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Aims: GR117289C is a non peptide, selective angiotensin (AT1) receptor antagonist. The purpose of this study was to determine whether this agent, given orally, could attenuate the vasoconstrictor effects of angiotensin II(AII) infused locally into the forearm circulation in man., Methods: Eight healthy male subjects were studied on four occasions in a randomized, double-blind, placebo controlled, crossover study. Five hours (approximate time of peak dynamic effect) following dosing with GR117289C (300 mg, 100 mg, 10 mg or placebo), A II was infused in incremental doses (0, 0.1, 0.4, 1.6, 6.2, 25 and 100 pmol min-1) into the left brachial artery, each for 10 min. Forearm blood flow was measured using venous occlusion plethysmography., Results: GR117289C inhibits the vasoconstrictor effects of A II in a dose dependent manner. The active treatment: placebo ratios of forearm blood flow in the infused arm during the highest dose of AII (100 pmol min-1) were: GR117289C 10 mg, 1.12 (95% C.I. 0.81-1.55; P = 0.478), 100 mg, 1.43 (95% C.I. 1.01-2.01; P = 0.042) and 300 mg, 1.62 (95% C.I. 1.17-2.24; P = 0.006). There was no significant difference in blood pressure between each of the treatment groups and placebo., Conclusions: GR117289C is a pharmacologically active, oral A II antagonist in healthy men.

Broad spectrum antibiotics are known to predispose towards oral candidiasis and gastroenteritis. Oral nitrite synthesis by commensal bacteria may be important in protecting the mouth and lower intestine from pathogenic organisms, including Candida albicans. The effect of 2 days administration of the broad spectrum antibiotic amoxycillin on salivary nitrite concentration, following a 200 mg potassium nitrate oral load, was studied in 10 healthy volunteers. The Cmax fell by 40% and the AUC was reduced by 1227 microM h (43%, 95% CI 273, 2181, P < 0.006) in the antibiotic treated group when compared with control. These findings suggest that destruction of nitrate reductase containing bacteria in the mouth by antibiotics may explain an increased incidence of infection with Candida and other pathogens.

Suppression of endogenous levels of angiotensin II by angiotensin converting enzyme inhibition, may result in up-regulation of vascular AT1 receptors. We have evaluated the effects of orally administered enalapril on angiotensin II induced vasoconstriction in the human forearm. Subjects received in random order, enalapril (20 mg) or matched placebo daily for 2 weeks. Forearm blood flow response to increasing doses of angiotensin II was measured using venous occlusion plethysmography at the beginning of the study and at the end of each 2 week treatment period. Treatment with enalapril significantly reduced plasma angiotensin II levels and supine blood pressure compared with placebo. The percentage reductions in forearm blood flow in the infused arm, in response to the maximum dose of angiotensin II (50,000 fmol min-1) were 48.1 +/- 3.6% at baseline, 57.5 +/- 3.6% on placebo and 54.5 +/- 4.2% on enalapril. The differences were not significantly different. This demonstrates that suppression of plasma angiotensin II for a 14 day period does not enhance the response to exogenous intra-arterial angiotensin II in the human forearm of healthy salt replete subjects.

1. Nitrate tolerance is a clinical problem. The cause is not known but it has been suggested that tolerance to organic nitrates occurs within the blood vessels to reduce sensitivity to the drug. We have determined the sensitivity of human forearm resistance vessels and veins to glyceryl trinitrate (GTN) at the beginning and end of a 7 day period of GTN administration in healthy volunteers using a clinically relevant dose of transdermal drug. 2. Eight healthy volunteers completed the study which entailed measurement of change in forearm venous compliance and change in forearm blood flow following intraarterial infusions of two doses of glyceryl trinitrate (0.5 and 2.0 micrograms min-1) before, after 2 h and after 7 days of transdermal GTN administration using one 10 mg patch each 24 h. 3. Changes in venous compliance and blood flow were measured by venous occlusion plethysmography using a basal infusion of noradrenaline (1 microgram min-1) to increase venous tone. 4. Noradrenaline produced the expected decrease in forearm blood flow and venous compliance. The effect of locally infused GTN on venous compliance and forearm blood flow was similar on the three study days. In particular there was no significant difference in the response to GTN following 7 days transdermal administration compared with that after 2 h. 5. We conclude from this study that local vascular tolerance to GTN is unlikely to explain the clinical problem of nitrate tolerance, and that other mechanisms such as neurohumoral activation may be important.

Ouabain inhibits endothelium-dependent vascular relaxation in vitro, but has not been studied in this regard in vivo. We have therefore measured blood flow responses to carbachol, bradykinin and sodium nitroprusside (endothelium-dependent and endothelium-independent vasodilators) infused into the brachial artery with and without co-infusion of ouabain (2 micrograms min-1). Six healthy male volunteers were each studied on two occasions. Ouabain reduced basal forearm blood flow, by 18.0 +/- 4.1% (mean +/- s.e. mean, 2P less than 0.05), but had no significant effect on responses to any of the three vasodilators. These results indicate that effects of ouabain on endothelium-dependent relaxation in vitro must be interpreted with caution.

Resistance vessel sensitivity to angiotensin II in vivo was studied in 13 primigravid normotensive women (16-24 weeks gestation), and in 10 non-pregnant control women. Angiotensin II was infused into the brachial artery at doses of 10, 100, 1,000 and 10,000 fmol min-1 and forearm blood flow measured by plethysmography. Reduction in forearm blood flow at all concentrations of angiotensin II was significantly greater in non-pregnant than in pregnant women. The dose-response relationships, plotted semi-logarithmically, were similar in shape in each group but sensitivity to angiotensin II was reduced in pregnant subjects compared with non-pregnant women. This is most simply explained by an effect of pregnancy on the sensitivity to angiotensin II of vascular smooth muscle in forearm resistance vessels.

The effect of pravastatin on low density lipoprotein (LDL) cholesterol and platelet activation was studied in 16 patients with mild hypercholesterolaemia who had two or more additional cardiovascular risk factors. Patients were treated with either pravastatin (20-40 mg day-1) or placebo for 1 year. Plasma LDL and urinary excretion of 2,3-dinor-thromboxane B2 (an index of platelet activation in vivo) were determined at 0, 3, 6 and 12 months. There was a significant reduction in LDL at 6 and 12 months (2P less than 0.05) but this was not associated with any significant change in thromboxane metabolite excretion.

It has been proposed that angiotensin converting enzyme (ACE) may play a part in the metabolism of substance P. Reduced metabolism following treatment with ACE inhibitors may cause accumulation of substance P to produce the adverse effect of cough. It has been shown in this study that, in contrast to angiotensin I and bradykinin, inhibition of local vascular ACE does not interfere with the vascular effects of substance P on forearm resistance vessels when this peptide is infused into the brachial artery of normal volunteers. These results suggest that endothelial ACE plays little part in the metabolism of intravascular substance P.

1. GR32191B is a potent and selective thromboxane receptor antagonist. Glyceryl trinitrate (GTN) also inhibits platelet function in vitro. Both have been reported to prolong bleeding time. Since they may be used together in patients with coronary artery disease, we have investigated the possibility of an interaction between them. 2. Twenty-four healthy male volunteers were treated with GR32191B using a double-blind placebo-controlled crossover design. Bleeding times were determined before and after GR32191B or placebo and during co-administration of GTN. Plasma GR32191B concentration was measured. Platelet aggregation in response to adenosine diphosphate and to a thromboxane mimetic, U46619, was measured ex vivo. Urinary excretion of thromboxane (TX)B2 and 2,3-dinor-TXB2 was determined in 24 h urine samples. 3. Twelve hours after GR32191B (80 mg; p.o.), the plasma concentration was 36.6 +/- 2.7 nM (mean +/- s.e. mean) and bleeding time was increased by 66%. Ninety minutes after a second dose (40 mg; p.o.) the plasma concentration was 431.9 +/- 23.6 nM but bleeding time was not further prolonged. 4. Responses of platelets to U46619 were selectively antagonised following GR32191B. Urinary excretion rates of TXB2 and 2,3-dinor TXB2 were similar after treatment with GR32191B or placebo. 5. GTN (1 mg sub-lingually) had no significant effect on bleeding time 90-100 min following either placebo or GR32191B. 6. We conclude that GR32191B, in a dose that causes profound yet specific blockade of thromboxane receptors, causes only a modest prolongation of bleeding time that is unaffected by a therapeutic dose of GTN. This may prove advantageous when GR32191B is used in patients with ischaemic heart disease.

1. The effect on skin and muscle blood flow of arterial infusion of atrial natriuretic peptide (ANP) directly into the forearm circulation, and on venous tone of direct infusion into a dorsal hand vein, was studied in normal subjects. 2. ANP produced a dose-dependent increase in both skin and muscle blood flow, but at equivalent doses, produced no dilatation of noradrenaline-preconstricted dorsal hand veins. These findings indicate that ANP acting locally, is an arterioselective dilator in the upper limb circulation in normal man. 3. Measurements of ANP in venous plasma during arterial infusion suggest marked clearance of ANP across the forearm vascular bed. Such peripheral clearance may, at least in part, account for the short plasma half-life of this peptide. 4. The lowest dose of ANP infused was calculated to produce plasma levels similar to those found in patients with heart failure. The findings with this dose suggest that, in heart failure, circulating levels of ANP may be within a range capable of influencing peripheral vascular resistance directly.

1. The effect of the K+ channel opening drug cromakalim on forearm blood flow during direct infusion into the brachial artery, and on the size of noradrenaline preconstricted hand veins during infusion directly into the vein, was studied in eight healthy volunteers. 2. Cromakalim (0.01-10.0 micrograms min-1) produced a dose-dependent increase in blood flow in the infused forearm, from 5.4 +/- 2.5 to 15.1 +/- 7.3 ml 100 ml-1 forearm min-1 at 10 micrograms min-1 (P less than 0.001). The half-time of offset of its action was 30 min. There was no change in blood flow in the non-infused forearm. 3. There was no increase in the size of noradrenaline pre-constricted dorsal veins during local infusion of cromakalim (0.001-1.0 microgram min-1). Glyceryl trinitrate (0.4 microgram min-1) however, completely reversed the constriction to noradrenaline (P less than 0.001). 4. The clear arterioselectivity of cromakalim, as with other members of this new class of drug, accords with the dependency of venoconstriction on receptor-operated, rather than potential-operated mechanisms which are of importance in resistance vessels. With this haemodynamic profile cromakalim may prove of value in the treatment of arterial hypertension.