Sally E. Brett

Diastolic Blood Pressure Changes During Exercise Positively Correlate With Serum Cholesterol and Insulin Resistance

BACKGROUNDnMetabolic factors, including plasma concentrations of cholesterol and insulin resistance, may influence blood pressure through effects on vascular reactivity. Such effects might influence blood pressure during exercise more strongly than at rest.nnnMETHODS AND RESULTSnWe examined whether there is an association between serum cholesterol or insulin resistance and change in blood pressure during mild exercise. Blood pressure was measured at rest and during fixed low-workload bicycle ergometry (50, 75, and 100 W, each for 3 minutes) in 75 healthy active men (age, 18 to 66 years). Blood pressure at rest was not significantly correlated with serum cholesterol or insulin resistance (estimated from the fasting glucose-insulin product). The change from resting values in diastolic but not systolic blood pressure during exercise was correlated with serum cholesterol (R>0.47, P<0.0001 for each workload) and insulin resistance (R>0.38, P<0.01 for each workload). Serum cholesterol and insulin resistance were the only independent predictors of the change in diastolic blood pressure during exercise in a stepwise regression model incorporating age, body mass index, serum cholesterol, triglycerides, HDL cholesterol, insulin resistance, and heart rate during exercise. In a further study, the change in diastolic blood pressure during exercise was greater in men with uncomplicated type 2 diabetes (13.6 mm Hg [95% CI, 8.5 to 18.8]; n=10) than in nondiabetic control men (2.7 mm Hg [95% CI, -2. 0 to 7.3]; n=10; P=0.002).nnnCONCLUSIONSnChanges in diastolic blood pressure during gentle exercise are strongly associated with serum concentrations of total cholesterol and insulin resistance. This may contribute to development of hypertensive complications in dyslipidemic and/or insulin-resistant patients.

Preserved endothelial function in patients with severe hypertriglyceridemia and low functional lipoprotein lipase activity

OBJECTIVESnWe sought to determine whether hypertriglyceridemia in patients with lipoprotein lipase (LPL) dysfunction is associated with endothelial dysfunction in resistance vessels of the forearm vasculature.nnnBACKGROUNDnVasodilator responses to acetylcholine, acting through stimulation of nitric oxide (NO) release from the endothelium, are impaired in hypercholesterolemia and normalized by L-arginine, suggesting dysfunction of the L-arginine/NO pathway. Similar abnormalities have been reported in conditions associated with hypertriglyceridemia, such as non-insulin-dependent diabetes. The relation between endothelial function and plasma triglyceride concentrations has, however, not previously been studied in vivo.nnnMETHODSnWe examined forearm blood flow responses to brachial artery infusions of acetylcholine (alone and with L-arginine) and nitroprusside (an NO donor) in 17 patients with severe hypertriglyceridemia (mean [+/- SD] plasma triglyceride concentration 1,914 +/- 1,288 mg/dl) but normal low density lipoprotein cholesterol (89 +/- 31 mg/dl) and in 34 normolipidemic control subjects. Severe LPL dysfunction was demonstrated in 10 of 17 patients.nnnRESULTSnAcetylcholine (7.5 and 15 microg/min) produced similar forearm blood flow responses in hypertriglyceridemic patients (mean [+/- SEM] 7.7 +/- 0.9 and 10.5 +/- 1.2 ml/min per 100 ml) and in control subjects (7.5 +/- 0.6 and 11.0 +/- 0.8 ml/min per 100 ml, p = 0.78 by analysis of variance). Responses to acetylcholine co-infused with L-arginine (10 mg/min) and nitroprusside (3 and 10 microg/min) were also similar in hypertriglyceridemic patients and control subjects (p = 0.93 and p = 0.27 for acetylcholine with L-arginine and nitroprusside, respectively). The ratio response to acetylcholine/response to nitroprusside differed between hypertriglyceridemic patients and control subjects by only 1%. The study had >90% power (alpha = 0.05) to detect a difference >30% in this ratio.nnnCONCLUSIONSnSevere hypertriglyceridemia associated with LPL dysfunction is not associated with the degree of endothelial dysfunction seen in moderate hypercholesterolemia when responses to acetylcholine are impaired by >40%.

Acute haemodynamic effects of lipolysis-induced increase of free fatty acids in healthy men

Circulating free fatty acids (FFA) are elevated in subjects with insulin resistance and Type II diabetes, and increase during myocardial ischaemia, but their haemodynamic effects are incompletely understood. During an investigation of the effects of FFA on endothelial function, we administered lipid emulsion (150 mg x min(-1) of soybean oil) with heparin (0.2 unit x kg(-1) x min(-1)) intravenously to eight healthy men for 2 h. This increased circulating FFA to 3.1+/-0.5 mmol/l. Forearm blood flow was measured by venous occlusion plethysmography during brachial artery infusions of saline, acetylcholine and nitroprusside before, and at 1 and 2 h. Lipid/heparin infusion had no significant effect on vasodilation to nitroprusside but progressively increased responses to acetylcholine (from 6.3+/-2.0 during 30 microg x min(-1) before-lipid infusion to 7.9+/-1.3 at 1 h and 12.2+/-1.1 ml x min(-1) x 100 ml(-1) at 2 h, P<0.001). Basal flow increased from 2.7+/-0.7 to 4.7+/-0.8 ml x min(-1) x 100 ml(-1) from 0 to 2 h. We performed a second study to clarify this effect on basal blood flow. Healthy men (n=8) received, on separate occasions, 4 h intravenous infusions of lipid emulsion with heparin and, as a control, saline with heparin. Lipid with heparin increased mean arterial blood pressure (maximum increment 8.2+/-2.7 mm Hg, P<0.01 compared with saline/heparin control) and forearm blood flow (from 1.7+/-0.2 to 2.9+/-0.3 ml x min(-1) x 100 ml(-1), P<0.01) without a significant effect on heart rate, and reduced calculated forearm vascular resistance (from 49.1+/-5.4 to 31.3+/-3.9 arbitrary units, P<0.01). In conclusion, acute elevation of FFA in healthy men increases arterial blood pressure and reduces vascular resistance. These haemodynamic changes could be clinically relevant.

Forearm vasoconstriction in response to noradrenaline and NG-monomethyl-L-arginine in essential hypertension.

A role for abnormal NO production in essential hypertension remains controversial. Blunted vasoconstriction of forearm resistance vasculature in response to N(G)-monomethyl-L-arginine (L-NMMA; an inhibitor of NO biosynthesis), relative to the response to noradrenaline, has been reported in hypertensive patients and interpreted as evidence of reduced basal NO biosynthesis. We sought to determine whether reduced sensitivity of forearm vasculature to the vasoconstrictor action of L-NMMA relative to that of noradrenaline is a consistent finding in essential hypertension. We studied a group of patients (n=32; blood pressure 176+/-4/102+/-2 mmHg; means+/-S.E.M.) and a group of healthy normotensive controls (n=32; blood pressure 130+/-2/75+/-1 mmHg). Noradrenaline (60-240 pmol.min(-1)) and L-NMMA (1-4 micromol.min(-1)) were infused into the brachial artery, and forearm blood flow was measured by venous occlusion plethysmography. The effects of each vasoconstrictor were similar in hypertensive and control subjects. The highest dose of L-NMMA reduced forearm blood flow by 0.75+/-0.12 ml.min(-1).dl(-1) in the control group and by 0.89+/-0.10 ml.min(-1).dl(-1) in the hypertensive group. The study had 90% power (with P=0.05) to detect a 10% difference in forearm blood flow response between the hypertensive and control groups. We conclude that reduced sensitivity of forearm resistance vasculature to the vasoconstrictor action of L-NMMA is not a universal feature of essential hypertension. This argues against a primary role for reduced basal NO biosynthesis in skeletal muscle resistance vessels in the pathogenesis of essential hypertension.

Comparison of the Effects of Nebivolol and Bisoprolol on Systemic Vascular Resistance in Patients with Essential Hypertension

AbstractObjective: To compare the haemodynamic effects of nebivolol, a highly selective antagonist of β1-adrenergic receptors with additional actions caused via the L-arginine/nitric oxide pathway, with those of bisoprolol, another selective β1-adrenergic receptor antagonist.n Patients and methods: The study had a double-blind, randomised, crossover design, and was performed in an outpatient setting. Study participants comprised 15 patients (11 men, four women, aged 29 to 69 years) with uncomplicated mild essential hypertension. Patients were randomised to receive nebivolol (5mg orally daily) or bisoprolol (10mg orally daily) for 2 weeks, followed by a 2-week washout and 2 weeks of the other treatment. Measurements (by mercury sphygmomanometer and bioimpedance) were made at the end of each baseline and each active treatment period.n Results: Mean heart rate fell during active treatment (from 65 ± 2 to 53 ± 3 beats/min during bisoprolol, p < 0.05, and from 64 ± 3 to 59 ± 3 beats/min during nebivolol). Systolic/diastolic blood pressure fell during active treatments to a similar extent with each treatment (bisoprolol: 143 ± 3/90 ± 2mm Hg to 127 ± 3/80 ± 2mm Hg; nebivolol: 144 ± 4/92 ± 2mm Hg to 131 ± 4/83 ± 3mm Hg; each p < 0.01). In contrast, the systemic vascular resistance index fell during nebivolol (from 2854 ± 201 to 2646 ± 186 dyn·sec·cm−5·m2, p < 0.05), but did not change significantly during bisoprolol treatment (baseline 2848 ± 177, with treatment 2787 ± 159 dyn·sec·cm−5·m2).n Conclusion: The fall in systemic vascular resistance index during nebivolol (but not bisoprolol) treatment can be explained on the basis of a systemic vasodilator action of nebivolol. The clinical importance of this action requires further investigation.