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Biomedical subjects

J R Cockcroft

Publications and source records attributed to J R Cockcroft.

At least 73 records · Page 4Linked to original sources
PubMed1994

Inhibition of bradykinin-induced vasodilation in human forearm vasculature by icatibant, a potent B2-receptor antagonist.

1. The effect of icatibant (D-Arg-[Hyp3, Thi5, D-Tic7, Oic8] bradykinin) a potent B2-kinin receptor antagonist, was studied on bradykinin-induced vasodilation in the human forearm. 2. Eight healthy normotensive men were studied in a rising dose random-placebo controlled study. Placebo and icatibant (20, 50 and 100 micrograms kg-1 i.v.) were administered double-blind. Forearm blood flow was measured by venous occlusion plethysmography during rising dose brachial artery infusions of bradykinin (10-3,000 ng min-1) 60-90 min after placebo or icatibant. 3. Plasma concentrations of icatibant fell exponentially following each of three doses, up to the final measurement. Elimination half-lives calculated from linear regression of the mean data were 25, 27 and 29 min after 20, 50 and 100 micrograms kg-1 doses respectively. 4. Icatibant inhibited the effect of bradykinin (P < 0.001 at each dose of icatibant) in a dose-dependent manner. Bradykinin (100 ng min-1) increased mean blood flow in the infused arm by 238 +/- 31% when infused following placebo, by 112 +/- 21% after icatibant 20 micrograms kg-1, by 71 +/- 14% after icatibant 50 micrograms kg-1 and by 48 +/- 9% after icatibant 100 micrograms kg-1. 5. These results demonstrate that icatibant antagonises B2-receptor mediated vasodilation in human forearm resistance vessels. The findings provide a quantitative basis for future studies of the role of bradykinin in the response to angiotensin converting enzyme inhibitors and in circulatory disease.

Adrenergic beta-2 Receptor Antagonists↗
PubMed1993

Inhibition of nitric oxide synthesis in forearm vasculature of insulin-dependent diabetic patients: blunted vasoconstriction in patients with microalbuminuria.

1. Microalbuminuria is a risk factor for cardiovascular disease in patients with insulin-dependent diabetes mellitus, and may be a marker of microvascular dysfunction including endothelial damage. The purpose of this study was to determine whether vasoconstrictor responses to NG-monomethyl-L-arginine, an inhibitor of endothelium-derived relaxing factor/nitric oxide biosynthesis, differ between healthy subjects and insulin-dependent patients with or without microalbuminuria. 2. Twenty-eight insulin-dependent diabetic patients (14 with normal albumin excretion, 14 with microalbuminuria) were studied under euglycaemic conditions, together with 14 healthy control subjects. Forearm vascular responses to brachial artery infusions of NG-monomethyl-L-arginine, sodium nitroprusside (an endothelium-independent nitrovasodilator) and carbachol (an endothelium-dependent vasodilator) were determined by strain gauge plethysmography. 3. Basal blood flow and vasodilator responses were similar in each group. NG-Monomethyl-L-arginine reduced blood flow by 41.3 +/- 2.3% (mean +/- SEM) in healthy control subjects, 34.0 +/- 3.4% in diabetic patients without microalbuminuria and 29.2 +/- 2.0% in diabetic patients with microalbuminuria. Diabetic patients differed from healthy subjects (P = 0.005), due to a difference between control subjects and microalbuminuric diabetic patients (P < 0.001). NG-Monomethyl-L-arginine did not influence nitroprusside responses but reduced carbachol responses in control subjects and normoalbuminuric diabetic patients but not in microalbuminuric diabetic patients. 4. These results provide evidence of abnormal endothelium-derived relaxing factor/nitric oxide biosynthesis in insulin-dependent diabetic patients with microalbuminuria.

Adult↗
PubMed1993

Comparison of angiotensin-converting enzyme inhibition with angiotensin II receptor antagonism in the human forearm.

The object of this study was to differentiate losartan, an AT1-selective angiotensin II (ANG II) receptor antagonist, from enalapril, an angiotensin-converting enzyme (ACE) inhibitor, by measuring forearm vascular responses to AI, AII, and bradykinin. Eight healthy men were studied in a randomised, 4-period crossover study in which placebo, enalapril (10 mg), losartan (20 mg) and losartan (100 mg) were given double-blind on separate occasions. Forearm blood flow was measured by venous occlusion plethysmography during sequential infusions of ANG I, ANG II, and bradykinin into the brachial artery 4-6 h after dosing. Analysis of variance for repeated measures indicated that losartan inhibited constriction to ANG I and ANG II (both p < 0.02) in a dose-dependent manner without significantly influencing vasodilator responses to bradykinin. Enalapril (10 mg) inhibited AI similarly to losartan 100 mg without significantly influencing responses to angiotensin II, and augmented vasodilator responses to bradykinin (p < 0.0001). In human forearm vasculature, oral losartan (20-100 mg) inhibits vasoconstriction to ANG I and ANG II without significantly influencing bradykinin-induced vasodilation, whereas enalapril selectively inhibits ANG I-induced vasoconstriction while potentiating the vasodilator effect of bradykinin.

Adult↗
PubMed1993

Lack of effect of enalaprilat on the action of vasoactive intestinal polypeptide in the human forearm.

It has been proposed that angiotensin converting enzyme (ACE) may play a role in the metabolism of the vasodilator peptide vasoactive intestinal polypeptide (VIP). Reduced metabolism following treatment with ACE inhibitors may cause accumulation of VIP which in turn may mediate some of the beneficial haemodynamic effects of ACE inhibition observed in patients with heart failure. This study has shown that inhibition of local vascular ACE does not interfere with the vascular effects of VIP on forearm resistance vessels when this peptide is infused into the brachial artery of normal volunteers. These results suggest that endothelial ACE plays little part in the metabolism of intravascular VIP.

Adult↗
PubMed1993

Differential inhibition by NG-monomethyl-L-arginine of vasodilator effects of acetylcholine and methacholine in human forearm vasculature.

1. We compared the effects of NG-monomethyl-L-arginine (L-NMMA), an NO synthase inhibitor, on vasodilatation produced by acetylcholine and methacholine in human forearm vasculature. 2. Acetylcholine (83 nmol min-1) infused into the brachial artery of 8 healthy volunteers caused a submaximal increase in forearm blood flow, measured by venous occlusion plethysmography, from 3.3 +/- 0.5 (mean +/- s.e. mean) to 13.3 +/- 1.7 ml min-1 100 ml-1. 3. Co-infusion of L-NMMA (4 mumol min-1) with acetylcholine (83 nmol min-1) over 6 min resulted in a 58% +/- 12% fall in the response to acetylcholine whereas during co-infusion of saline over the same time period in the same subjects (n = 8) on a different day the response to acetylcholine fell by only 9% +/- 17% (P < 0.01). 4. Methacholine (1.5 and 15 nmol min-1) increased forearm blood flow from 2.5 +/- 0.4 to 5.9 +/- 0.9 and from 3.2 +/- 0.4 to 17.0 +/- 1.9 ml min-1 100 ml-1 respectively. 5. Co-infusion of L-NMMA (4 mumol min-1) had no significant effect on the response to methacholine (1.5 or 15 nmol min-1) when compared with saline control (n = 8). Co-infusion of a higher dose of L-NMMA (8 mumol min-1) with methacholine (1.5 nmol min-1) did not significantly inhibit the vasodilator response (n = 7). 6. These results suggest that, in human forearm vasculature, methacholine acts predominantly through mechanisms other than the L-arginine/nitric oxide pathway.

Acetylcholine↗
PubMed1993

Blind drunk: alcoholic pancreatitis and loss of vision.

Acute loss of vision and alcoholic intoxication suggests the possibility of methanol poisoning. In this report we describe an alcoholic patient who complained of blindness after recovering from alcoholic pancreatitis and delirium tremens. Visual acuity was severely impaired and fundoscopy revealed florid bilateral cotton wool spots and a cherry red spot at the right macula. Such appearances have previously been reported in cases of post-traumatic visual loss, and may share a common aetiology of fat embolization. The association between alcoholic pancreatitis and visual loss is rare, and fundal examination should be performed on all patients with pancreatitis, especially those who complain of visual disturbance.

Acute Disease↗
PubMed1993

Clinical pharmacology of angiotensin and bradykinin in human forearm vasculature.

HYPOTHESIS: Losartan inhibits the renin-angiotensin system by blockade of angiotensin II receptors, whereas enalapril blocks the renin-angiotensin system by inhibiting the conversion of angiotensin I to angiotensin II by the angiotensin converting enzyme (ACE). Since ACE inactivates bradykinin in addition to its action on angiotensin I we hypothesized that losartan and enalapril have different effects on the response to angiotensin and bradykinin. METHODS: We studied healthy volunteers dosed with placebo, enalapril and losartan 4-6 h before measurement of forearm blood flow by venous occlusion plethysmography. Saline, angiotensin I, angiotensin II and bradykinin were infused into the left brachial artery. RESULTS: Losartan produced a similar inhibition of the vasoconstriction induced by angiotensin I and angiotensin II without significantly influencing the bradykinin-induced vasodilation, whereas enalapril potentiated the vasodilator effect of bradykinin and selectively inhibited the vasoconstriction induced by angiotensin I without altering the response to angiotensin II. CONCLUSION: These pharmacological differences suggest that angiotensin II receptor antagonists and ACE inhibitors may not be therapeutically equivalent.

Angiotensin II↗
PubMed1992

Impaired endothelium-dependent vasodilation of forearm resistance vessels in hypercholesterolaemia.

Endothelium-dependent vasodilation in response to acetylcholine is impaired in the coronary microvasculature of hypercholesterolaemic subjects. Outside the coronary circulation, however, it has been suggested that hypercholesterolaemia results in a functional abnormality of vascular smooth muscle rather than in endothelial dysfunction. We examined vasodilator responses to acetylcholine, methacholine, and the endothelium-independent vasodilator sodium nitroprusside in the forearm resistance vessels of 12 men with primary hypercholesterolaemia and 12 normocholesterolaemic male controls. Endothelium-dependent vasodilation in response to acetylcholine was impaired in hypercholesterolaemic patients compared with controls: at the highest dose of drug (15 micrograms per min) mean blood flow in the forearms of the hypercholesterolaemic group was only 52% (95% Cl 31-88%) of that in the control group. Responses to sodium nitroprusside and to methacholine in the two study groups were not significantly different. These results indicate that endothelial dysfunction in hypercholesterolaemic subjects is generalised and extends to vascular beds outside the coronary circulation. Selective impairment to acetylcholine suggests that, at a molecular level, the defect is limited to a specific pathway.

Acetylcholine↗
PubMed1992

Pituitary adenylate cyclase activating polypeptide is a potent vasodilator in humans.

The vasodilator effect of the novel peptide pituitary adenylate cyclase activating polypeptide (PACAP) was investigated in humans. Forearm blood flow was measured in six healthy men by venous occlusion plethysmography. Infusion of PACAP into the brachial artery at 0.01, 0.1, 1, 3, and 10 pmol/min produced a dose-related increase in forearm blood flow in the cannulated arm from 2.8 +/- 0.6 to 8.6 +/- 2.4 ml/100 ml/min at the highest dose (mean +/- SEM, p less than 0.05). In a subsequent experiment, where the highest dose of PACAP was repeated after a 36 min interval, there was no tachyphylaxis of the forearm blood flow response, with the forearm blood flow increasing by 129 +/- 9% during the first infusion and 128 +/- 31% during the second infusion (N.S.). In further experiments, microvascular blood flow was measured by a laser-Doppler flow probe to compare the effects of intradermally injected PACAP, vasoactive intestinal polypeptide (VIP), and calcitonin gene-related peptide (CGRP). When injected into the skin of normal volunteers at 10(-12) to 10(-11) mol/site, each peptide caused a rapid flare lasting 2-3 min, which became erythematous after 5 min. At 10(-12) mol/site, intradermally injected PACAP and VIP caused a maximum increase in skin blood flow at 15 min of 379 +/- 96 and 307 +/- 121% (% increase above basal +/- SEM), respectively, and these responses were not significantly affected by oral aspirin (600 mg) taken 1.5 h beforehand. The vasodilation induced by PACAP at 10(-12) mol/site lasted approximately 6 h, whereas the effect of the same dose of CGRP and VIP lasted less than 2 h. These data suggest that PACAP is a potent and long-lasting vasodilator in humans.

Adult↗
PubMed1991

Pharmacology of endothelin-1 in vivo in humans.

Endothelin-1 (ET-1) is a potent vasoconstrictor and pressor agent with a prolonged action in animal preparations. We have investigated the vascular pharmacology of ET-1 in healthy human volunteers. In arterial studies, blood flow was measured in both forearms and the left brachial artery cannulated for infusion of drugs and vehicle. Local blood flow was reduced in a dose-dependent manner by ET-1. At 5 pmol/min, the response was maximal by 60 min, and flow returned to baseline only after a further 120 min. ET-1 and angiotensin II, both at 5 pmol/min, reduced flow by 40% at 60 min. These responses were reversed to a similar degree by the dihydropyridine calcium antagonist nicardipine (0.3-10 micrograms/min). At 1 pmol/min, ET-1 did not affect sympathetic vasoconstriction to arterial norepinephrine or lower body negative pressure. In venous studies, the internal diameter of a dorsal hand vein was measured during local infusion of drugs and vehicle. ET-1 (5 pmol/min) produced local venoconstriction, with a maximal reduction in vein size of 83 +/- 12% at 60 min. Reversal of responses was slow, and unaffected by nicardipine (1.5 micrograms/min). We have shown that ET-1 is a potent vasconstrictor producing prolonged effects in resistance and capacitance vessels in humans. Low-dose ET-1 does not appear to affect sympathetically mediated vasoconstriction. Studies with nicardipine do not provide support for the hypothesis that ET-1 is an endogenous ligand of the dihydropyridine-sensitive calcium channel.

Adult↗
PubMed1991

The effect of intra-arterial endothelin on resting blood flow and sympathetically mediated vasoconstriction in the forearm of man.

1. The hypothesis that endothelin (ET) influences sympathetically mediated vasoconstriction was investigated in 13 healthy, male subjects. 2. ET (1 pmol min-1) was infused for 60 min into the left brachial arteries of seven healthy male subjects. Resting forearm blood flow, and sympathetic vasoconstriction produced by lower body negative pressure (LBNP; 15 mm Hg), was measured in both arms by strain gauge plethysmography. In a further six subjects, noradrenaline (NA) was infused intra-arterially at doses of 150-600 pmol min-1, with and without co-infusion of ET (1 pmol min-1), with blood flow measured in both forearms. 3. ET produced a small but significant reduction of blood flow in the infused forearm from 3.9 +/- 0.6 ml 100 ml-1 min-1 during infusion of saline, to 3.3 +/- 0.7 ml 100 ml-1 min-1 during infusion of ET at 60 min (P less than 0.05). Blood flow in the non-infused forearm was not altered by ET infusion. 4. NA produced a significant and dose-dependent reduction of blood flow in the infused forearm from 3.13 +/- 0.5 ml 100 ml-1 min-1 during saline infusion, to 1.49 +/- 0.2 ml 100 ml-1 min-1 with NA at 600 pmol min-1 (P less than 0.001). During co-infusion of ET, blood flow was reduced similarly in the infused arm from 3.15 +/- 0.7 ml 100 ml-1 min-1 during saline infusion to 1.55 +/- 0.2 ml 100 ml-1 min-1 with NA at 600 pmol min-1. Blood flow in the non-infused arm was not altered by ET and NA infusion.(ABSTRACT TRUNCATED AT 250 WORDS)

Adult↗
PubMed1990

Bradykinin has no acute effect on the response of forearm blood flow to sympathetic stimulation in man.

1. Six healthy male subjects received 0.9% (w/v) NaCl (saline) followed by incremental doses of bradykinin (1, 3 and 10 pmol/min), via the left brachial artery. Blood flow and the response of blood flow to lower-body negative pressure were measured in both forearms during infusion of saline and each dose of bradykinin. 2. Bradykinin produced a moderate and dose-dependent increase in blood flow in the infused, but not the non-infused, forearm. Lower-body negative pressure produced an approximately 15-20% reduction in blood flow in both forearms, and this response was unaffected by local infusion of bradykinin. 3. Bradykinin, in contrast to angiotensin II, had no acute effect on peripheral sympathetic responses to lower-body negative pressure. We conclude that, in forearm resistance vessels in man, withdrawal of angiotensin II, rather than accumulation of bradykinin, is likely to account for the attenuation of peripheral sympathetic responses after acute administration of a converting-enzyme inhibitor.

Adult↗
PubMed1990

Peptide histidine valine: its haemodynamic actions and pharmacokinetics in man differ from those of vasoactive intestinal peptide and peptide histidine methionine.

1. The effects of intravenous and intra-arterial infusion of the peptides derived from prepro-vasoactive intestinal peptide, vasoactive intestinal peptide, peptide histidine methionine and peptide histidine valine, were examined in six healthy volunteers. 2. Vasoactive intestinal peptide given intravenously caused a significant increase in heart rate and a decrease in diastolic, but not systolic, blood pressure, whereas peptide histidine valine caused an increase in heart rate alone, despite higher achieved circulating peptide concentrations. Peptide histidine methionine did not affect heart rate or blood pressure. Forearm blood flow was increased by vasoactive intestinal peptide and peptide histidine valine when infused locally intra-arterially, although vasoactive intestinal peptide was more potent than peptide histidine valine. 3. Plasma concentrations of cardiodilatin (the N-terminal peptide derived from pro-atrial natriuretic peptide) were increased by intravenous infusion of vasoactive intestinal peptide, but were unaffected by peptide histidine methionine or peptide histidine valine. Circulating plasma concentrations of adrenaline and noradrenaline did not change during infusion of vasoactive intestinal peptide, peptide histidine methionine or peptide histidine valine. 4. Peptide histidine valine had a long half-life when compared with peptide histidine methionine and vasoactive intestinal peptide. 5. We conclude that peptide histidine valine is active in the human cardiovascular system and has a similar, though less potent, vasodilating action to vasoactive intestinal peptide. The higher circulating levels of peptide histidine valine found in man suggest that it may be important in modulating vascular tone.

Adult↗
PubMed1990

Effects of non-steroidal anti-inflammatory drugs on prostacyclin and thromboxane biosynthesis in patients with mild essential hypertension.

1. The effects of non-steroidal anti-inflammatory drugs (NSAID) on prostacyclin and thromboxane biosynthesis and on blood pressure were determined in 46 patients with mild essential hypertension. Patients who had abstained from antihypertensive therapy for 2 weeks before study were treated with either aspirin, ibuprofen, sulindac or placebo for 7 days. 2. Excretion rates of 2,3-dinor-6-oxo-prostaglandin (PG) F1 alpha, 6-oxo-PGF1 alpha, 2,3-dinorthromboxane (TX) B2 and TXB2 were measured as indices of prostacyclin and TXA2 biosynthesis. Samples were assayed using immunoaffinity chromatography and gas chromatography/electron capture chemical ionisation mass spectrometry. 3. Aspirin and ibuprofen reduced urinary excretion of all prostacyclin- and thromboxane-derived products. Sulindac inhibited excretion of 2,3-dinor-6-oxo-PGF1 alpha, 6-oxo-PGF1 alpha and 2,3-dinor-TXB2, but had no significant effect on TXB2. 4. Systolic blood pressure increased in the ibuprofen-treated group when compared with the placebo group. There were no other significant changes in systolic or diastolic pressure in any of the treatment groups. Among the patients as a whole, there was a significant negative correlation between change in blood pressure and change in excretion of the prostacyclin-derived but not of the thromboxane-derived products. 5. We conclude that, in patients with mild essential hypertension, neither sulindac nor aspirin (in the doses used) selectively spares prostacyclin biosynthesis by the kidney. The significant relationship between increase in blood pressure and reduction in prostacyclin biosynthesis favours the possibility that in individuals who become hypertensive, prostacyclin biosynthesis determines, in part, the severity of the hypertensive state.

Adult↗
PubMed1990

Prostacyclin and thromboxane biosynthesis in mild essential hypertension.

The possibility that prostacyclin or thromboxane biosynthesis is abnormal in patients with established mild essential hypertension was investigated in 46 patients. These eicosanoids have opposing effects both on vascular smooth muscle and on platelets. An imbalance in their biosynthesis could therefore influence both vascular tone and predisposition to thrombosis. We studied the relation between blood pressure and the biosynthesis of prostacyclin and thromboxane A2 by measuring urinary excretion rates of stable breakdown products of prostacyclin (6-oxo-prostaglandin F1 alpha and 2,3-dinor-6-oxo-prostaglandin F1 alpha) and of thromboxane A2 (thromboxane B2 and 2,3-dinor-thromboxane B2) using immunoaffinity chromatography and gas chromatography/electron capture mass spectrometry. Excretion rates of both of the prostacyclin-derived products ranged from less than 5 to more than 100 ng/g creatinine; each was significantly negatively correlated with blood pressure (r = 0.36-0.45). A reduction of 2,3-dinor-6-oxo-prostaglandin F1 alpha excretion of 100 ng/g creatinine was associated with an increase in arterial pressure of 14 mm Hg (systolic) and 8 mm Hg (diastolic) in patients who had been without antihypertensive medication for 2 weeks. The same reduction in 6-oxo-prostaglandin F1 alpha excretion was associated with an increased pressure of 19 mm Hg (systolic) and 12 mm Hg (diastolic) (2p less than 0.05 for diastolic pressure and 2p less than 0.01 for systolic pressure in each case). There were similar correlations between the excretion rates of these products and blood pressure in the same patients while they were receiving antihypertensive therapy.(ABSTRACT TRUNCATED AT 250 WORDS)

Adult↗