their respective inhibitors. Myogenic reactivity was assessed constructing pressure-diameter curves in the presence and absence of calcium. At the age of 7 wk, renal arteries isolated from kidneys of FHH rats developed significantly lower myogenic tone compared with FHL, most likely because of excessive cyclo-oxygenase 1-mediated production of constrictive prostaglandins. Consequently, young FHH demonstrated reduced maximal myogenic tone (22 ± 4.8 vs. 10.8 ± 2.0%, P = 0.03) and the peak myogenic index (−6.9 ± 4.8 vs. 0.6 ± 0.8%/mmHg, P = 0.07 for FHL vs. FHH, respectively). Active myogenic curves obtained in mesenteric arteries isolated from 7-wk-old rats did not differ between either strain, demonstrating a similar level of systemic myogenic tone in FHL and FHH rats. Therefore, before any renal end-organ damage is present, myogenic response seems selectively impaired in renal vasculature of FHH rats. Aortic reactivity did not differ between FHL and FHH at the time points studied. The present study shows that vascular dysfunction in both small renal and systemic arteries precedes renal end-organ damage in a spontaneous model of hypertension-associated renal damage. These early vascular changes might be potentially involved in the increased susceptibility of FHH rats to renal injury.

Abstract 1436: CYP2J2 Endothelial Overexpression Increases Nitric Oxide and Cyclooxygenase Independent Renal Dilation and Attenuates Endothelin-1 Vasoconstriction

Circulation ◽  
2007 ◽  
Vol 116 (suppl_16) ◽  
Author(s):  
John D Imig ◽  
Craig R Lee ◽  
Alyce Bradbury ◽  
Joan P Graves ◽  
Laura M DeGraff ◽  
...  
Keyword(s):  
Nitric Oxide ◽  
Renal Vasculature ◽  
Specific Expression ◽  
Endothelin 1 ◽  
Afferent Arterioles ◽  
Oxide Synthase ◽  
Renal Vascular ◽  
Arteriolar Diameter ◽  
Regulation Of Vascular Tone

Human CYP2J2 is expressed in endothelial cells and active in the biosynthesis of epoxyeico-satrienoic acids (EETs). However, the functional role of CYP2J2 and its products in the renal vasculature remain poorly characterized. To address this, we developed transgenic (Tr) mice with constitutive, endothelial cell-specific expression of human CYP2J2 ( Tie2 promoter and full enhancer) and enhanced EET biosynthesis. Experiments were conducted in the juxtamedullary nephron preparation to determine renal microvascular responses to acetylcholine (ACh) and endothelin-1 in Tie2 -CYP2J2 Tr mice and wild type (Wt) littermate controls. Administration of phenylephrine to kidney perfusate decreased the diameter of afferent arterioles from 20.1±0.5 to 13.9±0.6 μm (n=21) in Wt mice and 19.4±0.6 to 13.5±0.6 μm (n=23) in Tie2 -CYP2J2 Tr mice. Following phenylephrine, the afferent arteriole diameter response to ACh (0.01nM-10μM) was determined. There was a leftward shift in the logEC50 in Tie2 -CYP2J2 Tr mice (−6.5±0.2, n=13) compared to Wt mice (−6.1±0.2, n=11). However, the maximal afferent arteriolar relaxation to ACh was decreased in Tie2 -CYP2J2 Tr mice (59±6%) compared to Wt mice (70±7%, p=0.12). Endothelial expression of CYP2J2 increased the maximal renal vascular response to ACh in the presence of nitric oxide synthase (100μM L-NAME) and cyclooxygenase (10μM indomethacin) inhibition. Afferent arterioles relaxed by 27±4% (n=12) in Wt mice and 44±6% (n=10, p=0.018) in Tie2 -CYP2J2 Tr mice (10μM ACh). The afferent arteriolar dose response curve to endothelin-1 (0.001–10nM) was significantly attenuated in Tie2 -CYP2J2 Tr compared to Wt mice. Afferent arteriolar diameter decreased by 24±4% (n=6) in Wt mice and 13±2% (n=5, p=0.023) in Tie2 -CYP2J2 Tr mice (3nM endothelin-1). These results demonstrate that the nitric oxide- and cyclooxygenase-independent afferent arteriolar dilation to ACh is enhanced by endothelial overexpression of CYP2J2, and endothelin-1 mediated constriction is attenuated. In conclusion, endothelial overexpression of CYP2J2 can oppose renal vascular constrictor responses and enhance dilator responses in mice, implicating the important role of CYP2J2-derived eicosanoids in the regulation of vascular tone.

scholarly journals Enhanced large conductance K+ channel activity contributes to the impaired myogenic response in the cerebral vasculature of Fawn Hooded Hypertensive rats

2014 ◽  
Vol 306 (7) ◽  
pp. H989-H1000 ◽  
Author(s):  
Mallikarjuna R. Pabbidi ◽  
Olga Mazur ◽  
Fan Fan ◽  
Jerry M. Farley ◽  
Debebe Gebremedhin ◽  
...  
Keyword(s):  
Congenic Strain ◽  
Cerebral Arteries ◽  
Bk Channel ◽  
Chromosome 1 ◽  
Brown Norway ◽  
K Channel ◽  
Myogenic Response ◽  
Voltage Sensitivity ◽  
Channel Activity ◽  
Open Probability

Recent studies have indicated that the myogenic response (MR) in cerebral arteries is impaired in Fawn Hooded Hypertensive (FHH) rats and that transfer of a 2.4 megabase pair region of chromosome 1 (RNO1) containing 15 genes from the Brown Norway rat into the FHH genetic background restores MR in a FHH.1BN congenic strain. However, the mechanisms involved remain to be determined. The present study examined the role of the large conductance calcium-activated potassium (BK) channel in impairing the MR in FHH rats. Whole-cell patch-clamp studies of cerebral vascular smooth muscle cells (VSMCs) revealed that iberiotoxin (IBTX; BK inhibitor)-sensitive outward potassium (K+) channel current densities are four- to fivefold greater in FHH than in FHH.1BN congenic strain. Inside-out patches indicated that the BK channel open probability ( NP o) is 10-fold higher and IBTX reduced NP o to a greater extent in VSMCs isolated from FHH than in FHH.1BN rats. Voltage sensitivity of the BK channel is enhanced in FHH as compared with FHH.1BN rats. The frequency and amplitude of spontaneous transient outward currents are significantly greater in VSMCs isolated from FHH than in FHH.1BN rats. However, the expression of the BK-α and -β-subunit proteins in cerebral vessels as determined by Western blot is similar between the two groups. Middle cerebral arteries (MCAs) isolated from FHH rats exhibited an impaired MR, and administration of IBTX restored this response. These results indicate that there is a gene on RNO1 that impairs MR in the MCAs of FHH rats by enhancing BK channel activity.

Calcium recruitment in renal vasculature: NE effects on blood flow and cytosolic calcium concentration

1999 ◽  
Vol 276 (5) ◽  
pp. F700-F710 ◽  
Author(s):  
Max Salomonsson ◽  
William J. Arendshorst
Keyword(s):  
Blood Flow ◽  
Dependent Manner ◽  
Free Solution ◽  
Sprague Dawley ◽  
Vascular Effects ◽  
Renal Vasculature ◽  
Afferent Arterioles ◽  
Renal Vascular ◽  
Dose Dependent

This study provides new information about the relative importance of Ca2+ mobilization and entry in the renal vascular response to adrenoceptor activation. We measured renal blood flow (RBF) in Sprague-Dawley rats in vivo using electromagnetic flowmetry. We measured intracellular free Ca2+ concentration ([Ca2+]i) in isolated afferent arterioles utilizing ratiometric photometry of fura-2 fluorescence. Renal arterial injection of NE produced a transient decrease in RBF. The response was attenuated, in a dose-dependent manner, up to ∼50% by nifedipine, an antagonist of L-type Ca2+ entry channels. Inhibition of Ca2+ mobilization by 3,4,5-trimethoxybenzoic acid-8-(diethylamino)octyl ester (TMB-8) inhibited the renal vascular effects of NE in a dose-dependent manner, with maximal blockade of ∼80%. No additional attenuation was observed when nifedipine and TMB-8 were administered together. In microdissected afferent arterioles, norepinephrine (NE; 10−6 M) elicited an immediate square-shaped increase in [Ca2+]i, from 110 to 240 nM. This in vitro response was blocked by nifedipine (10−6 M) and TMB-8 (10−5 M) to a degree similar to that of the in vivo experiments. A nominally calcium-free solution blocked 80–90% of the [Ca2+]iresponse to NE. The increased [Ca2+]ielicited by depolarization with medium containing 50 mM KCl was totally blocked by nifedipine. In contrast, TMB-8 had no effect. Our results indicate that both Ca2+ entry and mobilization play important roles in the renal vascular Ca2+ and contractile response to adrenoceptor activation. The entry and mobilization mechanisms activated by NE may interact. That a calcium-free solution caused a larger inhibition of the NE effects on afferent arterioles than nifedipine suggests more than one Ca2+ entry pathway.

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