scholarly journals Gender differences in coronary artery diameter reflect changes in both endothelial Ca2+ and ecNOS activity

1999 ◽  
Vol 276 (3) ◽  
pp. H961-H969 ◽  
Author(s):  
Harm J. Knot ◽  
Karen M. Lounsbury ◽  
Joseph E. Brayden ◽  
Mark T. Nelson
Keyword(s):  
Nitric Oxide ◽  
Gender Differences ◽  
Coronary Artery ◽  
Coronary Arteries ◽  
Maximal Activity ◽  
Female Rats ◽  
Male Rats ◽  
No Production ◽  
No Release ◽  
Constitutive Nitric Oxide Synthase

Elevation of nitric oxide (NO) release from the vascular endothelium may contribute to some of the gender-associated differences in coronary artery function. The mechanisms by which gender affects NO release from the endothelium of coronary arteries are not known. In this study, endothelial function was examined in pressurized coronary arteries from female and male rats. Diameter and endothelial cell intracellular Ca2+concentration ([Ca2+]i) in intact arteries, as well as enzymatic activity of endothelial constitutive nitric oxide synthase (ecNOS) in arterial lysates, was measured. Elevation of intravascular pressure to 60 mmHg constricted coronary arteries from female animals less than coronary arteries from male animals (18% and 31% constriction, respectively). The increased arterial diameter of coronary arteries from females was associated with elevated endothelial [Ca2+]i(female 174 nM, male 90 nM; P < 0.001). Elevation of Ca2+activated ecNOS with a similar slope and half-activation constant (∼160 nM) for both female and male coronary arteries. However, at [Ca2+] > 100 nM, ecNOS activity was significantly higher in coronary arteries from female rats compared with their male equivalents ( P < 0.01). Maximal activity for ecNOS at saturating Ca2+ (300 nM) was 37% higher in coronary arteries from female animals compared with male animals ( P < 0.05). Thus elevated [Ca2+]iin the endothelium of female coronary arteries alone is predicted to increase the production of NO (by nearly 2-fold). This gender difference combined with increased ecNOS activity at a given [Ca2+] in females indicates that tonic NO production should be nearly threefold greater in female coronary arteries compared with male coronary arteries. We conclude that, in the regulation of endothelial Ca2+ and ecNOS, gender differences contribute significantly to the overall decrease in myogenic tone observed in coronary arteries of females.

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

Circulation ◽  
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.

scholarly journals Testosterone-induced relaxation of coronary arteries: activation of BKCa channels via the cGMP-dependent protein kinase

2012 ◽  
Vol 302 (1) ◽  
pp. H115-H123 ◽  
Author(s):  
Viju Deenadayalu ◽  
Yashoda Puttabyatappa ◽  
Alexander T. Liu ◽  
John N. Stallone ◽  
Richard E. White
Keyword(s):  
Nitric Oxide ◽  
Coronary Artery ◽  
Protein Kinase ◽  
Coronary Arteries ◽  
Specific Inhibitor ◽  
No Production ◽  
Channel Activity ◽  
Dependent Protein Kinase ◽  
Cgmp Dependent Protein Kinase ◽  
Dependent Protein

Androgens are reported to have both beneficial and detrimental effects on human cardiovascular health. The aim of this study was to characterize nongenomic signaling mechanisms in coronary artery smooth muscle (CASM) and define the ionic basis of testosterone (TES) action. TES-induced relaxation of endothelium-denuded porcine coronary arteries was nearly abolished by 20 nM iberiotoxin, a highly specific inhibitor of large-conductance, calcium-activated potassium (BKCa) channels. Molecular patch-clamp studies confirmed that nanomolar concentrations of TES stimulated BKCa channel activity by ∼100-fold and that inhibition of nitric oxide synthase (NOS) activity by NG-monomethyl-l-arginine nearly abolished this effect. Inhibition of nitric oxide (NO) synthesis or guanylyl cyclase activity also attenuated TES-induced coronary artery relaxation but did not alter relaxation due to 8-bromo-cGMP. Furthermore, we detected TES-stimulated NO production in porcine coronary arteries and in human CASM cells via stimulation of the type 1 neuronal NOS isoform. Inhibition of the cGMP-dependent protein kinase (PKG) attenuated TES-stimulated BKCa channel activity, and direct assay determined that TES increased activity of PKG in a concentration-dependent fashion. Last, the stimulatory effect of TES on BKCa channel activity was mimicked by addition of purified PKG to the cytoplasmic surface of a cell-free membrane patch from CASM myocytes (∼100-fold increase). These findings indicate that TES-induced relaxation of endothelium-denuded coronary arteries is mediated, at least in part, by enhanced NO production, leading to cGMP synthesis and PKG activation, which, in turn, opens BKCa channels. These findings provide a molecular mechanism that could help explain why androgens have been reported to relax coronary arteries and relieve angina pectoris.

Effects of sex differences on constitutive nitric oxide synthase expression and activity in response to pressure overload in rats

2007 ◽  
Vol 293 (5) ◽  
pp. H2650-H2658 ◽  
Author(s):  
Xavier Loyer ◽  
Patricia Oliviero ◽  
Thibaud Damy ◽  
Estelle Robidel ◽  
Françoise Marotte ◽  
...  
Keyword(s):  
Nitric Oxide ◽  
Sex Differences ◽  
Nitric Oxide Synthase ◽  
Pressure Overload ◽  
Left Ventricular ◽  
Female Rats ◽  
Male Rats ◽  
Male And Female ◽  
Constitutive Nitric Oxide Synthase ◽  
Oxide Synthase

Clinical studies have documented sex differences in left ventricular (LV) hypertrophy patterns, but the mechanisms are so far poorly defined. This study aimed to determine whether 1) severe pressure overload altered expression and/or activity of cardiac constitutive nitric oxide synthase (NOS1 and NOS3) and 2) these changes were modulated according to sex. Analyses were performed 0.4–20 wk after thoracic aortic constriction (TAC) in male and female Wistar rats. Male rats with TAC exhibited early signs of cardiac dysfunction, as shown by echocardiographic and LV end-diastolic pressure measurements, whereas females with TAC exhibited higher LV hypertrophy (+96% vs. males at 20 wk; P < 0.05). After TAC, cardiac NOS1 expression was rapidly induced (0.4 wk) and stable afterward in males ( P < 0.05 vs. sham groups), whereas it was delayed in females. Accordingly, specific NOS1 activity was increased by 2 wk in male rats with TAC (+122%; P < 0.001 vs. sham groups) and only by 20 wk in females (+220%; P < 0.001 vs. sham groups). NOS1 activity was correlated with NOS1 level. Regarding cardiac NOS3, expression was unaffected by TAC, and the decrease in activity observed at early and late times in male and female rats with TAC, respectively, is shown to be related to NOS3 allosteric regulator caveolin-1 level. The data demonstrated a unique sex-dependent regulation of the constitutive NOSs in response to TAC in rats; such a difference might play a role in the sex-dependent adaptability of the heart in response to pressure overload.

β-Adrenergic regulation of constitutive nitric oxide synthase in cardiac myocytes

1997 ◽  
Vol 273 (4) ◽  
pp. C1371-C1377 ◽  
Author(s):  
Anthony J. Kanai ◽  
Stephan Mesaros ◽  
Mitchell S. Finkel ◽  
Carmine V. Oddis ◽  
Lori A. Birder ◽  
...  
Keyword(s):  
Nitric Oxide ◽  
Cardiac Myocytes ◽  
Ventricular Myocytes ◽  
Rank Order ◽  
No Production ◽  
Adrenergic Stimulation ◽  
Cyclic Monophosphate ◽  
Adult Rat ◽  
No Release ◽  
Constitutive Nitric Oxide Synthase

Nitric oxide (NO) has been implicated in endogenous control of myocardial contractility. However, NO release has not yet been demonstrated in cardiac myocytes. Accordingly, endogenous NO production was measured with a porphyrinic microsensor positioned on the surface of individual neonatal or adult rat ventricular myocytes ( n > 6 neonatal and adult cells per experiment). In beating neonatal myocytes, there was no detectable spontaneous NO release with each contraction. However, norepinephrine (NE; 0.25–1 μM) elicited transient NO release from beating neonatal (149 ± 11 to 767 ± 83 nM NO) and noncontracting adult (157 ± 13 to 791 ± 89 nM NO) cells. NO was released by adrenergic agonists with the following rank order of potency: isoproterenol (β1β2) > NE (α/β1) > dobutamine (β1) ≈ epinephrine (α/β1β2) > tertbutylene (β2); NO was not released by phenylephrine (α). NE-evoked NO release was reversibly blocked by N G-monomethyl-l-arginine, trifluoperazine, guanosine 5′- O-(2-thiodiphosphate), and nifedipine but was enhanced by 3-isobutyl-1-methylxanthine (0.5 mM = 14.5 ± 1.6%) and BAY K 8644 (10 μM = 11.9 ± 1%). NO was also released by A-23187 (10 μM = 884 ± 88 nM NO), guanosine 5′- O-(3-thiotriphosphate) (1 μM = 334 ± 56 nM NO), and dibutyryl adenosine 3′,5′-cyclic monophosphate (10–100 μM = 35 ± 9 to 284 ± 49 nM NO) but not by ATP, bradykinin, carbachol, 8-bromoguanosine 3′,5′-cyclic monophosphate, or shear stress. This first functional demonstration of a constitutive NO synthase in cardiac myocytes suggests its regulation by a β-adrenergic signaling pathway and may provide a novel mechanism for the coronary artery vasodilatation and enhanced diastolic relaxation observed with adrenergic stimulation.

The female intestine is more resistant than the male intestine to gut injury and inflammation when subjected to conditions associated with shock states

2005 ◽  
Vol 288 (3) ◽  
pp. G466-G472 ◽  
Author(s):  
Hiroshi Homma ◽  
Erik Hoy ◽  
Da-Zhong Xu ◽  
Qi Lu ◽  
Rena Feinman ◽  
...  
Keyword(s):  
Nitric Oxide ◽  
Gender Differences ◽  
Inflammatory Response ◽  
Barrier Function ◽  
Ex Vivo ◽  
Ussing Chamber ◽  
Mucosal Injury ◽  
Female Rats ◽  
Male Rats ◽  
Intestinal Segments

Having documented that proestrus female rats are more resistant to shock-induced acute gut and hence lung injury than male rats, we tested the hypothesis that the female gut is more resistant to injury and produces less of an inflammatory response than the male gut when exposed to conditions associated with shock states (hypoxia and acidosis) utilizing the ex vivo Ussing chamber system. Ileal mucosal membranes harvested from normal male and female rats mounted in Ussing chamber systems were exposed to normoxia or 40 min of hypoxia at a normal pH (pH 7.3) or acidosis (pH 6.8). Cytokine and nitric oxide levels in the serosal compartment of the Ussing chamber were measured at the end of the 3-h experimental period to assess the immunoinflammatory response, whereas FITC-dextran (mol wt 4,300) was employed to assess barrier function. Histomorphological changes were used to quantitate gut mucosal injury. Hypoxia, acidosis, or hypoxia plus acidosis was associated with a significant increase in proinflammatory cytokine production [interleukin (IL)-6, tumor necrosis factor, and macrophage inflammatory protein (MIP)-2] by the male compared with the female intestinal segments. In contrast, the female gut manifested a higher anti-inflammatory response (nitric oxide and IL-10) and improved intestinal barrier function as well as less evidence of mucosal injury than the male intestinal segments. Administration of estradiol or the testosterone receptor antagonist, flutamide, to male rats abrogated the increase in gut injury and the increased IL-6 and MIP-2 response observed after hypoxia plus acidosis. These results suggest that gender differences in the ex vivo intestinal response to stresses, such as hypoxia and acidosis, exist and that the administration of estradiol or blockade of the testosterone receptor to male rats mitigates these gender differences.

Gender Differences in Non-Obstructive Coronary Artery Disease

2020 ◽  
Vol 26 ◽  
Author(s):  
Maria Bergami ◽  
Marialuisa Scarpone ◽  
Edina Cenko ◽  
Elisa Varotti ◽  
Peter Louis Amaduzzi ◽  
...  
Keyword(s):  
Coronary Artery Disease ◽  
Gender Differences ◽  
Heart Disease ◽  
Coronary Artery ◽  
Ischemic Heart Disease ◽  
Coronary Arteries ◽  
Obstructive Coronary Artery Disease ◽  
Ischemic Heart ◽  
Current Evidence ◽  
Artery Disease

: Subjects affected by ischemic heart disease with non-obstructive coronary arteries constitute a population that has received increasing attention over the past two decades. Since the first studies with coronary angiography, female patients have been reported to have non-obstructive coronary artery disease more frequently than their male counterparts, both in stable and acute clinical settings. Although traditionally considered a relatively infrequent and low-risk form of myocardial ischemia, its impact on clinical practice is undeniable, especially when it comes to infarction, where the prognosis is not as benign as previously assumed. Unfortunately, despite increasing awareness, there are still several questions left unanswered regarding diagnosis, risk stratification and treatment. The purpose of this review is to provide a state of the art and an update on current evidence available on gender differences in clinical characteristics, management and prognosis of ischemic heart disease with non-obstructive coronary arteries, both in the acute and stable clinical setting.

Decrease in ambient [Cl-] stimulates nitric oxide release from cultured rat mesangial cells

1994 ◽  
Vol 267 (1) ◽  
pp. F190-F195 ◽  
Author(s):  
H. Tsukahara ◽  
Y. Krivenko ◽  
L. C. Moore ◽  
M. S. Goligorsky
Keyword(s):  
Nitric Oxide ◽  
Mesangial Cells ◽  
Ionic Composition ◽  
Juxtaglomerular Apparatus ◽  
Cytosolic Calcium ◽  
No Synthase ◽  
Tubuloglomerular Feedback ◽  
No Production ◽  
Rapid Reduction ◽  
No Release

It has been hypothesized that fluctuations of the ionic composition in the interstitium of juxtaglomerular apparatus (JGA) modulate the function of extraglomerular mesangial cells (MC), thereby participating in tubuloglomerular feedback (TGF) signal transmission. We examined the effects of isosmotic reductions in ambient sodium concentration ([Na+]) and [Cl-] on cytosolic calcium concentration ([Ca2+]i) in cultured rat MC. Rapid reduction of [Na+] or [Cl-] in the bath induced a concentration-dependent rise in [Ca2+]i. MC are much more sensitive to decreases in ambient [Cl-] than to [Na+]; a decrease in [Cl-] as small as 14 mM was sufficient to elicit a detectable [Ca2]i response. These observations suggest that MC can be readily stimulated by modest perturbations of extracellular [Cl-]. Next, we examined whether activation of MC by lowered ambient [Cl-] influences cellular nitric oxide (NO) production. Using an amperometric NO sensor, we found that a 13 mM decrease in ambient [Cl-] caused a rapid, Ca2+/calmodulin-dependent rise in NO release from MC. This response was not inhibitable by dexamethasone, indicating the involvement of the constitutive rather than the inducible type of NO synthase in MC. In addition, the NO release was blunted by indomethacin pretreatment, suggesting that a metabolite(s) of cyclooxygenase regulates the activation of NO synthase in MC. Our findings that small perturbations in external [Cl-] stimulate MC to release NO, a highly diffusible and rapidly acting vasodilator, provide a possible mechanism to explain the transmission of the signal for the TGF response within the JGA.

Endothelin stimulates endothelial nitric oxide synthase expression in the thick ascending limb

2004 ◽  
Vol 287 (2) ◽  
pp. F231-F235 ◽  
Author(s):  
Marcela Herrera ◽  
Jeffrey L. Garvin
Keyword(s):  
Nitric Oxide ◽  
Nitric Oxide Synthase ◽  
Receptor Antagonist ◽  
Endothelial Nitric Oxide Synthase ◽  
No Production ◽  
Thick Ascending Limb ◽  
Enos Expression ◽  
No Release ◽  
Oxide Synthase ◽  
Endothelial Nitric Oxide

Endothelin-1 (ET-1) acutely inhibits NaCl reabsorption by the thick ascending limb (THAL) by activating the ETB receptor, stimulating endothelial nitric oxide synthase (eNOS), and releasing nitric oxide (NO). In nonrenal tissue, chronic exposure to ET-1 stimulates eNOS expression via the ETB receptor and activation of phosphatidylinositol 3-kinase (PI3K). We hypothesized that ET-1 increases eNOS expression in the THAL by binding to ETB receptors and stimulating PI3K. In primary cultures of medullary THALs treated for 24 h, eNOS expression increased by 36 ± 18% with 0.01 nM ET-1, 123 ± 30% with 0.1 nM ( P < 0.05; n = 5), and 71 ± 30% with 1 nM, whereas 10 nM had no effect. BQ-788, a selective ETB receptor antagonist, completely blocked stimulation of eNOS expression caused by 0.1 nM ET-1 (12 ± 25 vs. 120 ± 40% for ET-1 alone; P < 0.05; n = 5). BQ-123, a selective ETA receptor antagonist, did not affect the increase in eNOS caused by 0.1 nM ET-1. Sarafotoxin c (S6c; 0.1 μM), a selective ETB receptor agonist, increased eNOS expression by 77 ± 30% ( P < 0.05; n = 6). Wortmannin (0.01 μM), a PI3K inhibitor, completely blocked the stimulatory effect of 0.1 μM S6c (77 ± 30 vs. −28 ± 9%; P < 0.05; n = 6). To test whether the increase in eNOS expression heightens activity, we measured NO release in response to simultaneous treatment with l-arginine, ionomycin, and clonidine using a NO-sensitive electrode. NO release by control cells was 337 ± 61 and 690 ± 126 pA in ET-1-treated cells ( P < 0.05; n = 5). Taken together, these data suggest that ET-1 stimulates THAL eNOS, activating ETB receptors and PI3K and thereby increasing NO production.

Regulation of renal CYP4A expression and 20-HETE synthesis by nitric oxide in pregnant rats

2003 ◽  
Vol 285 (2) ◽  
pp. F295-F302 ◽  
Author(s):  
Mong-Heng Wang ◽  
Jishi Wang ◽  
Hsin-Hsin Chang ◽  
Barbara A. Zand ◽  
Miao Jiang ◽  
...  
Keyword(s):  
Nitric Oxide ◽  
Blood Pressure ◽  
Rat Kidney ◽  
Late Pregnancy ◽  
Inhibitory Effect ◽  
Female Rats ◽  
Male Rats ◽  
Pregnant Rats ◽  
Renal Vasoconstriction ◽  
Dependent Inhibition

20-Hydroxyeicosatetraenoic acid (20-HETE), which promotes renal vasoconstriction, is formed in the rat kidney primarily by cytochrome P-450 (CYP) 4A isoforms (4A1, 4A2, 4A3, 4A8). Nitric oxide (NO) has been shown to bind to the heme moiety of the CYP4A2 protein and to inhibit 20-HETE synthesis in renal arterioles of male rats. However, it is not known whether NO interacts with and affects the activity of CYP4A1 and CYP4A3, the major renal CYP4A isoforms in female rats. Incubation of recombinant CYP4A1 and 4A3 proteins with sodium nitroprusside (SNP) shifted the absorbance at 440 nm, indicating the formation of a ferric-nitrosyl-CYP4A complex. The absorbance for CYP4A3 was about twofold higher than that of CYP4A1. Incubation of SNP or peroxynitrite (PN; 0.01–1 mM) with CYP4A recombinant membranes caused a concentration-dependent inhibition of 20-HETE synthesis, with both chemicals having a greater inhibitory effect on CYP4A3-catalyzed activity. Moreover, incubation of CYP4A1 and 4A3 proteins with PN (1 mM) resulted in nitration of tyrosine residues in both proteins. In addition, PN and SNP inhibited 20-HETE synthesis in renal microvessels from female rats by 65 and 59%, respectively. We previously showed that microvessel CYP4A1/CYP4A3 expression and 20-HETE synthesis are decreased in late pregnancy. Therefore, we investigated whether such a decrease is dependent on NO, the synthesis of which has been shown to increase in late pregnancy. Administration of NG-nitro-l-arginine methyl ester (l-NAME) to pregnant rats for 6 days ( days 15- 20 of pregnancy) caused a significant increase in systolic blood pressure, which was prevented by concurrent treatment with the CYP4A inhibitor 1-aminobenzotriazole (ABT). Urinary NO2/NO3 excretion decreased by 40 and 52% in l-NAME- and l-NAME + ABT-treated groups, respectively. Interestingly, renal microvessel 20-HETE synthesis showed a marked increase following l-NAME treatment, and this increase was diminished with coadministration of ABT. These results demonstrate that NO interacts with CYP4A proteins in a distinct manner and it interferes with renal microvessel 20-HETE synthesis, which may play an important role in the regulation of blood pressure and renal function during pregnancy.

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.

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