Henry L. Elliott

Insulin Action Is Associated With Endothelial Function in Hypertension and Type 2 Diabetes

A primary defect in the vascular action of insulin may be a key intermediate mechanism that links endothelial dysfunction with reduced insulin-mediated cellular glucose uptake in metabolic and cardiovascular disorders. The present study was designed to characterize more fully the relations between insulin action and endothelial function in male patients with essential hypertension (H, n=9) or type 2 diabetes (D, n=9) along with healthy control subjects (C) matched for age, body mass index, and lipid profile. They attended for measurement of whole-body insulin sensitivity (MCR) by the hyperinsulinemic clamp technique (day 1) and forearm vasoreactivity in response to intra-arterial infusions of insulin/glucose (day 2) and N(G)-monomethyl-L-arginine (L-NMMA) and norepinephrine (day 3) by bilateral venous-occlusion plethysmography. Results expressed as mean+/-SE MCR (mL/kg per minute) were 7.22+/-0. 99 (C), 6.32+/-0.78 (H), and 5.06+/-0.53 (D). Insulin/glucose-mediated vasodilation (IGMV) was 17.1+/-5.6% (C), 17. 2+/-5.5% (H), and 12.3+/-6.4% (D). L-NMMA vasoconstriction (LNV) was 37.9+/-5.1% (C), 37.5+/-2.3% (H), and 33.6+/-2.8% (D). There were no significant differences among groups for these parameters. Pooled correlation analyses revealed associations between MCR and IGMV (r=0. 46, P<0.05), MCR and LNV (r=0.44, P<0.05), and IGMV and LNV (r=0.52, P<0.01). This study supports functional coupling between insulin action (both metabolic and vascular) and basal endothelial nitric oxide production in humans.

Insulin as a vascular hormone: Implications for the pathophysiology of cardiovascular disease

1. Metabolic disorders, such as obesity and non‐insulin‐dependent diabetes mellitus, and cardiovascular disorders, such as essential hypertension, congestive cardiac failure and atherosclerosis, have two features in common, namely relative resistance to insulin‐mediated glucose uptake and vascular endothelial dysfunction.

Analysis of the pressor dose response

(1) When incremental infusions of drugs that increase blood pressure are given to human subjects to assess “pressor responsiveness,” only the lower part of the sigmoid dose‐response curve can be obtained. (2) Fitting a quadratic function does not involve discarding data points, which is usually the case with a linear fit, and it provides a more satisfactory fit to the lower part of a sigmoid dose‐response curve. (3) In the presence of a competitive antagonist, a pressor dose‐response curve will be shifted to the right. In this situation the dose‐response curves obtained before and after treatment with antagonist should be fitted simultaneously to a quadratic model in which the parallel shift is one of the parameters. (4) The use of quadratic fitting is illustrated by reference to clinical experiments to obtain the following three curves for drugs that modify peripheral alpha adrenoceptors: norepinephrine pressor response curves after placebo and doxazosin, an alpha1 antagonist; norepinephrine pressor response curves after placebo, labetalol, and medroxalol (drugs with combined alpha 1 and beta blocking properties); and phenylephrine pressor response curves before and after prazosin. (5) Fitting a quadratic function is the appropriate initial step in the analysis of pressor dose‐response curves in man.

Immediate cardiovascular responses to oral prazosin—Effects of concurrent β‐blockers

Initiation of prazosin therapy may be complicated by the first‐dose response of acute postural hypotension and tachycardia. The effects of β‐blocker on the responses to oral prazosin were studied in eight normotensive men. After 1 mg oral prazosin there was a marked postural fall in blood pressure to a lowest mean standing systolic pressure of 88 ± 7 mm Hg (x̄ ± SD), associated with a tachycardia of 117 ± 13 bpm, and an increase in mean plasma norepinephrine concentration to 9.6 ± 7.9 nmole/l. There was a linear relationship (r = 0.93) between plasma prazosin concentration and hypotensive effect. Concurrent propranolol 80 mg or primidolol 100 mg (a cardioselective β‐blocker) increased the severity and duration of the postural hypotensive response, with lowest mean systolic blood pressure (BP) of 79 ± 7 and 75 ± 9 mm Hg. There was no effect on the orthostatic release of norepinephrine but there was attenuation of the postural tachycardia. Concurrent β‐adrenergie blocking therapy, selective or nonselective, intensifies the immediate postural hypotensive response to the initial oral dose of prazosin.

THE EUGLYCAEMIC HYPERINSULINAEMIC CLAMP : AN EVALUATION OF CURRENT METHODOLOGY

1. The recognition of the role of insulin resistance in disease states and the recent development of new drugs that modify insulin‐dependent metabolism has led to increased use of the euglycaemic hyperinsulinaemic clamp to measure in vivo insulin sensitivity, but several key aspects of the technique are poorly documented in the literature.

Pharmacokinetic and pharmacodynamic modelling of trimazosin and its major metabolite

The pharmacokinetic and pharmacodynamic profiles of intravenous trimazosin, a postsynaptic α1antagonist, were analyzed empirically by integrated modelling techniques. The mean terminal elimination half-life for trimazosin was 186± 80 min and the mean elimination half-life of its alkyl hydroxylated metabolite (CP23445) was 93± 29 min. The placebo-corrected fall in systolic blood pressure after 5 min standing was most appropriately characterized in all subjects by a model that incorporated “effect” compartments for both parent drug and its metabolite.

Pressor and Subpressor Doses of Angiotensin II Increase Insulin Sensitivity in NIDDM: Dissociation of Metabolic and Blood Pressure Effects

There is evidence that the renin-angiotensin system may be involved in the metabolic as well as the cardiovascular features of diabetes and that pressor doses of angiotensin II (ANG II) increase insulin sensitivity in parallel with blood pressure (BP) in healthy subjects, but the effects of ANG II on insulin sensitivity have not been previously reported in patients with non-insulin-dependent diabetes mellitus (NIDDM). In a randomized, double-blind, placebo-controlled, crossover study, 11 patients with NIDDM attended 3 study days to evaluate the effects of a 3-h infusion of subpressor and pressor doses of ANG II on whole body insulin sensitivity using the euglycemic hyperinsulinemic clamp. BP and heart rate were recorded, and blood samples were collected for serum insulin, C-peptide, potassium, catecholamines, plasma renin activity, and plasma ANG II concentrations. Plasma levels of ANG II (means ± SD) were 9 ± 4, 29 ± 9, and 168 ± 47 pmol/ml after placebo, low dose infusion, and high dose infusion, respectively. The higher dose of ANG II was associated with significant increases in BP (e.g., 18 mmHg systolic BP at 150 min) and plasma aldosterone. Whole body insulin sensitivity was 23.8 ± 12.7 mumol glucose.kg−1 · min−1 after placebo and 30.6 ± 12.7 and 27.2 ± 13.3 following low and high dose ANG II infusions, respectively (P < 0.05, analysis of variance). In summary, acute infusion of ANG II, with or without an increase in BP, increases insulin sensitivity in normotensive patients with NIDDM. The dissociation of metabolic and BP effects of ANG II suggests that hemodynamic alterations and redistribution of cardiac output might not be the sole underlying mechanism in patients with NIDDM.

The determination of labetalol in plasma by high-performance liquid chromatography using fluorescence detection

A sensitive and specific assay for labetalol is described. The method employed is reverse phase high-performance liquid chromatography (HPLC) with fluorescence detection. Using 1 ml of plasma, the limit of detection of the assay was 8 ng/ml and the coefficient of variation over a typical calibration range is 5.5%. Various drugs that might be coadministered with labetalol are shown not to interfere in the assay. The method has been employed to study the pharmacokinetics of labetalol following intravenous and oral administration.

Clinical Pharmacology of Drugs Acting on Imidazoline and Adrenergic Receptors

Centrally acting antihypertensive drugs are recognized to be safe and effective treatment for high blood pressure. Centrally mediated side effects, such as sedation, are commonly dose- and treatment-limiting events. Imidazoline-preferring receptors, while functionally similar to alpha 2 adrenoceptors, are distinguishable not only on the basis of in vitro radioligand binding but also in vivo in terms of side effects. Drugs with an imidazoline structure lower blood pressure but are less likely to impair psychomotor function. A placebo-controlled study compared moxonidine 0.1 mg with clonidine 0.1 mg orally in nine normal subjects. Both active drugs lowered blood pressure compared to placebo (clonidine more than moxonidine). However, psychomotor function and self-scored sedation and dry mouth were significantly affected only by clonidine. In a long-term (4 weeks) double-blind cross-over study in essential hypertension, rilmenidine was well tolerated and had similar effects to those of atenolol on erect and supine blood pressure. Rilmenidine had no effect on a wide range of autonomic and psychomotor tests or on responses to mental or physical stress. Atenolol, by contrast, had the predicted effects of a beta adrenoceptor antagonist on heart rate during exercise and the Valsalva maneuver. Imidazoline-preferring drugs offer a new and realistic approach to antihypertensive therapy with blood pressure reduction not limited by marked sedation within the therapeutic dose range.

Angiotensin-converting enzyme inhibitors in the elderly

Although early studies suggested little role for angiotensin-converting enzyme (ACE) inhibitors in older hypertensive patients, more careful evaluation has confirmed their efficacy and good tolerability. Although the elderly tend to have low plasma renin levels, the fall in blood pressure after ACE inhibitors is at least as great (and in several studies greater) than in younger age groups. Because several ACE inhibitors, including captopril and enalaprilat, are eliminated by the kidneys, there are predictable age-related effects on pharmacokinetics. Reduced renal clearance will contribute, at least in part, to the enhanced intensity and duration of action seen in elderly patients. However, not all the effects of age on the kinetics and dynamics of ACE inhibitors are predictable. Studies with perindopril and benazepril in the elderly confirm the efficacy of this group of drugs but highlight other pharmacokinetic differences. ACE inhibitors are effective in reducing blood pressure and can be considered for wider use in elderly hypertensives.