Contractile responsiveness of coronary  arteries from exercise-trained rats

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.

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

AJP Heart and Circulatory Physiology ◽

10.1152/ajpheart.00531.2013 ◽

2013 ◽

Vol 305 (9) ◽

pp. H1321-H1331 ◽

Cited By ~ 13

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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Recombinant Gene Transfer of Endothelial Nitric Oxide Synthase Augments Coronary Artery Relaxations During Hypoxia

Circulation ◽

10.1161/circ.100.suppl_2.ii-335 ◽

1999 ◽

Vol 100 (suppl_2) ◽

Author(s):

David G. Cable ◽

Vincent J. Pompili ◽

Timothy O’Brien ◽

Hartzell V. Schaff

Keyword(s):

Nitric Oxide ◽

Coronary Artery ◽

Nitric Oxide Synthase ◽

Gene Transfer ◽

Coronary Arteries ◽

Endothelial Nitric Oxide Synthase ◽

No Production ◽

Viral Control ◽

Oxide Synthase ◽

Endothelial Nitric Oxide

Background —Coronary arteries respond to hypoxia with transient relaxations, which increases coronary blood flow, in part, by release of nitric oxide. We hypothesized that increased expression of nitric oxide synthase might further augment blood vessel relaxation during hypoxia. The present study examined the effect of adenovirus-mediated transfer of bovine endothelial nitric oxide synthase (eNOS) on hypoxia-induced transient relaxations in canine coronary arteries. Methods and Results —Paired segments of coronary arteries were exposed to vehicle (phosphate-buffered saline with albumin) or an adenovirus encoding either E coli β-galactosidase (Ad.CMVLacZ, viral control; 10 10 pfu/mL) or eNOS (Ad.CMVeNOS; 10 10 pfu/mL) for 2 hours at 37°C. Immunohistochemistry with a monoclonal antibody specific for eNOS documented both endothelial and adventitial expression in Ad.CMVeNOS arteries, whereas vehicle and viral controls demonstrated only constitutive expression. Levels of cGMP were increased 5-fold in Ad.CMVeNOS arteries compared with controls. In arteries exposed to Ad.CMVeNOS, maximum contraction to prostaglandin F 2α was reduced compared with viral controls, and this effect was eliminated by pretreatment with a competitive inhibitor of eNOS ( N G -monomethyl- l -arginine, 10 −3 mol/L). Hypoxia-induced transient relaxation (95% N 2 -5% CO 2 ) in Ad.CMVeNOS arteries (45.2±8.8%, n=6) was augmented compared with vehicle (26.3±6.0%) or viral (27.2±7.1%) controls. Conclusions —Adenovirus-mediated gene transfer of nitric oxide synthase reduces receptor-dependent contractions and augments hypoxia-induced relaxations in canine coronary arteries; this method of augmentation of NO production might be advantageous for reduction of coronary artery vasospasm.

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Promoter and Exon 7 Polymorphism of Endothelial Nitric Oxide Synthase: Impact on Endothelial Function and Its Correction by Exercise Training in Patients With Coronary Artery Disease

Arteriosclerosis Thrombosis and Vascular Biology ◽

10.1161/01.atv.0000111341.74938.0a ◽

2004 ◽

Vol 24 (2) ◽

Author(s):

Sandra Erbs ◽

Axel Linke ◽

Gerhard Schuler ◽

Rainer Hambrecht

Keyword(s):

Nitric Oxide ◽

Coronary Artery Disease ◽

Coronary Artery ◽

Nitric Oxide Synthase ◽

Exercise Training ◽

Endothelial Function ◽

Endothelial Nitric Oxide Synthase ◽

Artery Disease ◽

Oxide Synthase ◽

Endothelial Nitric Oxide

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

AJP Heart and Circulatory Physiology ◽

10.1152/ajpheart.00253.2003 ◽

2003 ◽

Vol 285 (5) ◽

pp. H2165-H2170 ◽

Cited By ~ 26

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.

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Chronic nitric oxide synthase inhibition blunts endothelium-dependent function of conduit coronary arteries, not arterioles

AJP Heart and Circulatory Physiology ◽

10.1152/ajpheart.00899.2006 ◽

2007 ◽

Vol 292 (6) ◽

pp. H2798-H2808 ◽

Cited By ~ 8

Author(s):

David G. Ingram ◽

Sean C. Newcomer ◽

Elmer M. Price ◽

Kevin E. Eklund ◽

Richard M. McAllister ◽

...

Keyword(s):

Nitric Oxide ◽

Nitric Oxide Synthase ◽

Coronary Arteries ◽

Tap Water ◽

Group Differences ◽

Miniature Swine ◽

Relaxation Responses ◽

Oxide Synthase ◽

Coronary Arterioles

Current literature suggests that chronic nitric oxide synthase (NOS) inhibition has differential effects on endothelium-dependent dilation (EDD) of conduit arteries vs. arterioles. Therefore, we hypothesized that chronic inhibition of NOS would impair EDD of porcine left anterior descending (LAD) coronary arteries but not coronary arterioles. Thirty-nine female Yucatan miniature swine were included in the study. Animals drank either tap water or water with NG-nitro-l-arginine methyl ester (l-NAME; 100 mg/l), resulting in control and chronic NOS inhibition (CNI) groups, respectively. Treatment was continued for 1–3 mo (8.3 ± 0.6 mg·kg−1·day−1). In vitro EDD of coronary LADs and arterioles was assessed via responses to ADP (LADs only) and bradykinin (BK), and endothelium-independent function was assessed via responses to sodium nitroprusside (SNP). Chronic NOS inhibition diminished coronary artery EDD to ADP and BK. Incubating LAD rings with l-NAME decreased relaxation responses of LADs from control pigs but not from CNI pigs such that between-group differences were abolished. Neither indomethacin (Indo) nor sulfaphenazole incubation significantly affected relaxation responses of LAD rings to ADP or BK. Coronary arteries from CNI pigs showed enhanced relaxation responses to SNP. In contrast to coronary arteries, coronary arterioles from CNI pigs demonstrated preserved EDD to BK and no increase in dilation responses to SNP. l-NAME, Indo, and l-NAME + Indo incubation did not result in significant between-group differences in arteriole dilation responses to BK. These results suggest that although chronic NOS inhibition diminishes EDD of LAD rings, most likely via a NOS-dependent mechanism, it does not affect EDD of coronary arterioles.

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

Clinical Science ◽

10.1042/cs0920139 ◽

1997 ◽

Vol 92 (2) ◽

pp. 139-145 ◽

Cited By ~ 11

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.

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Exercise training improves endothelium-mediated vasorelaxation after chronic coronary occlusion

Journal of Applied Physiology ◽

10.1152/jappl.1999.87.5.1948 ◽

1999 ◽

Vol 87 (5) ◽

pp. 1948-1956 ◽

Cited By ~ 47

Author(s):

Kawanza L. Griffin ◽

M. Harold Laughlin ◽

Janet L. Parker

Keyword(s):

Nitric Oxide ◽

Coronary Artery ◽

Nitric Oxide Synthase ◽

Exercise Training ◽

Coronary Occlusion ◽

Coronary Artery Occlusion ◽

Artery Occlusion ◽

Chronic Coronary Occlusion ◽

Enhanced Production ◽

Oxide Synthase

The present study evaluated combined effects of chronic coronary occlusion and exercise training on endothelial function. Gradual occlusion was produced by placement of an ameroid constrictor around the proximal left circumflex (LCX) coronary artery of female swine. Two months after placement of the ameroid, animals were restricted to their pens or exercise trained for 16 wk. Epicardial arteries (>500 μm ID) were isolated from the collateral-dependent LCX coronary artery distal to the occlusion and the nonoccluded left anterior descending (LAD) coronary artery. Bradykinin- and ADP-mediated relaxation of LCX and LAD coronary arteries was enhanced after exercise training. Inhibition of nitric oxide synthase with N G-nitro-l-arginine methyl ester decreased bradykinin- and ADP-mediated relaxation in LCX and LAD myocardial regions. Importantly, combined inhibition of effects of endothelium-derived hyperpolarizing factor with increased extracellular K+ (20–30 mM) and nitric oxide synthase completely abolished coronary LAD and LCX relaxation to bradykinin. Our data indicate that exercise training improves endothelium-mediated relaxation of arteries isolated after chronic coronary artery occlusion, likely as a result of enhanced production of nitric oxide and endothelium-derived hyperpolarizing factor.

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