To gain more insight into the complex pulmonary interactions of endothelins (ET), we studied airway and vascular responses
to endothelins in isolated perfused rat lungs in the presence of the novel ETB-receptor antagonist BQ788. In particular we focused on airway responses and on prostacyclin release. The effectiveness of
BQ788 in our system was shown by its ability to concentration-dependently prevent vasoconstriction (IC50 0.1μM), bronchoconstriction (IC50 0.1μM) and prostacyclin production (IC50<0.1μM) induced by the ETB-receptor agonist IRL1620 (1nmol). Airway responses to ET-1: ET-1-induced bronchoconstriction was aggravated by BQ123 (1 or
8μM), while BQ788 pretreatment (1 or 8μM) showed no significant effect. Simultaneous treatment with 8μM BQ123 and BQ788 attenuated
the ET-1-induced bronchoconstriction. Vascular responses to ET-1: ET-1 (1nmol)-induced vasoconstriction was potentiated by
BQ788 (1 or 8μM), but attenuated by the ETA-receptor antagonist BQ123 (1μM). In the presence of BQ788 diminished amounts of the stable prostacyclin metabolite 6-keto-PGF1α were detected in the perfusate. Simultaneous treatment with 8μM BQ123 and BQ788 completely prevented the ET-1-induced vasoconstriction.
Conclusions: Both ETA- and ETB-receptors contribute to ET-1-induced vasoconstriction and bronchoconstriction. The ET-1-induced vasoconstriction is attenuated
by stimulation of ETB-receptors, a response that is partly mediated by prostacyclin. Due to the mutual interactions between ETA- and ETB-receptors, simultaneous inhibition of both receptors is required to prevent the deleterious effects of ET-1 on lung functions.
Received: 17 October 1996 / Accepted: 16 May 1997 相似文献
Hyperosmotic hypovolemia impairs vasoconstriction during sedentary cold exposure. The purpose of this study was to determine whether hypohydration alters thermoregulation and cardiovascular responses to exercise in cold air. On four occasions, eight males [35.1 (2.7) years, 175.5 (3.1) cm, 73.3 (2.6) kg, 57.2 (2.6) ml kg–1 min–1 maximal oxygen uptake (O2max), 19.6 (2.4)% fat] walked, in t-shirt, shorts, and shoes, at 50%O2max, for 60 min in either a 4°C (Cold) or a 25°C (Temperate) environment in both hypohydrated state (HYPO, –4% body mass) and euhydrated state (EU). During exercise–cold stress, rectal temperature (Tre), mean weighted skin temperature, heart rate (HR), cardiac output (CO), and stroke volume (SV) were measured every 20 min. Mean weighted skin temperature values were not different between HYPO and EU but were lower (P<0.05) in Cold versus Temperate trials. Tre was not different (P>0.05) between HYPO–Cold and EU–Cold. CO and SV were not different within hydration states and were not different between Cold and Temperate trials (P<0.05). HR was not different between HYPO–Cold and EU–Cold. These data demonstrate that moderate intensity exercise in the cold while hypohydrated does not alter metabolic heat production, skin temperatures and heat loss, nor does it increase thermoregulatory and cardiovascular strain. 相似文献
Summary Uridine 5-triphosphate- (UTP-) and adenosine 5-triphosphate-(ATP) induced vasoconstriction was studied in the rabbit basilar artery. The arteries were incubated and perfused at a constant rate of flow. Vasoconstriction was measured as an increase in perfusion pressure.Serotonin, histamine and noradrenaline caused concentration-dependent vasoconstriction, with potency decreasing in that order. Of the nucleotides tested, UTP, UDP, UMP, CTP, ATP, ADP, adenosine 5-O-(3-thio)triphosphate (ATPS), and ,-imido adenosine 5-triphosphate (AMP-PNP) elicited concentration-dependent vasoconstriction, whereas AMP, 2-methylthio-ATP, , -methylene-ATP and ,-methylene-ATP up to 10–3 mol/l caused no or only a very small increase in perfusion pressure. The order of potency of the pyrimidine nucleotides was: UTP = UDP UMP = CTP; that of the purine nucleotides was: ATPS > AMP-PNP > ATP > ADP > 2-methylthio-ATP = , -methylene-ATP = ,-methylene-ATP. The vasoconstrictor effects of UTP and ATP were not or only to a minor degree influenced by: phentolamine; a mixture of atropine, diphenhydramine and methysergide; indometacin; nordihydroguaiaretic acid; denervation by 6-hydroxydopamine; or mechanical removal of endothelium. Prolonged exposure to ,-methylene-ATP elicited only a very small vasoconstriction and did not change the constrictor effects of UTP or ATP. Prolonged exposure to ATPS elicited marked vasoconstriction; subsequently, responses to ATP were reduced whereas those to UTP were, if anything, slightly enhanced. Reactive blue 2 reduced neither the UTP- nor the ATP-induced vasoconstriction. ATP 10–3 mol/l elicited marked additional vasoconstriction after precontraction with UTP 10–3 mol/l, whereas UTP elicited only a very small additional vasoconstriction when its concentration was doubled from 10–3 to 2 × 10–3 mol/l.It is concluded that, in the rabbit basilar artery, the vasoconstrictor response to UTP is mediated by a pyrimidine nucleotide receptor which is distinct from the P2-purinoceptor, and that the vasoconstrictor response to ATP is mediated by a P2-receptor which is distinct from the known P2-subtypes.Send offprint requests to I. v. Kügelgen at the above address 相似文献
The final depth of a necrosis resulting from burn trauma is determined within 3 days. The zone of stasis has the potential for complete regeneration or there may be ischemic influences that lead to necrosis. In our model, we examined the dermal influence of vasoconstrictors with reference to the development of burn necrosis. On the backs of New Zealand white rabbits (4.0–4.5 kg) standardized lesions were made with a heated aluminum stamp at 80°C, 14 s in duration.
The lesions were intradermal, whereby the border zone of the coagulated tissue was found in the middle two quarters of the dermis in 100% of untreated animals after 72 h. For dermal vasoconstriction epinephrine in a dose of 0.5 μg/kg/min was used.
There were two groups of seven animals each. One group received epinephrine and the dosage was dependent on the clinical state of the animal. Several cycles were administered within a 3-day period. The reduction of skin perfusion was documented by Laser–Doppler-flowmetry. After 3 days, the skin with the lesions was excised and using a hematoxylin dye, a histological examination followed. The parameter used to determine the efficacy was the thickness of the uncoagulated part of the excised dermis.
Over a period of 48 h, an average of 2.3 epinephrine cycles of average of 88 min per animal in duration resulted in an average reduction of skin diffusion of 41%. The uncoagulated part of the dermis in the epinephrine group was 28.6% average; in the control group, this was 43.5%. The statistical analysis revealed significant differences with a p-value of 0.0312 (significant, when value is less than 0.05). The test results indicate that temporary reduction of skin perfusion through external administration of vasocontrictors may lead to progression of burn necrosis in our animal model.
Clinically, this result indicates that for patients with burn injuries and systemic inflammatory response syndrome who have insufficient volume therapy, the administration of vasocontrictors may produce similar results in the injured area. 相似文献
The hypothesis that platelet-activating factor (PAF) plays a role in the modulation of the vasomotor tone and blood pressure
was put forward by our group in previous in vivo studies in anaesthetised rabbits. The present study was undertaken to investigate
the putative role of this lipid mediator in the vascular reactivity of the renal circulation, using the experimental model
of the isolated perfused rabbit kidney. Dose-response curves to noradrenaline-induced vasoconstriction were performed before
and after continuous infusions of two different PAF-receptor antagonists (WEB 2086 and yangambin) and of the phospholipase
A2 inhibitor mepacrine. The increases in renal perfusion pressure elicited by noradrenaline were potentiated by all the above-mentioned
treatments in a dose-dependent manner. Moreover, prostaglandin F2α-induced vasoconstriction was also potentiated by the administration of the PAF receptor antagonists and mepacrine. Furthermore,
the administration of PAF into the renal circulation induced dose-related and long-lasting vasodilator responses, which were
blocked by the PAF receptor antagonists. Nevertheless, PAF-induced renal vasodilation was also abolished by a pretreatment
with mepacrine or with the cyclooxygenase inhibitor indomethacin, suggesting that it enhances the secondary formation of vasodilator
arachidonic acid metabolites. The data indicate that PAF is involved in the modulation of the vasomotor tone in the renal
circulation, through the release of cyclooxygenase products, constituting an additional mechanism of modulation of smooth
muscle cell contractility to the ones exerted by well-known vasoactive substances of endothelial origin such as nitric oxide.
Received: 20 April 1998 / Accepted: 5 March 1999 相似文献
In our experience, for all surgeries in the hand, the optimal epinephrine effect from local anesthesia—producing maximal vasoconstriction and visualization—is achieved by waiting significantly longer than the traditionally quoted 7 min from the time of injection.
Methods
In this prospective comparative study, healthy patients undergoing unilateral carpal tunnel surgery waited either 7 min or roughly 30 min, between the time of injection of 1 % lidocaine with 1:100,000 epinephrine and the time of incision. A standardized incision was made through dermis and into the subcutaneous tissue followed by exactly 60 s of measuring the quantity of blood loss using sterile micropipettes.
Results
There was a statistically significant reduction in the mean quantity of bleeding in the group that waited roughly 30 min after injection and before incision compared to the group that waited only 7 min (95 % confidence intervals of 0.06 + −0.03 ml/cm of incision, compared to 0.17 + −0.08 ml/cm, respectively) (P = 0.03).
Conclusions
Waiting roughly 30 min after injection of local anesthesia with epinephrine as oppose to the traditionally taught 7 min, achieves an optimal epinephrine effect and vasoconstriction. In the hand, this will result in roughly a threefold reduction in bleeding—making wide awake local anesthesia without tourniquet (WALANT) possible. This knowledge has allowed our team to expand the hand procedures that we can offer using WALANT. The benefits of WALANT hand surgery include reduced cost and waste, improved patient safety, and the ability to perform active intraoperative movement examinations. 相似文献
Cerebral vasospasm is a poorly understood clinical condition that appears to result from complex biochemical and biomechanical
processes that manifest as yet another example of vascular growth and remodeling. We submit that mathematical modeling holds
great promise to help synthesize diverse types of data and thereby to increase our understanding of vasospasm. Toward this
ultimate goal, we present constitutive relations and parametric studies that illustrate the potential utility of a new theoretical
framework that combines information on wall mechanics, hemodynamics, and chemical kinetics. In particular, we show that chemical
and mechanical mediators of cellular and extracellular matrix turnover can differentially dominate the progression and resolution
of vasospasm. Moreover, based on our simulations, endothelial damage can significantly alter the time-course and extent of
vasospasm as can impairment of autoregulation. Although the present results are consistent with salient features of clinically
reported vasospasm, and thus provide some new insight, we suggest that most importantly they reveal areas of pressing need
with regard to the collection of additional experimental data. Without appropriate data, our understanding of cerebral vasospasm
will remain incomplete.
Address correspondence to J. D. Humphrey, Department of Biomedical Engineering, Texas A&M University, 337 Zachry Engineering
Center, 3120 TAMU, College Station, TX 77843-3120, USA. Electronic mail: jhumphrey@tamu.edu
相似文献
The amino acid intermediate homocysteine (Hcy) is formed during the metabolism of methionine to cysteine. Hyperhomocysteinemia (HHcy) is recognized as an independent risk factor for coronary atherosclerosis. The circulating levels of total Hcy (tHcy) can increase due to intake of foods rich in methionine or deficiencies of vitamins such as folate, pyridoxine and cyanocobalamin, which are required for the metabolism of Hcy. In addition, mutations in the genes coding for Hcy metabolizing enzymes can contribute to an increase in tHcy levels. Clinical and epidemiological studies have shown that an elevated level of tHcy measured in serum or plasma is a strong predictor of cardiovascular disease risk, which appears to be greatest in patients who have HHcy following a methionine load. Intimal hyperplasia (IH) (intima/media [I/M] ratio) is the universal response of a vessel to injury and may result in vasoconstriction when left unattended. The effect of dietary HHcy on balloon catheter-injured carotid artery and its modulation (if any) by the peroxisome proliferator-activated receptor agonist gamma rosiglitazone was evaluated in 12-week-old female Sprague-Dawley rats fed either a control diet or a diet containing 1% L-methionine. Once the rats were established on the diet, the group that was fed 1% L-methionine was further subdivided and either given an aqueous preparation of 3 mg/kg/day rosiglitazone or the vehicle via oral gavage for one week. This was followed by surgically injuring the left carotid artery using a Maverick Over-The-Wire catheter (2.0 mm × 20 mm, 3.2F; Boston Scientific, USA). The rats were continued on their respective diets and drug regimen for 21 days postsurgery. On day 22 of the procedure, the rats were sacrificed for collection of blood, the carotid arteries and liver for biochemical and histological evaluation. Compared with controls there was a significant increase in both tHcy levels and I/M ratio in the rats fed 1% L-methionine (5.4±0.28 μM versus 32.8±3.01 μM, P<0.002; and 0.175±0.05 versus 1.05±0.23, P<0.005, respectively). The effect of rosiglitazone in rats fed the control diet was not prominent. On the other hand, administration of rosiglitazone to the rats on the 1% L-methionine diet significantly reduced the levels of serum tHcy (16.6±2.1 μM versus 32.8±3.01 μM, P<0.001); however, the tHcy levels remained significantly elevated compared with animals on the control diet (P<0.002). The group receiving the L-methionine diet plus rosiglitazone had an inhibition in the development of IH compared with those receiving the L-methionine diet alone (I/M of 0.278±0.041 versus 1.05±0.23, P<0.01). Moreover, the development of IH in the group receiving the L-methionine diet plus rosiglitazone treatment was not significantly different from that observed in the group on the control diet without rosiglitazone (0.278±0.041 versus 0.175±0.05, respectively). These findings may have important implications in deciphering the molecular mechanisms involved in the augmentation of IH in HHcy and modulation of this process by rosiglitazone. 相似文献