Acute pancreatitis in the elderly - Can we perform better?

BACKGROUND: Despite age traditionally being a criterion for stratification of severity in acute pancreatitis (AP), the condition is not common in the elderly population (>80 years) and very few studies have examined outcome in this cohort. The aim of this study was to evaluate our experience and outcome in this expanding population. METHODS: A retrospective analysis was performed of all patients over 80 years of age who were admitted with AP (defined as a serum amylase >400 IU/L) between January 2004 and January 2007. The modified Glasgow score was used for severity stratification. RESULTS: Forty patients with AP were admitted during the study period, of whom 23 were females. The mean age was 84 (SD 4.1) years. Fifteen patients (37%) had severe AP as indicated by a Glasgow score of 3 or more. The aetiologies were gallstones (n = 28; 70%), drug-induced (n = 4; 10%) and idiopathic (n = 8; 20%). Ten patients (25%) died during their initial admission to hospital, of whom 5 died before undergoing any form of imaging to determine the cause of AP. Six patients, 5 of whom had gallstones were subsequently readmitted with a further attack of AP. Eleven patients underwent an ERCP during their initial admission and a further 4 patients underwent ERCP during their subsequent admission. Only 3 patients with gallstone-induced AP underwent a cholecystectomy, all performed laparoscopically. CONCLUSIONS: AP in octogenarians is a significant problem and carries a high mortality irrespective of the Glasgow severity score. Early intervention by means of ERCP is indicated to try and improve outcome in this group with biliary pancreatitis. Laparoscopic cholecystectomy must be considered as a definitive treatment in these patients as available evidence suggests that this can be performed with acceptable morbidity and mortality in this group.

Differential effect of isotype on efficacy of anti-tumor necrosis factor alpha chimeric antibodies in experimental septic shock.

Immune complexes containing human gamma (g)1 or murine g2a antibodies generate secondary effector mechanisms via Fc receptor binding or complement activation, whereas those containing human g4 or murine g1 antibodies generally do not. Therefore, isotype selection of therapeutic antibodies may have important clinical consequences. In a rabbit model of human tumor necrosis factor (rhuTNF)-induced pyrexia, a murine/human chimeric g4 anti-human TNF-alpha monoclonal antibody (mAb) (cCB0011) showed a dose-dependent inhibition of pyrexia, whereas a g1 isotype variant of the same mAb gave a marked pyrexia that was seen at all doses indicative of an immune complex-mediated response. To investigate whether isotype difference could influence mAb efficacy in pathological disease states, hamster/murine chimeric g1 and g2a anti-murine TNF-alpha mAbs (TN3g1, TN3g2a) were studied in experimental shock in mice and rats. In lipopolysaccharide-induced shock in mice, treatment with TN3g1 mAb at 30 and 3 mg/kg resulted in 90% survival by 72 h (p < or = 0.004), and prolonged survival to 45 h (p < or = 0.05), respectively, compared with 100% mortality by 27 h in controls. In contrast, a g2a isotype variant of the same mAb (30 mg/kg) resulted in only 10% survival by 72 h (p < or = 0.05). In a neutropenic sepsis model in rats there was greater survival in animals receiving the g1 isotype of TN3 compared with g2a isotype variant (70 vs. 27%; p < or = 0.005) with 100% mortality in the controls. These differences were not due to the pharmacokinetic profiles of the mAbs. In models of experimental shock antibody isotype can affect outcome with inactive isotypes (human g4 and murine g1) being more efficacious than active isotypes (human g1 and murine g2a).

Antagonistic effect of human alpha-calcitonin gene-related peptide (8-37) on regional hemodynamic actions of rat islet amyloid polypeptide in conscious Long-Evans rats.

Rat synthetic amidated islet amyloid polypeptide (IAPP) was infused into conscious Long-Evans rats chronically instrumented for the measurement of regional hemodynamics. Rat IAPP (0.25-2.5 nmol.kg-1.min-1) had dose-dependent tachycardiac and hypotensive effects. Renal blood flow increased at all dose levels in association with incremental rises in renal vascular conductances. Hindquarters blood flow and vascular conductance increased at the higher dose levels, but mesenteric blood flow fell with mean arterial blood pressure (i.e., there was no change in mesenteric vascular conductance). Concurrent infusion of 25 nmol.kg-1.min-1 human alpha-calcitonin gene-related peptide (CGRP) (8-37) abolished the hypotensive, tachycardiac, and renal and hindquarters vasodilator effects of rat IAPP, and during administration of both peptides, there was a transient renal and sustained mesenteric vasoconstriction. When the infusion of human alpha-CGRP (8-37) was stopped, the effects of the continued infusion of rat IAPP were reestablished. The results indicate that the reported ability of IAPP to induce insulin resistance cannot be due to decreased skeletal muscle blood flow. In addition, human alpha-CGRP (8-37) is an effective antagonist of the hemodynamic actions of rat IAPP. Because it has been shown previously that human alpha-CGRP (8-37) antagonizes the hemodynamic effects of human alpha-CGRP, these results, collectively, indicate that human alpha-CGRP and rat IAPP might act on the same receptor at which human alpha-CGRP (8-37) is an effective antagonist or that the latter is a nonselective antagonist of separate receptors on which human alpha-CGRP and rat IAPP act.

Models of adrenal regeneration hypertension in the rat.

Blood pressure was measured indirectly (using the tail-cuff method) and intra-arterially in conscious rats following one of three experimental procedures carried out in order to determine which resulted in the most marked and reproducible form of adrenal regeneration hypertension (ARH). All rats were unilaterally adrenalectomized and given NaCl solution (1%). In some rats, the remaining adrenal gland was either enucleated (AE rats) or compressed (AC rats) but both kidneys were left intact. During the fourth week after surgery, indirectly measured systolic blood pressure was higher in AE and AC rats than in sham-operated (SO) rats but, when measured intra-arterially, the magnitude of the developed hypertension was small (AC rats) or was absent altogether (AE rats). However, when a kidney was removed at the time of enucleation (AEN rats), the levels of systolic blood pressure, measured indirectly or intra-arterially, were markedly and consistently higher than in the corresponding group of uninephrectomized SO rats. The magnitude of the developed hypertension was similar in mature male and immature female AEN rats. We conclude that mature male rats, unilaterally nephro-adrenalectomized and given NaCl solution (1%), provide a marked and reproducible model of ARH.

The cardiovascular responses to sequential inhibition of alpha-adrenoceptors, the renin-angiotensin system and vasopressin in rats with adrenal regeneration hypertension.

The cardiovascular responses to selective alpha 1- and alpha 2-adrenoceptor antagonism (with prazosin and idazoxan, respectively) were assessed in rats 4 weeks after unilateral nephro-adrenalectomy, contralateral adrenal enucleation and the provision of a 1% NaCl solution as drinking fluid (AEN rats) and in sham-operated (SON) rats. Measurements were made between 0700 and 1000 h and between 1400 and 1700 h, since we have previously shown that resting blood pressures (BPs) in AEN rats are higher in the morning than in the afternoon. Following prazosin administration (morning or afternoon), BP fell to similar levels in both SON and AEN rats. Idazoxan, given 20 min after the start of prazosin infusion, caused similar transient falls in BP in all four groups of rats. Following the subsequent additional antagonism of angiotensin II (Ang II) production (with captopril) and vasopressin (V1) receptors [with d(CH2)5DAVP], BP in AEN rats studied in the morning was higher than in SON rats at that time of day, and higher than in AEN rats studied in the afternoon. These findings suggest than an additional underlying mechanism capable of increasing BP exists in AEN rats studied in the morning.

Prolongation of murine vascularized heart allograft survival by recipient-specific anti-major histocompatibility complex class II antibody.

BACKGROUND: Antibodies targeting recipient major histocompatibility complex (MHC) class II molecules have been demonstrated to be effective at prolonging allograft survival. However, antigen-presenting cell depletion would explain this effect and has not been definitively excluded as the mechanism of action of such antibodies. We have studied an anti-MHC class II antibody (OX6) proven to be noncytotoxic in the recipient strain used. METHODS: Antibody was administered the day before, 2 hr before, and the day after grafting. RESULTS: Antibody administration on the day before, 2 hr before, and the day after grafting significantly prolonged vascularized cardiac allograft survival. Importantly, treatment recognizing recipient MHC was effective, whereas a similar regimen recognizing donor MHC was not. CONCLUSIONS: Noncytotoxic recipient MHC class II-specific antibodies modify allograft rejection. Possible mechanisms for this therapeutic effect are discussed.

Anti-major histocompatibility complex class II treatment prevents graft rejection in the hamster-to-rat cardiac xenograft.

BACKGROUND: Several groups have achieved graft acceptance in the concordant hamster to rat model by using a combination of anti-proliferative drugs and conventional immunosuppressive therapy. However, such aggressive treatment often leads to the recipient dying with a functional xenograft, as a result of opportunistic infections. This study aimed to investigate the effects of a short course of therapy with an anti-MHC class II monoclonal antibody treatment (chimeric OX6 [cOX6]) in combination with cyclosporin A (CyA) in a concordant hamster-to-rat xenograft model. METHODS: Rats receiving hamster cardiac xenografts were given CyA or cOX6 alone or in combination and were monitored daily to assess the effect of treatment on graft survival. Additional studies monitored the effect of treatment on the production of cytolytic anti-hamster antibodies by the recipient and the deposition of immunoglobulin (Ig)M and complement factors within the xenograft. RESULTS: Treatment with CyA only had no effect on graft survival, whereas treatment with cOX6 increased graft survival time by 2 days. The median graft survival time for cOX6+CyA was 76 days. cOX6 treatment of rats having undergone transplants inhibited the rise in cytotoxic anti-hamster antibodies in peripheral blood until day 5, whereas combination therapy completely inhibited anti-hamster antibody formation. Fluorescence-activated cell sorter analysis showed treatment with cOX6 significantly reduced circulating B cell numbers until day 5. Anti-MHC class II treatment also markedly reduced the deposition of both IgM and C3. Anti-MHC class II treatment with CyA gives long term survival in concordant xenografts without severe side effects. CONCLUSIONS: The mechanism of action of this combination is complex and could be caused by an initial inhibition of B cell function by the anti-MHC class II treatment and the subsequent inhibition of T cell dependent pathways by CyA.

Phenotypic features and impact of beta blocker or calcium antagonist therapy on aortic lumen size in the Marfan syndrome.

Systematic, prospective data regarding phenotypic features, including echocardiographic findings, in pediatric patients with the Marfan syndrome are lacking. In addition, limited and conflicting information exists regarding the impact of pharmacologic therapy on aortic growth rate in children. Fifty-three children and adolescents with the Marfan syndrome underwent physical examination, anthropometric evaluation, and echocardiography. The relation of pharmacologic therapy to aortic growth rate was examined in the 44 subjects in whom serial echocardiograms were recorded. Although boys and girls did not differ in ocular, skeletal, or cardiovascular manifestations, aortic dilatation tended to be more common in boys (86% vs 72%). Children with aortic dilatation at baseline (42 of 53 or 79%) were more likely to also have scoliosis and mitral prolapse (both p <0.005). The medicated patients had slower aortic growth than the unmedicated patients with regard to both absolute aortic growth rate (p <0.01) and aortic growth rate adjusted for age and body size (p <0.005). Nevertheless, major cardiovascular complications developed in 5 patients despite long-term pharmacologic therapy. In conclusion, beta-blocker and calcium antagonist therapy retards aortic growth rate in children and adolescents with the Marfan syndrome.

The cardiodepressant and vasodepressant effects of tumour necrosis factor in rat isolated atrial and aortic tissues.

1. The ability of recombinant human tumour necrosis factor-alpha (rec huTNF) to elicit cardiodepressor and vasodepressor effects in rat isolated tissues was investigated. 2. rec huTNF (3 x 10(-11)-3 x 10(-8) M) administered directly to the organ bath, caused a concentration-dependent relaxation of the isoprenaline-induced inotropic response in electrically stimulated rat left atria. This occurred within 20 min of administration. In contrast, rec huTNF was without effect on the chronotropic response to isoprenaline in isolated spontaneously beating atria. 3. rec huTNF (1 microgram kg-1) was also given systemically to rats and the atria studied in vitro. Only 60 min of rec huTNF pretreatment was sufficient to cause a marked attenuation of the isoprenaline-induced inotropic response. This effect was not further augmented when rats were pretreated with rec huTNF for 24 h. 4. In isolated aortic rings taken from rats 60 min after rec huTNF (1 microgram kg-1, i.v.) administration, there was no effect seen on the constriction induced by phenylephrine in either endothelium-intact or denuded tissues. In addition, any responses to L-arginine or NG-nitro-L-arginine methyl ester (L-NAME) administration were unaffected by rec huTNF pretreatment. 5. In aortic rings taken from rats 24 h after rec huTNF administration, the phenylephrine-induced constriction was significantly attenuated in tissues with an intact endothelium. Furthermore, the relaxation to subsequent L-arginine administration was greater in these tissues than in those saline-treated rats. In addition, in both endothelium-intact and denuded tissues, the vasoconstrictor response to L-NAME (10-3M) was significantly augmented. 6. These data suggest that rec huTNF possesses both cardiodepressant properties with a rapid onset of action and vasodepressant properties with a slow onset of action. The latter could be mediated through the induction of a non-constitutive form of the NO-synthase enzyme present within the vascular wall.

Involvement of beta 2-adrenoceptors in the regional haemodynamic responses to bradykinin in conscious rats.

1. Bradykinin can release neuronal calcitonin gene-related peptide (CGRP) and adrenal medullary catecholamines, both of which could contribute to its cardiovascular effects in vivo. Therefore, in the main experiment, regional haemodynamic responses to bolus injections of bradykinin (3 nmol kg-1, i.v.) were assessed in the same chronically-instrumented, conscious, Long Evans rats in the absence and in the presence of human alpha-CGRP [8-37] or ICI 118551, antagonists of CGRP1-receptors and beta 2-adrenoceptors, respectively. The selected doses of these antagonists caused specific inhibition of responses mediated by exogenous human alpha-CGRP and beta 2-adrenoceptor agonists, respectively. 2. Bradykinin administered alone as an i.v. bolus had a slight pressor effect accompanied by a marked tachycardia. There were early (at about 30 s) increases in flow and conductance in the mesenteric vascular bed, and delayed (at about 90 s), but qualitatively similar, changes in the hindquarters vascular bed. There were only slight increases in flow and conductance in the renal vascular bed. 3. Human alpha-CGRP [8-37] had no statistically significant effects on the responses to bolus doses of bradykinin. However, in the presence of ICI 118551, the pressor effect of bradykinin was significantly enhanced while its tachycardic effect was significantly suppressed. The hindquarters vasodilator effect of bradykinin was converted to a vasoconstriction and there was a slight renal vasoconstriction, but the mesenteric vasodilator effect of bradykinin was unchanged by ICI 118551. 4. In subsidiary experiments, in other animals, it was found that infusion of bradykinin (36 nmol kg-1 min-1) elicited a pattern of haemodynamic responses similar to that seen with bolus injections and, as in the latter case, the hindquarters hyperaemic vasodilation was inhibited by ICI 118551. In the presence of mecamylamine (at a dose sufficient to block reflex heart rate responses to rises or falls in arterial blood pressure) bolus injection or infusion of bradykinin still elicited increases in renal, mesenteric and hindquarters blood flow. However, in additional experiments in adrenal demedullated rats (n = 4) the hindquarters hyperaemic effect of bradykinin was absent, although the mesenteric hyperaemic effect remained. 5. The results indicate that the increase in hindquarters blood flow following administration of bradykinin in vivo is largely due to activation of beta 2-adrenoceptors by catecholamines released subsequent to direct stimulation of the adrenal medulla by the peptide. However, the bradykinin-induced increase in mesenteric blood flow does not depend on this mechanism.

The effect of monoclonal antibodies to calcitonin gene-related peptide (CGRP) on CGRP-induced vasodilatation in pig coronary artery rings.

1. The modification of the vasodilator effect of calcitonin gene-related peptide (CGRP) by a panel of monoclonal antibodies (MAbs), which map to discrete epitopes on the CGRP molecule, was investigated in pig coronary artery rings (PCA). The preparations were pre-constricted with acetylcholine (3 x 10(-7) M) and concentration-response curves to CGRP (2 x 10(-10)-2.56 x 10(-8) M) were obtained in the presence or absence of each MAb. 2. CGRP caused a concentration-dependent relaxation of PCAs which reached a maximum (98.2 +/- 4.8%, n = 25) at 1.28 x 10(-8) M and gave an EC50 of 3.8 +/- 0.8 x 10(-9) M. 3. Two MAbs which map to the N-terminal, CN1 and CRA3, did not affect the CGRP response whilst a third, CRA5, significantly inhibited its effect. 4. The C-terminal MAb, CRA2, did not modify the CGRP response whilst, in contrast, CB3 (C-terminal) potentiated its effect. A similar augmentation of the CGRP-induced vasodilatation was seen in the presence of the middle-region MAb, CRA8. 5. These results suggest that regional specific MAbs can modify the vasodilator effect of CGRP causing either inhibition (CRA5, N-terminal) or potentiation (CB3, C-terminal; CRA8, middle region).

Differential effects of (+/-)-dobutamine and human alpha-CGRP on cardiac and on regional haemodynamics in conscious Long Evans rats.

1. Comparisons were made of the full haemodynamic profiles of the known cardiostimulant, (+/-)-dobutamine, and the putative inotropic peptide, human alpha-calcitonin gene-related peptide (human alpha-CGRP), in conscious, chronically-instrumented Long Evans rats. Both substances were administered continuously i.v. for 60 min at two doses ((+/-)-dobutamine, 2 and 10 mumol kg-1 h-1; human alpha-CGRP, 0.15 and 1.5 nmol kg-1 h-1). 2. In spite of their similar (small) effects on mean arterial blood pressure, the low doses of (+/-)-dobutamine and human alpha-CGRP influenced cardiac haemodynamics differently. Thus, (+/-)-dobutamine caused an increase in cardiac index (due to a tachycardia), accompanied by rises in peak aortic flow, maximum rate of rise of aortic flow (dF/dtmax) and total peripheral conductance. However, the latter waned during the infusion, and after the infusion there was a significant systemic vasoconstriction and reductions in peak aortic flow, dF/dtmax and stroke index. Such 'off' effects following dobutamine infusion have not been described previously. The infusion of the lower dose of human alpha-CGRP caused only a transient fall in central venous pressure. 3. The rise in total peripheral conductance during infusion of the lower dose of (+/-)-dobutamine was associated with increases in hindquarters and common and internal carotid vascular conductances. The fall in total peripheral conductance after infusion was associated with renal vasoconstriction. Although there was no significant change in total peripheral conductance during the infusion of the lower dose of human alpha-CGRP there were hindquarters and carotid vasodilatations together with mesenteric vasoconstriction. 4. Infusion of the higher dose of ( )-dobutamine had greater effects than the lower dose on all cardiac haemodynamic variables and additionally, increased stroke index. However, the negative cardiac haemodynamic effects following the offset of infusion were also enhanced in association with marked renal and mesenteric vasoconstrictions. While infusion of the higher dose of human alpha-CGRP increased cardiac index, peak aortic flow, dF/dtmax and total peripheral conductance, stroke index fell together with central venous pressure. 5. (+/-)-Dobutamine caused greater cardiostimulation and increases in hindquarters blood flow than did human alpha-CGRP. However, the latter at the higher dose caused substantially greater common and internal carotid hyperaemia than did (+/-)-dobutamine, possibly indicating a selective and additional effect of human alpha-CGRP on cranial blood flow. Furthermore, there were no adverse cardiovascular effects following infusion of human alpha-CGRP.

Regional haemodynamic effects of prolonged infusions of human alpha-calcitonin gene-related peptide in conscious, Long Evans rats.

1. Haemodynamic measurements were made in conscious, Long Evans rats chronically instrumented for the assessment of changes in regional blood flows (renal, mesenteric and hindquarters, or internal and common carotid) and systemic arterial blood pressure and heart rate, before, during and after 3 day infusions of vehicle or human alpha-calcitonin gene-related peptide (CGRP) (1.5 or 15 nmol kg-1 h-1). 2. In animals with renal, mesenteric and hindquarters flow probes (n = 8), during the first day of infusion of human alpha-CGRP (1.5 nmol kg-1 h-1) there was sustained tachycardia and hypotension, a sustained reduction in renal flow, a transient reduction in mesenteric flow and a relatively well-maintained increase in hindquarters flow. All these effects were significantly different from the changes seen in vehicle-infused rats (n = 8), but calculation of vascular conductances showed only the late mesenteric vasodilatation and the sustained hindquarters vasodilatation were different from the changes in vehicle-infused rats. However, by the second day of infusion and thereafter cardiovascular variables in the animals receiving vehicle and those receiving human alpha-CGRP were not different. 3. Nine animals instrumented with probes to monitor changes in internal and common carotid haemodynamics initially received human alpha-CGRP infused at a rate of 1.5 nmol kg-1 h-1. Three of these animals still showed some response to the human alpha-CGRP (tachycardia, hypotension, hyperaemic vasodilatation) throughout the second day of infusion and hence were taken through the 3 day infusion protocol. When the infusion was stopped on the fourth day all these animals showed reversal of the effects of human alpha-CGRP. 4. The results indicate substantial inter-individual variation in the haemodynamic effects of prolonged infusions of human alpha-CGRP in conscious, Long Evans rats. However, since increasing the dose of human alpha-CGRP overcame the desensitization, it is feasible that, in the clinical setting, maintained increases in internal carotid blood flow could be achieved by individually-adjusted infusions of human alpha-CGRP.

Haemodynamic effects of human alpha-calcitonin gene-related peptide following administration of endothelin-1 or NG-nitro-L-arginine methyl ester in conscious rats.

1 We investigated the peripheral haemodynamic effects of human alpha-calcitonin gene-related peptide (CGRP) following administration of endothelin-1 or NG-nitro-L-arginine methyl ester (L-NAME), an inhibitor of nitric oxide production, in conscious, chronically-instrumented, Long Evans rats. 2 Infusion of endothelin-1 (3 nmol kg-1 h-1) caused hypertension, bradycardia and renal, mesenteric and hindquarters vasoconstrictions. Co-infusion of human alpha-CGRP (1.5 nmol kg-1 h-1) reduced the hypertension and abolished the hindquarters vasoconstriction caused by endothelin-1 but the renal and mesenteric vasoconstrictor actions of endothelin-1 were not affected. 3 Infusion of human alpha-CGRP (15 nmol kg-1 h-1) in the presence of endothelin-1 caused hypotension and hyperaemic vasodilatation in the hindquarters; the mesenteric vasoconstrictor effects of endothelin-1 were diminished, but there was only a transient reversal of the renal vasoconstrictor effects of endothelin-1. 4 Pretreatment with the non-peptide angiotensin II receptor antagonist, DuP 753 (10 mg kg-1), caused slight hypotension associated with renal, mesenteric and hindquarters vasodilatations, but DuP 753 did not affect responses to endothelin-1 infusion. However, under these conditions co-infusion of human alpha-CGRP (15 nmol kg-1 h-1) caused a sustained reversal of the renal vasoconstrictor effects of endothelin-1. 5 These results indicate that the failure of human alpha-CGRP to cause sustained reversal of the renal vasoconstrictor effects of endothelin-1 in the absence of DuP 753 was due to activation of the reninangiotensin system (possibly as a consequence of the hypotension). 6. In the second experiment, L-NAME (l0mgkg-1) caused renal, mesenteric and hindquarters vasoconstrictions similar to those seen in the presence of endothelin-1. However, the renal vasoconstrictor effects of L-NAME were reversed completely by human alpha-CGRP (l5nmolkg- h-1), even though the latter caused hypotension comparable to that seen in the presence of endothelin-1. These results are consistent with a lack of functional activation of the renin-angiotensin system by human alpha-CGRP in the presence of L-NAME. 7. The vasoconstrictor effects of L-NAME on the hindquarters were completely reversed by infusion of human alpha-CGRP, but hindquarters flow and vascular conductance did not rise above baseline levels. Hence these results indicate the hindquarters hyperaemic vasodilator effects of human alpha-CGRP seen in the presence of endothelin-1 were contributed to by nitric oxide-mediated mechanisms.

Cardiovascular and steroid responses to graded haemorrhage in rats with adrenal regeneration hypertension.

Abstract Blood pressure (BP) and plasma steroid responses to haemorrhage (2 ml + 1 ml + 1 ml at 20-min intervals) were assessed in sham-operated (SO) rats and in rats with adrenal regeneration hypertension (ARH). Experiments were carried out between 0700 and 1000 h (a.m.) and between 1400 and 1700 h (p.m.), because rats with ARH have BPs that are higher a.m. than p.m. There were no differences in the BP responses following haemorrhage in SO or ARH rats either a.m. or p.m., although ARH rats were unable to increase their plasma steroid levels. Pretreatment with captopril alone, d(CH(2))(5) DAVP alone, or captopril and d(CH(2))(5)DAVP augmented the early hypotensive responses to haemorrhage but did not influence the later compensated levels of BP in either group of rats. There were no clear-cut a.m. to p.m. differences in the changes in BP in any of the drug-treated groups of SO or ARH rats. Under all conditions studied, the compensated level of systolic BP in ARH rats, 20 min after the final bleed, remained higher a.m. than p.m., indicating that this difference was not dependent on the renin-angiotensin system and vasopressin and suggesting that the sympathetic nervous system and/or other factors might be involved.

Differential vasodilator profile of calcitonin gene-related peptide in porcine large and small diameter coronary artery rings.

The vasodilator profile of calcitonin gene-related peptide (CGRP) was compared in large diameter (3-4 mm outer diameter) and small diameter (less than 1 mm outer diameter) rings from porcine left anterior descending coronary arteries (LAD). CGRP relaxed both sized rings in an endothelium-independent manner but was 10 X more potent in small compared to large diameter rings. Repeated administration of CGRP to small diameter rings did not cause the development of tolerance to its effects, whereas in the large diameter rings marked tolerance developed. Pretreatment with the CGRP peptide fragment, CGRP-(8-37) antagonised the vasodilator effects of CGRP in a concentration-dependent manner, but in large diameter rings, the antagonistic potency of CGRP-(8-37) was 10 X less than that seen in the small diameter rings. This differing vasodilator profile of CGRP in small and large diameter rings of pig LADs may be related to a differential CGRP receptor distribution along their length.

Hemodynamic and tubular effects of endothelin and thromboxane in the isolated perfused rat kidney.

We have investigated the effects of the endothelium-derived peptide, endothelin, and of a chemically stable analog of thromboxane (TX) A2, U46619, on the glomerular hemodynamics and tubular function of isolated, perfused rat kidneys. Endothelin (10(-11)-10(-9) M) dose dependently decreased the renal plasma flow to a significantly greater extent than it did the glomerular filtration rate. In contrast, U46619 (10(-9)-10(-7) M) had more pronounced effects on the glomerular filtration rate than on the renal plasma flow. As a consequence, the filtration fraction was increased by endothelin and decreased by U46619. Endothelin, unlike U46619, enhanced urinary Na+ excretion and reduced oxygen consumption at concentrations that greatly decreased the tubular load, thus suggesting that it has a direct effect on tubular Na+ reabsorption. Addition of the TXA2/PGH2-receptor antagonist, BM13177 (4.10(-4) M), or the cyclooxygenase inhibitor, acetylsalicylic acid (10(-3) M), to the perfusion medium failed to modify the endothelin-induced increase in Na+ excretion or the reduction in renal plasma flow, whereas acetylsalicylic acid, but not BM13177, partially prevented the decrease in the glomerular filtration rate. These results demonstrate that two contractile agonists produced by the kidney have specific and differential effects on cortical and tubular functions. Moreover, the intrarenal production of eicosanoids does not appear to play a major role in the renal effects of endothelin.

Human alpha-calcitonin gene-related peptide (CGRP)-(8-37), but not -(28-37), inhibits carotid vasodilator effects of human alpha-CGRP in vivo.

Human alpha-calcitonin gene-related peptide-(8-37) alone (up to doses of 30 nmol kg-1 min-1) had no significant effects on blood pressure, heart rate or common or internal carotid haemodynamics, although it caused significant, reversible, inhibition of the hypotensive, tachycardic, and common and internal carotid vasodilator effects of human alpha-CGRP (0.03 nmol kg-1 min-1) in conscious, Long Evans rats. Human alpha-CGRP-(28-37) up to doses of 300 nmol kg-1 min-1 had no cardiovascular effects itself and did not influence responses to human alpha-CGRP. These results are consistent with the carotid haemodynamic effects of human alpha-CGRP being due largely to activation of the CGRP1-receptor subtype.

Duct Excision is Still Necessary to Rule out Breast Cancer in Patients Presenting with Spontaneous Bloodstained Nipple Discharge.

Introduction. Spontaneous nipple discharge is the third most common reason for presentation to a symptomatic breast clinic. Benign and malignant causes of spontaneous nipple discharge continue to be difficult to distinguish. We analyse our experience of duct excisions for spontaneous nipple discharge to try to identify features that raise suspicion of breast cancer and to identify features indicative of benign disease that would be suitable for nonoperative management. Methods. Details of one hundred and ninety-four patients who underwent duct excision for spontaneous nipple discharge between 1995 and 2005 were analysed. Results. Malignant disease was identified in 11 (5.7%) patients, 4 invasive and 7 insitu, which was 10.2% of those presenting with bloodstained discharge. All patients with malignant disease had bloodstained discharge. Discharge due to malignant disease was more likely to be bloodstained than that due to benign causes (Fisher's exact test, 2-tailed P value = 0.00134). Conclusion. Our findings do not support a policy of conservative management of spontaneous bloodstained nipple discharge. Cases of demonstrable spontaneous bloodstained nipple discharge should undergo duct excision to prevent malignant lesions being missed.