Alteration of endothelium-mediated vasodilator response in the rat hindlimb vasculature consecutive to chronic hypoxic stress: NO and EDHF involvement

The previously documented impairment of hindlimb blood flow consecutive to chronic hypoxia might be related to endothelial vasomotor dysfunction. The aim of this study was to assess in-vivo the effect of chronic hypoxic stress on endothelium-mediated vasodilator response of hindlimb vascular bed, especially as regards to endothelium-derived hyperpolarizing factor (EDHF) and nitric oxide (NO) pathway contribution. Dark Agouti rats were randomly assigned to live at barometric pressure ≈ 760 mmHg (N rats) or ≈ 550 mmHg (CH rats). Under anesthesia, catheters were placed in the carotid artery for arterial pressure measurement, and in the saphenous vein and iliac artery for drug delivery. Hindlimb blood flow (HBF) was measured by transit-time ultrasound flowmetry, at baseline and during endothelium-dependent vasodilator response induced by intra-arterial injection of acetylcholine (0.75 ng and 7.5 ng) with and without specific blockers of NOS (L-NAME) and EDHF (Charybdotoxin + Apamin). HBF and hindlimb vascular conductance changes in response to ACh infusion were significantly lower in CH than in N rats. The mechanisms responsible for this blunted response involved impairment in both NO pathway and EDHF. The chronic hypoxia-induced alteration of NO pathway was mainly related to the bioavailability of its substrate l-Arginine, since the infusion of l-Arginine restored the endothelial response to ACh in CH rats to the level of N rats. These results demonstrate that the impairment in endothelium-mediated vasodilator response of the hindlimb vascular tree induced by chronic hypoxic stress involves both NO and EDHF.     

Contractile response of the human isolated urinary bladder to neurokinins: involvement of NK-2 receptors

The contractile response to substance P (SP), neurokinin A (NKA) and arginin-neurokinin B (Arg-NKB) (a water soluble analogue of NKB) was investigated in detrusor muscle strips from the dome of the urinary bladder obtained from patients undergoing total cystectomy for carcinoma of the bladder base. Spontaneous activity and response to nerve stimulation indicated that the material used in this study has characteristics similar to those described for 'normal' human detrusor muscle. All neurokinins induced a concentration-related contraction with sensitivity at nM concentrations and the following rank order of potency: NKA (90) greater than Arg-NKB (22) greater than SP (1). These findings indicate the involvement of NK-2 receptors in the contractile response of human detrusor muscle to neurokinins.     

Endothelium-dependent sensory NANC vasodilatation: involvement of ATP,CGRP and a possible NO store

1. Non-adrenergic non-cholinergic (NANC) vasodilator nerves regulate tone in certain vascular beds. We have investigated the mechanisms of the NANC dilator response in the isolated small mesenteric artery of the rabbit by use of the tension myograph.
2. Small second or third order (150–300 μm in diameter) arteries of the rabbit mesenteric bed were mounted in a Mulvany tension myograph. Responses to electrical field stimulation (EFS) and exogenous vasodilators were investigated.
3. EFS (0.5–16 Hz, 10 V, 0.3 ms for 5 s), in the presence of guanethidine (5 μM) and atropine (1 μM) produced frequency-dependent relaxation of small arteries. Pretreatment with tetrodotoxin (1 μM) abolished the relaxation and desensitization with capsaicin (10 μM) strongly inhibited the relaxation.
4. Pretreatment with a P2Y-purinoceptor antagonist, basilen blue (3 μM) or a human calcitonin gene-related peptide (hCGRP) receptor antagonist, hCGRP_8–37 (1 μM) suppressed the NANC relaxation by approximately 40–60 % in each case and combined pretreatment almost abolished the relaxation.
5. The EFS-induced relaxation was suppressed by endothelium-removal, pretreatment with the soluble guanylyl cyclase inhibitor ODQ (1 μM) and the NO scavenger oxyhaemoglobin (OxyHb; 20 μM) but not by NO synthase inhibitors N^G-nitro-L-arginine methyl ester (L-NAME; 300 μM) or N^G-nitro-L-arginine (L-NOARG; 300 μM). Combined pretreatment with ODQ and CGRP_8–37 almost abolished the relaxation.
6. A P2Y-purinoceptor agonist, 2-methylthio ATP, produced endothelium-dependent relaxation which was inhibited by L-NAME and ODQ (1 μM), whilst hCGRP produced endothelium-independent and ODQ-insensitive relaxation.
7. Ultraviolet light (320 nm, 5 shots over 20 s) produced relaxation that was blocked by both OxyHb and ODQ but not by N^G-monomethyl-L-arginine (L-NMMA, 300 μM).
8. The present study suggests that EFS-induced NANC relaxation of the mesenteric small artery of the rabbit is mediated mainly by capsaicin-sensitive sensory C-fibres and that both ATP and CGRP are involved. The action of ATP released by EFS appears to be endothelium-dependent and involve activation of soluble guanylyl cyclase, but is resistant to inhibitors of NO synthase. The response to CGRP is endothelium-independent. These results show that ATP and CGRP account fully for the NANC relaxation of this vessel type and that the endothelium is involved in NANC-induced relaxation. The endothelium-dependent part of the response is consistent with the release of NO, either from NO synthase, incompletely inhibited by the NO synthase inhibitors, or by some preformed stores.

     

Captopril reverses the reduced vasodilator response to bradykinin in hypertensive pregnant rats

1. Pregnancy in rats is characterized by a reduction in arterial pressure that is associated with a decreased response to vasoconstrictors. However, the responses to vasodilators in isolated vessels remain controversial and are not well established in hypertensive pregnant rats. 2. In the present study, we investigated the effect of pregnancy on the bradykinin (BK)-induced vasodilator responses of the isolated mesenteric arterial bed (MAB) from Wistar normotensive and spontaneously hypertensive rats (SHR) and determined the role of nitric oxide (NO), endothelium-derived hyperpolarizing factor (EDHF) and angiotensin-converting enzyme (ACE) in these responses. 3. Mean arterial pressure (MAP) in pregnant normotensive and pregnant hypertensive rats (93 +/- 1 and 122 +/- 2 mmHg, respectively) was lower than in non-pregnant controls (128 +/- 1 and 163 +/- 2 mmHg, respectively; P < 0.05). In MAB isolated from normotensive rats and precontracted with phenylephrine, the effects of bradykinin, acetylcholine (ACh) and nitroglycerine (NG) were not influenced by pregnancy. In contrast, the vasodilator responses to BK were significantly reduced in pregnant compared with non-pregnant SHR and seemed to be specific to BK. 4. The ACE inhibitor captopril potentiated BK vasodilator responses and abolished the differences between pregnant and non-pregnant SHR. Inhibition of nitric oxide (NO) synthase by N(G)-nitro-L-arginine methyl ester (l-NAME) significantly reduced the vasodilator effect of BK in all groups. In the presence of l-NAME plus high K+ solution (47 mmol/L), BK-induced vasodilation was completely blocked. The NO-dependent component of the responses seems to be more important in hypertensive rats and pregnancy does not modify this profile. 5. Our results suggest that increased ACE activity may be involved in the pregnancy associated reduction in vasodilator responses to BK in the MAB of hypertensive rats. Pregnancy does not modify the relative contribution of the EDHF and NO to the vasodilator effect of BK.     

A novel capsaicin derivative VOA induced relaxation in rat mesenteric and aortic arteries: involvement of CGRP, NO, cGMP, and endothelium-dependent activities

The vasorelaxant effects of N-[4-O-[2-methoxy, phenoxyethylaminobutyl]-3-methoxy benzyl]-nonamide (VOA), a novel capsaicin derivative, and associated releasing activities of nitric oxide (NO) and calcitonin gene-related peptide (CGRP) were investigated in this study. Systemic administration of VOA decreased blood pressure and heart rate in a dose-dependent manner in both normotensive as well as spontaneously hypertensive rats. Nw-nitro-L-arginine methyl ester (L-NAME), glibenclamide, and capsazepine inhibited VOA-induced hypotension. In phenylephrine-precontracted rat aortic rings and mesenteric arteries with intact endothelium, VOA caused a concentration-dependent relaxation. This relaxation was reduced after endothelium was removed or pretreated with L-NAME, methylene blue, 1 H-[1,2,4]oxidazolol [4,3-a] quinoxalin-1-one, tetraethylammonium, glibenclamide, CGRP (8-37), or capsazepine, respectively. In endothelially denuded vessel rings, tetraethylammonium, glibenclamide, CGRP (8-37), and capsazepine also reduced VOA-induced relaxation. In high potassium (80 mmol/L)-precontracted rat aortic rings with intact endothelium, VOA failed to induce relaxation. VOA induced a concentration-dependent increase of CGRP-like enzyme immunoreactivity, which was also significantly inhibited by capsazepine. In human umbilical vein endothelial cells, VOA increased NO release and guanosine-3', 5'-cyclic monophosphate level, which were significantly inhibited by L-NAME. The Western blot analysis on human umbilical vein endothelial cells indicated that VOA increased the expression of endothelium nitric oxide synthase. In conclusion, VOA might exert its relaxation effects in rat vascular smooth muscle through the CGRP/KATP channel and the NO/ cGMP pathway.     

Attenuated depressor response to arachidonic acid and prostaglandins in unclipped renal hypertensive rats.

1 In renal hypertensive rats (one-clip, two-kidney type) blood pressure returned to a normotensive level within 24 h after the removal of the renal artery clip (unclipping). 2 The decrease in blood pressure caused by intravenous administration of arachidonic acid, prostaglandin E2 and prostaglandin I2 was significantly reduced in these unclipped rats. 3 The hypotensive response to bradykinin and acetylcholine was the same in unclipped rats and in control rats. 4 Nephrectomy abolished the difference in blood pressure response to arachidonic acid and the two prostaglandins between unclipped and control rats. 5 An enhanced secretion of renin, as indicated by the absence of an increase in plasma renin activity, did not seem to be involved in the attenuated blood pressure response to arachidonic acid in unclipped rats.     

Radiation-induced increases in sensitivity of cataleptic behavior to haloperidol: possible involvement of prostaglandins

The effects of radiation exposure on haloperidol-induced catalepsy were examined in order to determine whether elevated prostaglandins, through an action on dopaminergic autoreceptors, could be involved in the radiation-induced increase in the potency of this neuroleptic. Cataleptic behavior was examined in animals irradiated with various doses of gamma photons (1-150 Gy) and pretreated with a subthreshold dose of haloperidol (0.1 mg/kg). This approach was chosen to maximize any synergistic effects of radiation and haloperidol. After irradiation with doses less than or equal to 30 Gy, the combined treatment of haloperidol and radiation produced catalepsy, whereas neither treatment alone had an effect. This observed catalepsy could be blocked with prior administration of indomethacin, a prostaglandin synthesis inhibitor. Animals exposed to doses of radiation less than or equal to 50 Gy and no haloperidol, however, displayed apparent catalepsy. This effect was also antagonized by indomethacin. Prostaglandins can induce catalepsy and when administered in subthreshold doses along with subthreshold doses of haloperidol, catalepsy was observed. In order to assess a possible action of prostaglandins and radiation on dopaminergic activity, the functioning of striatal dopaminergic autoreceptors was examined by determining the effects of varying concentrations of haloperidol on the K+-evoked release of dopamine from striatal slices obtained from parallel groups of animals treated as above. Results indicated that sensitivity to haloperidol increased (higher K+-evoked dopamine release) in slices from irradiated or prostaglandin-treated animals and that this increase in sensitivity was blocked by indomethacin. Results from both experiments suggest that radiation-induced increases in endogenous neuronal mediators, such as prostaglandins, can induce catalepsy through an action on dopaminergic autoreceptors.     

Blood pressure responses to local application of serotonergic agents in the nucleus tractus solitarii

The effects of serotonin applied directly to the region of the medulla oblongata which contains the nucleus tractus solitarii, nucleus intercalatus, nucleus originis dorsalis vagi and the nucleus origins nervi hypoglossi were investigated in anesthetized rats. A dose dependent increase in blood pressure with variable changes in heart rate was observed after unilateral application of serotonin into the nucleus tractus solitarius. The serotonergic antagonists, 2-bromolysergic acid diethylamide (locally applied) and metergoline (systemically administered) significantly attenuated the serotonin-induced pressor response. Fluoxetine, a serotonin uptake inhibitor, significantly enhanced the magnitude of the pressor response, but did not prolong it. The present data suggest that enhancement of serotonergic activity in the region of the nucleus tractus solitarius produces a neurogenic pressor response.     

Mechanisms of chloroquine-induced body-scratching behavior in rats: evidence of involvement of endogenous opioid peptides

Chloroquine is commonly used in the chemotherapy of malaria fever, and as an antiinflammatory disease-modifying agent in patients with rheumatoid arthritis or systemic lupus erythematosus. Administration of chloroquine (20.0 mg/kg IP) significantly (p < 0.05) increased the frequency of body scratching in rats to 29.5+/-9 in 30 min, compared to saline control animals (6.5+/-2/30 min). Morphine, a mu-opiate receptor agonist (1.0 mg/kg IP), potentiated the chloroquine-induced rat body scratching to 40+/-6.6, while the mu-opiate receptor antagonist, naltrexone (0.25 mg/kg, IP, given 15 min prior) blocked the chloroquine induced body scratching to 4.5+/-2 (p < 0.05 ANOVA). In addition, the frequency of chloroquine (20.0 mg/kg IP)-induced body scratching was significantly reduced to 9.1+/-3 in 30 min in rats rendered tolerant to morphine (p < 0.05 ANOVA) compared to the scratching frequency of 40+/-6.6 in morphine-naive rats. These suggests an involvement of mu-opioid receptors and/or endogenous opioid peptides in chloroquine induced body scratching in rats. Promethazine, a histamine-receptor antagonist (1.0 mg/kg IP, given 15 min prior to chloroquine) and the corticosteroid, dexamethasone (1.0 mg/kg, IP, given 15 min prior) separately and significantly (p < 0.01) inhibited the chloroquine-induced scratching in rats, in a similar manner to clinical studies in malaria. Collectively, the novel results implicate opioidergic mechanisms, and confirm the efficacy of antihistamine and corticosteroids in chloroquine body scratching in rats. It also strongly suggests that the chloroquine-induced body-scratching behavior in the rat may be a useful experimental model for chloroquine-induced pruritus in humans.     

Lack of involvement of leukotriene and platelet activating factor in passive cutaneous anaphylaxis in rats

Possible chemical mediators contributing to 48 hour passive cutaneous anaphylaxis (PCA) in rats were investigated. Forty-eight hour PCA was inhibited considerably by mepyramine and methysergide given intravenously, a finding suggestive of a major role for histamine and serotonin in the reaction. AA-861, a selective 5-lipoxygenase inhibitor did not inhibit the PCA, and leukotriene (LT)D4 or LTE4 and the combination with prostaglandin (PG)E2 had no significant skin reaction. In addition, only small amounts of slow reacting substance of anaphylaxis (SRS-A) were detected in skin fragments, in vitro. Although CV-3988, a selective platelet activating factor (PAF) antagonist, dose-dependently inhibited the PAF-induced skin reaction, the PCA was not affected by treatment with this compound. Indomethacin also had no inhibitory activity on PCA. Thus, sulfidopeptide LTs, PAF and arachidonate cyclooxygenase metabolites probably do not contribute to PCA, at least in rats.     

Contribution of NO and cytochrome P450 to the vasodilator effect of bradykinin in the rat kidney.

1. Inhibition of nitric oxide generation with Nw-nitro-L-arginine (nitroarginine) reduced vasodilator responses to bradykinin and acetylcholine and enhanced those to nitroprusside in the rat isolated perfused kidney, preconstricted with phenylephrine. 2. Inhibition of cyclo-oxygenase with indomethacin, decreased the vasodilator responses to bradykinin by approximately 25% without affecting those to acetylcholine or nitroprusside. 3. BW755c, a dual inhibitor of cyclo-oxygenase and lipoxygenase, reduced renal vasodilator responses to bradykinin, comparable to the effect of indomethacin suggesting an effect related to inhibition of cyclo-oxygenase rather than lipoxygenase. 4. ETYA, an inhibitor of all arachidonic acid metabolic pathways, markedly reduced vasodilator responses to bradykinin but was without effect on the renal vasodilatation induced by acetylcholine or nitroprusside. 5. Clotrimazole and 7-ethoxyresorufin, inhibitors of cytochrome P450, greatly attenuated vasodilator responses to bradykinin without affecting those to acetylcholine or nitroprusside. 6. These data suggest that the renal vasodilator response to bradykinin is subserved by arachidonic acid metabolites as well as nitric oxide, the former accounting for up to 70% of the vasodilator effect of bradykinin.     

Time-dependent synergistic interactions between the vasodilator neuropeptide, calcitonin gene-related peptide (CGRP) and mediators of inflammation.

1. The action of the long lasting neuropeptide vasodilator, calcitonin gene-related peptide (CGRP), in potentiating oedema formation and neutrophil accumulation was investigated in the dorsal skin of the rabbit, in vivo. Combinations of agents under test were administered by intradermal (i.d.) injection. Oedema formation and neutrophil accumulation were then measured by quantitative radiolabel techniques. 2. CGRP (1 x 10(-11) mol per site) potentiated neutrophil accumulation induced by zymosan activated plasma, (used as a source of C5a des Arg), N-formyl-methionyl-leucyl-phenylalanine (FMLP) and leukotriene B4 (LTB4). In contrast CGRP did not induce neutrophil accumulation when injected alone. 3. Oedema formation induced by a series of chemically distinct mediators of increased microvascular permeability; bradykinin, platelet activating factor (PAF), FMLP and zymosan-activated plasma; measured 0-30 min after i.d. injection was potentiated by CGRP (1 x 10(-11) mol per site). 4. Oedema formation induced by zymosan activated plasma and FMLP but not bradykinin and PAF, was also significantly potentiated by CGRP when oedema was measured 30-60 min after i.d. injection. The potentiation of oedema induced by zymosan activated plasma measured 30-60 min after i.d. injection was not observed in the presence of the shorter acting prostanoid vasodilator prostacyclin (PGI2, 3 x 10(-10) mol per site). 5. These results suggest that CGRP, as a consequence of its sustained vasodilator activity could have prolonged potentiating effects on neutrophil accumulation and oedema formation in inflammatory conditions.     

Mechanisms involved in the pressor response to noradrenaline injection into the cingulate cortex of unanesthetized rats

The cingulate cortex (CC) is involved in cardiovascular modulation. CC electrical or chemical stimulation may evoke either pressor or depressor responses, depending on the stimulated site and experimental conditions such as anesthesia. Noradrenaline (NA) is involved in cardiovascular regulation and it is present throughout the cortex. However, there is no report on the cardiovascular effects of intracortical injections of NA. We attempted to verify the effect of NA injection into the CC and to identify possible receptor and peripheral mechanisms involved. NA injection caused pressor responses accompanied by bradycardia, in unanesthetized rats. These responses were markedly reduced under urethane anesthesia. The pressor response was blocked by intracortical pretreatment with phenoxybenzamine or the selective alpha(1)-antagonist WB4101, and it was not affected by pretreatment with the selective alpha(2)-antagonist RX821002, suggesting that alpha(1)-adrenoceptors mediate the response. The pressor response was potentiated by pretreatment with the ganglion blocker mecamylamine and it was abolished by pretreatment with the vasopressin antagonist, dTyr(CH(2)) (5)(Me)AVP or by hypophysectomy. Circulating vasopressin levels were increased after NA injection into the CC. The present results indicate that the pressor response to local injection of NA within the CC is independent of sympathetic nerve activation and is mediated by vasopressin release.     

Topical application of oxifulvic acid suppresses the cutaneous immune response in mice

The antiinflammatory activity of topically applied coal‐derived fulvic acids (called oxifulvic acid) at 4.5% and 9% was compared with that of diclofene sodium at 1% and betamethasone at 0.1% in a murine model of contact hypersensitivity. Mice were sensitised with dinitrofluorobenzene and challenged 6 days later by application to the dorsal surface of the right ear. The inflamed ears of the mice were then treated topically, and the thickness of the ears was measured daily. Oxifulvic acid at both concentrations compared favourably with both diclofene sodium and betamethasone in suppressing the cutaneous inflammatory response. Oxifulvic acid possesses antiinflammatory properties and may be of clinical benefit in the treatment of inflammatory skin conditions in humans. Drug Dev. Res. 53:29–32, 2001. © 2001 Wiley‐Liss, Inc.     

Brain renin-angiotensin system modifies the blood pressure response to intracerebroventricular cadmium in rats

In order to elucidate the involvement of the brain renin-angiotensin system (RAS) in cadmium intracerebroventricular (ICV) hypertension, we evaluated the effects of a pretreatment with different drugs: clonidine, an α₂ adrenergic agonist, enalapril and captopril, both ACE inhibitors, and saralasin, a competitive nonselective AT₁ and AT₂ receptor antagonist. We used a rat strain with low levels of kallikrein (LKR) that was more sensitive to ICV cadmium hypertension, compared with normal kallikrein rats (NKRs), the control strain. The interplay between the kallikrein-kinin system and the RAS in the LKR strain caused various hemodynamic alterations, which we believe were the result of elevated RAS activity in these animals. Moreover, we suggest that the defective kallikrein-kinin system in LKR may also cause an alteration in the activation of brain RAS in these animals. The LKR displayed elevated concentrations of plasma AII, hypertrophy of the myocardium, and initial alterations in the renal glomerulotubular system. With the exception of clonidine, all of the other drugs showed greater antihypertensive effects of differing statistical significance in LKR, compared with NKR. Both ACE inhibitors were able to significantly reduce pressor response to cadmium ICV in LKR throughout the experiment, whereas in NKR, they were only able to reduce the hypertensive peak of cadmium. A significant protective effect was also observed in LKR pretreated with saralasin, while no effect was observed in NKR. These findings confirm the presence of brain RAS activation in LKR and its contribution to the central control of pressor response to cadmium ICV.     

Ischemic preconditioning, the most effective gastroprotective intervention: involvement of prostaglandins, nitric oxide, adenosine and sensory nerves

Various organs, including heart, kidneys, liver or brain, respond to brief exposures to ischemia with an increased resistance to severe ischemia/reperfusion and this phenomenon is called "preconditioning". No study so far has been undertaken to check whether such short, repeated gastric ischemic episodes protect gastric mucosa against severe damage caused by subsequent prolonged ischemia/reperfusion and, if so, what could be the mechanism of this phenomenon. The ischemic preconditioning was induced by short episodes of gastric ischemia (occlusion of celiac artery from one to five times, for 5 min each) applied 30 min before prolonged (30 min) ischemia followed by 3 h of reperfusion or 30 min before topical application of strong mucosal irritants, such as 100% ethanol, 25% NaCl or 80 mM taurocholate. Exposure to regular 30-min ischemia, followed by 3-h reperfusion, produced numerous severe gastric lesions and significant fall in the gastric blood flow and prostaglandin E(2) generation. Short (5-min) ischemic episodes (1-5 times) by itself failed to cause any gastric lesions, but significantly attenuated those produced by ischemia/reperfusion. This protection was accompanied by a reversal of the fall in the gastric blood flow and prostaglandin E(2) generation and resembled that induced by classic gastric mild irritants. These protective and hyperemic effects of standard preconditioning were significantly attenuated by pretreatment with cyclooxygenase-2 and cyclooxygenase-1 inhibitors, such as indomethacin, Vioxx, resveratrol and nitric oxide (NO)-synthase inhibitor, N(G)-nitro-L-arginine (L-NNA). The protective and hyperemic effects of standard preconditioning were restored by addition of 16,16 dm prostaglandin E(2) or L-arginine, a substrate for NO synthase, respectively. Gastroprotective and hyperemic actions of standard ischemic preconditioning were abolished by pretreatment with capsaicin-inactivating sensory nerves, but restored by the administration of exogenous CGRP to capsaicin-treated animals. Gene and protein expression of cyclooxygenase-1, but not cyclooxygenase-2, were detected in intact gastric mucosa and in that exposed to ischemia/reperfusion with or without ischemic preconditioning, whereas cyclooxygenase-2 was overexpressed only in preconditioned mucosa. We conclude that: (1) gastric ischemic preconditioning represents one of the most powerful protective interventions against the mucosal damage induced by severe ischemia/reperfusion as well as by topical mucosal irritants in the stomach; (2) gastric ischemic preconditioning resembles the protective effect of "mild irritants" against the damage by necrotizing substances in the stomach acting via "adaptive cytoprotection" and involves several mediators, such as prostaglandin derived from cyclooxygenase-1 and cyclooxygenase-2, NO originating from NO synthase and sensory nerves that appear to play a key mechanism of gastric ischemic preconditioning.     

Angiotensin AT(2) receptors mediate vasodepressor response to footshock in rats. Role of kinins, nitric oxide and prostaglandins

Footshocks increased mean arterial pressure and heart rate. Systemic administration of losartan, a specific angiotensin AT(1) receptor antagonist, not only inhibited the pressor response to footshocks, but also resulted in vasodepression. Administration of 1-[[4-(dimethylamino)3-methylphenyl]methyl]-5 (diphenylacetyl)-4,5,6, 7-tetrahydro-1H imidazol (4,5-c] pyridine-6-carboxilic acid, ditrifluoro acetatemonohydrate (PD 123319), a specific angiotensin AT(2) receptor antagonist, did not alter the hemodynamic response to footshocks. Simultaneous blockade of angiotensin AT(1) and AT(2) receptors by combined administration of losartan and PD 123319, eliminated the vasodepressor response to footshocks unmasked in losartan-pretreated rats. Saralasin, a non-specific angiotensin receptor antagonist, abolished the cardiovascular response to footshocks similarly like the losartan+PD 123319 treatment. Our data suggest that the vasodepressor response to footshocks in the presence of an angiotensin AT(1) receptor antagonist is triggered by activation of angiotensin AT(2) receptors. We studied the role of kinins, nitric oxide and prostaglandins in the vasodepressor response observed after footshocks. The decrease in mean arterial pressure observed after footshocks in losartan-treated rats was blunted by icatibant (HOE 140), N(G)-nitro-L-arginine-methyl ester (L-NAME) or indomethacin, indicating that kinins, nitric oxide and prostaglandins appear to be involved in the pressure response to footshocks during angiotensin AT(1) receptor blockade.     

应激性大鼠不同组织中NO浓度的变化与血压的关系

目的 :研究应激性大鼠不同组织中NO浓度的变化与血压的关系。方法 :给SD大鼠间断性足底电刺激并噪声刺激 1 5d ,观察其尾动脉BP的变化和血浆、心耳、心室、血管、肾上腺等组织中NO的浓度变化。结果 :应激组经 1 5d应激后BP显著性升高 ;应激 L arg (精氨酸 )组应激前后BP变化不明显。应激后血浆中NO的浓度明显降低 ,心耳、心室、血管、肾上腺中的NO几乎难以测出 ,而应激 L arg组的大鼠经过 1 5d的应激刺激 ,血浆及血管组织中的NO浓度 ,明显升高。心耳、心室、肾上腺中NO的浓度与对照组相比变化不明显。结论 :应激刺激可使BP升高 ,同时血浆、心耳、心室、血管、肾上腺等组织中NO的浓度降低 ,而L arg可抑制BP升高 ,血浆及血管组织中NO浓度增加 ,心耳、心室、肾上腺等组织中NO浓度不降低。应激性大鼠血压的升高与血管内皮细胞及其他组织中NO合成功能障碍有关     

Role of the endothelium in the vasodilator response of rat thoracic aorta to histamine

Despite their potent vasodilating action in vivo, acetylcholine and histamine often show a vasoconstricting action in vitro. As the endothelium has an important role in the vasodilating effect of acetylcholine, we investigated the possible role of the endothelium in the vasodilating effect of histamine in comparison to acetylcholine. Experiments were done on ring segments of rat thoracic aorta mounted for isometric tension measurements. We demonstrated that relaxation by histamine and acetylcholamine of pre-contracted rat aorta segments required the presence of endothelial cells. Acetylcholine acting on muscarinic receptors, and histamine acting on H₁-receptors seemed to initiate the production of mediator(s) from the endothelial cells, which leads to relaxation of the vascular smooth muscle cells. This production appeared to be depressed by ETYA and hydroquinone, and under hypoxic conditions.