Endothelial Function in Subcutaneous Resistance Arteries from Elderly Hypertensive and Normotensive Subjects

1997 ◽  
Vol 92 (2) ◽  
pp. 139-145 ◽  
Author(s):  
Martin A. James ◽  
Pamela A. C. Watt ◽  
John F. Potter ◽  
Herbert Thurston ◽  
John D. Swales
Keyword(s):  
Nitric Oxide ◽  
Nitric Oxide Synthase ◽  
Sodium Nitroprusside ◽  
Elderly Subjects ◽  
Resistance Arteries ◽  
Elderly Hypertensive ◽  
Normotensive Subjects ◽  
Relaxation Responses ◽  
Oxide Synthase ◽  
Endothelium Dependent Relaxation

1. Previous studies have indicated that younger hypertensive subjects may have abnormal endothelium-dependent relaxation, which could contribute to the elevated peripheral resistance seen in established hypertension. This study was designed to examine the functional behaviour of the endothelium of small arteries from elderly hypertensive and normotensive subjects. 2. Resistance arteries were obtained from gluteal biopsies taken under local anaesthesia in 28 subjects of mean age 70 (range 60–76) years, and studied in an isometric myograph. Eighteen subjects had untreated essential hypertension, and 10 were normotensive. 3. After measurement of the contractile response to noradrenaline, relaxation responses to a variety of endothelium-dependent (acetylcholine and bradykinin) and endothelium-independent (iloprost and sodium nitroprusside) mechanisms were assessed in vessels precontracted with noradrenaline. Endothelium-dependent responses were also studied after incubation with NG-nitro-l-arginine to inhibit nitric oxide synthase. 4. There were no significant differences in the contraction or relaxation responses between elderly subjects with or without high blood pressure. Inhibition of nitric oxide synthase prevented any relaxation with acetylcholine and significantly attenuated the relaxation with bradykinin. Near-complete relaxation was however achieved with the endothelium-independent vasodilator sodium nitroprusside. 5. Hypertension in elderly subjects is not associated with a reduction in endothelial vasodilating function in the subcutaneous vessels of the gluteal region compared with age-matched normotensive controls. The results of this study do not support the hypothesis of a defect of resistance artery endothelium-dependent relaxation in the pathophysiology of hypertension in the elderly.

scholarly journals Contractile responsiveness of coronary arteries from exercise-trained rats

1997 ◽  
Vol 83 (2) ◽  
pp. 434-443 ◽  
Author(s):  
Janet L. Parker ◽  
Mildred L. Mattox ◽  
M. Harold Laughlin
Keyword(s):  
Nitric Oxide ◽  
Coronary Artery ◽  
Nitric Oxide Synthase ◽  
Exercise Training ◽  
Sodium Nitroprusside ◽  
Coronary Arteries ◽  
Internal Diameter ◽  
Relaxation Responses ◽  
Proximal Coronary Artery ◽  
Oxide Synthase

Parker, Janet L., Mildred L. Mattox, and M. Harold Laughlin.Contractile responsiveness of coronary arteries from exercise trained rats. J. Appl. Physiol. 83(2): 434–443, 1997.—The purpose of this study was to determine whether exercise training alters vasomotor reactivity of rat coronary arteries. In vitro isometric microvessel techniques were used to evaluate vasomotor properties of proximal left anterior artery rings (1 ring per animal) from exercise-trained rats (ET; n = 10) subjected to a 12-wk treadmill training protocol (32 m/min, 15% incline, 1 h/day, 5 days/wk) and control rats (C; n = 6) restricted to cage activity. No differences in passive length-tension characteristics or internal diameter (158 ± 9 and 166 ± 9 μm) were observed between vessesls of C and ET rats. Concentration-response curves to K+ (5–100 mM), prostaglandin F2α(10−8–10−4M), and norepinephrine (10−8–10−4) were unaltered ( P > 0.05) in coronary rings from ET rats compared with C rats; however, lower values of the concentration producing 50% of the maximal contractile response in rings from ET rats ( P = 0.05) suggest that contractile sensitivity to norepinephrine was enhanced. Vasorelaxation responses to sodium nitroprusside (10−9-10−4M) and adenosine (10−9-10−4M) were not different ( P > 0.05) between vessels of C and ET rats. However, relaxation responses to the endothelium-dependent vasodilator acetylcholine (ACh; 10−10-10−4M) were significantly blunted ( P < 0.001) in coronary rings from ET animals; maximal ACh relaxation averaged 90 ± 5 and 46 ± 12%, respectively, in vessels of C and ET groups. In additional experiments, two coronary rings (proximal and distal) were isolated from each C ( n = 7) and ET ( n = 7) animal. Proximal coronary artery rings from ET animals demonstrated decreased relaxation responses to ACh; however, ACh-mediated relaxation of distal coronary rings was not different between C and ET groups. N G-monomethyl-l-arginine (inhibitor of nitric oxide synthase) blocked ACh relaxation of all rings. l-Arginine (substrate for nitric oxide synthase) did not improve the blunted ACh relaxation in proximal coronary artery rings from ET rats. These studies suggest that exercise-training selectively decreases endothelium-dependent (ACh) but not endothelium-independent (sodium nitroprusside) relaxation responses of rat proximal coronary arteries; endothelium-dependent relaxation of distal coronary arteries is unaltered by training.

GTP cyclohydrolase 1 inhibition attenuates vasodilation and increases blood pressure in rats

2003 ◽  
Vol 285 (5) ◽  
pp. H2165-H2170 ◽  
Author(s):  
Brett M. Mitchell ◽  
Anne M. Dorrance ◽  
R. Clinton Webb
Keyword(s):  
Nitric Oxide ◽  
Blood Pressure ◽  
Nitric Oxide Synthase ◽  
Sodium Nitroprusside ◽  
Isometric Force ◽  
Sprague Dawley ◽  
Gtp Cyclohydrolase ◽  
Before And After ◽  
Relaxation Responses ◽  
Oxide Synthase

GTP cyclohydrolase 1 is the rate-limiting enzyme in production of tetrahydrobiopterin, a necessary cofactor for endothelial nitric oxide synthase. We tested the hypothesis that inhibition of tetrahydrobiopterin synthesis impairs endothelium-dependent relaxation and increase blood pressure in rats. 2,4-Diamino-6-hydroxypyrimidine (DAHP), a GTP cyclohydrolase 1 inhibitor, was given in drinking water (∼120 mg · kg–1 · day–1) to male Sprague-Dawley rats for 3 days. Systolic blood pressures were measured (tail-cuff procedure) for 3 days before and each day during DAHP treatment. Blood pressure was significantly increased after DAHP treatment (122 ± 2 vs. 154 ± 3 mmHg before and after DAHP, respectively; P < 0.05). Endothelium-intact aortic segments from pentobarbital sodium-anesthetized rats were isolated and hung in organ chambers for measurement of isometric force generation. Aortas from DAHP-treated rats exhibited a decreased maximal relaxation to ACh compared with controls [% relaxation from phenylephrine (10–7 M)-induced contraction: DAHP 57 ± 6% vs. control 79 ± 4%; P < 0.05]. Relaxation responses to A-23187 were also decreased in aortas from DAHP-treated rats compared with controls. Incubation with sepiapterin (10–4 M, 1 h), which produces tetrahydrobiopterin via a salvage pathway, restored relaxation to ACh in aortas from DAHP-treated rats. Superoxide dismutase significantly increased ACh-induced relaxation in aortas from DAHP-treated rats, whereas catalase had no effect. Endothelium-independent relaxation to sodium nitroprusside in aortas from DAHP-treated rats was not different from control rats; however, nitric oxide synthase inhibition increased sensitivity to sodium nitroprusside in aortas from DAHP-treated rats. These results support the hypothesis that GTP cyclohydrolase 1 inhibition decreases relaxation and increases blood pressure in rats.

Abstract 322: Acute Inhibition of GTP Cyclohydrolase 1 Uncouples Endothelial Nitric Oxide Synthase and Elevates Blood Pressure

Circulation ◽  
2008 ◽  
Vol 118 (suppl_18) ◽  
Author(s):  
Shuangxi Wang ◽  
Jian Xu ◽  
Ping Song ◽  
Yong Wu ◽  
Junhua Zhang ◽  
...  
Keyword(s):  
Nitric Oxide ◽  
Blood Pressure ◽  
Nitric Oxide Synthase ◽  
Endothelial Nitric Oxide Synthase ◽  
De Novo ◽  
Gtp Cyclohydrolase ◽  
South Central ◽  
Oxide Synthase ◽  
Endothelial Nitric Oxide ◽  
Endothelium Dependent Relaxation

Objective: GTP cyclohydrolase 1 (GTPCH1) is the rate-limiting enzyme in de novo synthesis of tetrahydrobiopterin (BH4), an essential cofactor for endothelial nitric oxide synthase (eNOS) dictating at least partly, the balance of nitric oxide (NO) and superoxide (O 2 .− ) produced by this enzyme. The aim of this study is to determine the effects of acute inhibition of GTPCH1 on BH4, eNOS function, and blood pressure. Methods: The biopterin content was detected by HPLC. O 2 .− and NO productions were assayed by using DHE and DAF fluorescence respectively. The vessel relaxation was assayed by organ chamber. The blood pressure in wild-type (WT) or eNOS −/− mice was determined by a carotid catheter method. Results: Exposure of bovine or mouse aortic endothelial cells to GTPCH1 inhibitors (10 mM DAHP or 1 mM NAS) for 24 hours or GTPCH1 siRNA transfection significantly reduced both BH4 and NO levels, but increased O 2 .− levels. This increase was abolished by 10 μM L-sepiapterin (BH4 precursor) or 1 mM L-NAME (non-selective NOS inhibitor). Incubation of isolated WT mice aortas with DAHP or NAS for 24 hours impaired acetylcholine-induced endothelium-dependent relaxation, but not endothelium-independent relaxation. Aortas from GTPCH1 siRNA-injected mice, but not their control-siRNA injected mice, also exhibited impaired endothelium-dependent relaxation. Furthermore, GT-PCH1 siRNA injection in mice reduced BH4 levels in aortas, associated with increased aortic levels of O 2 .− , 3-nitrotyrosine, and adhesion molecules (ICAM1 and VCAM1). In addition, an elevated mean, systolic, and diastolic blood pressure was induced by GTPCH1 siRNA injection in vivo , but not control siRNA (mean blood pressure: 114.28±4.48 vs . 136.81±2.45 mmHg) in WT mice. GTPCH1 siRNA was unable to elicit the similar effects in eNOS −/− mice, including increased oxidative stress (O 2 .− , 3-nitrotyrosine, ICAM1, VCAM1) and blood pressure. Finally, sepiapterin supplementation, which had no effect on high blood pressure in eNOS −/− mice, partially reversed GTPCH1 siRNA-induced elevation of systemic blood pressure in WT mice. Conclusion: GTPCH1 via BH4 maintains normal blood pressure and endothelial function by preserving eNOS-dependent NO biosynthesis. This research has received full or partial funding support from the American Heart Association, AHA South Central Affiliate (Arkansas, New Mexico, Oklahoma & Texas).

Cardiac transplantation and resistance artery myogenic tone

2004 ◽  
Vol 82 (10) ◽  
pp. 840-848 ◽  
Author(s):  
Farzad Moien-Afshari ◽  
Peter L Skarsgard ◽  
Bruce M McManus ◽  
Ismail Laher
Keyword(s):  
Nitric Oxide ◽  
Nitric Oxide Synthase ◽  
Contractile Function ◽  
Myogenic Tone ◽  
Resistance Arteries ◽  
Interstitial Edema ◽  
Functional Changes ◽  
Ventricular Compliance ◽  
Myogenic Regulation ◽  
Oxide Synthase

Transplantation is an effective treatment for end-stage heart disease; however, most grafts eventually fail by progressive cardiac failure. Primarily, failure is ischemic due to the occlusive nature of transplant vascular disease (TVD). Early after transplantation and preceding TVD, alterations in coronary physiology such as reduced vascular myogenic tone occur. Resistance arteries possess an inherent ability to constrict in response to transmural pressure; this constrictive response (myogenic tone) is important in fluid homeostasis. Recent evidence suggests that a decline in myogenic tone leads to deficits in cardiac contractility. Factors that reduce myogenic tone in transplantation include constitutive nitric oxide synthase and inducible nitric oxide synthase catalyzed, NO-mediated vasodilation as well as deficits in arterial contractile function. Reduced myogenic tone in allograft resistance arteries increases coronary blood flow such that hydrostatic pressure surpasses oncotic pressure, causing cardiac interstitial edema. This generalized edema decreases ventricular compliance leading to heart failure during the course of acute immune rejection of the graft. Cyclosporine A treatment reduces immune mediated dysregulation of myogenic tone, resulting in reduced interstitial edema and improved cardiac function. In this review, we discuss aspects of TVD and myogenic tone signaling mechanisms and how aberrations in myogenic regulation of arterial tone contribute to functional changes observed in cardiac transplant.Key words: myogenic tone, smooth muscle, nitric oxide, transplantation, edema.

scholarly journals Exercise training enhances multiple mechanisms of relaxation in coronary arteries from ischemic hearts

2013 ◽  
Vol 305 (9) ◽  
pp. H1321-H1331 ◽  
Author(s):  
Rachel R. Deer ◽  
Cristine L. Heaps
Keyword(s):  
Nitric Oxide ◽  
Blood Flow ◽  
Coronary Artery ◽  
Nitric Oxide Synthase ◽  
Exercise Training ◽  
Coronary Arteries ◽  
Vascular Function ◽  
Channel Inhibition ◽  
Oxide Synthase ◽  
Endothelium Dependent Relaxation

Exercise training of coronary artery disease patients is of considerable interest, since it has been shown to improve vascular function and, thereby, enhance blood flow into compromised myocardial regions. However, the mechanisms underlying exercise-induced improvements in vascular function have not been fully elucidated. We tested the hypothesis that exercise training increases the contribution of multiple mediators to endothelium-dependent relaxation of coronary arteries in the underlying setting of chronic coronary artery occlusion. To induce gradual occlusion, an ameroid constrictor was placed around the proximal left circumflex coronary artery in Yucatan miniature swine. At 8 wk postoperatively, pigs were randomly assigned to sedentary or exercise (treadmill, 5 days/wk) regimens for 14 wk. Exercise training significantly enhanced the contribution of nitric oxide, prostanoids, and large-conductance Ca2+-dependent K+ (BKCa) channels to endothelium-dependent, bradykinin-mediated relaxation in nonoccluded and collateral-dependent arteries. Combined nitric oxide synthase, prostanoid, and BKCa channel inhibition ablated the enhanced relaxation associated with exercise training. Exercise training significantly increased nitric oxide levels in response to bradykinin in endothelial cells isolated from nonoccluded and collateral-dependent arteries. Bradykinin treatment significantly increased PGI2 levels in all artery treatment groups and tended to be further enhanced after nitric oxide synthase inhibition in exercise-trained pigs. No differences were found in whole cell BKCa channel currents, BKCa channel protein levels, or arterial cyclic nucleotide levels. Although redundant, upregulation of parallel vasodilator pathways appears to contribute to enhanced endothelium-dependent relaxation, potentially providing a more refined control of blood flow after exercise training.

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