Colm McGurk

Impaired Vasoconstriction to Endothelin 1 in Patients With NIDDM

Microvascular disease is an important cause of morbidity in diabetes. There is evidence that impaired autoregulation of blood flow is involved in the pathogenesis of diabetic microangiopathy. The vascular endothelium plays a central role in the regulation of vascular tone. Endothelin (ET)-1 is a potent endothelium-derived vasoconstrictor substance that contributes to basal vascular tone. Impaired vasoconstriction in response to endogenous ET could result in hyperperfusion and subsequent microvascular damage. The purpose of our study was to determine whether vascular responses to locally administered ET-1 are impaired in NIDDM. Nine patients with NIDDM and 12 control subjects underwent cannulation of the nondominant brachial artery. Forearm blood flow (FBF) was measured at baseline and during the drug infusion using strain-gauge venous occlusion plethysmography. ET-1 (5 pmol/min) was infused for 60 min at a rate of 1 ml/min. FBF was measured during the first 5 min of the infusion and at 5-min intervals thereafter. Results were expressed as change in FBF from baseline (ml.100 ml−1 · min−1) and were analyzed using repeated measures analysis of variance and Dunnetts test of multiple comparisons. Control subjects showed a gradual onset of vasoconstriction in response to ET-1, which reached maximum at 35 min (1.1 ml.100 ml−1 · min−1; P < 0.01). There was no reduction in FBF in response to ET-1 in the diabetic group. The differences between the diabetic and control groups were significant (P < 0.03). In conclusion, ET-1 infused locally at 5 pmol/min does not cause vasoconstriction in patients with NIDDM.

Vasoconstriction to endogenous endothelin-1 is impaired in patients with Type II diabetes mellitus

Endothelin-1 has potent vasoconstrictor and vasopressor actions contributing to basal vascular tone and maintenance of blood pressure acting predominantly through endothelin-A receptors. Endothelin antagonists may be of value in the treatment of hypertension and heart failure. However, the role of endothelin-1 in the regulation of vascular tone and the potential benefits of endothelin antagonists in non-insulin-dependent diabetes mellitus (Type II diabetes) are less clear. Vasoconstriction to exogenous endothelin-1 is impaired in Type II diabetes. The purpose of this study was to determine whether vasoconstriction to endogenous endothelin-1 acting through the endothelin-A receptor is impaired in Type II diabetes. In ten patients with Type II diabetes and nine controls the endothelin-A receptor antagonist BQ123 was infused intra-arterially at 100 nmol/min for 60 min followed by normal saline for 30 min. Forearm blood flow was measured using venous occlusion plethysmography. Control subjects showed gradual onset of vasodilation in response to BQ123 (P < 0.001). Diabetic subjects, however, showed no significant response (P > 0.05). There was a significant difference between the diabetic and control groups (P < 0.05). Blockade of the endothelin-A receptor is associated with impaired vasodilation in Type II diabetes indicating vasoconstriction to endogenous endothelin-1 mediated by the endothelin-A receptor is impaired.

Sources of inaccuracy in the use of the Hawksley random-zero sphygmomanometer.

Objective To identify possible causes of inaccuracy in the use of the Hawksley random-zero sphygmomanometer and methods that could reduce this. Methods Four Hawksley random-zero sphygmomanometers were compared with a standard sphygmomanometer under static conditions. Two methods (standard and rapid) were used to release pressure from the inflated cuff with pressures recorded by independent blinded observers. The rate at which the hand valve released pressure was analysed. The effects of varying filling times and pressures on the size of the final zero correction were investigated. Results The Hawksley devices all under-recorded pressure compared with that measured by using a standard machine. A rapid means of pressure release approximately halved this error in each case. Pressure release through the hand valve was shown to have a characteristic and prolonged exponential decay. Using low filling times and pressures reduced the observed range of zeros seen, with the production of a correlation between the size of the zero and the inflation pressure used. Conclusion These findings suggest that overestimation of the final zero correction is a common and major source of error in the use of the Hawksley sphygmomanometer. A simple change in the design of the final pressure release would improve the machines reliability in clinical usage. The machines zero mechanism is susceptible to unintentional misuse. Such misuse could occur when the machine is used in accordance with current sphygmomanometry guidelines.

Effect of Methionine Supplementation on Endothelial Function, Plasma Homocysteine, and Lipid Peroxidation

BACKGROUND Acetaminophen (paracetamol) poisoning is a major source of morbidity and mortality. It has been proposed that methionine be incorporated into acetaminophen tablets routinely as a protective mechanism. Methionine has been shown to be effective in the treatment of acetaminophen toxicity and a combination preparation of acetaminophen and methionine may prevent toxicity. However, there has been some concern that chronic methionine supplementation may be associated with vascular disease. The aim of the study was to investigate if methionine supplementation causes changes in endothelial function, plasma homocysteine, or lipid peroxidation which may be associated with atherosclerosis. METHODS Sixteen healthy volunteers were studied. Forearm blood flow in response to local intra-arterial infusion of acetylcholine to assess endothelium-dependent vasodilatation and sodium nitroprusside to assess endothelium-independent vasodilatation was measured by venous occlusion plethysmography. Plasma homocysteine and lipid peroxidation, measured as thiobarbituric acid reactive substances, were measured using high-performance liquid chromatography. Forearm vascular responses, plasma homocysteine concentrations, and thiobarbituric acid reactive substances were measured at baseline and following methionine supplementation. RESULTS There was no significant difference in endothelial-dependent vascular responses after acute (methionine 250 mg orally, p > 0.05), 1 month of low-dose (methionine 250 mg daily, p > 0.05), or 1 week of high-dose (methionine 100 mg/kg daily, p > 0.05) methionine administration. There was no significant difference in plasma homocysteine concentrations after acute (p > 0.05) or 1 month of low-dose (p > 0.05) methionine administration. However, 1 week of high-dose methionine (100 mg/kg) administration daily significantly increased homocysteine concentrations (p < 0.0015). Thiobarbituric acid reactive substances were unchanged during the period of study (p > 0.05). CONCLUSIONS Methionine supplementation does not impair endothelial-dependent vascular responses in healthy volunteers. Although high-dose methionine administration causes elevation of plasma homocysteine concentrations, doses similar to those used in combination preparations with acetaminophen do not affect plasma homocysteine concentrations.

The Effect of Drug Therapy on Quality of Life in Heart Failure

SummaryQuality of life (QOL) analysis provides a unique insight into the global impact of drug therapy as seen from the patient’s perspective. Because of their relative novelty, these measurements have been preferentially applied to more recently developed drugs. There are little data of this type available for most of the more established heart failure agents.Modern QOL measurement techniques appear robust and have provided support for the use of angiotensin converting enzyme inhibitors in heart failure and the use of β-adrenoceptor blockade in dilated cardiomyopathy.QOL analyses raise ethical questions when such measures indicate an apparent improvement in measured QOL in response to a drug whilst, at the same time, being associated with decreased survival amongst users.There are some unresolved methodological problems with the interpretation of QOL data. Despite these, QOL analyses represent an important advance as they provide valuable complementary data to more traditional indices in the assessment of the effect of treatment on the disease process and patient well being.

Bradykinin infusion in chronic cardiac failure and the effects of captopril

Patients with chronic cardiac failure (CCF) have abnormal vascular responses. Bradykinin (BK) is thought to contribute to the vasodilator effects of ACE inhibitors, but the effect of BK itself in patients with CCF has not been examined.