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PubMed1993

Contraction and endothelium dependent relaxation via alpha adrenoceptors are variable in various pig arteries.

OBJECTIVE: The aim was to examine differences in the vascular response to alpha adrenoceptor stimulation on both smooth muscle and endothelium among large arteries perfusing various organs. METHODS: In ring preparations of coronary, carotid, iliac, mesenteric, and renal arteries from pigs (n = 24), the magnitudes of contraction to noradrenaline (with beta blocker), with or without endothelium, and endothelium dependent relaxation to noradrenaline (with alpha 1 and beta blocker) were compared in vitro. RESULTS: In both endothelium-intact and denuded groups, the contractions to noradrenaline were significantly smaller in coronary and carotid arteries than in iliac, mesenteric, and renal arteries. The presence of endothelium significantly suppressed the contractions in coronary and carotid arteries, but did not affect the contractions in iliac, mesenteric, and renal arteries. The endothelium dependent relaxations to noradrenaline, which were abolished by LNMMA, were more prominent in coronary and carotid arteries than in iliac, mesenteric, and renal arteries. CONCLUSIONS: The contractions via alpha adrenoceptors were small, and endothelium dependent relaxations via alpha 2 adrenoceptors were large, in the coronary and carotid arteries, which perfuse the vital organs (heart and brain), as compared with those in iliac, mesenteric, and renal arteries. These results suggest that in the state of activation of the sympathetic nervous system, arterial tone in response to alpha adrenoceptor stimulation may be regulated not only by alpha adrenoceptors on vascular smooth muscle but also by those on endothelium, through release of endothelium derived relaxing factor (EDRF) via alpha 2 adrenoceptors.

Animals↗
PubMed1995

Endothelium-modulated proliferation of medial smooth muscle cells: influence of angiotensin II and converting enzyme inhibition.

This study investigated the role of the endothelium and angiotensin II (Ang II) in regulating medial smooth muscle cell (SMC) proliferation. [3H]-thymidine incorporation into medial SMC of rat arteries was examined in vivo, using ballooned rat carotid arteries, as well as in vitro, using cultures of aortic tissue rings (organoids). In vivo, maximal medial [3H]-thymidine incorporation occurred within 3 days post-ballooning. In endothelium-denuded organoids, maximum medial DNA synthesis was achieved after 7 days of culture. [3H]-thymidine-labelling of SMC in intact organoids (with endothelium) increased minimally during culture, indicating that the endothelium provided protection with respect to medial proliferation under basal conditions (culture in the presence of 1% plasma-derived serum). Inclusion of 10(-7) M Ang II significantly elevated medial [3H]-thymidine incorporation above that in control cultures. The stimulatory effect of Ang II was much more pronounced in intact organoids that in endothelium-denuded organoids, indicating synergistic growth regulation by Ang II and endothelium-derived factors. When organoids were cultured in the combined presence of Ang II and the ACE inhibitor cilazaprilat, labelling indices of intact organoids were also significantly increased above control, but to a lower level than those obtained in the presence of Ang II alone. However, for endothelium-denuded organoids, medial [3H]-thymidine incorporation in the combined presence of Ang II and cilazaprilat was not significantly different from that in untreated controls. Thus, cilazaprilat exerts both endothelium-dependent and endothelium-independent negative regulatory effects on medial SMC proliferation.

Angiotensin II↗
PubMed1989

Endothelium-derived relaxing and contracting factors: potential role in coronary artery disease.

Endothelial cells can release substances which profoundly affect vascular tone and platelet function. The inhibitory substances include endothelium-derived relaxing factor (EDRF or nitric oxide), prostacyclin and probably an endothelium-derived hyperpolarizing factor. Endothelin is a potent vasoconstrictor peptide released from endothelial cells. Under certain conditions, the endothelium can also produce angiotensin II, thromboxane A2 and a cyclooxygenase-dependent endothelium-derived contracting factor. In normal arteries, the effects of EDRF appear to dominate. In diseased arteries, the release and action of EDRF is impaired and that of endothelium-derived contracting factors is increased. Hyperlipidaemia, atherosclerosis and hypertension reduce endothelium-dependent relaxations. Hypoxia inhibits the release of EDRF and prolonged ischaemia severely impairs the response. Regenerated endothelium at sites of mechanical injury exhibits selective defects in response to aggregating platelets. The more effective release of EDRF in arterial compared with venous bypass grafts further suggests an involvement of the factor in preventing vascular occlusion. Therapeutic interventions with specific drugs and diets can augment the impaired endothelium-dependent relaxation of diseased arteries. Thus, functional changes of the endothelium in coronary artery disease may be an important factor in the development of vasospasm, ischaemia and thrombosis.

Animals↗
PubMed1999

Salutary effects of ATP-MgCl2 on the depressed endothelium-dependent relaxation during hyperdynamic sepsis.

OBJECTIVES: Studies have shown that endothelium-dependent relaxation (mediated by endothelium-derived nitric oxide) is depressed during the early, hyperdynamic stage of sepsis. Although it is known that ATP-MgCl2 produces beneficial effects following various adverse circulatory conditions, it remains unknown whether this agent attenuates the depressed endothelium-dependent relaxation during early sepsis. The aim of this study, therefore, was to determine whether or not the administration of ATP-MgCl2 early after the onset of sepsis improves or maintains endothelium-dependent relaxation. DESIGN: Prospective, controlled animals study. SETTING: A university research laboratory. SUBJECTS: Adult male Sprague-Dawley rats were subjected to polymicrobial sepsis by cecal ligation and puncture (CLP), followed by administration of 3 mL/100 g body weight normal saline to these and sham-operated rats. INTERVENTIONS: At 1 hr after CLP, ATP-MgCl2 (50 micromol/kg body weight) or an equivalent volume of normal saline was infused intravenously over 90 mins. MEASUREMENTS AND MAIN RESULTS: At 5 hrs or 10 hrs after CLP (i.e., the early, hyperdynamic stage of sepsis), the thoracic aorta was isolated, cut into rings, and placed in organ chambers. Norepinephrine was used to preconstrict vessel rings. Dose responses for an endothelium-dependent vasodilator, acetylcholine (ACh, via endothelium-dependent nitric oxide), and an endothelium-independent vasodilator, nitroglycerin, were determined. These results indicate that endothelium-dependent relaxation induced by ACh was significantly depressed at 5 and 10 hrs after CLP. Administration of ATP-MgCl2 after the onset of sepsis, however, maintained ACh-induced vascular relaxation. In contrast, no significant difference in nitroglycerin-induced vascular relaxation as well as norepinephrine-induced contraction was observed, irrespective of administration of ATP-MgCl2. CONCLUSION: Since administration of ATP-MgCl2 prevents the impaired vascular relaxation to the endothelium-dependent vasodilator ACh, this agent may be a useful adjunct for maintaining endothelial cell function during the hyperdynamic stage of sepsis.

Adenosine Triphosphate↗
PubMed1985

Heterogeneity of endothelium-dependent responses in mammalian blood vessels.

A number of naturally occurring substances can evoke endothelium-dependent responses in isolated blood vessels. In most arteries studied, acetylcholine, adenosine diphosphate (ADP), adenosine triphosphate (ATP), arachidonic acid, bradykinin, and thrombin cause endothelium-dependent relaxations. In veins, however, the endothelium-dependent inhibitory effect of acetylcholine, ATP, and thrombin often is transient and/or modest, as it is masked by the direct stimulating action of these substances on the venous smooth muscle; arachidonic acid evokes endothelium-dependent augmentation of the contractile response to norepinephrine. Aggregating platelets cause an endothelium-dependent relaxation of certain but not all arteries and veins that is probably mediated by released serotonin and ADP. The endothelium of the coronary artery may enhance the relaxations caused by catecholamines. Vasopressin causes endothelium-dependent relaxations in cerebral and coronary arteries but not in systemic blood vessels. Hypoxia causes endothelium-dependent increases in tension in systemic arteries and in pulmonary arteries and veins but not in limb veins. The heterogeneity in endothelium-dependent responsiveness may reflect variations in sensitivity of either endothelial or vascular smooth-muscle cells of different anatomical origin.

Acetylcholine↗
PubMed1993

Effect of endothelium on diabetes-induced changes in constrictor responses mediated by 5-hydroxytryptamine in rat aorta.

We investigated constrictor responses to 5-hydroxytryptamine (5-HT) and 1-(2,5-dimethoxy-4-iodophenyl)-2-aminopropane (DOI, a 5-HT2/5-HT1C receptor agonist) of aortic rings from 2- and 6-week streptozotocin-diabetic and vehicle control rats. At 10 g resting tension, maximum responses and -log EC50 values to 5-HT were significantly reduced in endothelium-intact and denuded aortas from 2- and 6-week diabetic rats relative to those from control rats (except for -log EC50 of endothelium-intact rings from 6-week diabetic rats). Removal of endothelium from aortas of 2- and 6-week diabetic and control rats caused significant increases both in -log EC50 values and in maximum responses to 5-HT. DOI caused marked contraction of endothelium-denuded aortas from control rats, but not of endothelium-intact aortas from control rats or aortas (either with or without endothelium) from diabetic rats. The nitric oxide (NO) synthase inhibitor N-nitro-L-arginine (NOLA) significantly potentiated constrictor responses to 5-HT in endothelium-intact aortas from control and diabetic rats. NOLA significantly potentiated constrictor responses to DOI in endothelium-intact aortas from control rats, but not in endothelium-intact aortas from diabetic rats. These results suggest that for aortas from 2- and 6-week diabetic rats, the diminished responses to 5-HT and DOI may be a result of reductions in 5-HT2-receptor-mediated responses of smooth muscle. The results also suggest that 5-HT and DOI can stimulate NO release from endothelial cells.

Amphetamines↗
PubMed1998

Endothelium-independent relaxation and hyperpolarization to C-type natriuretic peptide in porcine coronary arteries.

Endothelial cells produce C-type natriuretic peptide (CNP), which has been proposed as an endothelium-derived hyperpolarizing factor. In porcine coronary arteries, we investigated the vasodilatory effects of CNP and compared them with endothelium-dependent relaxations and hyperpolarizations to bradykinin. Isolated epicardial porcine coronary arteries were studied in organ chambers, and concentration-response curves to CNP and bradykinin were obtained. Membrane potential was measured in endothelial cells and smooth muscle of intact porcine coronary arteries during stimulation with CNP or bradykinin. In precontracted porcine coronary arteries with or without endothelium, CNP (10[-10]-10[-6] M) evoked relaxations (maximum, 42 +/- 4%) smaller than those evoked by bradykinin (100 +/- 1%), blunted in preparations contracted by KCl instead of U46619 (9,11-dideoxy-11a,9a-epoxymethano-prostaglandin F2alpha; p < 0.05) and unaffected by inhibition of NO synthase (NS). CNP evoked hyperpolarization of vascular smooth muscle of similar magnitude in endothelium-intact (-4.4 +/- 1 mV) and endothelium-denuded (-4.6 +/- 1 mV) porcine coronary arteries. Bradykinin (10[-10]-10[-6] M) evoked concentration-dependent relaxations in preparations with endothelium only. Although atrial natriuretic peptide-receptor antagonist HS-142-1 (25 microM) slightly reduced the sensitivity to bradykinin (log shift at IC50, twofold; p < 0.05), it had no effect on the maximal response to bradykinin. Inhibition of NO synthase partially attenuated, whereas high potassium chloride (30 mM) markedly inhibited relaxations to bradykinin (p < 0.05). Hyperpolarization to bradykinin was much more pronounced than that to CNP (-17 +/- 3 mV; p < 0.05 vs. CNP) and was observed in endothelium-intact preparations only and unaffected by HS-142-1. In conclusion, in contrast to bradykinin, CNP induces endothelium-independent and weaker relaxation and hyperpolarization of coronary artery vascular smooth muscle, suggesting that CNP is an unlikely mediator of endothelium-dependent hyperpolarization of porcine coronary arteries.

Animals↗
PubMed2003

Endothelium-dependent, vasopressin-induced contractions in rabbit renal arteries.

OBJECTIVES: To identify and quantify the stimulatory and inhibitory activity of endothelial factors on Arginine vasopressin (AVP)-induced contractions. METHODS: In a standard organ bath set-up for isometric force recording, rabbit isolated renal artery rings were exposed to cumulative concentrations of AVP. Experiments were performed in the presence or absence of functional endothelium, or in the presence of N-Nitro-L-Arginine 10 microM (L-NNA) (NO-synthase inhibitor). RESULTS: Arginine vasopressin induced a maximal contractile response of 6.5 +/- 0.1 mN in vessels with and 6.3 +/- 0.3 mN in vessels without endothelium. The preincubation with l-NNA resulted in an enhanced response to AVP of 12.6 +/- 0.8 mN (P < 0.05). The augmentation of the AVP induced contractile response by NOS inhibition, which was not seen in preparations after the removal of the endothelium, suggests an endothelium dependent factor that is co-released with NO. The unknown nature of this endothelium dependent contractile factor was not influenced by indomethacin 100 microM (cyclooxygenase inhibitor), meclofenamic acid 20 microM (cyclooxygenase and lipoxygenase inhibitor), or bosentan 100 microM (endothelin antagonist). Charybdotoxin 0.1 microM (inhibitor of Ca2+ -activated K+ channels) specifically increased the contractile force in preparations with and without endothelium, or in the presence of l-NNA to 11.2 +/- 0.4 mN, 14.0 +/- 0.8 mN, and 19.0 +/- 0.8 mN, respectively (P < 0.05 compared with the experiments without charybdotoxin). SR 49059 (vasopressin 1 receptor (V1) antagonist) antagonized the effects of AVP, whereas SR 121463 B (V2 antagonist) was ineffective. In contrast to the results obtained with AVP, desmopressin (V2 agonist) showed no effect. CONCLUSION: The completely V1 dependent AVP-induced contraction is partly inhibited by the stimulated release of NO. This was only demonstrable in endothelium intact vessels in the presence of l-NNA and not after removal of the endothelium. This strongly suggests the involvement of an unknown endothelium V1 receptor dependent contractile factor that is not influenced by inhibition of the prostaglandin, lipoxygenase, or endothelin pathway, or by blockade of the V2 receptor.

Animals↗
PubMed1993

Removal of natural human xenoantibodies to pig vascular endothelium by perfusion of blood through pig kidneys and livers.

We have examined the nature of the binding of human xenoantibodies to pig liver and kidney vascular endothelium. Our results demonstrate that human serum contains IgM and IgG xenoantibodies that bind to pig vascular endothelium, and that the pattern of antibody binding is similar for both livers and kidneys. Immunohistochemical analysis of pig kidneys after perfusion with human blood demonstrated the binding of both IgM and IgG xenoantibodies, complement (C3), and fibrinogen to the vascular and glomerular endothelium. An ELISA assay of the perfusate after perfusion of 500 ml of human blood through a single pig kidney for 60 min demonstrated a significant reduction in the amount of human IgM (67%) and IgG (55%) binding to pig aortic endothelium. Similar perfusion experiments conducted with pig livers were associated with minimal immunohistochemical evidence of the binding of human xenoantibodies to liver vascular endothelium. Immunofluorescence staining for IgM, IgA, C3, and C1q was negative or minimally positive in the liver vascular endothelium. Sinusoidal endothelium were weakly positive for IgG and fibrinogen. The perfusion of the pig liver with human blood was, however, associated with a significant reduction in the subsequent binding of IgM and IgG to pig kidney vascular endothelium. Pig liver perfusion was also responsible for the removal of both IgM and IgG xenoantibodies capable of reacting with pig aortic endothelium, as measured by an ELISA assay of the perfusate. These results suggest that both pig kidney and livers are capable of absorbing the xenoantibodies that may be responsible for mediating a hyperacute rejection of pig xenografts and that the distribution of the target antigens for these antibodies is similar in the two organs.

Animals↗
PubMed2006

Technique for preparation of the corneal endothelium-Descemet membrane complex for transplantation.

PURPOSE: Replacing diseased corneal endothelium with a preparation of Descemet membrane carrying functional endothelium and no stroma may be a feasible method for treating corneal endothelial decompensation. To obtain a viable donor of a Descemet membrane endothelium disc, we modified the Descemet membrane stripping technique and monitored the percentage of endothelial damage to the donor tissue preparation. METHODS: Forty-eight human corneas were used. Cornea buttons were mounted on an artificial anterior chamber, endothelial side up. Endothelia were stained with alizarin red, examined under the microscope, and photographed at 5 different sites (microscope, x100; digital magnification, x2.83). A 6 x 7-mm rectangular piece of endothelium-Descemet membrane complex was obtained using a Grieshaber microsurgical knife and Kelman-McPherson forceps. Digital photographs of endothelia were analyzed with a computer, and the percentage of endothelial damage was calculated. Specimens were processed for hematoxylin-eosin staining. RESULTS: Forty of 48 endothelium-Descemet membrane preparations (83.3%) were complete peels with minimal endothelial damage. Endothelial damage before and after the surgery was 1.57 +/- 2.11% and 2.61 +/- 1.77%, respectively. Eight preparations (16.7%) failed because of tearing. Multiple hematoxylin-eosin-stained sections showed the presence of endothelium with intact Descemet membrane and no stromal tissue. CONCLUSION: We modified the technique of Melles and obtained a sheet of Descemet membrane and endothelium with minimal endothelial damage and with no remaining stroma observed. This simple technique can be used to obtain the endothelium-Descemet membrane complex in minutes. It may be useful for corneal endothelium transplantation.

Adult↗
PubMed1989

Role of endothelium on phenylephrine-triggered contractile events in aorta of spontaneously hypertensive rats.

The ability of basal release of endothelium derived relaxing factor (EDRF) to alter contractile events in phenylephrine (PE)-triggered contraction was tested on ring segments of the thoracic aorta removed from spontaneously hypertensive rats (SHR) and normotensive Wistar-Kyoto rats (WKY). In normal medium, PE (1 microM) elicited similar whole contractions in endothelium denuded arteries of SHR and WKY. The presence of endothelium only reduced the WKY response. On aorta incubated in a Ca2+ free-medium, PE (1 microM) induced an initial phasic contraction due to intracellular Ca2+ release. This was followed by a tonic contraction after Ca2+ (2.5 mM) was restored to the bath. This sustained contraction was dependent on extracellular calcium influx. Identical phasic and tonic contractions were observed in endothelium denuded rings of SHR and WKY. However, the presence of endothelium only reduced the sustained contraction of WKY arteries. When experiments were carried out in medium containing D600 (1 microM), the presence of endothelium diminished the whole contraction of both SHR and WKY rings whereas the sustained but not the phasic contractions of WKY was also inhibited. This inhibitory effect of endothelium on WKY sustained contraction was significantly higher in the presence of D600. The calcium antagonist reduced both the whole and the tonic contractions of all preparations but was ineffective on the phasic one. The D600 inhibitory action on the sustained contraction was more pronounced in denuded SHR rings than in the corresponding WKY arteries. Thus it is concluded that there is a basal influence of endothelium in both SHR and WKY. Under our conditions, the endothelial function inhibited the extracellular Ca2+ influx and especially the part of Ca2+ influx insensitive to D600. This part of Ca2+ influx is diminished in SHR and thus the efficacy of endothelium products (e.g. EDRF) is reduced in this strain.

Animals↗
PubMed1995

Influence of the vascular endothelium on angiotensin II-induced contractions in rabbit renal artery.

The influence of vascular endothelium on angiotensin II-induced contraction and the underlying mechanisms in the rabbit renal artery were investigated. In endothelium-intact preparations, angiotensin II (3-100 nM) caused a concentration-dependent increase in tension by maximally (Emax) 0.74 +/- 0.05 g. Removal of the endothelium significantly enhanced the angiotensin II-induced contractions (Emax: 3.91 +/- 0.19 g). Indomethacin (10 microM) did not influence the angiotensin II-induced contractions. Methylene blue (10 microM) and NG-methyl-l-arginine (L-NMMA, 5 microM) significantly enhanced angiotensin II-induced contractions by 418 +/- 29% and 200 +/- 14%, respectively, in endothelium intact preparations, but not in those devoid of endothelium. L-arginine (1 mM), but not D-arginine, reversed the L-NMMA-induced enhancement of the angiotensin II-induced contraction. The present results suggest that angiotensin II-induced contractions in rabbit renal artery are largely subject to the influence of the endothelium. The endothelium-derived relaxant factor (EDRF), rather than cyclo-oxygenase products, appears to be involved in mediating the inhibitory effects of the endothelium. Nitric oxide (NO) derived from endothelium may play a major role in inhibiting angiotensin II-induced contractions in this preparation.

Angiotensin II↗
PubMed1990

Effects of basal and acetylcholine-induced release of endothelium-derived relaxing factor on contraction to alpha-adrenoceptor agonists in a rabbit artery and corresponding veins.

1. The effects of an endothelium-dependent (acetylcholine) and an endothelium-independent (sodium nitroprusside) relaxant against noradrenaline-induced contractions were compared in three isolated superficial blood vessels of the rabbit, the lateral saphenous vein, plantaris vein and distal saphenous artery. Both produced concentration-related relaxations of all three vessels and were more effective against submaximal than maximal contractions to noradrenaline. Transient contractions to high concentration of acetylcholine occurred only in endothelium-intact preparations of saphenous vein and were inhibited by flurbiprofen. 2. In endothelium-denuded preparations sodium nitroprusside was 3 times more effective than in endothelium-intact preparations, while acetylcholine (less than 3 microM) was inactive. Sensitivity was similar for each relaxant: lateral saphenous vein greater than or equal to plantaris vein greater than distal saphenous artery. The similar profile of sodium nitroprusside and acetylcholine suggests that differences in susceptibility to endothelium-derived relaxing factor (EDRF) are caused by inter-vessel variations in the excitation-coupling process for noradrenaline. 3. Haemoglobin inhibited acetylcholine-induced relaxations in the endothelium-intact preparation of the lateral saphenous vein and distal saphenous artery, which suggests a similar EDRF in each preparation and the likelihood that this is a single substance, presumably nitric oxide. 4. The influence of basal, spontaneously released EDRF on alpha-adrenoceptor function was tested either by mechanical disruption of the endothelium or by adding haemoglobin to endothelium-intact segments. Endothelial disruption slightly reduced contractions to noradrenaline (NA) in distal saphenous artery but increased response size of lateral saphenous and plantaris veins, in the latter also increasing sensitivity to NA: haemoglobin mimicked endothelial disruption. Thus, basal release of EDRF like acetylcholine and nitroprusside was more effective in the veins than in the corresponding artery. 5. In lateral saphenous vein responses to phenylephrine were enhanced by endothelial disruption, but without change in sensitivity: responses to UK-14304, B-HT 920 and cirazoline, which had a relatively slow speed of onset of contraction were not affected. There was no correlation between enhancement and alpha-adrenoceptor sub-type although the agonists which were enhanced all activate alpha 1-adrenoceptors. Competitive antagonists failed to reveal an alpha-adrenoceptor subtype enhanced by endothelial disruption. However, effects of phenoxybenzamine suggest that alpha 1-adrenoceptors are necessary for the influence of basal EDRF.

Acetylcholine↗
PubMed1992

Calmidazolium, a calmodulin inhibitor, inhibits endothelium-dependent relaxations resistant to nitro-L-arginine in the canine coronary artery.

1. The role of calmodulin in endothelium-dependent relaxations in the canine coronary artery, was investigated by use of the inhibitor of calmodulin, calmidazolium. 2. The endothelium-dependent relaxations to adenosine diphosphate (ADP) and nebivolol, a beta-adrenoceptor antagonist, in control solution, and to bradykinin in high potassium solution (to inhibit endothelium-dependent hyperpolarization), were abolished by nitro-L-arginine (30 microM), an inhibitor of nitro oxide-synthase. Calmidazolium (10 microM) did not inhibit these relaxations. 3. Calmidazolium did not affect the endothelium-independent relaxations to SIN-1, an exogenous donor of nitric oxide (NO). 4. The relaxations to bradykinin and to the calcium ionophore A23187 in control solution were inhibited to a small extent by calmidazolium (10 microM). 5. Bradykinin and A23187 induced relaxations in the presence of nitro-L-arginine (30 microM) that were abolished by calmidazolium (10 microM) but not affected by glibenclamide (10 microM), an inhibitor of ATP-sensitive K+ channels. 6. The endothelium-independent relaxations to lemakalim, an ATP-sensitive K+ channel opener, were not affected by calmidazolium (10 microM) but were inhibited by glibenclamide (10 microM). 7. These results suggest that calmidazolium does not inhibit the endothelium-dependent relaxations due to endothelium-derived NO in the canine coronary artery but inhibits either the production of endothelium-derived hyperpolarizing factor (EDHF) from endothelial cells or its effects on vascular smooth muscle cells. Furthermore these results suggest that EDHF contributes to endothelium-dependent relaxations in the canine coronary artery.

Adenosine Diphosphate↗
PubMed1994

Mediation by M3-muscarinic receptors of both endothelium-dependent contraction and relaxation to acetylcholine in the aorta of the spontaneously hypertensive rat.

1. Experiments were designed to characterize the subtype(s) of endothelial muscarinic receptor that mediate(s) endothelium-dependent relaxation and contraction in the aorta of spontaneously hypertensive rats (SHR). 2. Rings of SHR aorta with endothelium were suspended in organ baths for the measurement of isometric force. Ecothiopate (an inhibitor of acetylcholinesterase) was present throughout the experiments. Endothelium-dependent contraction to acetylcholine was studied in quiescent aortic rings in the presence of NG-nitro-L-arginine (to prevent the formation of nitric oxide). Endothelium-dependent relaxation to acetylcholine was obtained during contraction to phenylephrine and in the presence of indomethacin (to inhibit cyclo-oxygenase activity). Responses to acetylcholine were assessed against the non-preferential muscarinic receptor antagonist, atropine, and the preferential antagonists pirenzepine (M1), methoctramine (M2) and 4-diphenylacetoxy-N-methylpiperidine methobromide (4-DAMP; M3). 3. The potency of acetylcholine in inducing endothelium-dependent contraction was 6.54 +/- 0.07 (EC50). Atropine, pirenzepine, methoctramine and 4-DAMP displayed competitive antagonism towards the endothelium-dependent contraction to acetylcholine. The pA2 values for these muscarinic receptor antagonists were estimated from Arunlakshana-Schild plots to be (-log M) 9.48 +/- 0.07, 6.74 +/- 0.22, 6.30 +/- 0.20 and 9.39 +/- 0.22 respectively. The potency of acetylcholine in inducing endothelium-dependent relaxation was 7.82 +/- 0.09 (IC50). Atropine, pirenzepine and 4-DAMP displayed competitive antagonism towards the endothelium-dependent relaxation to acetylcholine but methoctramine had no effect. The pA2 values for atropine and 4-DAMP for the relaxation to acetylcholine were estimated from Arunlakshana-Schild plots to be (-log M) 9.15 +/- 0.23 and 9.63 +/- 0.28, respectively. These results suggest that the muscarinic M3 receptor subtype mediates both endothelium-dependent relaxation and contraction to acetylcholine in SHR aorta.

Acetylcholine↗
PubMed1996

Dual regulation of cerebrovascular tone by UTP: P2U receptor-mediated contraction and endothelium-dependent relaxation.

1. The mechanisms of vascular tone regulation by extracellular uridine 5'-triphosphate (UTP) were investigated in bovine middle cerebral arterial strips. Changes in cytosolic Ca2+ concentration ([Ca2+]i) and force were simultaneously monitored by use of front-surface fluorometry of fura-2. 2. In the arterial strips without endothelium, UTP (0.1 microM-1 mM) induced contraction in a concentration-dependent manner. However, when the endothelium was kept intact, cumulative application of UTP (0.1-100 microM) (and only at 1 mM) induced a modest phasic contraction in arterial strips. This endothelium-dependent reduction of the UTP-induced contraction was abolished by 100 microM N omega-nitro-L-arginine (L-NOARG) but not by 10 microM indomethacin. In the presence of intact endothelium, UTP (30 microM) induced a transient relaxation of the strips precontracted with 30 nM U-46619 (a stable analogue of thromboxane A2), which was completely inhibited by pretreatment with L-NOARG but not with indomethacin. 3. In the endothelium-denuded strips, the contractile response to UTP was abolished by desensitization to either ATP gamma S or ATP (P2U receptor agonists), but not by desensitization to alpha, beta-methylene-ATP (P2x receptor agonist) or to 2-methylthio-ATP (P2Y receptor agonist). Desensitization to UTP abolished the contractile response to ATP. 4. In the endothelium-denuded artery, a single dose application of UTP induced an initial transient, and subsequently lower but sustained increase in [Ca2+]i and force. In the absence of extracellular Ca2+, UTP induced only the initial transient increases in [Ca2+]i and force, while the sustained increases in [Ca2+]i and force were abolished. UTP (1 mM) had no effect on the basic [Ca2+]i-force relationship obtained on cumulative application of extracellular Ca2+ at steady state of 118 mM K(+)-depolarization-induced contraction. 5. We conclude that in the presence of an intact endothelium, UTP-induced relaxation of preconstricted middle cerebral artery is mainly mediated indirectly, by the production of an endothelium-derived relaxing factor, but at high doses of UTP, vascular smooth muscle contraction is mediated directly via activation of P2U purinoceptor and [Ca2+]i elevation without Ca(2+)-sensitization of the contractile apparatus. UTP may thus exert a dual regulatory effect upon cerebrovascular tone, but in cases where the endothelium is impaired, it may also act as a significant vasoconstrictor.

15-Hydroxy-11 alpha,9 alpha-(epoxymethano)prosta-5↗
PubMed2005

Effect of pravastatin on impaired endothelium-dependent relaxation induced by lysophosphatidylcholine in rat aorta.

AIM: To investigate the effects of pravastatin, a potent 3-hydroxy-3-methylglutaryl coenzyme A (HMG-CoA) reductase inhibitor, on impaired endothelium-dependent relaxation induced by lysophosphatidylcholine (LPC), the major component of oxidized low-density lipoprotein, in rat thoracic aorta. METHODS: Both the endothelium-dependent relaxation response to acetylcholine and the endothelium-independent relaxation response to sodium nitroprusside of aortic rings were measured by recording isometric tension after the rings were exposed to LPC in the absence or presence of pravastatin to estimate the injury effect of LPC and the protective effect of pravastatin on the aortic endothelium, respectively. RESULTS: Exposure of aortic rings to LPC (1-10 micromol/L) for 30 min induced a significant concentration-dependent inhibition of endothelium-dependent relaxation to acetylcholine, but did not affect endothelium-independent relaxation in response to sodium nitroprusside. Pre-incubation of aortic rings with pravastatin (0.3-3 mmol/L) for 15 min and then co-incubation of the rings with LPC (3 micromol/L) for another 30 min significantly attenuated the inhibition of endothelium-dependent relaxation induced by LPC. This protective effect of pravastatin (1 mmol/L) was abolished by NG-nitro-L-arginine methyl ester (30 micromol/L), an inhibitor of nitric oxide synthase, but not by indomethacin (10 micromol/L), an inhibitor of cyclooxygenase. Moreover, protein kinase C inhibitor chelerythrine (1 micromol/L) the superoxide anion scavenger superoxide dismutase (200 kU/L), and the nitric oxide precursor L-arginine (3 mmol/L) also improved the impaired endothelium-dependent relaxation induced by LPC, similar to the effects of pravastatin. CONCLUSION: Pravastatin can protect the endothelium against functional injury induced by LPC in rat aorta, a fact which is related to increasing nitric oxide bioavailability.

Alkaloids↗
PubMed1984

Isolated perfused rabbit coronary artery and aortic strip preparations: the role of endothelium-derived relaxant factor.

Isolated perfused coronary arteries and aortic ring preparations of rabbits were studied, both with intact endothelium and with endothelium removed by K-rich solution and friction respectively. Constrictor dose-responses to histamine, acetylcholine, phenylephrine and 5-hydroxytryptamine (5-HT) were measured. They were greatly depressed by the presence of endothelium in coronary preparations. In aortic preparations endothelium affected dose-responses relatively little, depressing the response to acetylcholine but apparently increasing the responses to the other three agents. Acetylcholine relaxed pre-constricted coronary or aortic preparations but only when endothelium was present. This relaxation was inhibited by quinacrine or hydroquinone. Aortic preparations had resting tone which could be increased by hydroquinone if endothelium was present, suggesting continual release of endothelium-derived relaxant factor (EDRF) at rest. When allowance was made for basal EDRF activity in aortic preparations, the maximal constrictor response to acetylcholine remained lower in the presence of endothelium, consistent with acetylcholine stimulation of EDRF, but maximal constrictor responses to the other three agents were the same with and without endothelium, suggesting that the direct constrictor response overrides EDRF activity.

Acetylcholine↗