This Article Abstract Full Text (PDF) Alert me when this article is cited Alert me if a correction is posted Citation Map Services Email this article to a friend Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Request Permissions Citing Articles Citing Articles via HighWire Citing Articles via Google Scholar Google Scholar Articles by Qiu, H. Y. Articles by Levy, B. I. Search for Related Content PubMed PubMed Citation Articles by Qiu, H. Y. Articles by Levy, B. I.

(Hypertension. 1998;32:1098-1103.)
© 1998 American Heart Association, Inc.

Scientific Contributions

Decreased Flow-Induced Dilation and Increased Production of cGMP in Spontaneously Hypertensive Rats

Hong Ying Qiu; Daniel Henrion; Joëlle Benessiano; Christophe Heymes; Bruno Tournier; Bernard I. Levy

From the Institut National de la Santé et de la Recherche Médicale (INSERM) Unit 141 and Unit 127 (C.H.), IFR Circulation-Lariboisière, Université Paris VII, Hôpital Lariboisière, Paris, France.

Correspondence to Dr Bernard Levy, INSERM U 141, 41 Blvd de la Chapelle, Hôpital Lariboisière 75475 Paris cedex 10, France. E-mail levy{at}infobiogen.fr

	Abstract

Top Abstract Introduction Methods Results Discussion References

 
Abstract—We investigated flow (shear stress)– and agonist-induced cGMP release in mesenteric vascular beds of spontaneously hypertensive rats (SHR) and normotensive Wistar Kyoto rats (WKY). The mesenteric vascular bed was perfused in situ with Tyrode's solution. Vascular relaxation and cGMP release in the perfusate were determined on stimulation by flow or by acetylcholine (0.1 µmol/L) or sodium nitroprusside (0.1 mmol/L). Flow-induced release of cGMP was significantly greater in SHR than in WKY (P<0.01), despite a lower flow-induced dilation in SHR. In both strains, N^G-nitro-L-arginine methyl ester (L-NAME) completely inhibited cGMP release in response to flow (P<0.001), although flow-induced dilation was not affected by L-NAME in SHR. Moreover, the activity of the constitutive nitric oxide synthase (NOS) was significantly greater in SHR (82±3.5 fmol/min) than in WKY (66±3.5 fmol/min; P<0.05) and was associated with increased expression of endothelial NOS mRNA in SHR. Sodium nitroprusside induced larger increases in cGMP release in SHR (3593±304 fmol/min) than in WKY (2467±302 fmol/min; P<0.05). The release of cGMP in response to acetylcholine was significantly lower in SHR (292±80 fmol/min) than in WKY (798±218 fmol/min; P<0.05) in parallel with smaller acetylcholine-induced relaxation in SHR. Despite increased cGMP production in response to flow and NOS activity, flow-induced dilation was decreased in SHR, suggesting an upregulation of the NO/cGMP pathway to compensate for the increased vascular tone in SHR.

Key Words: endothelium • cyclic GMP • nitric oxide synthase • mesenteric arteries

	Introduction

Top Abstract Introduction Methods Results Discussion References

 
Nitrovasodilators produce vascular smooth muscle relaxation through activation of the soluble isoform of guanylate cyclase and increase cellular cGMP,^{1 2} which lowers intracellular Ca²⁺ levels.^{3 4} Nitric oxide (NO), a major endogenous vasodilator synthesized from L-arginine, is released by endothelial cells.^{5 6 7}

In several models of hypertension, endothelium-dependent responses are altered⁸; the increase in peripheral resistance would be caused at least in part by a decrease in endothelium-dependent dilation and/or to increased release of endothelium-derived constricting factors.⁹ Endothelial dysfunction in large conduit arteries^{9 10} and in resistance arteries of hypertensive rats^{11 12 13} has also been shown. Similar alterations occur in hypertensive patients.^{14 15 16} Functional alterations of the endothelial L-arginine/NO pathway may be important in cardiovascular disease, since depressed activity of this dilator mechanism would reduce local blood flow.

In most experimental and clinical studies, acetylcholine (ACh) was used to test the endothelial function. However, the main in vivo physiological stimulus of endothelial responses is the wall shear stress directly related to the blood flow rate, blood viscosity, and vessel diameter.¹⁷ Interestingly, in the coronary¹⁸ and forearm¹⁹ circulations of hypertensive subjects, flow-dependent vasodilatation was reported to remain intact, although the response to ACh was abnormal. However, we have previously reported that the arterial wall cGMP content was greater in spontaneously hypertensive rats (SHR) than in normotensive Wistar Kyoto rats (WKY).²⁰ To test the hypothesis that response to flow may be primarily decreased in hypertension, leading to compensatory mechanisms such as an increased NO/cGMP pathway responsiveness, we measured cGMP release and vessel dilation on flow or agonist stimulation in mesenteric arteries from SHR and WKY.

	Methods

Top Abstract Introduction Methods Results Discussion References

 
In Situ Mesenteric Bed Perfusion and Effluent Collection
All experiments were performed on 12-week-old SHR and age-matched WKY obtained from Center d'Elevage R. Janvier (St Berthevin, France). A medial laparotomy was performed after sodium pentobarbital (50 mg/kg IP) anesthesia was administered. The last loop of the small intestine was exposed and placed in a container, which allowed superfusion of the preparation as described previously.¹³ All second-generation branches of the mesenteric artery were sutured except one irrigating a 3- to 4-cm segment of small intestine that was cut from the remaining small intestine laid on a glass container. This second-generation mesenteric artery branch was then perfused, and the effluent was collected. Samples of effluent were immediately frozen in liquid nitrogen and stored at -80°C until cGMP measurement.

In a first group of experiments, the isolated mesenteric arterial beds were perfused at flow rates ranging from 0.5 to 4 mL/min with Tyrode's solution containing 0.2 mmol/L IBMX. Each flow step was maintained for 6 minutes, and 2 mL of effluent was collected. The same procedure was performed 20 minutes after addition of N^w-nitro-L-arginine methyl ester (L-NAME; 1 mmol/L), an inhibitor of NO synthase (NOS), to the perfusate. Flow rates from 0.5 to 4 mL/min are compatible with the in vivo flow shown previously.²¹ There is no difference in blood flow between WKY and SHR.²¹

In a second series of experiments, we measured mesenteric arterial diameter changes and cGMP release in response to ACh or sodium nitroprusside (SNP) stimulation. After preconstriction of the mesenteric arteries with phenylephrine (PE, 10 µmol/L), ACh (n=8 in each strain, 0.1 µmol/min) or SNP (n=10 in each strain, 0.1 mmol/L) was added to the perfusate for 10 minutes. The mesenteric arterial diameter was continuously measured. Samples of effluent were collected under control conditions or after a 10-minute perfusion with ACh (n=8 per strain, 0.1 µmol/min) or SNP (n=10 per strain, 0.1 mmol/L).

In a third group of experiments, the mesenteric vascular bed was perfused with Tyrode's solution at a constant flow (500 µL/min) and then dissected and removed from the gut for measurement of constitutive NOS (cNOS) activity (21 SHR and 21 WKY) and for determination of NOS mRNA expression (5 SHR and 5 WKY).

Mesenteric Artery Perfused and Pressurized In Vitro
A segment of mesenteric artery, 400 µm ID, was isolated, cannulated at both ends, and mounted in a video-monitored perfusion system as previously described.^{22 23} Briefly, the artery was bathed in a 5-mL organ bath containing Tyrode's solution. Pressure in the proximal end of the artery segment was monitored by use of a pressure transducer and controlled by a servoperfusion system. Arterial diameter was recorded by use of a video-monitoring system (Living System Instrumentation Inc). Diameter changes were measured under no flow, when intraluminal pressure was set at 25, 50, 75, 100, 125, and 150 mm Hg. Flow rate in the artery ranged from 0 to 150 µL/min (under a pressure of 75 mm Hg). Step increases in pressure and flow were subsequently repeated after addition of either L-NAME (10 µmol/L) or indomethacin (3 µmol/L) to the perfusate and superfusate. Arteries were then perfused and superfused with Ca²⁺-free PSS containing EGTA (2 mmol/L) and SNP (10 µmol/L) to determine the passive diameter of the vessel after full relaxation. Results are given in micrometers for diameters of arteries. Myogenic tone was expressed as active tone (passive diameter-measured diameter). Flow-induced relaxation was expressed as increases in diameter induced by flow.

Determination of cGMP Production in Mesenteric Vascular Bed
Samples of effluent were treated with 6% trichloroacetic acid and centrifuged at 2000g for 15 minutes at 4°C. Supernatant fractions were extracted 4 times with 5 volumes of water-saturated diethyl ether; the organic phase was discarded each time. Residual aqueous phase was lyophilized and assayed for cGMP after acetylation by use of an immunoenzymatic assay as previously described.²⁴ Levels of cGMP in the effluents were expressed as femtomoles per milliliter, and production of cGMP by the mesenteric bed (fmol/min) was calculated as the product of cGMP concentration and the mesenteric flow value.

Determination of cNOS Activity in the Mesenteric Arterial Bed
cNOS activity was determined by measuring the conversion of [³H]L-arginine to [³H]L-citrulline.²⁵ Tissues were homogenized at 4°C in 500 µL of homogeneization buffer.²⁶ The assay was terminated by the addition of 1 mL of 30 mmol/L HEPES and 3 mmol/L EDTA, pH 5.5 ice-cold buffer. The terminated reaction was applied to a Dowex AG50W-X8 (Na⁺ form) column, and [³H]L-citrulline was eluted with 2 mL of distilled water. Radioactivity was measured in a liquid scintillation counter. Ca²⁺-dependent NOS activity was evaluated by the difference in activity between samples assayed in the presence of CaCl₂ and those assayed in the presence of EDTA.

Reverse Transcriptase–Polymerase Chain Reaction of NOS Isoforms
Total RNA was extracted according to Trizol reagent protocol (Life Technologies Inc). Purified RNA was dissolved in water, and the concentration was measured by absorbance at 260 nm. Reverse transcriptase–polymerase chain reaction (RT-PCR) was performed for NOS type I, type II, and type III (NOS I, neuronal NOS; NOS II, inducible NOS; and NOS III, endothelial NOS, respectively) and for GAPDH gene expression. The primers chosen for sense were 5'-CTGGCTCAACAGAATACAGG-CT-3' for NOS I, 5'-AAGACCCAGTGCCCTGCTTT-3' for NOS II, and 5'-TTCCGGCTGCCACCTGATCCTAA-3' for NOS III. For antisense, the primers chosen were 5'-ACAGTGTACAGCTCTCTGAAGA-3' for NOS I, 5'-CGCAAACATAGAGGTGGCC-3' for NOS II, and 5'-AACATGTGTCCTTGCTCGAGGCA-3' for NOS III, thus amplifying a 293-bp, a 388-bp, and a 340-bp fragment, respectively. For GAPDH, the following primers were used: sense 5'-TGAAGGTCGGTGTCAACGGATTTGGC-3' and antisense 5'-CATGTAGGCCATGAGGTCCACCAC-3', resulting in a 982-bp band.

First-strand cDNA was performed on 50 ng of total RNA. The single-strand cDNA synthesis was carried out in 20 µL of reaction buffer [20 mmol/L Tris-HCl (pH 8.3), 50 mmol/L KCl, 1.6 mmol/L MgCl₂, 1 mmol/L dNTP, 10 mmol/L DTT, 0.2 µmol/L oligo-p(dT)]. The reaction mixture was incubated 10 minutes at 25°C and then 60 minutes at 37°C. The resultant cDNA was amplified using 2.5 U of Taq DNA polymerase (Boehringer, Meylan, France) and 0.5 µmol/L of the sense and antisense primers in 50 µL of 50 mmol/L KCl, 10 mmol/L Tris-HCl (pH 8.3), 3 mmol/L MgCl₂, 1 mmol/L dNTP, and 0.01% gelatin. Thirty-two, 26, 25, and 25 amplification cycles for NOS I, NOS II, NOS III, and GAPDH, respectively, were carried out as follows: denaturation at 94°C for 1 minute, annealing at 62°C for NOS isoforms and at 60°C for GAPDH for 1 minute, and extension at 72°C for 1 minute. The final extension was carried out for 10 minutes.

The linear phase of the amplification was determined for each primer set to allow semiquantitative PCR analysis. To quantify NOS isoforms and GAPDH mRNA levels, a trace amount of [³²P]dCTP was included in the PCR reaction. The PCR products were then electrophoresed on a 5% polyacrylamide gel, and radioactive signals were analyzed by use of a computer-based imaging system (Fuji Bas 1000, Fuji Medical Systems). To normalize signals for NOS I, NOS II, and NOS III, the value was divided by the signal for GAPDH, a widely invariant and highly expressed gene.

Drugs
[³H]L-arginine (44.2 Ci/mmol) was purchased from Amersham, and Dowex AG50-X8 cation exchange resin and protein assay reagent were obtained from Bio-Rad Laboratories. All other reagents were obtained from Sigma Chemical Co.

Statistical Analysis
Results are expressed as mean±SEM. The experimental design allowed us to perform 2-way ANOVA with factorial and repeated measurement to provide evidence of differences related to strains and experimental conditions (flow, agonist application). Differences were considered significant when P<0.05.

	Results

Top Abstract Introduction Methods Results Discussion References

 
Mean arterial pressure was 104±11 in WKY and 154±15 in SHR. The cross-sectional area in mesenteric arteries from SHR is significantly greater (19 033±342 µm²) than that from WKY (14 563±208 µm²; P<0.001).

Flow-Induced cGMP Release
Figure 1 shows the relation between flow rate and cGMP release in mesenteric vascular beds from SHR (n=7) and WKY (n=11). Under control conditions, a significant linear flow-dependent release of cGMP was observed in SHR (from 232±42 fmol/min at 0.5 mL/min to 969±271 fmol/min at 4 mL/min; P<0.001) and in WKY (from 123±17 fmol/min at 0.5 mL/min to 627±95 fmol/min at 4 mL/min; P<0.001). Flow-dependent release of cGMP was significantly greater in SHR than in WKY (P<0.01). L-NAME significantly inhibited the release of cGMP at all flow rates in both strains.

View larger version (28K): [in this window] [in a new window]   Figure 1. Mean±SEM of cGMP release in effluent from the perfused mesenteric vascular bed (0.5, 1, 2, 3, and 4 mL/min) under control conditions and after addition of L-NAME in WKY and SHR. The flow-induced cGMP release was significantly greater in SHR than in WKY (P<0.01). L-NAME inhibited the release of cGMP at all tested flow rates in both strains (P<0.001).

Flow-Induced Dilation and Myogenic Tone
In isolated mesenteric arteries, step increases in intraluminal pressure induced development of myogenic tone that was greater in SHR than in WKY (Figure 2). Passive arterial diameter in the absence of tone ranged from 257±6 to 395±16 µm in WKY and from 252±2 to 368±2 µm in SHR (P<0.01 versus WKY, n=6 per group) for pressure steps from 25 to 150 mm Hg. Step increases in flow, under a pressure of 100 mm Hg, induced significant dilation in WKY (Figure 3). In SHR, flow-induced dilation was significantly attenuated compared with WKY (P<0.001). L-NAME (100 µmol/L) significantly attenuated flow-induced dilation in WKY but not in SHR (Figure 3).

View larger version (10K): [in this window] [in a new window]   Figure 2. Active tone (difference between active and passive diameter) in mesenteric arteries isolated from SHR and WKY in response to pressure steps. Data are expressed as mean±SEM. *P<0.001, SHR vs WKY.

View larger version (14K): [in this window] [in a new window]   Figure 3. Flow-induced dilation in mesenteric artery segments isolated from WKY or SHR under control conditions and after inhibition of NO synthesis by L-NAME. Data are expressed as mean±SEM. *P<0.001, SHR vs WKY.

Agonist- or Exogenous Nitrovasodilator–Induced Relaxation and cGMP Release From Perfused Mesenteric Vascular Bed
Under control conditions (2 mL/min flow rate), cGMP release by the mesenteric vascular bed was significantly greater in SHR than in WKY (792±76 versus 394±44 fmol/min; P<0.001) (Figure 4). Under stimulation by ACh, cGMP release reached similar levels in SHR (916±126 fmol/min) and in WKY (1062±273 fmol/min). However, the increase in cGMP release induced by ACh was significantly less (P<0.05) in SHR (292±80 fmol/min) than in WKY (798±218 fmol/min). In parallel, relaxation to ACh was significantly less in SHR than in WKY (43±9% versus 87±3%; P<0.01). After SNP stimulation, cGMP release was significantly greater in SHR than in WKY (3593±304 versus 2467±302 fmol/min; P<0.02), whereas the relaxation obtained was similar in both strains (126±19% in SHR versus 114±3% in WKY).

View larger version (32K): [in this window] [in a new window]   Figure 4. Mean±SEM of cGMP release in effluent from the perfused mesenteric vascular bed for flow rate of 2 mL/min before (control) and after stimulation by ACh or SNP in WKY and SHR. *P<0.05, SHR vs WKY under control conditions; §P<0.05, SHR vs WKY after SNP stimulation.

cNOS Activity in Mesenteric Arterial Bed
cNOS activity was significantly greater in SHR (85±3.5 fmol/min) than in WKY (66±3.5 fmol/min; P<0.05), and inducible NOS activity of the mesenteric arterial bed (citrulline produced in absence of calcium) was not detectable in either strain.

NOS mRNA in Mesenteric Arterial Bed
RT-PCR of NOS isoforms revealed the presence of NOS I, NOS II, and NOS III in mesenteric arteries from SHR and WKY (Figure 5). Expression of all 3 isoforms of NOS was significantly greater (P<0.01) in SHR than in WKY.

View larger version (63K): [in this window] [in a new window]   Figure 5. Typical RT-PCR analysis of NOS isoforms and GAPDH mRNA levels in mesenteric arteries of WKY and SHR. Fifty (NOS I), 50 (NOS II), 20 (NOS III), or 50 ng (GAPDH) of total RNA were assayed for NOS isoforms and GAPDH. Amplified products are electrophoresed on a 5% polyacrylamide gel. MWM indicates molecular weight marker. **P<0.01, SHR vs WKY.

	Discussion

Top Abstract Introduction Methods Results Discussion References

 
The main finding of the present study is that flow-induced dilation was impaired in SHR mesenteric resistance arteries despite greater NO-dependent cGMP production and greater NOS activity in SHR than in WKY.

An increase in peripheral vascular resistance, thought to result from increased vasoconstrictor and/or decreased vasodilator tone, is one of the hallmarks of hypertension. Functional alterations of the endothelial L-arginine/NO pathway could contribute to regulation of peripheral resistance and, in turn, of blood pressure. Earlier experimental and clinical studies have reported endothelium dysfunctions in large arteries^{9 10 27 28} and in resistance arteries of hypertensive animals^{11 12 13 29} and patients.^{14 15 16}

In the present study, cGMP released by the mesenteric circulation was proportional to flow rate and was completely blocked by L-NAME in both WKY and SHR. These findings support the concept that flow induces a shear stress–dependent stimulation of the vascular L-arginine/NO/cGMP pathway in both strains. Flow-induced cNOS activity and cGMP release were significantly greater in SHR than in WKY despite markedly decreased flow-induced dilation in SHR. Increased cNOS activity in SHR was confirmed by increased mRNA expression of endothelial NOS. Beside endothelial NOS mRNA, neuronal NOS mRNA and inducible NOS mRNA were also increased in SHR. Together, these results are consistent with a marked increase in cGMP production in SHR after stimulation of the L-arginine/NO pathway by flow. A possible explanation could be that shear stress is greater in resistance arteries of SHR than in those of WKY because, in the present study, flow rate was set at the same value in both strains. Arterial rarefaction and narrowing have been reported in genetic hypertension^{30 31} and could be responsible for greater shear stress in the resistance arteries of SHR. Another possible explanation for increased cGMP production in SHR could be related to increased cNOS activity. The greater flow-induced cGMP release in SHR could be the consequence of an upregulation of the NO/cGMP pathway to compensate for an increase in vascular tone and arterial resistance observed with the development of hypertension, as shown in the present work and in previous studies.³² Another possible explanation for the increase in flow-induced cGMP production and the decrease in flow-induced dilation could be that cGMP is less efficient in SHR in inducing a smooth muscle relaxation; thus, a full relaxation may be obtained but more cGMP is required. In fact, flow may trigger not only a NO/cGMP-dependent dilation but also a release of contractile substances such as vasoconstrictor cyclooxygenase products³² and/or endothelin-1.³³ Moreover, because of the presence of a phosphodiesterase inhibitor (IBMX) in the perfusate, we can conclude that the observed greater cGMP release by the mesenteric bed from SHR under stimulation by flow was the result of greater production of cGMP and not of decreased degradation of cGMP by phosphodiesterases. Our results are in agreement with our previous study reporting higher baseline (unstimulated) cGMP content in carotid arteries from SHR than from WKY.²⁰ In the same way, overproduction of NO in vascular smooth muscle cells or coronary circulation has been previously reported in SHR.^{34 35}

Finally, it is generally accepted that endothelium-dependent relaxation is impaired in hypertension on the basis of ACh-induced dilation as a test.^{9 10 15 16} In SHR, vasorelaxation and cGMP production induced by ACh were found to be reduced compared with in WKY.^{36 37} In the present study, ACh-induced increase in cGMP release was significantly less in SHR than in WKY. This alteration may be specific for ACh-induced stimulation, as SNP- and flow-induced cGMP release were greater in SHR than in WKY. These results are in agreement with previous studies of the mesenteric vascular bed³⁸ and of cultured smooth muscle cells and aortic rings.³⁹ Thus, decreased ACh-induced dilation in hypertension may reflect an alteration in affinity for muscarinic receptors.⁴⁰

In conclusion, in genetically hypertensive rats, the mesenteric arterial network exhibited an overactivated endothelium-dependent L-arginine/NO/cGMP pathway associated with decreased flow-induced dilation. Although we may hypothesize that an increase in NO/cGMP activity occurred to compensate for an elevated constrictor tone, we cannot exclude that increased vascular tone and upregulation of the NO/cGMP pathway could be unrelated phenotypes of the SHR strain.

Received November 20, 1997; first decision December 11, 1997; accepted July 16, 1998.

	References

Top Abstract Introduction Methods Results Discussion References

 
1. Katsuki S, Arnold WP, Mittal C, Murad F. Stimulation of guanylate cyclase by sodium nitroprusside, nitroglycerin and nitric oxide in various tissue preparations and comparison to the effects of sodium azide and hydroxylamine. J Cyclic Nucleotide Res. 1977;3:23–35.[Medline] [Order article via Infotrieve]

2. Katsuki S, Murad F. Regulation of adenosine cyclic 3',5'-monophosphate and guanosine cyclic 3',5'-monophosphate levels and contractility in bovine tracheal smooth muscle. Mol Pharmacol. 1977;13:330–341.[Abstract/Free Full Text]

3. Cornwell TL, Lincoln TM. Regulation of intracellular Ca²⁺ levels in cultured vascular smooth muscle cells. J Biol Chem. 1989;262:1146–1155.

4. Murad F. Cyclic guanosine monophosphate as a mediator of vasodilation. J Clin Invest. 1986;78:1–5.

5. Palmer RMJ, Ferrige AG, Moncada S. Nitric oxide release accounts for the biological activity of endothelium-derived relaxing factor. Nature. 1987;327:524–526.[Medline] [Order article via Infotrieve]

6. Ignarro LJ, Buga GM, Wood KS, Byrns RE, Chaudhuri G. Endothelium-derived relaxing factor from artery and vein is nitric oxide. Proc Natl Acad Sci U S A. 1987;84:9265–9269.[Abstract/Free Full Text]

7. Palmer RMJ, Ashton DS, Moncada S. Vascular endothelial cells synthesize nitric oxide from L-arginine. Nature. 1988;333:664–666.[Medline] [Order article via Infotrieve]

8. Lüscher TF, Vanhoutte PM, Boulanger C, Dohi Y, Bühler FR. Endothelial dysfunction in hypertension. In: Rubanyi GM, ed. Cardiovascular Significance of Endothelium-Derived Vasoactive Factors. Mt Kisco, NY: Futura Publishing Co Inc; 1991.

9. Lüscher TF, Vanhoutte PM. Endothelium-dependent contractions to acetylcholine in the aorta of the spontaneously hypertensive rat. Hypertension. 1986;8:344–348.[Abstract/Free Full Text]

10. Lüscher TF, Vanhoutte PM, Raij L. Antihypertensive therapy normalizes endothelium-dependent relaxations in salt-induced hypertension of the rat. Hypertension. 1987;9(suppl III):III-193–III-197.

11. Diederich D, Yang Z, Bühler FR, Lüscher TF. Impaired endothelium-dependent relaxations in hypertensive resistance arteries involve the cyclooxygenase pathway. Am J Physiol. 1990;258:H445–H451.[Abstract/Free Full Text]

12. Dohi Y, Thiel MA, Bühler FR, Lüscher TF. Activation of endothelial L-arginine pathway in resistance arteries: effect of age and hypertension. Hypertension. 1990;16:170–179.[Abstract/Free Full Text]

13. Qiu HY, Henrion D, Levy BI. Alterations in flow-dependent vasomotor tone in spontaneously hypertensive rats. Hypertension. 1994;24:474–479.[Abstract/Free Full Text]

14. Linder L, Kiowski W, Bühler FR, Lüscher TF. Indirect evidence for release of endothelium-derived relaxing factor in the human forearm circulation in vivo: blunted response in essential hypertension. Circulation. 1990;81:1762–1767.[Abstract/Free Full Text]

15. Calver A, Collier J, Moncada S, Vallance P. Effect of local intra-arterial N^G-monomethyl-L-arginine in patients with hypertension: the nitric oxide dilator mechanism appears abnormal. J Hypertens. 1992;10:1025–1031.[Medline] [Order article via Infotrieve]

16. Panza JA, Casino PR, Bader DM, Quyyumi AA. Role of endothelium-derived nitric oxide in the abnormal endothelium-dependent vascular relaxation of patients with essential hypertension. Circulation. 1993;87:1468–1474.[Abstract/Free Full Text]

17. Nollert MU, Diamond SL, Mcintire LV. Hydrodynamic shear stress and mass transport modulation of endothelial cell metabolism. Biotechnol Bioeng. 1991;38:588–602.

18. Drexler H, Zeiher AM, Wollschläger H, Meinertz T, Just H, Bonzel T. Flow-dependent coronary artery dilatation in human. Circulation. 1989;80:466–474.[Abstract/Free Full Text]

19. Laurent S, Lacolley P, Brunel P, Laloux B, Pannier B, Safar M. Flow dependent vasodilation of brachial artery in human essential hypertension. Am J Physiol. 1990;258:H1004–H1011.[Abstract/Free Full Text]

20. Mourlon-Le Grand MC, Benessiano J, Levy BI. cGMP pathway and mechanical properties of carotid artery wall in WKY and SHR: role of endothelium. Am J Physiol. 1992;263:H61–H67.[Abstract/Free Full Text]

21. Qiu HY, Henrion D, Levy BI. Endogenous angiotensin II enhances phenylephrine-induced tone in hypertensive rats. Hypertension. 1994;24:317–321.[Abstract/Free Full Text]

22. Halpern W, Osol G, Coy GS. Mechanical behavior of pressurized in vitro prearteriolar vessels determined with a video system. Ann Biomed Eng.. 1984;12:463–479.[Medline] [Order article via Infotrieve]

23. Henrion D, Terzi F, Matrougui K, Duriez M, Boulanger CM, Colucci-Guyon E, Babinet C, Briand P, Friedlander G, Poitevin P, Lévy BI. Impaired flow-induced dilation in mesenteric resistance arteries from mice lacking vimentin. J Clin Invest. 1997;100:2909–2914.[Medline] [Order article via Infotrieve]

24. Caputo L, Benessiano J, Boulanger CM, Levy BI. Angiotensin II increases cGMP content via endothelial angiotensin II AT1 subtype receptors in the rat carotid artery. Arterioscler Thromb Vasc Biol. 1995;15:1646–1651.[Abstract/Free Full Text]

25. Salter M, Knowles RG, Moncada S. Widespread tissue distribution, species distribution and changes in activity of Ca²⁺-dependent and Ca²⁺-independent nitric oxide synthases. FEBS Lett. 1991;291:145–149.[Medline] [Order article via Infotrieve]

26. Nadaud S, Philippe M, Arnal JF, Michel JB, Soubrier F. Sustained increase in aortic endothelial nitric oxide synthase expression in vivo in a model of chronic high blood flow. Circ Res. 1996;79:857–863.[Abstract/Free Full Text]

27. Konishi M, Su C. Role of endothelium in dilator responses of spontaneously hypertensive rat arteries. Hypertension. 1983;5:881–886.[Abstract/Free Full Text]

28. Van de Voorde J, Vanheel B, Leusen I. Endothelium-dependent relaxation and hyperpolarization in aorta from control and renal hypertensive rats. Circ Res. 1992;70:1–8.[Abstract/Free Full Text]

29. Li J, Bukoski RD. Endothelium-dependent relaxation of hypertension resistance arteries is not impaired under all conditions. Circ Res. 1993;72:290–296.[Abstract/Free Full Text]

30. Mulvany MJ, Hansen PK, Aalkjaer C. Direct evidence that the greater contractility of resistance vessels in spontaneously hypertensive rats is associated with a narrowed lumen, a thickened media, and an increased number of smooth muscle cell layers. Circ Res. 1978;43:854–864.[Abstract/Free Full Text]

31. Seki J. Flow pulsation and network structure in mesenteric microvasculature of rats. Am J Physiol. 1994;266:H811–H821.[Abstract/Free Full Text]

32. Matrougui K, Maclouf J, Lévy BI, Henrion D. Impaired nitric oxide- and prostaglandin-mediated responses to flow in resistance arteries of hypertensive rats. Hypertension. 1997;30:942–947.[Abstract/Free Full Text]

33. Kuchan MJ, Frangos JA. Shear stress regulates endothelin-1 release via protein kinase C and cGMP in cultured endothelial cells. Am J Physiol. 1993;264:H150–H156.[Abstract/Free Full Text]

34. Xiao J, Pang PK. Does a general alteration in nitric oxide synthesis system occur in spontaneously hypertensive rats? Am J Physiol. 1994;266:H272–H278.[Abstract/Free Full Text]

35. Kelm M, Feelisch M, Krebber T, Deussen A, Motz W, Strauer BE. Role of nitric oxide in the regulation of coronary vascular tone in hearts from hypertensive rats. Maintenance of nitric oxide-forming capacity and increased basal production of nitric oxide. Hypertension. 1995;25:186–193.[Abstract/Free Full Text]

36. Miyata N, Tsuchida K, Tanaka M, Otomo S. Impairment of endothelium-dependent relaxation and changes in levels of cyclic GMP in carotid arteries from stroke-prone spontaneously hypertensive rats. J Pharm Pharmacol. 1990;42:763–766.[Medline] [Order article via Infotrieve]

37. Shirasaki Y, Kolm P, Nickoles GA, Lee TJF. Endothelial regulation of cyclic GMP and vascular response in hypertension. J Pharmacol Exp Ther. 1988;245:53–58.[Abstract/Free Full Text]

38. Fukuda N, Izumi Y, Minato M, Soma M, Watanabe Y, Watanabe M, Hatano M. Cyclic GMP formation of resistance vessel in the development of hypertension in spontaneously hypertensive rats. Jpn Circ J. 1991;55:721–728.[Medline] [Order article via Infotrieve]

39. Papapetropoulos A, Marczin N, Snead MD, Cheng C, Milici A, Catravas JD. Smooth muscle cell responsiveness to nitrovasodilators in hypertensive and normotensive rats. Hypertension. 1994;23:476–484.[Abstract/Free Full Text]

40. Sim MK, Manjeet S. Muscarinic receptors in the aortae of normo- and hypertensive rats: a binding study. Clin Exp Hypertens. 1993;15:409–421.

This article has been cited by other articles:

				X. Zhou, H. G. Bohlen, S. J. Miller, and J. L. Unthank NAD(P)H oxidase-derived peroxide mediates elevated basal and impaired flow-induced NO production in SHR mesenteric arteries in vivo Am J Physiol Heart Circ Physiol, September 1, 2008; 295(3): H1008 - H1016. [Abstract] [Full Text] [PDF]

				D. I. Palen, S. Belmadani, P. A. Lucchesi, and K. Matrougui Role of SHP-1, Kv.1.2, and cGMP in nitric oxide-induced ERK1/2 MAP kinase dephosphorylation in rat vascular smooth muscle cells Cardiovasc Res, November 1, 2005; 68(2): 268 - 277. [Abstract] [Full Text] [PDF]

				P. M. Hassoun, G. Filippov, M. Fogel, C. Donaldson, U. S. Kayyali, L. A. Shimoda, and K. D. Bloch Hypoxia Decreases Expression of Soluble Guanylate Cyclase in Cultured Rat Pulmonary Artery Smooth Muscle Cells Am. J. Respir. Cell Mol. Biol., June 1, 2004; 30(6): 908 - 913. [Abstract] [Full Text] [PDF]

				G. Iaccarino, M. Ciccarelli, D. Sorriento, E. Cipolletta, V. Cerullo, G. L. Iovino, A. Paudice, A. Elia, G. Santulli, A. Campanile, et al. AKT Participates in Endothelial Dysfunction in Hypertension Circulation, June 1, 2004; 109(21): 2587 - 2593. [Abstract] [Full Text] [PDF]

				R. KOHLER, R. KREUTZ, A. GRUNDIG, L. ROTHERMUND, C. YAGIL, Y. YAGIL, A. R. PRIES, and J. HOYER Impaired Function of Endothelial Pressure-Activated Cation Channel in Salt-Sensitive Genetic Hypertension J. Am. Soc. Nephrol., August 1, 2001; 12(8): 1624 - 1629. [Abstract] [Full Text] [PDF]

This Article Abstract Full Text (PDF) Alert me when this article is cited Alert me if a correction is posted Citation Map Services Email this article to a friend Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Request Permissions Citing Articles Citing Articles via HighWire Citing Articles via Google Scholar Google Scholar Articles by Qiu, H. Y. Articles by Levy, B. I. Search for Related Content PubMed PubMed Citation Articles by Qiu, H. Y. Articles by Levy, B. I.