Cardiovascular Effects of Angiotensin (1-7) in Essential Hypertension

Pharmacologic approaches to increase levels or actions of the vasodilatory peptide
Angiotensin (1-7) are currently in development for the treatment of hypertension based on
findings from animal studies. There are limited and contradictory clinical studies, however,
and it is unclear if this peptide even contributes to blood pressure regulation in humans.
The purpose of this study is to learn more about the cardiovascular effects of Angiotensin
(1-7) in essential hypertension, and to examine interactions of this peptide with the
autonomic nervous system for blood pressure regulation. The investigators propose that the
difficulties in showing Angiotensin (1-7) cardiovascular effects in previous clinical studies
relates to the buffering capacity of the baroreceptor reflex to prevent changes in blood
pressure. In this study, the investigators will test the hypothesis that Angiotensin (1-7)
produces negligible effects with intact baroreceptors, and that the cardiovascular effects of
this peptide are unmasked following elimination of baroreflex buffering. To test this
hypothesis, the investigators will examine the effects of acute intravenous Angiotensin (1-7)
infusion on blood pressure in subjects with essential hypertension under intact conditions
and following acute autonomic withdrawal with the ganglionic blocker trimethaphan. The
primary outcome will be the decrease in systolic blood pressure produced by Angiotensin (1-7)
infusion, with comparisons made between intact and blocked study days. As a secondary
objective, the investigators will examine for changes in systemic hemodynamics and
circulating hormones in response to the Angiotensin (1-7) infusion, to determine potential
mechanisms underlying any changes in blood pressure.

Inclusion Criteria:

- Males and females of all races between 18 and 60 years of age

- Hypertension defined by two or more properly measured seated blood pressure readings
>130/85 mmHg. This will allow us to include subjects with "pre-hypertension."

- Able and willing to provide informed consent

Exclusion Criteria:

- Pregnancy or breast feeding

- Current smokers or history of heavy smoking (>2 packs/day)

- History of alcohol or drug abuse

- Previous allergic reaction to study medications

- Evidence of type I or type II diabetes (i.e. fasting glucose >126 mg/dl, use of
anti-diabetic medications)

- Cardiovascular disease other than hypertension such as myocardial infarction within 6
months prior to enrollment, presence of angina pectoris, significant arrhythmia,
congestive heart failure (LV hypertrophy acceptable), deep vein thrombosis, pulmonary
embolism, second or third degree heart block, mitral valve stenosis, aortic stenosis,
or hypertrophic cardiomyopathy

- History of serious cerebrovascular disease such as cerebral hemorrhage, stroke, or
transient ischemic attack

- History or presence of immunological or hematological disorders

- Impaired hepatic function [aspartate amino transaminase (AST) and/or alanine amino
transaminase (ALT) > 2.0 x upper limit of normal range]

- Impaired renal function (serum creatinine >1.5 mg/dl)

- Anemia (hemoglobin <13.5 g/dl in males or <12.5 g/dl in females)

- Treatment with phosphodiesterase 5 inhibitors

- Treatment with anticoagulants

- Treatment with chronic systemic glucocorticoid therapy (more than 7 consecutive days
in 1 month)

- Treatment with any investigational drug in the 1 month preceding the study

- Inability to give, or withdraw, informed consent

- Other factors which in the investigator's opinion would prevent the subject from
completing the protocol (i.e. clinically significant abnormalities on clinical, mental
examination or laboratory testing or inability to comply with protocol)