Bernadette Hughes

Involvement of β2‐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 α‐CGRP [8–37] or ICI 118551, antagonists of CGRP1‐receptors and β2‐adrenoceptors, respectively. The selected doses of these antagonists caused specific inhibition of responses mediated by exogenous human α‐CGRP and β2‐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 α‐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 vasodilatation 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 β2‐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.

Haemodynamic effects of human α-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 α‐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 α‐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 α‐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 α‐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 α‐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 renin‐angiotensin system (possibly as a consequence of the hypotension). 6 In the second experiment, l‐NAME (10 mg kg−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 α‐CGRP (15 nmol kg−1 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 α‐CGRP in the presence of l‐NAME. 7 The vasoconstrictor effects of l‐NAME on the hindquarters were completely reversed by infusion of human α‐CGRP, but hindquarters flow and vascular conductance did not rise above baseline levels. Hence these results indicate the hindquarters hyperaemic vasodilator effects of human α‐CGRP seen in the presence of endothelin‐1 were contributed to by nitric oxide‐mediated mechanisms.

Safety and Efficacy of Esreboxetine in Patients With Fibromyalgia: A Fourteen-Week, Randomized, Double-Blind, Placebo-Controlled, Multicenter Clinical Trial

OBJECTIVE To evaluate the efficacy, tolerability, and safety of multiple fixed dosages of esreboxetine for the treatment of fibromyalgia. METHODS Patients meeting the American College of Rheumatology criteria for fibromyalgia were randomized to receive esreboxetine at dosages of 4 mg/day (n=277), 8 mg/day (n=284), or 10 mg/day (n=283) or matching placebo (n=278) for 14 weeks. The primary efficacy outcomes were the weekly mean pain score and the Fibromyalgia Impact Questionnaire (FIQ) total score at week 14. Secondary efficacy measures included scores for the Patients Global Impression of Change (PGIC) scale, the Global Fatigue Index (GFI), and the 36-item Short-Form health survey (SF-36; physical function scale only) at week 14. The safety profile of esreboxetine was evaluated based on adverse events and other safety measures. RESULTS Patients receiving all dosages of esreboxetine demonstrated statistically significant improvements in the pain score (P≤0.025), the FIQ score (P≤0.023), and the PGIC score (P≤0.007) compared with patients in the placebo group. Additionally, patients receiving esreboxetine at dosages of 4 mg/day and 8 mg/day showed statistically significant improvements in the GFI score compared with those receiving placebo (P=0.001). No significant differences in SF-36 physical function scores were observed between patients receiving esreboxetine (any dosage) and those receiving placebo. Adverse events were mostly mild to moderate in severity; insomnia, constipation, dry mouth, nausea, dizziness, hot flush, headache, hyperhidrosis, and palpitations were reported most frequently. CONCLUSION Esreboxetine was generally well tolerated and was associated with significant improvements in pain, FIQ, PGIC, and fatigue scores compared with placebo. The lack of a dose-response relationship in both the efficacy and safety analyses suggests that esreboxetine at a dosage of 4 mg/day would offer clinical benefit with the least risk of drug exposure.

Regional haemodynamic effects of prolonged infusions of human α‐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 α‐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 α‐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 α‐CGRP were not different. 3 Nine animals instrumented with probes to monitor changes in internal and common carotid haemodynamics initially received human α‐CGRP infused at a rate of 1.5 nmol kg−1 h−1. Three of these animals still showed some response to the human α‐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 α‐CGRP. The other 6 animals in the original group showed complete desensitization to the effects of human α‐CGRP by the end of the second day of infusion (as seen in the group instrumented with renal, mesenteric and hindquarter probes). Therefore, in order to assess the extent of desensitization, at the beginning of the third day the dose of human α‐CGRP was increased to 15 nmol kg−1 h−1. The resulting tachycardia, hypotension and hyperaemia in the carotid vascular beds were significant, (but no greater than the initial responses to human α‐CGRP at 1.5 nmol kg−1 h−1). These effects were maintained throughout the third infusion day, but there was some desensitization to the effects of this higher dose of human α‐CGRP by the beginning of the fourth infusion day. However, when the infusion was stopped there was clear reversal of the effects of human α‐CGRP. 4 The results indicate substantial inter‐individual variation in the haemodynamic effects of prolonged infusions of human α‐CGRP in conscious, Long Evans rats. However, since increasing the dose of human α‐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 α‐CGRP.

Validation of the Chinese Western Ontario and McMaster Universities Osteoarthritis Index in patients from mainland China with osteoarthritis of the knee

To establish the reliability, validity, and sensitivity to change of the Western Ontario and McMaster Universities Osteoarthritis Index (WOMAC) among Chinese subjects with osteoarthritis (OA) of the knee, living in mainland China.

Differential effects of (±)‐dobutamine and human α‐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 α‐calcitonin gene‐related peptide (human α‐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 μmol kg−1h−1; human α‐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 α‐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 α‐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 α‐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 α‐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 α‐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 α‐CGRP on cranial blood flow. Furthermore, there were no adverse cardiovascular effects following infusion of human α‐CGRP.

Haemodynamic effects of the selective phosphodiesterase 5 inhibitor, UK-357,903, in conscious SHR

Regional haemodynamic responses to a continuous, 4‐day infusion of the selective phosphodiesterase type 5 inhibitor, UK‐357,903 (0.133 or 1.33 mg kg−1 h−1) were measured in conscious spontaneously hypertensive rats, and compared with those of enalapril (1 mg kg−1 h−1). Both doses of UK‐357,903 caused modest reductions in mean blood pressure that were not dose‐dependent and only significantly different from the vehicle effects on Day 1 of the study (mean −11.8 and −15.3 mmHg for low and high doses, respectively). UK‐357,903 had mesenteric and hindquarters vasodilator effects, which were, again, similar for both dose levels and only significantly different from vehicle on Day 1. Neither dose of UK‐357,903 affected renal vascular conductance or heart rate. Although the haemodynamic effects of UK‐357,903 were not clearly dose‐related and some appeared to wane with time, geometric mean plasma levels of UK‐357,903 increased in proportion to dose, and were sustained throughout the infusion period. Furthermore, plasma cyclic guanosine monophosphate, a biomarker of phosphodiesterase 5 inhibition, was persistently elevated, and increased with increasing dose. Enalapril caused a fall in mean blood pressure on day 1 (−14.1 mmHg) that was associated with dilatation in renal, mesenteric and hindquarters vascular beds. The haemodynamic effects of enalapril were sustained or increased over the 4‐day infusion, although plasma free drug levels were stable. In conclusion, we have shown regional and temporal changes in the haemodynamic effects of UK‐357,903, which may be due to activation of compensatory mechanisms, but there were no signs of functional compensation to the cardiovascular effects of enalapril.