Central pathology review in clinical trials for patients with malignant glioma. A Report of Radiation Therapy Oncology Group 83-02

We previously described delayed pressor response (DPR) 3 h after endothelin (ET)-1 injection in normotensive rats. In the current study, we examined effects of the ETA receptor antagonist BQ123 (0.01 mumol/kg/min intravenously, i.v.), phosphoramidon (100 mumol/kg i.v.), the neutral endopeptidase inhibitor SQ28603 (112 mumol/kg + 0.04 mumol/kg/min i.v.), the angiotensin-converting enzyme inhibitor enalaprilat (10 mumol/kg i.v.), and the thromboxane receptor antagonist, SQ29548 (0.5 mumol/kg + 0.5 mumol/kg/h i.v.) on DPR. Vehicle and ET-1 (1.0 nmol/kg i.v.) were administered on day 1; vehicle or drug and ET-1 were administered on day 2. BQ123 inhibited DPR 36% (vehicle 44 +/- 5, BQ123 28 +/- 3 mm Hg); phosphoramidon inhibited DPR 56% (vehicle 45 +/- 4, and phosphoramidon 20 +/- 5 mm Hg). DPR was unchanged after SQ28603 (vehicle 39 +/- 2 and SQ28603 44 +/- 2 mm Hg), enalaprilat (vehicle 39 +/- 2 and enalaprilat 38 +/- 7 mm Hg), or SQ29548 (vehicle 46 +/- 6 and SQ29548 43 +/- 3 mm Hg). The results suggest that DPR 3 h after ET-1 injection in rats is mediated in part through ETA receptors. DPR does not appear to involve thromboxane or synthesis of angiotensin II (AII), but may be related to synthesis of ET-1.     

Effects of the angiotensin II type-1 receptor antagonist ZD7155 on angiotensin II-mediated regulation of renin secretion and renal renin gene expression, renal vasoconstriction, and blood pressure in rats

Angiotensin II receptors have recently been subclassified as type-1 or type-2 receptors. The in vitro and in vivo effects of blocking the angiotensin II type-1 receptor with ZD7155, an angiotensin II type-1 selective receptor antagonist, have been studied in angiotensin II-mediated increases in cytosolic calcium in rat mesangial cells, in angiotensin II-induced renal and systemic vasoconstriction, and in angiotensin II-mediated regulation of renin secretion and renal renin gene expression. ZD7155 completely blocked the ability of angiotensin II to elicit an increase in free intracellular calcium concentrations in rat mesangial cells. In isolated perfused rat kidneys, ZD7155 completely abolished the angiotensin II-induced vasoconstriction and increased renin secretion to 700% of baseline levels. Furthermore, ZD7155 decreased systolic blood pressure by 16 mm Hg, increased plasma renin activity 3.7-fold, and stimulated renal renin gene expression 4.2-fold in Sprague-Dawley rats in vivo. Our results suggest that ZD7155 is a potent antagonist of the angiotensin II type-1 receptor, which mediates angiotensin II-induced increases of free intracellular calcium concentrations in (e.g., renal mesangial cells), constriction of the renal and systemic vasculature, and inhibition of renin secretion and synthesis.     

Maintenance of baseline angiotensin II potentiates insulin hypertension in rats

Chronic insulin infusion in rats increases mean arterial pressure (MAP) by a mechanism dependent on angiotensin II (Ang II). However, the fact that plasma renin activity (PRA) decreases with insulin infusion suggests that Ang II sensitivity is increased and that the parallel reduction in Ang II may partly counteract any hypertensive action of insulin. This study tested that hypothesis by clamping Ang II at baseline levels during chronic insulin infusion. Sprague-Dawley rats were instrumented with artery and vein catheters, and MAP was measured 24 hours per day. In seven angiotensin clamped rats (AC rats), renin-angiotensin II system activity was clamped at normal levels throughout the study by continuous intravenous infusion of the angiotensin-converting enzyme inhibitor benazepril at 5 mg/kg per day (which decreased MAP by 18+/-2 mm Hg) together with intravenous Ang II at 5 ng/kg per minute. Control MAP in AC rats after clamping averaged 99+/-1 mm Hg, which was not different from the 101+/-2 mm Hg measured before clamping Ang II levels. Control MAP in the 8 vehicle-infused rats averaged 105+/-2 mm Hg. A 7-day infusion of insulin (1.5 mU/kg per minute IV) plus glucose (20 mg/kg per minute IV) increased MAP in both groups of rats; however, the increase in MAP was significantly greater in AC rats (12+/-1 versus 5+/-1 mm Hg). This enhanced hypertensive response to insulin in AC rats was associated with a greater increase in renal vascular resistance (153+/-10% versus 119+/-6% of control) and a significant increase in renal formation of thromboxane (149+/-11% of control). Thus, decreased Ang II during insulin infusion limits the renal vasoconstrictor and hypertensive actions of insulin, and this may be caused, at least in part, by attenuation of renal thromboxane production.     

Cohort size rather than follicle-stimulating hormone threshold level determines ovarian sensitivity in polycystic ovary syndrome

BACKGROUND: Hypertension and nephrotoxicity are well-known side-effects of cyclosporine A (CsA). CsA-induced vasoconstriction of the afferent glomerular arteriole probably plays a role in at least the nephrotoxicity. Frequently renal transplant recipients on CsA have to be treated with antihypertensive drugs and for this purpose also beta-blockers are used. Tertatolol is a new beta-blocker with specific vasodilatory properties, and thus might be particularly useful in CsA-treated transplant recipients. METHODS: We studied the systemic and renal haemodynamic effects of atenolol and tertatolol in 12 hypertensive renal transplant recipients on cyclosporine A (CsA). In a cross-over way, all patients were treated with atenolol and tertatolol for 4 weeks each, separated by a wash-out period also of 4 weeks. At the end of each period, the mean arterial pressure (MAP), heart rate, glomerular filtration rate (GFR) and renal plasma flow (RPF) were measured. RESULTS: The mean arterial pressure was lower (P < 0.05) during atenolol (124 +/- 2 mm Hg) and tertatolol (125 +/- 2 mm Hg) treatment compared with washout (132 +/- 4 mm Hg). Also the heart rate was lower (P < 0.01) during atenolol and tertatolol (54 +/- 3 and 55 +/- 2 beats/min respectively) than in the wash-out period (65 +/- 3 beats/min). GFR and RPF were not changed by either beta-blocker. CONCLUSION: In CsA treated renal transplant recipients both atenolol and tertatolol effectively reduced blood pressure. In these patients we found no evidence of a specific vasodilatory effect of tertatolol. Both beta-blockers had no negative influence on renal function. Hence, these cardioprotective agents are an attractive and safe choice for the treatment of hypertension in such patients.     

Converting-enzyme inhibitor versus calcium antagonist in cyclosporine-treated renal transplants

The influence of antihypertensive treatment on the long-term evolution of arterial pressure and renal function was studied in a prospective controlled trial conducted in renal transplant recipients treated by cyclosporine. Within six months after transplantation, patients were randomly allocated to treatment by the angiotensin-converting enzyme inhibitor, lisinopril (ACEI, alone or associated with frusemide; N = 14), or the calcium antagonist, nifedipine (CA, alone or associated with atenolol; N = 11). Glomerular filtration rate (TcDTPA clearance) and effective renal plasma flow (hippuran clearance) as well as 24-hour urinary excretion of electrolytes and albumin were estimated at about 1 and 2.5 years of follow-up. Before initiation of antihypertensive therapy, the two groups were similar with regards to mean arterial pressure (119 +/- 2 vs. 120 +/- 4 mm Hg), effective renal plasma flow (285 +/- 26 vs. 248 +/- 33 ml/min/1.73 m2) and glomerular filtration rate (59 +/- 4 vs. 61 +/- 8 ml/min/1.73 m2 in the ACEI and CA groups, respectively). Both ACEI and CA treatments were associated with no change in renal function, a similar change in mean arterial pressure (ACEI -18 +/- 3; CA -13 +/- 5 mm Hg) and identical trough blood levels of cyclosporine. Urinary albumin excretion did not change significantly in any groups. Of interest, only in the ACEI group did filtration fraction significantly decrease (from 0.22 +/- 0.01% to 0.19 +/- 0.01% at final studies). These results indicate that in cyclosporine-treated transplant recipients, a satisfactory control of hypertension is obtained by chronic ACEI, which is as effective on arterial pressure as a combination of CA and atenolol.(ABSTRACT TRUNCATED AT 250 WORDS)     

Effects of BQ-123 on systemic and renal hemodynamic responses to endothelin-1 in the rat split hydronephrotic kidney

OBJECTIVE: To assess the site of action of endothelin-1 in vessels of different sizes in the kidney in vivo and investigate the function of endothelin A (ET(A)) receptors in mediating renal and systemic vasoconstriction. DESIGN: The luminal diameters of different vessels were measured and glomerular blood flow in cortical glomeruli was determined by intravital videomicroscopy in the split hydronephrotic kidney of anesthetized female Wistar rats. METHODS: The rats were infused with endothelin-1 (40 pmol/kg per min) with or without pretreatment with the selective ET(A)-receptor antagonist BQ-123 (0.5 mg/kg). Aortic clamping was used to control renal blood pressure during the endothelin-1 infusion. RESULTS: Exogenous endothelin-1 induced a significant rise (30+/-3%) in mean arterial pressure and a marked, long-lasting fall in glomerular blood flow (53+/-3%) related to reduction of the inner diameter of arcuate (-30%), interlobular arteries (-33%) and afferent arterioles (-17%). Aortic clamping to normalize renal blood pressure did not attenuate the vasoconstriction and reduction in glomerular blood flow. Pretreatment with BQ-123 significantly reduced both the endothelin-1-induced rise in mean arterial pressure (12+/-1%) and the fall in glomerular blood flow (-23+/-11%). BQ-123 blunted the response to endothelin-1 in arcuate (-12%), interlobular (-11%) and afferent vessels (-5%). Acetylcholine and nitroprusside completely reversed the vasoconstriction in BQ-123-pretreated animals. CONCLUSIONS: BQ-123 largely prevented the hemodynamic effects of exogenously administered endothelin-1. Our direct in-vivo techniques showed that ET(A) receptors are, at least in part, involved in endothelin-1 -mediated vasoconstriction in the rat kidney, and support the hypothesis that ET(A) receptors may help to control arterial pressure in anesthetized rats.     

Renal vascular responses to angiotensin II in conscious spontaneously hypertensive and normotensive rats

It has been postulated that exaggerated renal sensitivity to angiotensin II may be involved in the development and maintenance of hypertension in the spontaneously hypertensive rat (SHR). The purpose of this study was to compare the renal vascular responses to short-term angiotensin II infusions (50 ng/kg/min, i.v.) in conscious SHRs and Wistar-Kyoto (WKY) rats. Renal cortical blood flow was measured in conscious rats by using quantitative renal perfusion imaging by magnetic resonance, and blood pressure was measured by an indwelling carotid catheter attached to a digital blood pressure analyzer. Renal vascular responses to angiotensin II were similar in control SHRs and WKY rats. Pretreatment with captopril to block endogenous production of angiotensin II significantly augmented the renal vascular response to exogenous angiotensin II in the SHRs but not in the WKY rats. The renal vascular responses to angiotensin II were significantly greater in captopril-pretreated SHRs than in WKY rats (cortical blood flow decreased by 1.66 +/- 0.13 ml/min/g cortex in WKY rats compared with 2.15 +/- 0.14 ml/min/g cortex in SHR; cortical vascular resistance increased by 10.5 +/- 1.4 mm Hg/ml/min/g cortex in WKY rats compared with 15.6 +/- 1.7 mm Hg/ml/min/g cortex in SHRs). Responses to angiotensin II were completely blocked in both strains by pretreatment with the angiotensin II AT1-receptor antagonist losartan. Results from this study in conscious rats confirm previous findings in anesthetized rats that (a) the short-term pressor and renal vascular responses to angiotensin II are mediated by the AT1 receptor in both SHRs and WKY rats, and (b) the renal vascular responses to angiotensin II are enhanced in SHRs compared with WKY rats when endogenous production of angiotensin II is inhibited by captopril pretreatment.     

EndothelinA receptor blockade improves nitric oxide-mediated vasodilation in monocrotaline-induced pulmonary hypertension

BACKGROUND: Nitric oxide (NO) and endothelin (ET) have been implicated in the pathogenesis of pulmonary hypertension (PH). Chronic ETA antagonist therapy reduces PH in monocrotaline (MCT)-treated rats. Interactions between the L-arginine-NO pathway and the ET system have been described. We therefore studied the effect of long-term treatment with an oral ETA antagonist (LU 135252) on NO-related vasodilation in isolated lungs from control rats and rats with MCT-induced PH. METHODS AND RESULTS: Three weeks after MCT injection, PH was associated with an increase in right ventricular pressure (from 27.4 +/- 0.9 to 66.6 +/- 4.1 mm Hg) and a decrease in endothelium-independent vasodilation in response to sodium nitroprusside (10(-10) to 10(-5) mol/L; delta Emax, from 11.1 +/- 0.9 to 2.7 +/- 0.3 mm Hg). Endothelium-dependent vasodilation in response to acetylcholine (10(-9) to 10(-4) mol/L) and the calcium ionophore A23187 (10(-9) to 10(-7) mol/L) remained unaffected. Treatment with LU 135252 did not significantly affect the endothelium-dependent and -independent vasodilations in control rats. However, in MCT-treated rats, LU 135252 therapy significantly reduced right ventricular pressure (39.7 +/- 2.1 mm Hg), potentiated acetylcholine-induced vasodilatation (delta Emax, from 1.6 +/- 0.2 to 3.7 +/- 0.4 mm Hg), and improved the responses to sodium nitroprusside (delta Emax, from 2.7 +/- 0.3 to 5.6 +/- 0.6 mm Hg). LU 135252 did not significantly alter the non-receptor-mediated endothelium-dependent vasodilation to A23187 or pulmonary constitutive NO synthase activity. CONCLUSIONS: MCT PH is associated with a reduced smooth muscle responsiveness to NO but a maintained endothelium-dependent vasodilatory potency. Long-term ETA antagonist therapy not only restores smooth muscle responsiveness to NO but also increases endothelium-dependent dilation in response to acetylcholine. This mechanism may contribute to the therapeutic benefit of ETA antagonists in PH.     

Endothelin-1 and thromboxane A2 increase pulmonary vascular resistance in granulocyte-mediated lung injury

OBJECTIVE: To examine the pathophysiologic role of vasoactive eicosanoids and endothelin-1 in granulocyte-mediated effects in the pulmonary vasculature. DESIGN: Prospective experimental study in rabbits. SETTING: Experimental laboratory in a university teaching hospital. SUBJECTS: Thirty adult rabbits. INTERVENTIONS: The experiments were performed on 30 isolated and ventilated rabbit lungs that were perfused with a cell- and plasma-free buffer solution. MEASUREMENTS AND MAIN RESULTS: The pulmonary arterial pressure and the lung weight gain were continuously registered. Intermittently perfused samples were taken to determine endothelin-1 and thromboxane A2 concentrations. Six experiments without intervention served as the sham group. The granulocytes in the pulmonary circulation were stimulated with N-formyl-L-leucin-methionyl-L-phenylalanine (FMLP; 10(-6) M; control, n = 6). To investigate whether activated granulocytes influence the pulmonary vasculature via endothelin-1, the endothelin-A receptor antagonist LU135252 (10(-6) M) was added to the perfusate before FMLP injection (n = 6). The potential involvement of thromboxane A2 in granulocyte-endothelial interaction was investigated by pretreatment with the cyclooxygenase inhibitor diclofenac (10 microg/mL; n = 6). Activation of granulocytes resulted in an acute increase in pulmonary arterial pressure (>9 mm Hg), which was followed by a second delayed pressure increase after 60 mins (>14 mm Hg) and was paralleled by a massive generation of thromboxane A2 (>250 pg/ mL). Fifteen minutes after FMLP-injection, endothelin-1 was detectable in the perfusate. Pretreatment with the selective endothelin-A antagonist LU135252 significantly (p< .01) reduced the initial pressure response after FMLP stimulation, while diclofenac significantly reduced (p < .05) the delayed pressure increase. Using diclofenac (10 microg/mL) in conjunction with LU135252 (10(-6) M; n = 6) before FMLP injection significantly reduced the early and the delayed pressure increase. CONCLUSIONS: Activated granulocytes seem to enhance pulmonary vascular resistance via endothelin-1 and thromboxane A2. The endothelin-1 effects are probably mediated via endothelin-A receptors since the endothelin-A receptor antagonist LU135252 was able to suppress the early pressure reaction after FMLP injection, whereas the cyclooxygenase inhibitor diclofenac was able to reduce the second pressure increase.     

Acute and chronic effects of capsaicin in perfused rat muscle: the role of tachykinins and calcitonin gene-related peptide

In perfused rat skeletal muscle (hindlimb), capsaicin either stimulates (submicromolar concentrations) or inhibits (micromolar concentrations) oxygen consumption (VO2). Both VO2 effects are associated with vasoconstriction, evident as an increase in perfusion pressure (PP), under constant flow. We have proposed that these effects are mediated by two vanilloid receptor subtypes: VN1 (stimulation of VO2) and VN2 (inhibition of VO2) (; ). In the present study, the role of capsaicin-sensitive neurons and sensory neuropeptides in the VN1/VN2 receptor actions of capsaicin was investigated. The observed maximum stimulation of VO2 by capsaicin (0.4 microM; DeltaVO2, 1.35 +/- 0.14 micromol g-1 h-1) was accompanied by mild vasoconstriction (DeltaPP, 5.8 +/- 0.6 mm Hg). In contrast, 2 microM capsaicin produced strong inhibition of VO2 (DeltaVO2, -2.25 +/- 0.23 micromol g-1 h-1) with pronounced vasoconstriction (DeltaPP, 28.0 +/- 1.3 mm Hg). VO2 stimulation was significantly inhibited (P <.05) by the selective NK1 receptor antagonist CP-99994 (1 microM) and the NK2 receptor antagonist SR 48968 (1 microM) (by 42% and 51%, respectively), but PP was not altered. Infused SP and neurokinin A (NKA) stimulated VO2 (observed maximum DeltaVO2, 0.52 +/- 0.06 and 0.53 +/- 0.08 micromol g-1 h-1, respectively; EC50 values, 269 +/- 23 and 21.2 +/- 3.0 nM, respectively) and induced mild vasoconstriction (4.30 +/- 0.33 and 6. 75 +/- 1.18 mm Hg, respectively; EC50 values, 352 +/- 25.7 and 25.5 +/- 2.7 nM, respectively). Neurokinin B (NKB) also stimulated VO2 (maximum not determined) and vasoconstriction (maximum DeltaPP, 3.40 +/- 0.25 mm Hg; EC50, 34.4 +/- 5.2 nM). The rank order of potency for the tachykinins in this preparation was NKA > NKB > SP, which suggests stimulation primarily of NK2 receptors. Although infused calcitonin gene-related peptide (CGRP) did not alter hindlimb VO2 or PP, the selective CGRP antagonist CGRP(8-37) markedly potentiated the inhibition of VO2 produced by 1 microM capsaicin (84%) and the maximum capsaicin-induced vasoconstriction (57%), which indicates that endogenously released CGRP may act as a vasodilator. Hindlimbs perfused 1 day after capsaicin pretreatment showed attenuation of capsaicin-induced (0.4 microM) stimulation of VO2 (92%) (P <.05) and vasoconstriction (64%), but this returned to normal after 7 days. The inhibition of VO2 by 1 microM capsaicin was significantly (P <. 05) enhanced 7 and 14 days after pretreatment (66% and 140%, respectively), as was the maximum vasoconstriction (64% and 68%, respectively). These data suggest that capsaicin-sensitive neurons, presumably via release of SP and NKA, are involved in VN1 responses and that capsaicin pretreatment potentiates VN2 responses, either by depletion of CGRP reserves or by upregulation of putative VN2 receptors.     

A prospective controlled study of the efficacy of short-term anticoagulation therapy in patients with deep vein thrombosis of the lower extremity

This study was undertaken to investigate changes in aortic geometry and compliance after long-term blockade of angiotensin receptors type 1 (AT1) and AT2 receptors under basal conditions and after myocardial infarction (MI). Sham-operated (sham) or MI rats received either no treatment, AT1 antagonist GR138950C (GR; 2 mg/kg/day i.v.), or AT2 antagonist PD123319 (PD; 3 mg/kg/day s.c.). After 3 weeks, mean arterial blood pressure (MAP) was measured. Thoracic aorta diastolic diameter (D[dia]), compliance coefficient (CC), and distensibility coefficient (DC) were determined noninvasively in anesthetized rats by using ultrasound and wall tracking. After the rats were killed, histologic measurements were made on aortic cross sections. In sham rats, MAP was reduced by GR treatment (76 +/- 6 vs. 106 +/- 5 mm Hg), but not by PD. D(dia) was reduced in both GR-treated (1.74 +/- 0.08 vs. 2.09 +/- 0.05 mm) and PD-treated (1.83 +/- 0.05 vs. 2.09 +/- 0.05 mm) sham rats. CC and DC were not modified by either treatment. Although media cross-sectional area was not affected by either GR or PD treatment in sham rats, media thickness and media/lumen ratio were increased in both cases. Induction of MI had no effect on aortic structure, geometry, or mechanics; however, treatment with either GR or PD improved DC versus untreated MI rats. We conclude that AT1 and AT2 receptors are involved in angiotensin II-mediated effects on aortic geometry and mechanics under both basal conditions and after MI. Whereas blockade of AT1 receptors most likely influences vascular properties through a depressor mechanism, AT2 receptors induce pressure-independent remodeling.     

Estrogen receptor alpha and beta expression in upper gastrointestinal tract with regulation of trefoil factor family 2 mRNA levels in ovariectomized rats

STUDY OBJECTIVE: To investigate the effect of short-term inhalation of nitric oxide (NO) on transpulmonary angiotensin II formation in patients with severe ARDS. DESIGN: Prospective, clinical study. SETTING: Anesthesiology ICU of a university hospital. PATIENTS: Ten ARDS patients who responded to inhalation of 100 ppm NO by decreasing their pulmonary vascular resistance (PVR) by at least 20 dyne x s x cm(-5) were included in the study. INTERVENTIONS AND MEASUREMENTS: In addition to standard treatment, the patients inhaled 0, 1, and 100 ppm NO in 20-min intervals. Fraction of inspired oxygen was 1.0. Hemodynamics were measured and recorded online. Mixed venous (pulmonary arterial catheter) and arterial (arterial catheter) blood samples were taken simultaneously for hormonal analyses at the end of each inhalation period. RESULTS: Pulmonary arterial pressure decreased from 33+/-2 mm Hg (0 ppm NO, mean+/-SEM) to 29+/-2 mm Hg (1 ppm NO, p<0.05), and to 27+/-2 mm Hg (100 ppm NO, p<0.05, vs 0 ppm). PVR decreased from 298+/-56 (0 ppm NO) to 243+/-45 dyne x s x cm(-5) (1 ppm NO, not significant [NS]), and to 197+/-34 dyne x s x cm(-5) (100 ppm NO, p<0.05, vs 0 ppm). Arterial oxygen pressure increased from 174+/-23 mm Hg (0 ppm NO) to 205+/-26 mm Hg (1 ppm NO, NS), and to 245+/-25 mm Hg (100 ppm NO, p <0.05, vs 0 ppm). Mean plasma angiotensin II concentrations were 85+/-20 (arterial) and 57+/-13 pg/mL (mixed venous) during 0 ppm NO and did not change during inhalation of 1 and 100 ppm NO. Mean transpulmonary plasma angiotensin II concentration gradient (=difference between arterial and mixed venous blood values) was 28+/-8 pg/mL (range, 0 to 69) during 0 ppm NO and did not change during inhalation of 1 and 100 ppm NO. Mean transpulmonary angiotensin II formation (transpulmonary angiotensin II gradient multiplied with the cardiac index) was 117+/-39 ng/min/m2 (range, 0 to 414) during 0 ppm NO and did not change during inhalation of 1 and 100 ppm NO. Mean arterial plasma cyclic guanosine monophosphate concentration was 11+/-2 pmol/mL (0 ppm NO), did not change during 1 ppm NO, and increased to 58+/-8 pmol/mL (100 ppm NO, p<0.05). Arterial plasma concentrations of aldosterone (142+/-47 pg/mL), atrial natriuretic peptide (114+/-34 pg/mL), angiotensin-converting enzyme (30+/-5 U/L), and plasma renin activity (94+/-26 ng/mL/h of angiotensin I) did not change. CONCLUSION: The decrease of PVR by short-term NO inhalation in ARDS patients was not accompanied by changes in transpulmonary angiotensin II formation. Our results do not support any relationship between transpulmonary angiotensin II formation and the decrease in PVR induced by inhaled NO.     

Mechanisms of kinin B1-receptor-induced hypotension in the anesthetized dog

Our study was performed to investigate the mechanism underlying the phypotensive effect of kinin B1-receptor activation with des-Arg9-bradykinin (des-Arg9-BK), in comparison with B2-receptor activation with bradykinin (BK), in anesthetized dogs. Bolus intravenous and intraarterial injections of both kinins were compared. BK (0.6 microgram/kg) produced a transient hypotension of the same magnitude, regardless of the route of administration (from 110 +/- 6 mm Hg to 66 +/- 6 mm Hg, or -41 +/- 5%). In contrast, intraarterial injection of des-Arg9-BK (0.6 microgram/kg) induced a weaker hypotension compared with its intravenous injection (-27 +/- 2% vs. -39 +/- 3%, p < 0.05). The hypotension induced by both kinins was accompanied by increases in heart rate, maximum left ventricular dP/dt, and aortic blood flow, suggesting a reduction in peripheral resistance. The positive inotropic and chronotropic effects of BK and des-Arg9-BK were found to be mediated by the sympathetic nervous system, because they were abolished by propranolol. The hypotension induced by intravenous and intraarterial injections of BK and intravenous injections of des-Arg9-BK was only slightly reduced after nitric oxide (NO) synthase inhibition with NG-nitro-L-arginine (L-NNA). In contrast, the hypotensive effect of intraarterial injection of des-Arg9-BK was reduced by half after treatment with L-NNA (p < 0.05). Neither bilateral vagotomy nor ganglionic blockade with pentolinium reduced the hypotension induced by both kinins. In conclusion, the hypotensive effect of des-Arg9-BK and BK results from a peripheral vasodilation. The contribution of NO in this vasodilation is substantial for des-Arg9-BK when administered intraarterial but limited for BK and intravenous des-Arg9-BK.     

Porous-coated total hip arthroplasty in the young

OBJECTIVE: To evaluate whether thromboxane A2 participates in the ischemia-reperfusion injury associated with acute compartmental syndrome (ACS) and if by using a cyclooxygenase inhibitor this can be either reduced or abolished. DESIGN: To assess the role of thromboxane A2 in ACS, a tourniquet was applied for 2 hours to the hind limb of 12 dogs. Group 1 (n = 6) served as controls while group 2 (n = 6) was pretreated with lysine-acetyl-salicylate (Lysoprim). Blood thromboxane B2 levels and intracompartmental pressures were assayed prior to inflation of the tourniquet and at 5 minutes, 90 minutes, and 24, 72, and 144 hours after deflation. RESULTS: Five minutes after deflation, the compartmental pressure increased from 11.2 +/- 2.2 mm Hg to 16.1 +/- 3.3 mm Hg and 17 +/- 2.2 mm Hg (mean +/- SD) in groups 2 and 1, respectively. At 90 minutes and 24 hours, pressures were 17.1 +/- 3.3 mm Hg and 23.2 +/- 3.3 mm Hg (P<.01) and 15.3 +/- 2.6 mm Hg and 25.2 +/- 1.8 mm Hg (mean +/- SD) (P<.001), respectively, in groups 2 and 1. A similar effect, although of a lesser magnitude, was observed in the counterlateral limb. Thromboxane B2 levels increased from a mean (+/- SD) of 46 +/- 5.5 pg/0.1 mL to 132 +/- 7.5 pg/0.1 mL at 90 minutes in group 1, while remaining unchanged in group 2. CONCLUSIONS: Thromboxane A2 plays a major role in the ischemia-reperfusion injury of acute compartmental syndrome. By using a cyclooxygenase inhibitor both the levels of thromboxane and the compartmental pressures can be reduced.     

Possible modulation by endothelin-1, nitric oxide, prostaglandin I2 and thromboxane A2 of vasoconstriction induced by an alpha-agonist in mesenteric arterial bed from diabetic rats

We hypothesized that in diabetes arterial reactivity to constrictors is attenuated by certain endothelium-derived substances. We examined the vasoconstriction induced by methoxamine (alpha1-agonist) in isolated mesenteric arterial beds from streptozotocin (STZ)-induced diabetic rats and age-matched control rats. The dose-response curve for methoxamine was shifted to the right and the maximum contractile response was impaired in mesenteric arterial beds from diabetic rats. The methoxamine vasoconstriction was reduced in endothelium-denuded preparations from controls rats, but increased in those from diabetic rats. Treatment with the nitric oxide synthase inhibitor NG-nitro-L-arginine enhanced the vasoconstrictions induced by methoxamine in both control and diabetic rats. Indomethacin had no effect on the methoxamine vasoconstriction in control rats, but it shifted the dose-response curve to the left in diabetic rats. Whether given with or without indomethacin, BQ-123, (an ET(A)-receptor antagonist) plus BQ-788 (an ET(B)-receptor antagonist) shifted the dose-response curve for methoxamine to the right in control rats (while reducing the maximum response) but to the left in diabetic rats. The methoxamine-stimulated release of 6-keto-prostaglandin F1alpha from the mesenteric arterial bed in diabetic rats was approximately four times that seen in the control rats, while the methoxamine-induced release of thromboxane B2 (TXB2), a metabolite of thromboxane A2 (TXA2), was less in diabetic rats than in the control animals. These results suggest that an increased production of prostaglandin I2 (PGI2) and decreased formation of TXA2 could be responsible for the attenuation of the methoxamine-induced mesenteric vasoconstriction seen in diabetic rats, and these changes in the diabetic state could be partly responsible for the lower blood pressure seen in our diabetic rats.     

Fetoplacental vascular tone during fetal circuit acidosis and acidosis with hypoxia in the ex vivo perfused human placental cotyledon

OBJECTIVES: Our purpose was to determine the effects of acidosis and acidosis-hypoxia on fetoplacental perfusion pressure and its response to angiotensin II. STUDY DESIGN: Perfused cotyledons from 14 placentas were studied with either an acidotic fetal circuit perfusate (n = 7) or an acidotic-hypoxic fetal circuit perfusate (n = 7). Each cotyledon's fetal vasculature was initially perfused under standard conditions and bolus injected with 1 x 10(-10) moles of angiotensin II. Fetoplacental perfusate was then replaced with either an acidotic medium (pH 6.90 to 7.00 and Po2 516 to 613 mm Hg) or an acidotic-hypoxic medium (pH 6.90 to 7.00 and Po2 20 to 25 mm Hg) followed by an angiotensin II injection. The vasculature was subsequently recovered with standard perfusate and again injected with angiotensin II. Perfusion pressures within each group were compared by one-way analysis of variance, and results were expressed as mean pressure +/- SEM. RESULTS: Resting fetoplacental perfusion pressure did not change when the fetal circuit perfusate was made acidotic (28 +/- 1 mm Hg vs 25 +/- 2 mm Hg) or acidotic-hypoxic (26 +/- 2 mm Hg vs 25 +/- 2 mm Hg). The maximal fetoplacental perfusion pressure achieved in response to angiotensin II did not differ with an acidotic perfusate (41 +/- 2 mm Hg vs 38 +/- 1 mm Hg) or with an acidotic-hypoxic perfusate (39 +/- 2 mm Hg vs 36 +/- 2 mm Hg). CONCLUSIONS: In the perfused placental cotyledon fetoplacental perfusion pressure and pressor response to angiotensin II are not affected by fetal circuit acidosis or acidosis-hypoxia. This suggests that neither fetal acidosis nor fetal acidosis combined with hypoxia has a direct effect on fetoplacental vascular tone.     

Endogenous angiotensin II and bradykinin delay and attenuate the hypotension after N-type calcium channel blockade in conscious rabbits

The effects of N-type calcium channel inhibition with omega-conotoxin GVIA (omega-CTX) on cardiovascular parameters and vagally mediated autonomic reflexes and the role of the renin-angiotensin system were assessed in conscious rabbits. Omega-CTX (10 microg/kg, i.v.) resulted in hypotension, tachycardia, and attenuation of the sympathetic and vagal components of the baroreceptor-heart rate reflex (baroreflex). In the control group (no pretreatment), the peak decrease in mean arterial pressure (MAP) of 13 +/- 3 mm Hg from 72 +/- 2 mm Hg occurred after 33 +/- 3 min, with a corresponding tachycardia of 80 +/- 20 beats/min (n = 6). The tachycardia was due to vagal withdrawal, as a similar increase in heart rate (84 +/- 8 beats/min) after omega-CTX was observed after pretreatment with the beta-adrenoceptor antagonist, propranolol (n = 6). Angiotensin-converting enzyme (ACE) inhibition with enalaprilat revealed a larger, more rapid decrease in MAP in response to omega-CTX (-19 +/- 4 mm Hg from 65 +/- 1 mm Hg after 18 +/- 2 min; n = 6) compared with the control group. Similar larger decreases in MAP were also observed in the presence of the AT1-receptor antagonist, losartan, or the bradykinin B2 receptor antagonist, HOE-140 (n = 5-6). Pretreatment with enalaprilat, losartan, or HOE-140 caused a 50% decrease in the reflex tachycardia after omega-CTX compared with that observed in the control group, and omega-CTX caused a greater attenuation of the vagal component of the baroreflex and a decrease in the bradycardia evoked by the Bezold-Jarisch-like reflex. Also, there was a significant decrease in the bradycardia induced by the nasopharyngeal reflex after omega-CTX in the presence of ACE inhibition and HOE-140. Thus in the conscious rabbit, angiotensin II and bradykinin have a role in attenuating and slowing the hypotensive effect of N-type calcium channel inhibition. Vagolytic effects of omega-CTX on the baroreflex are augmented, and on other vagal reflexes are unmasked, via inhibition of the renin-angiotensin system. The complexity and mechanism of the interaction between N-type calcium channels and the renin-angiotensin system remain to be elucidated.     

Vasodilator actions of urocortin and related peptides in the human perfused placenta in vitro

Urocortin, is a recently isolated peptide belonging to the CRH family that binds with high affinity to the CRH2 receptor. Like CRH, urocortin causes hypotension in the rat, but its vasoactive actions have not yet been studied in the human. We have compared the vasoactive properties of urocortin, CRH, and urotensin-1 in the human fetal placental vasculature in vitro. Single placental lobules were bilaterally perfused (maternal and fetal sides, 5 mL/min each; 95% O2-5% CO2; 37 C), and changes in fetal arterial perfusion pressure were recorded. Submaximal vasoconstriction was induced by PGF2alpha (4+/-0.7 micromol/L), which increased perfusion pressure from 19.6+/-1.4 to 100.7+/-3.1 mm Hg (n=38; P < 0.001). Subsequent fetal arterial infusion of urocortin (0.001-1 nmol/L) caused concentration-dependent vasodilatation. Urocortin was equipotent with urotensin-1 and 25 times more potent than CRH in causing vasodilatation. Nevertheless, the maximum vasodilator responses to each of the peptides were similar (P > 0.05). The CRH receptor antagonist, alpha-helical CRH-(9-41) (0.2 nmol/L) significantly attenuated the vasodilatation produced by urocortin, urotensin-1, and CRH (P < 0.05). These results indicate a possible physiological role for urocortin in the modulation of human fetal placental vascular tone by activation of CRH2-like receptors.     

Chronic sodium balance and blood pressure response to captopril in conscious mice

The influence of chronic administration of the converting enzyme inhibitor captopril on blood pressure and sodium balance was evaluated in conscious Swiss Webster mice. Arterial pressure was measured with chronic indwelling catheters, and sodium balance was determined by infusing sodium intravenously in isotonic saline and collecting urine 24 h/d. Experiments to validate sodium balance measurements in mice demonstrated recovery of 100+/-3% of sodium intake under steady-state conditions (n=20 mice on 70 individual days, sodium intake range 160 to 1000 micromol/d). It was further demonstrated that mean arterial pressure, heart rate, and body weight were unaltered from 115+/-7 mm Hg, 646+/-12 bpm, and 34+/-0.6 g, respectively, as sodium intake was increased stepwise from 150 to 900 micromol NaCl per day. An additional validation group (n=7) demonstrated that daily and cumulative sodium balance can be accurately determined during and after the intravenous administration of an agent known to alter renal sodium handling (furosemide 50 mg. kg-1. d-1). Experiments were then performed to examine the influence of intravenous captopril infusion (40 mg. kg-1. d-1, n=7) in mice in which the daily sodium intake was fixed at approximately 200 micromol/d. This dose of captopril was determined to significantly decrease the pressor response to a 10-ng bolus of angiotensin I (Ang I) from 24+/-5 in the control state to 6+/-2 mm Hg (n=5). After 5 days of infusion of the converting enzyme inhibitor, mean arterial pressure significantly fell from 114+/-3 to 58+/-2 mm Hg, body weight significantly decreased from 36+/-1 to 33+/-1 g, and cumulative sodium balance significantly decreased to -270+/-55 micromol. These parameters returned toward control during 5 postcontrol days. Results of this study demonstrate that accurate sodium balance measurements can be obtained from individual conscious mice over a 5-fold range of sodium intake. The experiments also indicate that converting enzyme inhibition has a potent influence to lower blood pressure in normal mice; the hypotensive response appears to be due in part to increased urinary sodium excretion.     

Major histocompatibility complex class II expression and parathyroid autoantibodies in primary hyperparathyroidism

We evaluated whether kinins exert a protective action against the development of two-kidney, one clip (2K1C) hypertension, a model characterized by an activated renin-angiotensin system in the ischemic kidney and increased expression of the bradykinin (BK) B2 receptor in the contralateral kidney. BK B2-receptor knockout (B2-/-), wild-type (B2+/+), and heterozygous (B2+/-) mice underwent clipping of the left renal artery, with the other kidney remaining untouched. Basal systolic blood pressure (SBP, via tail-cuff plethysmography) was higher in B2-/- mice than in B2+/- or B2+/+ mice (121+/-2 versus 113+/-2 and 109+/-1 mm Hg; P<0.05 for both comparisons). SBP did not change from basal values after sham operation, but it increased in mice that underwent clipping. The increase in SBP was greater in 2K1C B2-/- mice than in B2+/- or B2+/+ mice (28+/-2 versus 14+/-2 and 14+/-2 mm Hg, respectively, at 2 weeks; P<0.05 for both comparisons). Blockade of the BK B2 receptor by Icatibant enhanced the pressure response to clipping in B2+/+ mice (29+/-2 mm Hg at 2 weeks). Intra-arterial mean blood pressure (MBP) was higher in 2K1C than in respective sham-operated mice, with the MBP difference being higher in B2-/- mice (32 and 38 mm Hg, at 2 and 4 weeks, respectively), and higher in B2+/+ mice given Icatibant (30 and 32 mm Hg) than in B2+/+ mice without Icatibant (17 and 18 mm Hg). At 4 weeks, acute injection of an angiotensin type 1 receptor antagonist normalized the MBP of 2K1C hypertensive mice. A tachycardic response was observed 1 week after clipping in B2-/- and B2+/- mice, but this effect was delayed in B2+/+ mice. However, the HR response to clipping in B2+/+ mice was enhanced by Icatibant. Within each strain, heart weight to body weight ratio was greater in 2K1C hypertensive mice than in sham-operated control animals (B2-/-: 5.7+/-0.1 versus 5.2+/-0.1; B2+/+: 5.1+/-0.1 versus 4.5+/-0.1; P<0.01 for both comparisons). The clipped kidney weight to nonclipped kidney weight ratio was consistently reduced in mice with 2K1C hypertension. Our results indicate that kinins acting on the BK B2 receptor exert a protective action against excessive blood pressure elevation during early phases of 2K1C hypertension.