G. D. Johnston

Impaired endothelium-dependent and independent vasodilation in patients with type 2 (non-insulin-dependent) diabetes mellitus.

SummaryThe endothelium plays a pivotal role in modulating the reactivity of vascular smooth muscle through the formation of several vasoactive substances. We examined the effects of endothelium-dependent and independent vasodilators on forearm blood flow in 29 patients with Type 2 (non-insulin-dependent) diabetes mellitus and in 21 control subjects, using venous occlusion plethysmography. Via a brachial artery cannula, increasing amounts of acetylcholine and glyceryl trinitrate were infused in doses of 60, 120, 180 and 240 mmol per min and 3, 6 and 9 nmol per min respectively. NG monomethyl-l-arginine, a stereospecific inhibitor of endothelium derived relaxing factor, was infused to inhibit basal and stimulated release of this dilator substance. Reactive hyperaemic forearm blood flow did not differ between groups. Forearm blood flow responses to each dose of acetylcholine were significantly greater in control than diabetic subjects (p<0.01 for all doses). NG monomethyl-l-arginine attenuated forearm blood flow from maximal stimulated values when responses were compared with the natural decline to acetylcholine in forearm flow in both control and diabetic subjects (p<0.05 for both groups), but had no effect on basal blood flow responses. Forearm blood flow responses to each dose of glyceryl trinitrate were significantly greater in control than diabetic subjects (p<0.05 for all). These data provide evidence for endothelial and smooth muscle dysfunction in diabetes which may have important therapeutic implications.

Dietary fish oil augments nitric oxide production or release in patients with Type 2 (non-insulin-dependent) diabetes mellitus

SummaryDecreased release of nitric oxide from damaged endothelium is responsible for the impaired endothelium-dependent vasodilator responses found in animal models of vascular disease. Dietary supplementation with fish oils has been shown to augment endothelium-dependent relaxations, principally by improving the release of nitric oxide from injured endothelium. Using forearm venous occlusion plethysmography we studied vascular responses to 60, 120, 180 and 240 nmol/min of acetylcholine (an endothelium-dependent vasodilator) and 3, 6 and 9 nmol/min of glyceryl trinitrate (an endothelium-independent vasodilator) infused into the brachial artery in 23 patients with Type 2 (non-insulin-dependent) diabetes mellitus. NG monomethyl-l-arginine was employed to inhibit stimulated and basal release of nitric oxide from the endothelium. On completion of the baseline studies patients randomly received either fish oil or matching olive oil capsules in a double-blind crossover fashion for 6 weeks followed by a 6-week washout period and a final 6-week treatment phase. Studies, identical to the initial baseline studies, were performed at the end of the active treatment periods at 6 and 18 weeks. Fish oil supplementation significantly improved forearm blood flow responses to each dose of acetylcholine when compared to the vasodilator responses recorded at baseline and after olive oil administration (p<0.01). Neither fish oil nor olive oil supplementation produced any significant changes in forearm blood flow to the incremental infusions of glyceryl trinitrate when compared with responses recorded during the baseline studies. NG monomethyl-l-arginine significantly reduced forearm blood flow from maximal stimulated values to acetylcholine when compared to the uninhibited decline in flow to acetylcholine infusions at comparable time points (p<0.01). Treatment with fish oils improved endothelium-dependent responses to acetylcholine without altering endothelium-independent responses to glyceryl trinitrate. By increasing stimulated nitric oxide release from the endothelium fish oils may afford protection against vasospasm and thrombosis in patients with diabetes mellitus.

A comparison of the effects of low- and conventional-dose thiazide diuretic on insulin action in hypertensive patients with NIDDM

SummaryIn conventional doses, thiazide diuretics impair glucose tolerance and decrease insulin sensitivity, making them an unpopular choice for treating diabetic patients with hypertension. However, use of low-dose thiazide diuretics may avoid the adverse metabolic effects seen with conventional doses. In a double-blind, randomised crossover study we assessed peripheral and hepatic insulin action in 13 hypertensive non-insulin-dependent diabetic patients after a 6-week placebo run-in and following two 12-week treatment periods with either low (1.25 mg) or conventional (5.0 mg) dose bendrofluazide. There were no differences between doses in their effects on systolic and diastolic blood pressure. Bendrofluazide 1.25 mg had significantly less effect on serum potassium, uric acid, fasting glucose and HbA1c concentrations than the 5.00 mg dose. Exogenous glucose infusion rates required to maintain euglycaemia were significantly different between doses (p < 0.05) with conventional-dose bendrofluazide worsening peripheral insulin resistance compared to baseline (23.8±2.9 vs 27.3±3.5 μmol · kg-1 · min-1, p< 0.05) and low-dose bendrofluazide producing no change compared to baseline (26.8±3.6 vs 27.3±3.5 μmol · kg-1 · min-1, p = NS). Postabsorptive endogenous glucose production was higher on treatment with bendrofluazide 5.0 mg compared to 1.25 mg (11.7 ±0.5 vs 10.2±0.3 μol · kg-1 · min-1p < 0.05) and suppressed to a lesser extent following insulin (4.0±0.7 vs 2.0±0.4 μ±mol · kg-1 · min-1, p < 0.05). Treatment with bendrofluazide 5.0 mg increased postabsorptive endogenous glucose production compared to baseline (11.7±0.5 vs 10.6±0.4 μmol · kg-1 · min-1, p<0.05) whereas bendrofluazide 1.25 mg did not (10.2±0.3 vs 10.6±0.4 μmol · kg-1 · min-1p = NS). At a dose of 1.25 mg bendrofluazide is as effective as conventional doses but has less adverse metabolic effects. In contrast to conventional doses which worsen both hepatic and peripheral insulin resistance, low-dose bendrofluazide has no effect on insulin action in non-insulin-dependent diabetic subjects.

The effect of probucol and vitamin E treatment on the oxidation of low-density lipoprotein and forearm vascular responses in humans

Abstract This study investigates the hypothesis that lipid soluble antioxidants may increase the resistance of low‐density lipoprotein (LDL) to oxidation and also enhance vascular endothelial responses in humans. In a double‐blind parallel group study, 24 hypercholesterolaemic patients, already on treatment with simvastatin (20mg day‐1), were randomized to supplementary treatment with probucol (500 mg bd), vitamin E (400 IU daily) or placebo for 8 weeks. Mean serum cholesterol before antioxidant treatment was 7·00 mmol l‐1. Resistance of LDL to oxidation by copper was increased by 830% in the probucol group and by 30% in the vitamin E group. However, thiobarbituric acid reacting substances in whole serum were not altered by either antioxidant. Probucol lowered HDL‐and LDL‐cholesterol levels and increased the QT interval. Forearm vascular responses, as measured by venous occlusion plethysmography, to acetylcholine, glyceryl trinitrate and NG‐monomethyl‐L‐arginine, were not significantly changed by antioxidant treatment. Probucol has a major, and vitamin E a minor, effect on LDL resistance to oxidation but neither compound appears to alter forearm vascular responses in vivo.

Effects of low dose versus conventional dose thiazide diuretic on insulin action in essential hypertension

Objective: To see whether low dose thiazide diuretics given to patients with essential hypertension might avoid the adverse metabolic consequences seen with conventional doses. Design: Double blind randomised crossover study of two 12 week treatment periods with either low dose (1.25 mg) or conventional dose (5.0 mg) bendrofluazide given after a six week placebo run in period. Setting: Outpatient clinics serving the greater Belfast area. Subjects: 16 white non-diabetic patients (9 male) under 65 with essential hypertension recruited from general practices within the greater Belfast area. Main outcome measures: Systolic and diastolic blood pressure and peripheral and hepatic insulin action. Results: One man failed to complete the study. There were no differences between doses in their effects on systolic and diastolic blood pressure. Bendrofluazide 1.25 mg had substantially less effect20on serum potassium concentration than the 5.0 mg dose. There were no intertreatment differences in fasting glucose, insulin, cholesterol, and triglyceride concentrations. Bendrofluazide 5.0 mg significantly increased postabsorptive endogenous glucose production compared with baseline (mean 10.9 (SD 1.2) v 10.0 (0.8) μmol/kg/min), whereas bendrofluazide 1.25 mg did not. Postabsorptive endogenous glucose20production was significantly higher with bendrofluazide 5.0 mg compared with 1.25 mg (10.9 (1.2) v 9.9 (0.8) μmol/kg/min) but was suppressed to a similar extent after insulin (bendrofluazide 5.0 mg202.8 (1.5) μmol/kg/min v bendrofluazide 1.25 mg 2.2 (1.5) μmol/kg/min). Exogenous glucose infusion rates required to maintain euglycaemia were not significantly different between doses and were20similar to baseline. Conclusions: Bendrofluazide 1.25 mg is as effective as conventional doses but has less adverse metabolic effect. In contrast with conventional doses, how dose bendrofluazide has no effect on hepatic insulin action. There is no difference between low and conventional doses of bendrofluazide in their effect on peripheral insulin sensitivity.

A double-blind cross-over study of nifedipine retard in patients with Raynaud's phenomenon

SummaryThe effectiveness of nifedipine retard as a treatment for Raynauds phenomenon was assessed in 15 patients in a placebo controlled double blind study. An associated connective tissue disease was evident in 7 patients. Changes in finger and forearm blood flow (venous occlusion plethysmography), digital skin temperature and digital systolic pressure were measured acutely before and after a 2-week treatment period. Subjective assessment of efficacy was based on patient diary data. In addition alpha2-adrenoceptor density on platelets was measured before and after chronic nifedipine therapy in both the patient group and in an age-and-sex-matched control group. No significant haemodynamic changes were observed. Nifedipine retard significantly reduced the frequency (p<0.05) with no change in either the duration or severity of vasospastic attacks. Side effects were commono following nifedipine retard. A reduction in alpha2-adrenoceptor density on platelets was observed in patients compared to a control group (p<0.05). Alpha2-adrenoceptor density was unchanged following a 2-week treatment period with nifedipine retard. This study concludes that nifedipine retard is not effective in the treatment of Raynauds phenomenon over a short time course. Patients with Raynauds phenomenon have reduced alpha2-adrenoceptor densities on their platelets.

The effect of chronic captopril therapy on adrenergic receptors, plasma noradrenaline and the vascular responses to infused noradrenaline

SummaryAdrenergic receptors (alpha2, beta2), plasma noradrenaline, heart rate and the pressor responsiveness to infused noradrenaline were examined in ten healthy male volunteers before and after 2 weeks of placebo or captopril therapy in a double blind cross-over study. No significant differences in these measurements were observed between the captopril and placebo treated groups. The study shows that in sodium replete normotensive subjects, long-term angiotensin converting enzyme inhibition does not lead to changes in adrenoceptor density. There is also no alteration in plasma noradrenaline levels nor in the pressor responsiveness to infused noradrenaline. These data suggest that the known interaction between the renin-angiotensin system and the sympathetic nervous system observed in animals is probably of little significance in man.

Peripheral vascular effects of bufuralol in hypertensive and normal subjects: A comparison with propranolol and pindolol

SummaryIn a double-blind, single oral dose, crossover study, the effects of bufuralol (60 mg) on heart rate, blood pressure, and peripheral vascular responses were compared with those of propranolol (160 mg), pindolol (10 mg), and placebo in a group of 12 healthy volunteers.All three beta-adrenoceptor antagonists reduced exercise tachycardia, but at the doses chosen the effects of bufuralol were less than those of propranolol.Forearm blood flow was reduced by propranolol and pindolol, but not by bufuralol.The antihypertensive and peripheral vascular effects of bufuralol (30–60 mg bd) were also compared with those of propranolol (40–80 mg bd) in a double-blind crossover study in 10 patients with mild hypertension.Propranolol and bufuralol produced comparable reductions in systemic blood pressure over a two-week period, but the decreases in forearm and finger blood flow were greater with propranolol.These studies suggest that bufuralol is a beta-adrenoceptor antagonist with antihypertensive properties, and that it produces less peripheral vasoconstriction than propranolol or pindolol.

The effect of chronic captopril therapy on platelet angiotensin II receptor density and vascular responsiveness to angiotensin II infusion

SummaryThe density of angiotensin II (Ang II) receptors on the platelet and the vascular responsiveness to infused angiotensin II before and after two weeks of captopril therapy were examined in ten healthy male volunteers. There was a significant increase in blood flow to the forearm, but no significant changes in either the density of angiotensin II receptors or the pressor response to infused angiotensin II following captopril therapy. The study demonstrates that long term reduction of angiotensin II formation by captopril in man does not increase the responsiveness of the receptors to infused angiotensin, nor results in an „up regulation“ of the angiotensin receptors. It also provides further evidence that some of the long term vasodilator effects of captopril may be mediated by mechanisms other than inhibition of angiotensin I (Ang I) converting enzyme.

A comparison of the haemodynamic and hormonal effects of low and conventional dose cyclopenthiazide in normal volunteers.

SummaryIn this study we compared low (125 μg) and conventional (500 μg) doses of cyclopenthiazide on the renin angiotensin system, plasma and extracellular fluid volumes and the pressor responsiveness to angiotensin II since we have previously shown that the two doses have the same antihypertensive effect but different effects on plasma renin activity.Following a two week placebo run-in period, 8 healthy male volunteers received 125 μg or 500 μg of cyclopenthiazide for 2 treatment periods of 4 weeks as part of a double blind, 2-part crossover study with treatment periods separated by a 4-week placebo washout phase. Measurements were made on two study days at the beginning and end of the active treatment periods. On the first day serum potassium, plasma renin activity and plasma angiotensin II levels were measured after a 1 h period of supine rest. Plasma and extracellular fluid volumes were also measured after appropriate equilibration times. The blood pressure responses to angiotensin II were assessed on day 2.The 500 μg dose of cyclopenthiazide had a greater effect than the 125 μg dose on plasma renin activity, serum potassium, angiotensin II levels and extracellular fluid volumes. Neither drug had any effect on plasma volume or the responsiveness to infused angiotensin II.Low dose cyclopenthiazide failed to increase angiotensin II levels, contract body fluid volumes or attenuate vascular reactivity in normotensive volunteers.