ACh-induced Vasorelaxation Research Articles

Calcitonin Gene-Related Peptide Mediates Acetylcholine-Induced Endothelium-Independent Vasodilation in Mesenteric Resistance Blood Vessels of the Rat

The role of calcitonin gene-related peptide (CGRP)-containing vasodilator nerves in acetylcholine chloride (ACh)-induced vasodilation was studied in the perfused mesenteric vascular bed isolated from the rat. Bolus infusions of ACh at smaller doses (0.1 and 1 nmol) produced rapid and short-lived vasodilation. However, larger doses (10 and 100 nmol) of ACh caused a rapid and subsequent long-lasting vasodilator response in which the duration of vasodilation was prolonged in a concentration-dependent manner. Pretreatment with capsaicin (1 mumol/L for 20 minutes) significantly shortened the duration of vasodilator response to ACh but did not affect the initial rapid phase of ACh-induced vasodilation. Chemical removal of the vascular endothelium by perfusion with sodium deoxycholate (1.75 to 1.80 mg/mL) for 30 seconds and subsequent treatment with N omega-nitro-L-arginine (100 mumol/L) to inhibit nitric oxide synthesis abolished the initial rapid vasodilator action of ACh at any given concentration. However, in the same preparation, increasing concentrations (from 1 to 1000 nmol) of ACh produced only the long-lasting vasodilator responses in a concentration-dependent manner. This long-lasting vasodilator response to ACh infusion was abolished by capsaicin pretreatment (1 mumol/L), human CGRP[8-37] (CGRP receptor antagonist, 1 mumol/L), and atropine (muscarinic ACh receptor antagonist, 1, 10, and 100 nmol/L) but not by hexamethonium (nicotinic ACh receptor antagonist, 1 and 10 mumol/L). In the preparations without endothelium, the bolus infusion of ACh (300 nmol for 30 seconds) evoked a long-lasting vasodilation and release of CGRP-like immunoreactivities into the perfusate.(ABSTRACT TRUNCATED AT 250 WORDS)

Endothelium-derived relaxing factors in the kidney of spontaneously hypertensive rats

Acetylcholine (ACh)-induced vasodilation is mainly due to endothelium-derived nitric oxide (EDNO) and hyperpolarizing factor (EDHF). To explore the mechanisms underlying attenuated endothelium-dependent vasodilation in hypertensive arteries, we measured the EDNO released from isolated kidneys of spontaneously hypertensive rats (SHR) using a sensitive chemiluminescence assay system of NO. ACh-induced renal vasodilation was significantly smaller in SHR than in the normotensive control, Wistar-Kyoto rats (WKY). However, ACh-induced NO release did not differ between SHR and WKY (10 −7 M: SHR +37 ± 2 [SE] vs. WKY +32 ± 4 fmol/min/g kidney). Perfusion with a 20 mEq/L high-K + buffer, which is reported to inhibit action of EDHF, significantly reduced ACh-induced vasorelaxation in WKY but not in SHR, resulting in identical renal perfusion pressure in SHR and wKY under these conditions. These results indicate that attenuated ACh-induced vasorelaxation in the SHR kidney may be attributed to a decrease in EDHF rather than that in EDNO.

Mechanisms for altered endothelium-dependent vasorelaxation in isolated kidneys from experimental hypertensive rats

To study mechanisms for attenuated endothelium-dependent vasorelaxation in hypertension, we examined the effects of acetylcholine (ACh) on renal vascular resistance (RVR) and release rates of endothelium-derived relaxing factor (EDRF) in kidneys isolated from spontaneously hypertensive rats (SHR), deoxycorticosterone acetate (DOCA) salt-hypertensive (DOCA salt) rats, and Dahl salt-sensitive (Dahl S) rats. Decreases in RVR by ACh were smaller in hypertensive rats than in their normotensive controls. The release rate of nitric oxide into the perfusate, which was estimated using nitrite-nitrate as an index, did not differ between SHR and Wistar-Kyoto rats (WKY). However, the release rate of EDRF was markedly decreased in both DOCA salt rats and Dahl S rats compared with their normotensive controls (10(-7) M ACh: DOCA salt 45 +/- 6 vs. control 410 +/- 60 pmol.min-1.g-1 kidney wt, P < 0.001). In SHR, high-K+ perfusion or pretreatment with glibenclamide, inhibitors of endothelium-derived hyperpolarizing factor (EDHF), significantly reduced ACh-induced vasorelaxation only in WKY, resulting in no differences in the RVR reduction between SHR and WKY. Thus attenuated ACh-induced vasorelaxation in the SHR kidney may be attributed to a decrease in EDHF, but to a decrease in EDRF in DOCA salt rats and Dahl S rats.

L‐NG‐nitro arginine (l‐NOARG), a novel, l‐arginine‐reversible inhibitor of endothelium‐dependent vasodilatation in vitro

1. The effect of L-NG-nitro arginine (L-NOARG) was compared with that of L-NG-monomethyl arginine (L-NMMA) on vasodilatation of the isolated aorta of the rabbit and perfused mesentery of the rat in response to acetylcholine (ACh) and sodium nitroprusside (NP). 2. L-NOARG (1.5-100 microM) and L-NMMA (3-100 microM) produced concentration-related contraction of the rabbit aorta precontracted with phenylephrine (700-900 nM). Similarly, L-NOARG (10-200 microM) and L-NMMA (30-100 microM) elevated perfusion pressure of the noradrenaline (NA, 0.6-2.5 mM)-preconstricted rat mesentery preparation. 3. L-NOARG (1.5-100 microM) and L-NMMA (3-100 microM) caused concentration-related inhibition of the vasodilator effect of ACh (0.01-1.0 microM) on the rabbit aorta without influencing responses to NP (0.03-0.5 microM). L-NOARG methyl ester (30 microM) also inhibited ACh-induced vasorelaxation with similar potency to NOARG. L-arginine (30-150 microM) but not D-arginine (100 microM) caused graded reversal of the inhibitory effect of both L-NOARG (15 microM) and L-NMMA (30 microM). Complete reversal of the effect of both inhibitors was achieved with 150 microM L-arginine. L-Alanine (50 microM), L-arginosuccinic acid (5 microM), L-citrulline (50 microM), L-methionine (50 microM) and L-ornithine (50 microM) failed to reverse the inhibitory effect of L-NOARG (15 microM). 4. L-NOARG (10-200 microM) and L-NMMA (30-100 microM) inhibited the vasodilator effect of ACh (0.006-18.0 nmol) in the rat mesentery without affecting vasodilatation due to NP (1.1-11.1 nmol). L-Arginine (100 microM) but not D-arginine (100 microM) produced partial reversal of the effect of L-NOARG (30 microM) and L-NMMA (30 microM). 5. L- and D-N'-butyloxycarbonyl No-nitro arginine (100 microM) produced modest (approximately 20%) inhibition of the effect of ACh on the rabbit aorta; this effect was not reversible with L-arginine (100 microM). L-Namonocarbobenzoxy arginine (L-NMCA, 5O microM), L-N-NG-dicarbobenzoxy arginine (L-NDCA, 5 microM) and L-NG-tosyl arginine (50 microM) were inactive. 6. These results identify L-NOARG as a potent, L-arginine reversible inhibitor of endothelium-dependent vasodilatation. The available data suggests that L-NOARG, like L-NMMA, inhibits endothelial nitric oxide (NO) biosynthesis.

A submaximal test for dogs: evaluation of effects of training, detraining, and cage confinement.

ArticleA submaximal test for dogs: evaluation of effects of training, detraining, and cage confinement.C M Tipton, R A Carey, W C Eastin, and H H EricksonC M Tipton, R A Carey, W C Eastin, and H H EricksonPublished Online:01 Aug 1974https://doi.org/10.1152/jappl.1974.37.2.271MoreSectionsPDF (1 MB)Download PDF ToolsExport citationAdd to favoritesGet permissionsTrack citations ShareShare onFacebookTwitterLinkedInWeChat Previous Back to Top Next Download PDF FiguresReferencesRelatedInformation Cited ByClinical use of submaximal treadmill exercise testing and assessments of cardiac biomarkers NT-proBNP and cTnI in dogs with presymptomatic mitral regurgitation14 June 2018 | PLOS ONE, Vol. 13, No. 6Exercise-Induced Cardiac Remodeling: Lessons from Humans, Horses, and Dogs12 February 2017 | Veterinary Sciences, Vol. 4, No. 4Howard H. 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Fred Downey1 August 2001 | American Journal of Physiology-Heart and Circulatory Physiology, Vol. 281, No. 2Interaction of gender and exercise training: vasomotor reactivity of porcine skeletal muscle arteriesM. Harold Laughlin, William G. Schrage, Richard M. McAllister, H. A. Garverick, and A. W. Jones1 January 2001 | Journal of Applied Physiology, Vol. 90, No. 1SOD-1 expression in pig coronary arterioles is increased by exercise trainingJames W. E. Rush, M. Harold Laughlin, Christopher R. Woodman, and Elmer M. Price1 November 2000 | American Journal of Physiology-Heart and Circulatory Physiology, Vol. 279, No. 5Exercise training restores adenosine-induced relaxation in coronary arteries distal to chronic occlusionCristine L. Heaps, Michael Sturek, Julie A. Rapps, M. Harold Laughlin, and Janet L. Parker1 June 2000 | American Journal of Physiology-Heart and Circulatory Physiology, Vol. 278, No. 6Chronic exercise training does not alter pulmonary vasorelaxation in normal pigsLynelle R. Johnson, and M. Harold Laughlin1 June 2000 | Journal of Applied Physiology, Vol. 88, No. 6Chronic exercise training improves ACh-induced vasorelaxation in pulmonary arteries of pigsLynelle R. Johnson, Janet L. Parker, and M. Harold Laughlin1 February 2000 | Journal of Applied Physiology, Vol. 88, No. 2Exercise training improves endothelium-mediated vasorelaxation after chronic coronary occlusionKawanza L. Griffin, M. Harold Laughlin, and Janet L. Parker1 November 1999 | Journal of Applied Physiology, Vol. 87, No. 5Effect of endurance training on cardiac morphology in Alaskan sled dogsR. L. Stepien, K. W. Hinchcliff, P. D. Constable, and J. Olson1 October 1998 | Journal of Applied Physiology, Vol. 85, No. 4Vasoconstrictor responses of coronary resistance arteries in exercise-trained pigsM. Harold Laughlin, and Judy M. 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An extra small metacentric autosome in a mentally retarded boy with multiple malformations.

This study tested the hypothesis that increased nitric oxide (NO) inactivation and concurrent peroxynitrite formation is responsible for endothelial dysfunction in the spontaneously hypertensive stroke-prone rat (SHRSP). In SHRSP, the aortic vasorelaxation to acetylcholine (ACh) was decreased (<i>p</i> &lt; 0.05), but NO production was unchanged. Nitrotyrosine staining, a footprint of peroxynitrite (ONOO⁻) formation, was detected. Exposure of SHRSP to a high-salt, high-fat diet (SFD) further exacerbated hypertension and accelerated end-organ disease. A severe endothelial dysfunction [maximal ACh relaxation: 49.8 ± 2.1 versus 94.5 ± 1.8% in Wistar-Kyoto rats (WKY), <i>p</i> &lt; 0.01], increased basal NO production (482 ± 17 versus 356 ± 21 nM,<i>p</i> &lt; 0.01), decreased ACh-stimulated NO production (57 ± 6 versus 112 ± 6 nM, <i>p</i> &lt; 0.01), extensive inducible NO synthase and nitrotyrosine staining, elevated nitrotyrosine content (21-fold increase over WKY), and a high percentage of cells with DNA damage were observed in the aortic tissues from these animals. Treatment of SHRSP on SFD with carvedilol restored ACh-induced vasorelaxation and NO production, inhibited nitrotyrosine formation, reduced vascular cell DNA damage, and reduced end-organ injury. These data demonstrate that endothelial dysfunction was caused by increased NO inactivation alone (SHRSP) or in combination with decreased NO production from endothelial NO synthase (SHRSP on SFD). Antioxidant treatment with carvedilol exerted significant vascular protective effects, attenuated end-organ damage, and decreased mortality under these conditions.