Effects of Rosiglitazone on Blood Vessels in Patients With High Blood Pressure and High Cholesterol
Effects of Rosiglitazone on Blood Vessels in Patients With High Blood Pressure and High Cholesterol
Cells in the lining of blood vessels produce various substances that cause the vessels to
 dilate (relax) and constrict (tighten), thereby regulating blood flow. In patients with high
 blood pressure and high cholesterol, the blood vessels do not dilate properly. This study
 will investigate the effects of rosiglitazone-a drug used to improve the action of insulin in
 diabetic patients-on blood flow by examining its effects on endothelin (a substance that
 causes vessel constriction), and other substances produced by the vessel-lining cells.

 Adults with blood pressure recordings of 140/90 mmHg or higher on at least three separate
 days or with a blood cholesterol level of at least 240 mg/dl may be eligible for this study.
 Candidates will be screened with a medical history and physical examination, blood pressure
 recordings, blood and urine tests.

 This "crossover" study involves two separate treatment periods; that is, participants will
 take either rosiglitazone or placebo (an inactive look-alike pill) once a day for 8 weeks,
 then no drug for 4 weeks, and then the alternative treatment for the next 8 weeks. Patients
 will continue to take their high blood pressure medicines during the first 6 weeks of each
 treatment period. They will stop the medication 2 weeks before the following procedures,
 which are done at the end of each 8-week treatment period:

 Strain gauge plethysmography-A small catheter is placed through a needle into an artery at
 the bend of the arm for measuring blood pressure and drawing blood samples during the study.
 Pressure cuffs are placed on the wrist and upper arm, and a strain gauge (a rubber band
 device) is placed around the forearm to measure forearm blood flow. When the cuffs are
 inflated, blood flows into the arm, stretching the strain gauge at a rate proportional to the
 flow, and the measurement is recorded.

 Small doses of four drugs-acetylcholine, bradykinin, sodium nitroprusside and BQ-123-are
 given through the catheter. Acetylcholine slows the heart rate. Bradykinin stimulates the
 release of a substance that causes blood vessels to dilate and can lower blood pressure.
 Sodium nitroprusside causes blood vessels to dilate and is used to treat high blood pressure
 and heart failure. BQ-123 blocks the blood vessel-constricting activity of endothelin.

 Brachial ultrasound reactivity study-A baseline ultrasound image (picture produced using
 sound waves) of the brachial artery (artery located at the bend of the arm) is taken and
 blood flow measurements are recorded. Then, a pressure cuff is placed around the upper
 forearm, inflated for 5 minutes to stop blood flow to the forearm, and then released. Images
 of the artery and flow measurements are repeated. After a 15-minute rest, new baseline images
 are taken and flow measurements obtained. A small amount of nitroglycerin is then sprayed
 under the tongue and after 3 minutes, blood flow measurements and brachial artery images are
 recorded once more.
Since the publication of the data of the San Antonio Heart Study, the link between metabolic
 and cardiovascular disorders has been increasingly recognized, as well as the features these
 disorders have in common: insulin resistance and vascular endothelial dysfunction. Therefore,
 we are interested in the mechanisms underlying the impairment of endothelial function in
 insulin-resistant states. In particular, we have recently found that insulin stimulates the
 vascular activity of both ET-1 and NO in the normal human vasculature. It is therefore
 reasonable to speculate that the occurrence of insulin resistance and/or endothelial
 dysfunction may lead to an imbalance in this mechanism with a resulting increased vascular
 activity of ET-1.

 A new class of insulin sensitizing agents, the thiazolidinediones, have been shown to
 possess, in addition to their numerous metabolic roles, positive effects on blood pressure
 and on vascular endothelial function, including decreased endothelin-1 production and reduced
 circulating levels of endothelial surface molecules. Based on these data, we plan to
 investigate the hypothesis that thiazolidinediones may improve both insulin resistance and
 endothelial dysfunction in essential hypertension and hypercholesterolemia. We hypothesize
 that treatment with rosiglitazone improves endothelium-dependent vascular relaxation in both
 conductance and resistance vessels, decreases vascular endothelin-1 activity and reduces
 plasma levels of leptin and of markers of endothelial activation.
Patients must discontinue all hypertensive therapy two weeks prior to entering this study.

 Patient with a serum cholesterol value of 240 mg/dl or greater.

 Patients must discontinue all lipid-lowering agents 1 month prior to entering this study.

 No patients with evidence of active liver disease (e.g. ALT greater than 1.5 times the
 upper limit of normal).

 No history of diabetes, peripheral vascular disease, coagulopathy, or any other disease
 predisposing to vasculitis or Raynaud's phenomenon.

 No women with childbearing potential unless they use an effective contraceptive method.