Losartan, an Angiotensin Type 1
Receptor Antagonist, Improves Endothelial
Function in Non-Insulin-Dependent Diabetes
Craig Cheetham, BSc,* Julie Collis, BSc,* Gerard O’Driscoll, MB, BCh, BAO, FRACP,‡§
Kim Stanton, MB, BS, FRACP, Roger Taylor, MB, BS, FRACP,†‡ Daniel Green, P
H
D*‡§
Perth, Australia
OBJECTIVES The present study examined the effect on forearm endothelial function of an angiotensin II
type 1 receptor antagonist, losartan, in subjects with non-insulin-dependent diabetes mellitus
(NIDDM).
BACKGROUND Angiotensin-converting enzyme (ACE) inhibition with enalapril improves acetylcholine
(ACh)-dependent endothelial function in patients with NIDDM. This could be mediated
through angiotensin II and the type 1 receptor or could be due to inhibition of kininase II and
a bradykinin preserving effect. It is therefore relevant to determine whether a type 1 receptor
antagonist improves endothelial function.
METHODS The influence of losartan (50 mg daily for four weeks) on endothelium-dependent and
independent vasodilator function was determined in 9 NIDDM subjects using a double-
blinded placebo-controlled crossover protocol. Forearm blood flow was measured using
strain-gauge plethysmography.
RESULTS Losartan significantly decreased infused arm vascular resistance in response to three
incremental doses of intrabrachial acetylcholine (p Ͻ 0.05, ANOVA). The forearm blood
flow ratio (flow in infused to noninfused arm) was also increased (p Ͻ 0.01). Responses to
sodium nitroprusside and monomethyl arginine were not significantly changed.
CONCLUSIONS Losartan administration at 50 mg per day improved endothelium-dependent dilation of
resistance vessels in patients with NIDDM. That is, blockade of the angiotensin II type 1
receptors improves endothelial function in NIDDM. At least some of the similarly beneficial
effect of ACE inhibition is probably mediated also through the angiotensin II-type 1 receptor
pathway. The use of a type 1 receptor antagonist seems a reasonable alternative to an ACE
inhibitor to maintain endothelial function in NIDDM subjects. (J Am Coll Cardiol 2000;36:
1461–6) © 2000 by the American College of Cardiology
Angiotensin-converting enzyme (ACE) inhibitors improve
endothelial NO-related vasodilator function in patients
with depressed function, including those with both insulin-
dependent (1) and non-insulin-dependent (2) diabetes mel-
litus (NIDDM). The mechanisms are not well defined and
may involve greater NO production and/or reduced NO
inactivation by oxygen-derived free radicals (3) or by other
compounds. Since the introduction of angiotensin II type 1
receptor blocking drugs there has been considerable specu-
lation on the relative merits of these drugs and ACE
inhibitors, especially in hypertension (4 –6) and cardiac
failure (7). The receptor blocking drugs can potentially
produce greater inhibition of effects mediated by angioten-
sin II. During the administration of a competitive ACE
inhibitor, angiotensin II can still be produced from angio-
tensin I, probably attributable both to the higher concen-
trations of angiotensin I that accompany ACE inhibition
and to conversion by other enzyme systems such as chymase.
In contrast, type 1 receptor inhibition with currently used
drugs is partly noncompetitive, or insurmountable, although
the degree varies with the particular inhibitor. Furthermore,
it is speculated that type 1 receptor inhibition might result
in buildup of angiotensin II with stimulation of type 2
receptors and beneficial effects. These considerations would
favor the type 1 receptor blocking drugs over ACE inhibi-
tors. On the other hand, ACE inhibitors additionally
inhibit the breakdown of bradykinin, and there is consider-
able evidence that increase in release of NO, induced by the
accumulation of bradykinin, contributes to the augmented
endothelium dependent vasodilator responses resulting from
ACE inhibition (8–12).
As a clear improvement in endothelium-dependent vaso-
dilation has been found to result from four weeks adminis-
tration of the ACE inhibitor, enalapril, in NIDDM (2), it
was of interest to examine the effect of the type 1 receptor
antagonist, losartan in a similar group.
METHODS
Subjects. Nine subjects (7 men, 2 women, average age
54 Ϯ 2 years) with NIDDM without evidence of microvas-
cular or macrovascular complications were recruited. They
From the Departments of *Human Movement and Exercise Science, and †Med-
icine, The University of Western Australia, Royal Perth Hospital and West
Australian Heart Research Institute, Perth, Australia; ‡Department of Cardiology,
§Cardiac Transplant Unit, and Endocrinology and Diabetic Unit, Royal Perth
Hospital and West Australian Heart Research Institute, Perth, Australia. This study
was supported by the Arnold Yeldham and Mary Raine Medical Research Founda-
tion.
Manuscript received October 21, 1999; revised manuscript received April 11, 2000,
accepted June 15, 2000.
Journal of the American College of Cardiology Vol. 36, No. 5, 2000
© 2000 by the American College of Cardiology ISSN 0735-1097/00/$20.00
Published by Elsevier Science Inc. PII S0735-1097(00)00933-5