摘要:

The metabolism of arachidonic acid (AA) into vasoactive products by cyclooxygenase and lipoxygenase enzymes has been well described, as has their biological relevance. Recently, a number of studies have demonstrated the ability of cytochrome P-450 (P450) enzymes to metabolize AA into biologically important regulators of vascular tone. There are two categories of vasoactive P450 metabolites, namely those catalyzed by epoxygenase enzymes which generate epoxyeicosatrienoic acids (EETs) and those enzymes which generate hydroxyeicosatetraenoic acids (HETEs). Except for 20-HETE, P450 metabolites of AA occur as stereo- and regioisomers which determine, to some extent, their biological activity. 5, 6-, 8, 9-, 11, 12- and 14, 15-EETs are generally potent dilators in a number of vascular beds with a sensitivity which appears to increase as the vasculature decreases in size toward capillaries. HETEs, such as 12R- and 20-HETE, can be potent activators of vascular tissue with 20-HETE contracting cerebral and renal microvessels at concentrations of < 10-10M. Both EETs and HETEs can be made by vascular and extravascular tissue. Available data suggests that EETs are formed by endothelial and parenchymal tissue while HETEs can be endogenously formed in arterial muscle where they appear to act as second messengers. This review will discuss the molecular biology, stereochemistry, biological activity and importance of P450 metabolites of AA as para- and autocrine controllers of organ blood flow. We will also discuss the large diversity of P450 enzyme isoforms and how such diversity can provide for precise physiological control of vascular tone.

ISSN:1018-1172    

DOI:10.1159/000159080

出版商:S. Karger AG    

年代:1995

数据来源: Karger

摘要:

To examine the possible role of calcitonin gene-related peptide (CGRP) in the control of human coronary vascular tone, we have investigated the action of this peptide in healthy and atheromatous human epicardial coronary arteries and localised [125I]CGRP-binding sites in these vessels. Isolated arteries were obtained from 10 cardiomyopathic patients and 6 patients with ischaemic heart disease (IHD), who were undergoing heart transplantation. CGRP elicited concentration-dependent vasodilatation in preconstricted vessels. Both healthy and diseased coronary arteries exhibited similar maximum responses and sensitivity to this peptide. Removal of the endothelium did not diminish the vasodilator action of CGRP in non-atherosclerotic coronary arteries. [125I]CGRP bound to tissue sections in a concentration-dependent manner. Binding was similar in healthy and atheromatous vessels, with a Bmax value of 10.2 ± 5.6 and 18.9 ± 3.0 amol/mg protein, and dissociation constant (Kd) of 0.07 ± 0.1 and 0.18 ± 0.1 nM, respectively. Dense [125I]CGRP binding was mainly associated with vascular smooth muscle cells of both normal and diseased vessels with some patches of binding to regions of atherosclerotic plaque in vessels from patients with IHD. These data indicate that CGRP is a potent endothelium-independent vasodilator in the human coronary vasculature. The preservation of dilator function and CGRP receptor binding in atherosclerotic coronary arteries suggests that this peptide may play a role in the control or maintenance of vascular tone in certain disease sta

ISSN:1018-1172    

DOI:10.1159/000159081

出版商:S. Karger AG    

年代:1995

数据来源: Karger

摘要:

The vasconstrictor vasopressin has been reported to induce paradoxical local vasodilation in the basilar vasculature through stimulation of the endothelium-derived relaxing factor nitric oxide (NO). We investigated the possibility that at subpressor doses, exogenous arginine vasopressin (AVP) might have a similar effect in the kidney. Ten Inactin-anesthetized rats were infused with sequential doses of AVP from 25 to 6,400 µU/min in 30-min increments. Subpressor infusion resulted in progressive renal vasodilation; renal blood flow (RBF) increased significantly going from 14 ± 6% above basal at 200 µU/min (p < 0.02) to 27 ± 5% (p < 0.01) at 1,600 µU/min accompanied by a 24 ± 5% decrease in renal vascular resistance (RVR). At 6,400 µU/min, blood pressure (BP) increased 29 ± 6 mm Hg and RVR increased. A second group of 8 rats were first given 10 mg/kg b.w. of the NO synthesis inhibitor NG-nitro-L-arginine methyl ester (L-NAME) before infusion of AVP. L-NAME increased BP 22 ± 3 mm Hg (p < 0.001), and decreased RBF 16 ± 3% (p < 0.005). After L-NAME, no dose of AVP had any further effect on either BP, RBF, or RVR. Continuous infusion of a single subpressor dose of 100 µU AVP resulted in a 26% increase in RBF (from 7.52 ± 0.68 to 9.49 ± 0.54 ml/min/g kidney weight, p < 0.001). AVP doubled urinary cyclic guanosine monophosphate excretion, a marker for renal NO synthesis, from 8.51 ± 1.01 to 17.48 ± 4.26 pM/min (p < 0.025). We conclude that AVP at subpressor doses induces renal vasodilation, which is eliminated by prior inhibition o

ISSN:1018-1172    

DOI:10.1159/000159082

出版商:S. Karger AG    

年代:1995

数据来源: Karger

摘要:

Regional variation in the response of the thoracic aorta to contractile agonists has previously been demonstrated. Since the net contractile response reflects the interaction between smooth muscle activation and the release of endothelial substances, we hypothesize that agonist-stimulated release of endothelium-derived nitric oxide (NO) also varies along the length of the thoracic aorta. The distribution of thoracic aorta estrogen receptors is also regionalized. Since pregnancy augments the release of endothelium-derived NO by acetylcholine (ACh) in some arterial beds, we further hypothesize that pregnancy enhances the stimulated release of NO from the thoracic aorta. Aortae were removed from nonpregnant and near term pregnant guinea pigs and cut into ring segments numbered sequentially proximal to distal. The rings were suspended at their optimal passive tension and submaximally contracted with prostaglandin F2α. Endothelium-derived NO-dependent relaxation to ACh increased moving proximal to distal along the aorta independent of pregnancy and ACh relaxation was unaffected by pretreatment with physostigmine to inhibit cholinesterase. The magnitude of the relaxation to carbachol among the different segments was similar to ACh. Pregnancy decreased the ED50 for ACh of segments from the middle and distal segments of the thoracic aorta. Relaxation to the NO donor sodium nitropmsside and the nonreceptor-mediated endothelium-dependent relaxing agent A23187 was uniform along the length of the aorta and independent of pregnancy. These experiments demonstrate regional variation in the stimulated release of endothelium-derived NO in the guinea pig thoracic aorta which is increased by pregnancy

ISSN:1018-1172    

DOI:10.1159/000159083

出版商:S. Karger AG    

年代:1995

数据来源: Karger

摘要:

Elastin peptides are present in human blood. As elastin receptors exist on several cell types, especially endothelial cells, this investigation was carried out to study the effect of elastin peptides on vascular tone. For this purpose, rat aortic rings were mounted in an organ bath for isometric tension measurements. Elastin peptides (ĸ-elastin) were added in the concentration range of 0.1 ng/ml to 1 µg/ml, concentrations similar to those found in the circulating blood. In rat aortic rings, precontracted or not with noradrenaline (10–6M), elastin peptides induced an endothelium-dependent vasodilation. The pretreatment of aortic rings with N-ω-nitro-L-arginine methyl ester (10–5M), an inhibitor of nitric oxide (NO) production, or with indomethacin (10–5M), an inhibitor of cyclooxygenase, prevented elastin peptide-induced vasodilation. These findings suggest that elastin peptides act through the synthesis of prostanoids, leading to the production of NO. Moreover, this relaxant effect of elastin peptides was decreased or inhibited when aortic rings were treated with lactose (10–5 to 10–2M) or laminin (10–6 to 10–4 mg/ml) whereas lactose or laminin was unable to inhibit acetylcholine-induced vasodilation. These findings suggest that the inhibitory effects of lactose and laminin are specific for elastin peptide receptors and are in agreement with previous studies on these receptors. As there is evidence of the degradation of elastin in several vascular diseases, the concept that elastin peptides may contribute to the control of vascular t

ISSN:1018-1172    

DOI:10.1159/000159084

出版商:S. Karger AG    

年代:1995

数据来源: Karger

ISSN:1018-1172    

DOI:10.1159/000159085

出版商:S. Karger AG    

年代:1995

数据来源: Karger

摘要:

Several studies have indicated that antigen-presenting endothelial cells represent the primary initiator of acute arterial graft rejection, leading to decreased arterial patency rates. Patency rates dramatically increase upon endothelial removal (denudation) prior to orthotopic transplantation into antigenically disparate hosts. Although patent, the biomechanical and functional changes seen in these allograft vessels (ACI rats to Lewis rats) have not been described. The present investigation examined functional differences between these allograft arteries and normal rat femoral arteries. Moreover, endothelial removal may also alter function; thus, an autograft injury model (Lewis to Lewis) was employed to discern the differences between injury and rejection. The results indicate that denudation injury alone caused no change in the passive stress-strain curve, the muscle length at which stress was maximum (Lo), or in phenylephrine- or nitroglycerin-induced concentration-response curves. Similarly, concentration-response curves were not affected by allograft transplantation; however, both the passive stress-strain curve and Lo values were shifted to significantly longer lengths (0.25 and 0.20 mm, respectively), suggesting an increase in arterial plasticity but not compliance. Furthermore, allografts produced significantly weaker KCl-induced contractions than did autografts (22 vs. 66% of control values, p allograft. In conclusion, these data suggest that vascular rejection involves subendothelial tissues, is distinct from vascular injury, and that the denudation allograft transplantation model can be employed to examine this process.

ISSN:1018-1172    

DOI:10.1159/000159086

出版商:S. Karger AG    

年代:1995

数据来源: Karger

摘要:

The involvement of the endothelial cell in the vasoconstriction induced by angiotensin I and II (AI, AII), and norepinephrine (NE) was studied in micro-vessels of the hamster cheek pouch before and after the following procedures: endothelial impairment by light-dye treatment, inhibition of angiotensin-converting enzyme (ACE), blockade of endothelium-derived relaxing factor (EDRF) and inhibiting prostaglandin (PG) synthesis. The results showed that in large 2nd-order arterioles, endothelial impairment did not affect the vasoconstrictor activity of AII and NE, nor did it alter ACE activity. However, in small 4th-order arterioles, endothelial impairment significantly reduced angiotensin conversion without altering the vasoconstrictor responses to either AII or NE. Thus, the endothelium plays differential roles in the modulation of local angiotensin conversion in these distinct segments of serial-arranged arterioles. Furthermore, it is unlikely that the vasoconstrictor response to AII in these arterioles is modulated by the endothelium through a pathway involving the release of EDRF or PGs.

ISSN:1018-1172    

DOI:10.1159/000159087

出版商:S. Karger AG    

年代:1995

数据来源: Karger

摘要:

The contribution of ATP-sensitive potassium channel (KATP channel) blockade in the vasoconstriction produced by vasopressin was studied. All experiments were performed using rat thoracic aorta cut in 4-mm rings, denuded from their endothelium and mounted into 20-ml organ baths. Glibenclamide (0.01–10 µM), a KATP channel antagonist, did not induce any measurable contraction, nor did it reduce the maximum contraction induced by vasopressin and phenylephrine. The specific inhibition of lemakalim-induced (a KATP channel activator) relaxation by vasopressin was investigated. Lemakalim (0.01–0.3 µM) relaxed both vasopressin (0.1 µM) and phenylephrine (0.3 µM) preconstricted vessels. However, in contrast to what would be expected from KATP blockade by vasopressin, rings preconstricted with vasopressin were more sensitive to the relaxant action of lemakalim, compared to phenylephrine preconstricted vessels (log[EC50] of –7.82 ± 0.01 and –7.10 ± 0.02, respectively, p < 0.05). Dose-response curves to papaverine (3–30 µM) in rings preconstricted with vasopressin and phenylephrine were comparable. When aortic rings were pretreated with lemakalim (0.1 µM), the maximum active tension induced by vasopressin was reduced (2.68 ± 0.23 in control conditions vs. 0.62 ± 0.08 g on pretreated vessels, p < 0.001), whereas that by phenylephrine was slightly increased. In order to explain the stronger relaxant action of lemakalim against vasopressin-induced constriction, the contribution of calcium influx through L-type calcium channels in the constriction of aortic rings to vasopressin and phenylephrine was compared. Nifedipine (0.1 nM–30 µM) was more potent (lower EC50 and higher maximal response) in vasopressin (0.1 µM) preconstricted vessels, compared to phenylephrine (0.3 µM). In conclusion, vasoconstriction produced by vasopressin does not involve blockade of KATP channels in the isolated rat aorta. The more potent relaxant action of lemakalim in vasopressin preconstricted vessels, compared to phenylephrine, can be explained by a higher dependency of vasopressin-induced vasoconstriction on calcium influx through voltage-sensitive calcium channels and, conseque

ISSN:1018-1172    

DOI:10.1159/000159088

出版商:S. Karger AG    

年代:1995

数据来源: Karger