Joseph G. Collier

The effect of endothelium-derived nitric oxide on ex vivo whole blood platelet aggregation in man

SummaryThe effects of changes in endogenous endothelium-derived nitric oxide (NO) on forearm blood flow and ex vivo platelet aggregation have been studied in 7 healthy volunteers.Measurements were made of forearm blood flow and ex vivo collagen-stimulated platelet aggregation during unilateral brachial artery infusions of saline, acetylcholine (ACh), NG monomethyl-L-arginine (L-NMMA), and prostacyclin (PGI2). The uninfused arm acted as a control.Forearm blood flow was increased by ACh, an agent which stimulates NO release, and decreased by L-NMMA, an agent which stereospecifically inhibits NO synthesis.Collagen-stimulated platelet aggregation measured ex vivo in whole blood draining the infused arm was unaltered by either ACh or L-NMMA. Conversely, PGI2, an agent which acts independently of NO, caused an increase in forearm blood flow which was accompanied by significant inhibition of platelet aggregation.The results suggest that release of endothelium-derived NO in quantities sufficient to cause substantial changes in blood vessel tone does not lead to changes in platelet aggregation in the blood flowing through the vessels. It is, however, still possible that endothelium-derived NO modulates platelet activity at the level of the endothelium.

Sympathetically mediated vasoconstriction is augmented by angiotensin II in man

In order to determine whether angiotensin II may influence sympathetically mediated arteriolar constriction in man, we have examined the effect of angiotensin II, infused directly into the left brachial artery of normal subjects, on the reduction in forearm blood flow produced by a lower-body negative pressure (LBNP) of 15 mmHg. Angiotensin II (320 fmol/min) caused no reduction in blood flow when given alone but significantly augmented the reduction in blood flow in response to LBNP. The same dose of angiotensin II did not affect a similar reduction in forearm blood flow produced by infused noradrenaline (12.5–50 ng/min). We conclude that angiotensin II augments sympathetically mediated constriction of resistance vessels in man at concentrations with no direct effect on vessel tone. The lack of an effect of angiotensin II on constriction in response to infused noradrenaline suggests the involvement of a presynaptic mechanism.

Influence of ramipril diacid on the peripheral vascular effects of angiotensin I

Studies were performed to examine the effect on forearm blood flow of local brachial artery infusions of angiotensin I, angiotensin II and of the converting enzyme inhibitor ramipril diacid (the active metabolite of ramipril). Acute infusions of both angiotensins produced dose-dependent decreases in blood flow (measured by venous occlusion plethysmography). To produce equivalent effects the dose of angiotensin I was 2 to 4 times that of angiotensin II. After ramipril diacid the response to angiotensin II was unchanged, while the dose of angiotensin I required to produce an equipotent response was increased 20-fold. Ramipril diacid given alone produced a small, nonsignificant increase in forearm flow, although the response was significantly related to basal plasma renin. The study confirms the presence of converting enzyme activity within human resistance vessels, and suggests that inhibition of converting enzyme, at sites other than the pulmonary vascular bed, might contribute to the hypotensive action of converting enzyme inhibitors.

Vascular angiotensin conversion in humans.

Studies were performed in normotensive volunteers and hypertensive subjects to examine the effect on forearm blood flow (FBF) of brachial artery infusions of angiotensin I (ANG I), angiotensin II (ANG II), and ramiprilat [the active metabolite of the angiotensin converting enzyme (ACE) inhibitor, ramipril]. Ramiprilat (10 mcg/min for 10 min) produced a 71% mean increase in FBF (n = 8; range, 26-130%; p less than 0.001) in vessels preconstricted with ANG I (64-128 pmol/min), with the effect maximal at the end of ramiprilat infusion and subsiding over 30 min. Doses of ANG I required to produce equivalent reductions of FBF were 2 to 4 times those of ANG II before ramiprilat, but after ramiprilat the dose of ANG I required to produce equivalent constriction was increased 20-fold (n = 6; p = 0.01) while that of ANG II was unaltered. Ramiprilat given alone produced only a small nonsignificant increase in FBF of 7 +/- 4% (n = 12; p = 0.29), though this increase did correlate significantly with plasma renin (r = 0.60; p = 0.04). These results confirm the presence of ACE within human resistance vessels and suggest the possibility that inhibition of ACE at sites other than the pulmonary bed might contribute to the hypotensive action of ACE inhibitors.