Hemodynamic and renal effects of U-46619, a TXA2/PGH2 analog, in late-pregnant rats. (9/3794)

The vasoconstrictor effects of pressor agents are attenuated during pregnancy. Thromboxane A2 (TXA2) is produced in great quantities during hypertension in pregnancy, and therefore it is important to know whether pregnancy modifies the pressor effects of TXA2. The TXA2 analog U-46619 was infused in anesthetized, acutely prepared and conscious, chronically prepared late-pregnant and nonpregnant female rats to examine its systemic hemodynamic and renal effects. Mean arterial pressure (MAP) and total peripheral resistance (TPR) were lower in anesthetized pregnant than nonpregnant rats (P < 0.01). The infusion of U-46619 into the aortic arch resulted in elevation of MAP only in pregnant rats, due to a greater elevation of TPR (60 +/- 17%) compared with nonpregnant rats (36 +/- 6%, P < 0.05). The pressor effect of intravenously infused U-46619 was also enhanced in conscious pregnant versus nonpregnant rats, and the increase in renal vascular resistance was undiminished. U-46619 increased hematocrit and plasma protein concentration more during pregnancy, which suggested greater reduction of plasma volume. The urinary excretion of sodium (-1.49 +/- 0.25 vs. -0.54 +/- 0.24 micromol/min) and water was reduced more in pregnant than nonpregnant rats during U-46619 (P < 0.01). Thus the MAP and renal effects of the TXA2 analog are exaggerated during pregnancy in the rat.  (+info)

Cyclooxygenase-2 plays a significant role in regulating the tone of the fetal lamb ductus arteriosus. (10/3794)

Nonselective cyclooxygenase (COX) inhibitors are potent tocolytic agents but have adverse effects on the fetal ductus arteriosus. We hypothesized that COX-2 inhibitors may not affect the ductus if the predominant COX isoform is COX-1. To examine this hypothesis, we used ductus arteriosus obtained from late-gestation fetal lambs. In contrast to our hypothesis, fetal lamb ductus arteriosus expressed both COX-1- and COX-2-immunoreactive protein (by Western analysis). Although COX-1 was found in both endothelial and smooth muscle cells, COX-2 was found only in the endothelial cells lining the ductus lumen (by immunohistochemistry). The relative contribution of COX-1 and COX-2 to PGE2 synthesis was consistent with the immunohistochemical results: in the intact ductus, PGE2 formation was catalyzed by both COX-1 and COX-2 in equivalent proportions; in the endothelium-denuded ductus, COX-2 no longer played a significant role in PGE2 synthesis. NS-398, a selective inhibitor of COX-2, was 66% as effective as the selective COX-1 inhibitor valeryl salicylate and the nonselective COX inhibitor indomethacin in causing contraction of the ductus in vitro. At this time, caution should be used when recommending COX-2 inhibitors for use in pregnant women.  (+info)

Heat shock protein expression in umbilical artery smooth muscle. (11/3794)

Postpartum vasospasm in the umbilical arteries may be due to impaired vasorelaxation secondary to alterations in the expression of heat shock proteins. The contractile responses of pre- and full-term bovine umbilical artery smooth muscles were determined in a muscle bath. Heat shock protein expression was determined in bovine and human arterial tissues using western blotting with specific antisera. Full-term bovine and human umbilical artery smooth muscle was refractory to relaxation induced by the nitric oxide donor, sodium nitroprusside. This impaired vasorelaxation was associated with the expression of the inducible form of the heat shock protein, HSP70i, and increases in the expression of the small heat shock protein, HSP27. Small heat shock proteins have been implicated in modulating contraction and relaxation responses in vascular smooth muscles. Thus, alterations in heat shock protein expression may play a role in umbilical artery vasospasm.  (+info)

Angiotensin II-stimulated nitric oxide release from porcine pulmonary endothelium is mediated by angiotensin IV. (12/3794)

In this study, a nitric oxide (NO) sensor was used to examine the ability of angiotensin II (AngII), AngIV, and bradykinin (Bk) to stimulate NO release from porcine pulmonary artery (PPAE) and porcine aortic endothelial (PAE) cells and to explore the mechanism of the AngII-stimulated NO release. Physiologic concentrations of AngII, but not Bk, caused release of NO from PPAE cells. In contrast, Bk, but not AngII, stimulated NO release from PAE cells. AngIII-stimulated NO release from PPAE cells required extracellular L-arginine and was inhibited by L-nitro-arginine methyl ester. AT1 and AT2 receptor inhibition had no affect on AngII-mediated NO release or activation of NO synthase (NOS). AngIV, an AngII metabolite with binding sites that are pharmacologically distinct from the classic AngII receptors, stimulated considerably greater NO release and greater endothelial-type constitutive NOS activity than the same amount of AngII. The AngIV receptor antagonist, divalinal AngIV, blocked both AngII- and AngIV-mediated NO release as well as NOS activation. The results demonstrate that AngIV and the AngIV receptor are responsible, at least in part, for AngII-stimulated NO release and the associated endothelium-dependent vasorelaxation. Furthermore, these results suggest that differences exist in both AngII- and Bk-mediated NO release between PPAE and PAE cells, which may reflect important differences in response to these hormones between vascular beds.  (+info)

Endothelium-dependent hyperpolarization in resting and depolarized mammary and coronary arteries of guinea-pigs. (13/3794)

1. The membrane potential responses in guinea-pig coronary and mammary arteries attributable to endothelium-derived nitric oxide (NO), prostaglandin (PG) and hyperpolarizing factor (EDHF), and to exogenous NO and the prostacyclin analogue, iloprost, were compared at rest and when depolarized with the thromboxane analogue, U46619. 2. In the coronary artery, stimulation of the endothelium with acetylcholine (ACh) evoked hyperpolarization attributable to NO and a PG with similar pD2s at rest and in the presence of U46619. However, in depolarized tissues, the pD2 of the response attributed to EDHF required a 10 fold lower concentration of ACh compared with at rest. 3. In the mammary artery, lower concentrations of ACh were required to evoke NO- and EDHF-dependent hyperpolarizations in depolarized mammary artery compared with at rest, while PG-dependent hyperpolarization did not occur until the concentration of ACh was increased some 10 fold both at rest and in U46619. 4. The smooth muscle of the coronary artery of guinea-pigs was some 4 fold more sensitive to exogenous NO and iloprost than was the mammary artery. 5. In conclusion, the membrane potential response in arteries at rest, that is, in the absence of constrictor, may be extrapolated to events in the presence of constrictor when NO and PG are under study. However, the sensitivity to ACh and the magnitude of the hyperpolarization attributed to EDHF obtained in tissues at rest may underestimate these parameters in depolarized tissues.  (+info)

Characterization of alpha1-adrenoceptor subtypes mediating vasoconstriction in human umbilical vein. (14/3794)

1. The present study attempted to characterize pharmacologically the subtypes of alpha-adrenoceptors mediating contractions in human umbilical vein (HUV). 2. HUV rings were mounted in isolated organ baths and cumulative concentration-response curves were constructed for the alpha-adrenoceptor agonists phenylephrine and adrenaline. Adrenaline was more potent than phenylephrine (pD2=7.29 and 6.04 respectively). 3. Isoproterenol exhibited no agonism on KCl pre-contracted HUV rings. Propranolol (1 microM) and rauwolscine (0.1 microM) did not affect the concentration-response curves to adrenaline. These results demonstrate the lack of involvement of functional beta-or alpha2-adrenoceptors in adrenaline-induced vasoconstriction. 4. The non subtype selective alpha1-adrenoceptor antagonist prazosin was evaluated on phenylephrine and adrenaline concentration-response curves. The effects of the competitive alpha1A and alpha1D-adrenoceptor antagonists, 5-methyl urapidil and BMY 7378 and the irreversible alpha1B selective compound chloroethylclonidine (CEC) were also evaluated on adrenaline concentration-response curves. 5. The potencies of prazosin against responses mediated by adrenaline (pA2= 10.87) and phenylephrine (pA2= 10.70) indicate the involvement of prazosin-sensitive functional alpha1-adrenoceptor subtype in vasoconstriction of the HUV. 6. The potencies of 5-methyl urapidil (pA2 = 6.70) and BMY 7378 (pA2= 7.34) were not consistent with the activation of an alpha1A- or alpha1D-adrenoceptor population. 7. Exposure to a relatively low CEC concentration (3 microM) abolished the maximum response to adrenaline suggesting that this response was mediated by an alpha1B-adrenoceptor subtype. 8. We conclude that HUV express a prazosin-sensitive functional alpha1-adrenoceptor resembling the alpha1B-subtype according with the low pA2 values for both 5-methyl urapidil and BMY 7378 and the high sensitivity to CEC.  (+info)

Endothelin receptor expression and pharmacology in human saphenous vein graft. (15/3794)

1. We have investigated the expression and pharmacology of endothelin (ET) receptors in human aortocoronary saphenous vein grafts. 2. Subtype-selective ligands were used to autoradiographically identify ET(A) ([125I]-PD151242) and ET(B)([125I]-BQ3020) receptors. In graft saphenous vein ETA receptors predominated in the media, with few ET(B) receptors identified. Neither subtype was detected in the thickened neointima. 3. The ratio of medial ET(A):ET(B) receptors was 75%: 25% in both graft and control saphenous vein. 4. ET-1 contracted control (EC50 2.9 nM) and graft (EC50 4.5 nM) saphenous vein more potently than diseased coronary artery (EC50 25.5 nM). 5. In all three blood vessels ET-1 was 100 times more potent than ET-3 and three times more potent than sarafotoxin 6b (S6b). Little or no response was obtained in any vessel with the ET(B) agonist sarafotoxin 6c (S6c). 6. The ET(A) antagonist PD156707 (100 nM) blocked ET-1 responses in all three vessels with pKb values of approximately 8.0. 7. For individual graft veins the EC50 value for ET-1 and 'age' of graft in years showed a significant negative correlation. 8. In conclusion there is no alteration in ET receptor expression in the media of saphenous veins grafted into the coronary circulation compared to control veins. ETA receptors predominantly mediate the vasoconstrictor response to ET-1 in graft vein, with no apparent up-regulation of ET(B) receptors. The sensitivity of the graft vein to ET-1 increased with graft 'age', suggesting that these vessels may be particularly vulnerable to the increased plasma ET levels that are detected in patients with cardiovascular disease.  (+info)

Endogenous nitric oxide in the maintenance of rat microvascular integrity against widespread plasma leakage following abdominal laparotomy. (16/3794)

1. The role of nitric oxide (NO) in the maintenance of microvascular integrity during minor surgical manipulation has been evaluated in the rat. 2. The NO synthase inhibitors, NG-nitro-L-arginine methyl ester (L-NAME, 5 mg kg(-1), s.c.) and N(G)-monomethyl-L-arginine (L-NMMA, 50 mg kg(-1), s.c.) had no effect on microvascular leakage of radiolabelled albumin over 1 h in the stomach, duodenum, jejunum, colon, lung and kidney in the un-operated conscious or pentobarbitone-anaesthetized rat. 3. In contrast, in anaesthetized rats with a midline abdominal laparotomy (5 cm), L-NAME (1-5 mg kg(-1), s.c.) or L-NMMA (12.5-50 mg kg(-1), s.c.) dose-dependently increased gastrointestinal, renal and pulmonary vascular leakage, effects reversed by L-arginine pretreatment (300 mg kg(-1), s.c., 15 min). These actions were not observed in anaesthetized rats that had only received a midline abdominal skin incision (5 cm). 4. Pretreatment with a rabbit anti-rat neutrophil serum (0.4 ml kg(-1), i.p.), 4 h before laparotomy, abolished the plasma leakage induced by L-NAME in all the organs investigated. 5. These results indicate that the following abdominal laparotomy, inhibition of constitutive NO synthase provokes vascular leakage in the general microcirculation, by a process that may involve neutrophils. Such effects could thus confound studies on the microvascular actions of NO synthase inhibitors using acute surgically prepared in vivo models. The findings thus suggest that constitutively-formed NO has a crucial role in the maintenance of acute microvascular integrity following abdominal surgical intervention.  (+info)