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PubMed1991

A new relaxing factor in supernatant of incubated rat peritoneal neutrophils.

It was found that when rat peritoneal neutrophils were added to an organ bath, they released an unstable vasoactive substance designated as neutrophil-derived relaxing factor (NDRF), which is similar to endothelium-derived relaxing factor. Besides NDRF, a more stable (activity maintained for at least 7 days at -80 degrees C) relaxing factor was found to be generated in the supernatant after the incubation of rat peritoneal neutrophils in buffer. This supernatant relaxing factor (SRF) induced an increase in the guanosine 3',5'-cyclic monophosphate content of aortic strips. Its relaxing activity was potentiated by superoxide dismutase. It was inhibited by hemoglobin, hydroquinone, or methylene blue but not by catalase or mannitol. Preincubation of polymorphonuclear neutrophils with aspirin, quinacrine, metyrapone, or AA-861 had no effect on the relaxing activity of SRF. L-Arginine dose dependently increased the relaxing activity of SRF, whereas NG-monomethyl-L-arginine (L-NMMA) decreased it, and this decrease was reversed by L-arginine. In contrast, neither L-arginine nor L-NMMA affected the relaxing activity of NDRF. These data suggest that SRF may represent a relaxing factor that is synthesized de novo from L-arginine.

Animals↗
PubMed1991

Prostaglandin F2 alpha-induced endothelium-dependent relaxation in isolated monkey cerebral arteries.

Effects of prostaglandin F2 alpha (PGF2 alpha) on isolated monkey and dog cerebral arteries were investigated to reevaluate PGF2 alpha's possible action on the endothelium. Low concentrations of PGF2 alpha ranging from 10(-11) to 10(-8) M produced a dose-dependent relaxation in the monkey arteries. PGF2 alpha (10(-7) M) produced a transient contraction followed by a small relaxation, whereas higher concentrations (greater than 10(-6) M) of PGF2 alpha induced only contractions. The PGF2 alpha-induced relaxation was not observed in the canine cerebral arteries. The PGF2 alpha-induced relaxation of the monkey cerebral arteries was not affected by treatment with 10(-7) M propranolol, 10(-7) M atropine, or 10(-6) M cimetidine. In monkey cerebral arteries without endothelium, PGF2 alpha in concentrations ranging from 10(-11) to 10(-6) M caused no relaxation. Treatment with 5 X 10(-5) M aspirin, 3 X 10(-5) M NG-monomethyl-L-arginine, and 10(-5) M oxyhemoglobin significantly suppressed the PGF2 alpha-induced relaxation. These results suggest that low concentrations of PGF2 alpha may produce an endothelium-dependent relaxation in monkey cerebral arteries and that the relaxation may be mediated by release of both endogenous vasodilative prostaglandins and endothelium-derived relaxing factor from endothelial cells.

Animals↗
PubMed1991

Mechanisms of calcium relaxation of vascular smooth muscle.

We examined mechanisms of relaxation in intact and endothelium-denuded thoracic aortic rings of rat in response to various concentrations of calcium (from 1.6 to 10.1 mM) after contraction induced by 30 mM KCl. The relaxation to calcium was concentration dependent in intact and denuded rings. This effect was greater in intact preparations than in denuded preparations or in intact preparations treated with methylene blue (10(-5) M). This indicates that the relaxation by calcium is partly mediated by releasing endothelium-derived relaxing factors (EDRFs). In the presence of A23187, the relaxation to calcium was attenuated in intact rings but not in denuded rings, whereas calcium relaxation was not significantly altered by sodium nitroprusside. These observations suggest that the calcium-induced relaxation is reduced if EDRF has already been released by A23187. We conclude that, paradoxically, the same increase in extracellular Ca2+ concentration that causes an increase in endothelial intracellular calcium concentration ([Ca2+]i) to produce EDRF also results in membrane stabilization of the vascular smooth muscle cell to decrease [Ca2+]i and cause relaxation. These two mechanisms are additive in producing calcium relaxation in the intact artery.

Acetylcholine↗
PubMed1993

Role of PGI2 and epoxyeicosatrienoic acids in relaxation of bovine coronary arteries to arachidonic acid.

Metabolites of arachidonic acid regulate several physiological processes, including vascular tone. The purpose of this study was to determine which metabolites of arachidonic acid are produced by bovine coronary arteries and which may regulate coronary vascular tone. Arachidonic acid induced a concentration-related, endothelium-dependent relaxation [one-half maximum effective concentration (EC50) of 2 x 10(-7) M and a maximal relaxation of 91 +/- 2% at 10(-5) M] of bovine coronary arteries that were contracted with U-46619, a thromboxane mimetic. The concentration of 6-ketoprostaglandin F1 alpha (6-keto-PGF1 alpha), a metabolite of prostaglandin I2 (PGI2), increased from 82 +/- 6 to 328 +/- 24 pg/ml with arachidonic acid (10(-5) M). Treatment with the cyclooxygenase inhibitor indomethacin attenuated arachidonic acid-induced relaxations by approximately 50% and blocked the synthesis of 6-keto-PGF1 alpha. PGI2 caused a concentration-related relaxation (EC50 of 10(-8) M and a maximal relaxation of 125 +/- 11% at 10(-7) M). BW755C, a cyclooxygenase and lipoxygenase inhibitor, inhibited arachidonic acid-induced relaxation to the same extent as indomethacin. When vessels were treated with both indomethacin and BW755C, the inhibition of relaxation was the same as either inhibitor alone. SKF 525a, a cytochrome P-450 inhibitor, reduced arachidonic acid-induced relaxation by approximately 50%. When SKF 525a was given in combination with indomethacin, the relaxation by arachidonic acid was almost completely inhibited. SKF 525a inhibited the synthesis of epoxyeicosatrienoic acids (EETs).(ABSTRACT TRUNCATED AT 250 WORDS)

8,11,14-Eicosatrienoic Acid↗
PubMed1993

Monkey cerebral arterial relaxation caused by hypercapnic acidosis and hypertonic bicarbonate.

In helical strips of Japanese monkey cerebral arteries contracted with vasoconstrictors, applications of high CO2 (15% compared with 5% CO2 in control media) and hypertonic NaHCO3 (50 mM) produced relaxations. Similar relaxations were also obtained in human cerebral arterial strips. Hypercapnia increased PCO2 and resulted in acidosis in the bathing media, and the addition of NaHCO3 restored the pH to normal with high PCO2 and increased the osmotic pressure. The relaxant responses were not influenced by endothelium denudation and treatment with indomethacin. The hypercapnia-induced relaxation was suppressed by ouabain but was unaffected by amiloride. On the other hand, hypertonic bicarbonate-induced relaxations were inhibited by ouabain as well as by amiloride. Removal of Na+ from the bathing media abolished the hypercapnia-induced relaxation but did not alter the hyperosmolar relaxation. In contrast to hypertonic NaHCO3, isotonic bicarbonate solutions contracted the arterial strips by neutralizing the pH under hypercapnia. It may be concluded that relaxations elicited by hypercapnic acidosis are associated with a fall of extracellular pH and an activation of the electrogenic Na+ pump, and those caused by hyperosmolarity are due to stimulation of the Na(+)-H+ exchange and the Na+ pump. Endothelium-derived vasoactive substances and cyclooxygenase products do not appear to be involved in these relaxations of monkey cerebral arteries under the experimental conditions used.

Acidosis↗
PubMed1994

Comparison of acetylcholine-dependent relaxation in large and small arteries of rat mesenteric vascular bed.

The relative contributions of nitric oxide (NO) to in vitro relaxation responses elicited by acetylcholine (ACh) were compared in vessels of different sizes from the rat mesenteric vascular bed. ACh elicited an endothelium-dependent relaxation in phenylephrine-contracted superior mesenteric arteries (SMA, unstretched luminal diam 650 microns), which was blocked by compounds that inhibited NO, such as hemoglobin (10 microM), methylene blue (10 microM), and NG-monomethyl-L-arginine (1 mM). In contrast, the endothelium-dependent relaxation induced by ACh in phenylephrine-contracted mesenteric resistance arteries (MRA, unstretched luminal diam 200 microns) was not blocked by hemoglobin, methylene blue, or NG-monomethyl-L-arginine. KCl (25 mM) partially inhibited the ACh-dependent relaxation in MRA. Furthermore, the ACh-dependent relaxation in MRA was selectively inhibited by the Ca(2+)-activated K+ channel blocker charybdotoxin (0.1 microM). In contrast, the ATP-sensitive K+ channel blocker glibenclamide (50 microM) did not block the ACh-dependent relaxation in MRA. We conclude that 1) NO is a major component of the ACh-dependent relaxation in SMA and 2) the ACh-dependent relaxation of MRA is resistant to NO inhibitors but sensitive to a Ca(2+)-activated K+ channel blocker. This suggests that an endothelium-derived hyperpolarization factor may be involved in the relaxation of MRA.

Acetylcholine↗
PubMed1995

Decreased endothelium-dependent relaxation in subarachnoid hemorrhage-induced vasospasm: role of ET-1.

The purpose of this study was to test whether endothelium-dependent relaxation is decreased during acute vasospasm following subarachnoid hemorrhage (SAH) and the mechanism underlying the decrease. Basilar artery in situ was 35% constricted 3 days following injection of autologous arterial blood into the rabbit cisterna magna compared with vessels from control rabbits. In situ suffusion with the endothelium-dependent relaxant, acetylcholine (ACh; 10 microM), relaxed resting and serotonin (5-HT)-contracted control vessels but not vasospastic and 5-HT-contracted vasospastic vessels. In contrast, the relaxant potency and efficacy of ACh was similar in control and vasospastic vessels contracted with 5-HT in vitro. In situ suffusion with the ETA-receptor antagonist, BQ-123 (1 microM), reversed the vasospasm by 51% and restored the magnitude of ACh relaxation of vasospastic and 5-HT-contracted vasospastic vessels to that of controls. ACh in situ and in vitro relaxed endothelin-1 (ET-1)-contracted control vessels to a smaller magnitude than 5-HT-contracted control vessels. These results suggest, in contrast to previous studies, that endothelium-dependent relaxation is decreased during acute vasospasm following SAH. The decreased endothelium-dependent relaxation is secondary to the underlying ET-1-mediated spasm. The inhibition of endothelium-dependent relaxation observed in situ following SAH cannot be demonstrated in vitro, presumably due to loss of the ET-1-mediated vasospasm.

Acetylcholine↗
PubMed1997

Inhibition of K(V) and K(Ca) channels antagonizes NO-induced relaxation in pulmonary artery.

Endogenous nitric oxide (NO) may contribute to the maintenance of normal pulmonary vasomotor tone, and inhaled NO is used to treat patients with pulmonary hypertension. Because pulmonary vascular tone is regulated by intracellular free Ca2+ concentration and membrane potential, which are controlled by the K+ channel activity in pulmonary artery (PA) smooth muscle cells, we sought to determine whether K+ channels are involved in NO-induced relaxation and, if so, which types of K+ channels are responsible. Authentic NO (approximately 0.3 microM) and sodium nitroprusside (SNP, 10 pM) both produced significant relaxation in isolated PA rings precontracted by increasing extracellular K+ concentration. Further elevation of the K+ concentration from 20 to 60 mM resulted in a significant increase in contraction but caused a marked decline in SNP- and NO-mediated PA relaxation. The dependence of SNP- and NO-induced relaxation on transmembrane K+ gradient suggests that K+ efflux through K+ channels is involved in these effects. Furthermore, 4-aminopyridine (4-AP, 5-10 mM), which blocks voltage-gated K+ channels (K(V)), and charybdotoxin (200 nM), which blocks Ca2+-activated K+ channels (K(Ca)), both significantly inhibited NO- and SNP-induced PA relaxation. The ATP-sensitive K+ channel blocker glibenclamide, however, had no effect on the relaxation response. The blocking of guanylate cyclase diminished, but did not abolish, the NO-induced relaxation, whereas 4-AP further decreased the NO-induced relaxant response in the presence of the guanylate cyclase inhibitor LY-83583. These data suggest that activation of both K(V) channels and K(Ca) channels by guanosine 3',5'-cyclic monophosphate-dependent and -independent pathways is a mechanism, at least in part, by which NO induces PA relaxation.

4-Aminopyridine↗
PubMed1999

Inhibition of guanylate cyclase stimulation by NO and bovine arterial relaxation to peroxynitrite and H2O2.

The inhibitor of soluble guanylate cyclase (sGC) stimulation by nitric oxide (NO), 1H-[1,2,4]oxadiazolo[4,3-a]quinoxalin-1-one (ODQ), was examined for its effects on the prolonged relaxation of endothelium-removed bovine coronary (BCA) and pulmonary (BPA) arteries to peroxynitrite (ONOO-) and on H2O2-elicited relaxation and sGC stimulation. Our previous studies suggest that ONOO- causes a prolonged relaxation of BPA by regenerating NO and that a 2-min exposure of BCA or BPA to 50 nM NO causes an ONOO--elicited relaxation. The relaxation of K+-precontracted BCA to 50 nM NO or 100 microM ONOO- was essentially eliminated by 10 microM ODQ. ODQ also eliminated relaxation to 0.1 nM-10 microM of NO donor S-nitroso-N-acetyl-penicillamine (SNAP), but it did not alter relaxation to 1-300 microM H2O2. Similar responses were also observed in BPA. ODQ did not increase lucigenin-detectable superoxide production in BCA, and it did not alter luminol-detectable endogenous ONOO- formation observed during a 2-min exposure of BCA to 50 nM NO. In addition, ODQ did not affect tissue release of NO after 2 min exposure of BCA to 50 nM NO. The activity of sGC in BPA homogenate that is stimulated by endogenous H2O2 was not altered by ODQ, whereas sGC activity in the presence of 10 microM SNAP (+fungal catalase) was reduced by ODQ. Thus relaxation of K+-precontracted BCA and BPA to ONOO- appears to be completely mediated by NO stimulation of sGC, whereas the actions of ODQ suggest that NO is not involved in H2O2-elicited relaxation and sGC stimulation. This study did not detect evidence for the participation of additional mechanisms potentially activated by ONOO- in the responses studied.

Animals↗
PubMed2000

BK(Ca) channels compensate for loss of NOS-dependent coronary artery relaxation in cardiomyopathy.

Previously, we showed that development of myocardial necrotic lesions is associated with impaired endothelium-dependent coronary artery relaxation in young cardiomyopathic hamsters. Since active necrosis declines with aging, this study was designed to determine whether coronary artery endothelium-dependent relaxation to ACh is restored and to identify the mechanisms mediating this effect. Intraluminal diameter was recorded in coronary arteries (150-250 micrometer) from control (C, 297 +/- 5 days old) and cardiomyopathic (M, 296 +/- 4 days old) hamsters. Relaxation to ACh (10(-9)-3 x 10(-5) M) was similar in vessels from C and M hamsters. However, mechanisms mediating relaxation to ACh were altered. Inhibition of nitric oxide synthase (NOS) activity with N-nitro-L-arginine (1 mM) had a greater inhibitory effect in vessels from C hamsters, indicating a reduction in NOS-dependent relaxation in vessels from M hamsters. Conversely, inhibition of large Ca(2+)-dependent K(+) (BK(Ca)) channels with charybdotoxin (CTX, 0.1 microM) had a greater inhibitory effect in vessels from M hamsters. In the presence of both N-nitro-L-arginine and CTX, relaxation to ACh was abolished in both groups. CTX (0.1 micrometer) produced a 50 +/- 4 and 30 +/- 3% contraction of vessels from M and C hamsters, respectively, indicating an enhanced role for BK(Ca) channels in regulation of coronary artery tone in M hamsters. Finally, vasodilatory cyclooxygenase products contributed to ACh-induced relaxation in vessels from M, but not C, hamsters. In conclusion, NOS-dependent relaxation of coronary small arteries is reduced in the late stage of cardiomyopathy. An increase in relaxation mediated by BK(Ca) channels and vasodilatory cyclooxygenase products compensates for this effect.

Acetylcholine↗
PubMed1997

Adenosine receptor-mediated relaxation of rabbit airway smooth muscle: a role for nitric oxide.

In this study, we investigated the relaxant effect of adenosine receptor agonists on KCl-precontracted airway smooth muscle from rabbits and characterized the type of receptor involved in bronchorelaxation in the presence and absence of epithelium. We further defined the role of epithelium-derived relaxing factor, i.e., nitric oxide (NO), on these responses. In both epithelium-intact and -denuded tertiary airway rings from rabbits, the adenosine receptor agonists 2-[p-(2-carboxyethyl)]phenylethylamino-5-N'-ethylcarboxamidoadenos ine (CGS-21680), 5'-(N-ethyl-carboxamido)adenosine (NECA), 2-chloroadenosine (CAD), and (-)-N6-(2-phenylisopropyl)adenosine (R-PIA) relaxed airway smooth muscle with a potency order of CGS-21680 > NECA > CAD > R-PIA. A 98.5, 89.7, 73.2, and 64.7% relaxation was observed at 10(-5) M by CGS-21680, NECA, CAD, and R-PIA in the epithelium-intact bronchial rings, respectively. The 50% maximum effective concentration (EC50; x 10(-7) M) values for CGS-21680, NECA, CAD, and R-PIA were 2, 4, 9, and 80, respectively. Denuded rings, however, showed much less relaxant responses to various adenosine agonists compared with epithelium-intact rings. The adenosine receptor antagonist 8-(sulfophenyl)theophylline significantly attenuated the relaxant responses to all the agonists in the epithelium-intact and -denuded rings. The epithelium-dependent relaxant effect of the agonists in airway rings was inhibited by NG-monomethyl-L-arginine (L-NMMA; 30 microM). The EC50 (x 10(-6) M) values for CGS-21680, NECA, CAD, and R-PIA in the presence of inhibitor were 5.5, 8, 30, and 200, respectively. The L-NMMA produced an insignificant inhibitory effect in the epithelium-denuded rings. L-Arginine but not D-arginine (100 microM) reversed the inhibitory effect of L-NMMA on adenosine agonist-induced relaxation. In primary epithelial cells in culture, CGS-21680 (10(-5) M) induced a fourfold increase in NO production over the control. The CGS-21680-induced NO production in epithelial cells was significantly inhibited by NG-nitro-L-arginine methyl ester (L-NAME). Moreover, L-arginine reversed the inhibitory effect of L-NAME in the epithelial cells. The data suggest that adenosine relaxes rabbit airway smooth muscle through an A2 adenosine receptor and the epithelium serves as a source of NO.

2-Chloroadenosine↗
PubMed1997

Effects of hypoxia on diaphragm relaxation rate during fatigue.

Skeletal muscle fatigue is associated with a slowing of relaxation rate. Hypoxia may increase the rate at which fatigue occurs, but, surprisingly, mild to moderate hypoxia has not been found to augment the degree of slowing of relaxation during fatigue. The present study tested the hypothesis that severe hypoxia interacts with fatigue in slowing the rate of muscle relaxation and that this can be modulated by altering membranous ionic conductances. Rat diaphragm muscle strips were studied in vitro while aerated with 95% O2-5% CO2 (normoxia) or 95% N2-5% CO2 (hypoxia). During continuous 0.1-Hz stimulation, relaxation rate and force remained stable over time, and relaxation rate was not slowed by hypoxia. Hypoxia accelerated force decline during continuous 5-Hz but not intermittent 20-Hz stimulation. During both 5- and 20-Hz stimulation, relaxation rate became slower over time as force declined, the extent of which was increased significantly by hypoxia. The extent of hypoxia-augmented slowing of relaxation rate during fatigue increased over time and was greater than expected for a given degree of force loss. 4-Aminopyridine did not attenuate or partially attenuated, whereas lowering extracellular Cl-concentration fully attenuated, the hypoxia-induced prolongation of relaxation rate during repetitive stimulation. Thus hypoxia slows relaxation rate to a greater extent than expected for a given degree of force decline, an effect that increases over time, is at most partially attenuated by lowering K+ conductance, and is fully attenuated by lowering membranous Cl-conductance.

4-Aminopyridine↗
PubMed2005

Endurance exercise training improves endothelium-dependent relaxation in brachial arteries from hypercholesterolemic male pigs.

We tested the hypothesis that exercise (Ex) training attenuates hypercholesterolemia-induced impairment of endothelium-dependent relaxation (EDR) in brachial (Br) arteries of adult male pigs by enhancing nitric oxide (NO)-mediated EDR. Adult male pigs were fed a normal-fat (NF) or high-fat/cholesterol (HF) diet for 20 wk. Four weeks after the diet was initiated, pigs were trained or remained sedentary (Sed) for 16 wk, yielding four groups: 1) NF-Sed, 2) NF-Ex, 3) HF-Sed, and 4) HF-Ex. EDR of Br artery rings was assessed in vitro with acetylcholine (ACh) and bradykinin (BK). ACh- and BK-induced relaxation was not impaired by HF; however, relaxation responses were enhanced by Ex in NF and HF arteries. To determine the mechanism(s) by which Ex improved EDR, ACh- and BK-induced relaxation was assessed in the presence of N(G)-nitro-l-arginine methyl ester (l-NAME; to inhibit NO synthase), indomethacin (Indo; to inhibit cyclooxygenase), or l-NAME + Indo. ACh- and BK-induced relaxation was inhibited by l-NAME, and l-NAME + Indo, in all groups of arteries. Indo did not inhibit ACh-induced relaxation in any group but did inhibit BK-induced relaxation in HF-Ex arteries. In the presence of l-NAME or l-NAME + Indo, ACh- and BK-induced relaxation in HF-Ex arteries remained greater than in HF-Sed arteries. However, in the presence of Indo, ACh-induced relaxation in HF-Ex arteries was no longer greater than in HF-Sed arteries. These results indicate that EDR is not impaired by hypercholesterolemia in Br arteries from adult male pigs; however, Ex improves EDR in HF Br arteries by enhancing production of endothelium-derived hyperpolarizing factor and/or prostacyclin.

Acetylcholine↗
PubMed2003

Exercise attenuates the effects of hypercholesterolemia on endothelium-dependent relaxation in coronary arteries from adult female pigs.

We tested the hypothesis that exercise training (Ex) attenuates the effects of hypercholesterolemia on endothelium-dependent relaxation in left anterior descending coronary arteries. Adult female pigs were fed a normal-fat (NF) or high-fat (HF) diet for 20 wk. Four weeks after the diet was initiated, pigs were trained or remained sedentary (Sed) for 16 wk, yielding four groups of pigs: 1) NF-Sed, 2) NF-Ex, 3) HF-Sed, and 4) HF-Ex. Sensitivity (EC(50)) to bradykinin (BK) was impaired in HF-Sed arteries. Ex improved BK-induced relaxation such that the EC(50) and maximal response to BK in HF-Ex arteries was not different from that in NF-Sed and NF-Ex. ACh-induced constriction was less in HF-Ex arteries than in HF-Sed, NF-Sed, and NF-Ex. To determine the mechanism(s) by which HF and Ex affected responses to BK and ACh, vasoactive responses were assessed in the presence of N(G)-nitro-L-arginine methyl ester [L-NAME; to inhibit nitric oxide (NO) synthase], indomethacin (Indo; to inhibit cyclooxygenase), and L-NAME + Indo. L-NAME inhibited BK-induced relaxation in NF (not HF) arteries. Indo did not significantly alter relaxation to BK in NF arteries; however, relaxation was enhanced in HF-Sed arteries. Double blockade with L-NAME + Indo attenuated BK-induced relaxation in NF arteries and eliminated relaxation in HF arteries. Neither L-NAME nor Indo altered constrictor responses to ACh in NF or HF arteries; however, double blockade with L-NAME + Indo attenuated constriction to ACh in NF-Ex arteries. Endothelium-independent relaxation to sodium nitroprusside was enhanced in HF-Sed and HF-Ex arteries. Collectively, these results indicate that HF impaired endothelial function in coronary arteries by impairing production of NO and by enhancing production of a constrictor that was inhibited by Indo. Ex attenuated the effects of hypercholesterolemia by improving NO-mediated, endothelium-dependent relaxation and by reducing the influence of the Indo-sensitive constrictor.

Animals↗
PubMed1986

Regional variation in beta-adrenoceptor-mediated relaxation of canine veins.

Three types of vasorelaxants were used to test the responses of canine veins isolated from 13 different sites: isoproterenol, papaverine and nitroglycerin. Strips were preconstricted with methoxamine (5 X 10(-6)-10(-5) M), KCl (50 mM) and PGF2 alpha (1 microgram/ml), and were relaxed by cumulative addition of relaxants. Isoproterenol caused more than 80% relaxation after preconstriction with methoxamine in cephalic, external jugular, azygos, renal, femoral, lateral saphenous veins and the supradiaphragmatic and infrarenal portions of the inferior vena cava, all of which are veins of the body wall. Pulmonary and splenic veins also showed marked relaxation with isoproterenol. However, maximal relaxation responses of portal, mesenteric veins and segment C of the inferior vena cava (a portion between liver and renal veins), which are embryologically related to the digestive tube, were less than 30%. Similar regional differences in the relaxation responses to isoproterenol were obtained after preconstriction with KCl or PGF2 alpha. Papaverine and nitroglycerin caused nearly uniform relaxation in all veins, although relaxations of segment C of the inferior vena cava were slightly less than those of other veins. These results indicated that there is a regional difference in the relaxation responses of the canine venous system to isoproterenol, and such a difference may be related to its embryogenesis.

Animals↗
PubMed1995

Relaxation of the carotid artery to hypoxia is impaired in Watanabe heritable hyperlipidemic rabbits.

We tested the hypothesis that relaxation of the carotid artery during hypoxia is mediated by activation of glibenclamide-sensitive potassium channels and that this response is impaired in hyperlipidemic rabbits. In New Zealand White rabbits (plasma cholesterol, 69 +/- 12 mg/dL, mean +/- SEM) and Watanabe heritable hyperlipidemic (WHHL) rabbits (plasma cholesterol, 677 +/- 99 mg/dL), tension of the carotid artery was measured in an organ bath under control conditions and during two levels of hypoxia. In normal rabbits, mild hypoxia produced 21 +/- 2% relaxation in arteries precontracted with phenylephrine. Removal of endothelium or the nitric oxide synthase inhibitor NG-nitro-L-arginine (10(-4) mol/L) almost abolished relaxation in response to mild hypoxia in normal rabbits. Glibenclamide (10(-6) mol/L), an inhibitor of ATP-sensitive potassium channels, attenuated relaxation during mild hypoxia by almost 60%. In WHHL rabbits mild hypoxia relaxed the carotid artery by only 9 +/- 4% (P < .05 versus normal rabbits). Severe hypoxia produced greater relaxation of the carotid artery in normal than in WHHL rabbits (85 +/- 5% versus 52 +/- 8%, respectively, P < .05). Glibenclamide but not endothelial denudation or NG-nitro-L-arginine attenuated relaxation during severe hypoxia in normal and WHHL rabbits. Relaxation of the carotid artery to sodium nitroprusside was similar in normal and WHHL rabbits. These findings suggest that relaxation of the carotid artery in response to mild and severe hypoxia is impaired in WHHL rabbits and is mediated, in large part, by activation of glibenclamide-sensitive potassium channels.(ABSTRACT TRUNCATED AT 250 WORDS)

Acetylcholine↗
PubMed1993

Congestive heart failure alters receptor-dependent cAMP-mediated relaxation of canine pulmonary arteries.

BACKGROUND: Alterations in myocardial function and systemic vascular tone are well documented in congestive heart failure (CHF), but little information is available on the effects of CHF on pulmonary vessels. We examined the mechanisms of tone regulation of canine pulmonary arteries during pacing-induced CHF. METHODS AND RESULTS: Rings 3-4 mm wide from lobar pulmonary arteries were prepared from normal dogs, dogs paced at 210 beats per minute for 3 weeks (paced group, nonfailure), and dogs also paced at 240 beats per minute during the fourth week to induce severe heart failure (CHF group). Contractile responses to 60 mmol/L KCl and phenylephrine and relaxation responses to acetylcholine, bradykinin (endothelium-dependent cyclic GMP [cGMP]-mediated), isoproterenol, arachidonic acid, prostacyclin (receptor-dependent cyclic AMP [cAMP]-mediated), forskolin (direct stimulator of adenylate cyclase), a forskolin analogue (devoid of adenylate cyclase-dependent activity), and RO 20-1724 (phosphodiesterase inhibitor) were characterized. The paced group did not show alterations in vascular reactivity. Contractile response to phenylephrine and cGMP-mediated relaxation responses were not altered in the CHF group; however, receptor-mediated cAMP-induced relaxation responses were significantly inhibited (p < 0.05). Relaxation responses to isoproterenol (10(-6) mol/L), arachidonic acid (10(-5) mol/L), and prostacyclin (10(-5) mol/L) were reduced by 56%, 72%, and 74%, respectively. The relaxation response to RO 20-1724 was not affected by CHF, and this probe did not enhance the impaired relaxation response to isoproterenol. Forskolin-induced relaxation was not altered, and the forskolin analogue produced minimal relaxation compared with forskolin. CONCLUSIONS: These findings suggest that in pacing-induced CHF, canine pulmonary arteries show a selective defect in receptor coupling to cAMP-dependent relaxation mechanisms. There is no evidence of enhanced degradation of cAMP.

4-(3-Butoxy-4-methoxybenzyl)-2-imidazolidinone↗
PubMed2005

Stable 5,6-epoxyeicosatrienoic acid analog relaxes coronary arteries through potassium channel activation.

5,6-epoxyeicosatrienoic acid (5,6-EET) is a cytochrome P450 epoxygenase metabolite of arachidonic acid that causes vasorelaxation. However, investigations of its role in biological systems have been limited by its chemical instability. We developed a stable agonist of 5,6-EET, 5-(pentadeca-3(Z),6(Z),9(Z)-trienyloxy)pentanoic acid (PTPA), in which the 5,6-epoxide was replaced with a 5-ether. PTPA obviates chemical and enzymatic hydrolysis. In bovine coronary artery rings precontracted with U46619, PTPA (1 nmol/L to 10 micromol/L) induced concentration-dependent relaxations, with maximal relaxation of 86+/-5% and EC50 of 1 micromol/L. The relaxations were inhibited by the cyclooxygenase inhibitor indomethacin (10 micromol/L; max relaxation 43+/-9%); the ATP-sensitive K+ channel inhibitor glybenclamide (10 micromol/L; max relaxation 49+/-6%); and the large conductance calcium-activated K+ channel inhibitor iberiotoxin (100 nmol/L; max relaxation 38+/-6%) and abolished by the combination of iberiotoxin with indomethacin or glybenclamide or increasing extracellular K+ to 20 mmol/L. Whole-cell outward K+ current was increased nearly 6-fold by PTPA (10 micromol/L), which was also blocked by iberiotoxin. Additionally, we synthesized 5-(pentadeca-6(Z),9(Z)-dienyloxy)pentanoic acid and 5-(pentadeca-3(Z),9(Z)-dienyloxy)pentanoic acid (PDPA), PTPA analogs that lack the 8,9 or 11,12 double bonds of arachidonic acid and therefore are not substrates for cyclooxygenase. The PDPAs caused concentration-dependent relaxations (max relaxations 46+/-13% and 52+/-7%, respectively; EC50 1micromol/L), which were not altered by glybenclamide but blocked by iberiotoxin. These studies suggested that PTPA induces relaxation through 2 mechanisms: (1) cyclooxygenase-dependent metabolism to 5-ether-containing prostaglandins that activate ATP-sensitive K+ channels and (2) activation of smooth muscle large conductance calcium-activated K+ channels. PDPAs only activate large conductance calcium-activated K+ channels.

8,11,14-Eicosatrienoic Acid↗