Search PubMed⌕ Search

Biomedical subjects

R W Harper

Publications and source records attributed to R W Harper.

At least 37 records · Page 2Linked to original sources
PubMed1999

Contribution of vasodilator prostanoids and nitric oxide to resting flow, metabolic vasodilation, and flow-mediated dilation in human coronary circulation.

BACKGROUND: Endothelial dysfunction is associated with atherosclerosis and may contribute to ischemic syndromes. We assessed the contribution of endothelium-derived nitric oxide (NO) and vasodilator prostanoids to resting blood flow, metabolic vasodilation, and flow reserve in the human coronary circulation. METHODS AND RESULTS: Coronary hemodynamics were assessed before and after inhibition of vasodilator prostanoids and NO with intracoronary aspirin (acetylsalicylic acid [ASA]) and N(G)-monomethyl-L-arginine (L-NMMA), respectively. Angiographically smooth or mildly irregular vessels, with normal adenosine-induced coronary flow reserve, were studied in 25 patients undergoing clinically indicated procedures. Coronary blood velocity was measured by Doppler flow wire, and coronary blood flow (CBF) was calculated. ASA reduced resting conduit vessel diameter by 11% (P = 0.003) and CBF by 27% (P = 0.008) and increased coronary vascular resistance (CVR) by 24% (P<0.0001). ASA attenuated pacing-induced hyperemia by 28% (45.0+/-4.6 versus 32.6+/-3.4 mL/min, P = 0.005) and increased minimum CVR by 39% (2.8+/-0.3 versus 3.9+/-0.5 mm Hg x mL(-1) x min(-1), P = 0.007). L-NMMA reduced resting conduit vessel diameter by 9% (P = 0.05) and CBF by 20% (P = 0.08) and increased CVR by 19% (P = 0.03). L-NMMA attenuated pacing-induced hyperemia by 20% (42.4+/-5.1 versus 34.1+/-3.4 mL/min, P = 0.04) and increased minimum CVR by 33% (2.9+/-0.4 versus 3.8+/-0.5 mm Hg x mL(-1) x min(-1), P = 0.02). ASA (7.7+/-2.3% versus -1.6+/-3.2%, P = 0.06) and L-NMMA (12.1+/-3.9% versus 0.0+/-2.9%, P = 0.02) abolished pacing-induced conduit vessel flow-mediated dilation. Conclusions-Tonic release of vasodilator prostanoids and NO contributes to resting conduit and resistance vessel tone and to peak functional hyperemia and flow-mediated dilation after metabolic stimulation. This underscores the importance of normal endothelial function for metabolic vasodilation and suggests that it may be a key mechanism for preventing myocardial ischemia in coronary artery disease.

Adenosine↗
PubMed1999

Inverse relation of haematocrit to cardiac index in mitral stenosis and atrial fibrillation.

We investigated the relationship between atrial fibrillation and the red cell parameters haematocrit, red cell concentration and mean corpuscular volume in 95 female patients with mitral stenosis (mean age 51+/-11 years, 38 patients in atrial fibrillation, 57 patients in sinus rhythm) who had undergone full blood examination and right and left heart catheterisation. Haematocrit was a positive correlate of atrial fibrillation (r=0.29, p<0.009) and a negative correlate of cardiac index (r=-0.37, p<0.003), but cardiac index was the only independent correlate of haematocrit on multivariate analysis (r2=0.14). The mean corpuscular volume was a positive correlate of age (r=0.42, p<0.0001) and atrial fibrillation (r=0.29, p<0.005) and a negative correlate of cardiac index (r=-0.22, p<0.04) and red cell concentration (r=-0.56, p<0.0001). On multivariate analysis, however, only age and red cell concentration were independent correlates of mean corpuscular volume (r2=0.43). Cardiac index was inversely correlated with both haematocrit and red cell concentration in the subgroup of patients with atrial fibrillation but not those with sinus rhythm. This study demonstrates that the major determinant of the higher haematocrit in mitral stenosis patients with atrial fibrillation is an associated reduction in cardiac index.

Adult↗
PubMed1999

Metabolic vasodilation in the human forearm is preserved in hypercholesterolemia despite impairment of endothelium-dependent and independent vasodilation.

OBJECTIVE: Hypercholesterolemia has been shown to impair endothelium-mediated, nitric oxide (NO)-dependent responses to acetylcholine (ACh), serotonin, substance P and flow-mediated dilation. We have recently shown that NO contributes to metabolic vasodilation in the human forearm. We sought to determine whether metabolic vasodilation is impaired in healthy subjects with hypercholesterolemia. METHODS: We compared the forearm blood flow (FBF) responses to isotonic exercise, ACh and the endothelium-independent vasodilator sodium nitroprusside in young, otherwise healthy volunteers with hypercholesterolemia and controls before and after the NO inhibitor NG-monomethyl-L-arginine (L-NMMA). FBF was measured using venous occlusion plethysmography. Hypercholesterolemic (n = 20) and control (n = 20) subjects were age- and gender-matched. RESULTS: Total cholesterol (6.9 +/- 0.3 vs. 4.6 +/- 0.1 mmol/l, P < 0.0001), low density lipoprotein (4.9 +/- 0.4 vs. 2.7 +/- 0.1 mmol/l, P < 0.001) and triglyceride (1.3 +/- 0.2 vs. 0.8 +/- 0.1 mmol/l, P = 0.005) levels were higher in the hypercholesterolemic group. Basal FBF and resistance were similar in the two groups. Hypercholesterolemia impaired the peak FBF response to ACh (11.1 +/- 1.9 vs. 17.6 +/- 2.2 ml/100 ml/min, P = 0.03), and reduced the peak response to sodium nitroprusside (6.0 +/- 0.4 vs. 8.1 +/- 0.6 ml/100 ml/min, P < 0.01). However, hypercholesterolemia did not affect peak hyperemic FBF (13.1 +/- 1.0 vs. 13.2 +/- 1.0 ml/100 ml/min, P = 1.0) or the FBF volume repayment during the 1 or 5 min after exercise. Resting FBF was reduced by L-NMMA to a similar degree (by 33% vs. 40%, P = 0.17) in both groups. Although L-NMMA reduced peak hyperemic FBF (by 16% vs. 17%, P = 0.93) and the volume repaid after exercise in both groups, there were no differences between the two groups. CONCLUSIONS: Exercise-induced metabolic vasodilation is in part dependent on NO release. Hypercholesterolemia impairs NO-mediated vasodilation, but is not associated with a reduction in exercise-induced hyperemia. This may indicate that multiple compensatory mechanisms are operative in skeletal muscle metabolic vasodilation.

Acetylcholine↗
PubMed1999

Dibasic benzo[b]thiophene derivatives as a novel class of active site directed thrombin inhibitors: 2. Sidechain optimization and demonstration of in vivo efficacy.

Potent, subnanomolar thrombin inhibitors 4, 5, and 6 are developed through side chain optimization of novel, benzo[b]thiophene-based small organic entities 2 and 3 and through SAR additivity studies of the new structural elements identified. X-ray crystallographic studies of 4b-thrombin complex revealed a hydrophobic and an electrostatic interaction of these new elements with thrombin at the S2 and S3 binding sites. In vitro and in vivo pharmacological studies showed that 4, 5, and 6 are potent anticoagulants in human plasma with demonstrated antithrombotic efficacy in a rat model of thrombosis.

Animals↗
PubMed1999

Synthesis and in vitro biological activity of 4alpha-(2-propenyl)-5alpha-cholest-24-en-3alpha-ol: a 24,25-dehydro analog of the hypocholesterolemic agent 4alpha-(2-propenyl)-5alpha-cholestan-3alpha-ol.

4Alpha-(2-propenyl)-5alpha-cholestan-3alpha-ol (LY295427) was previously identified from a Chinese hamster ovary (CHO) cell-based low density lipoprotein receptor/luciferase (LDLR/Luc) assay to be a potent transcriptional activator of the LDL receptor promoter in the presence of 25-hydroxycholesterol. To investigate the effect of the 24,25-unsaturation in the D-ring side chain (desmosterol D-ring side chain) on antagonizing the repressing effect of 25-hydroxycholesterol, 4alpha-(2-propenyl)-5alpha-cholest-24-en-3alpha-ol (17), a 24,25-dehydro analog of LY295427, was thus synthesized from lithocholic acid via the formation of 3alpha-[[(1,1-dimethylethyl)dimethylsilyl]oxy]-4alpha- (2-propenyl)-5alpha-cholan-24-al (15). Test results showed that 17 had an EC30 value of 2.6 microM, comparable to 2.9 microM of LY295427, in the CHO cell-based LDLR/Luc assay in the presence of 25-hydroxycholesterol. Apparently, the built-in 24,25-unsaturation in the D-ring side chain of 17 had added little effect to antagonizing the repressing effect of 25-hydroxycholesterol. In the [1-14C-acetate]cholesterol biosynthesis inhibition assay, 17 at 10 microg/ml (23 microM) has been shown to inhibit the cholesterol biosynthesis in CHO cells by 38% relative to the vehicle control; whereas LY295427 showed no inhibition in the same assay in our previous studies. In contrast to LY295427, the built-in 24,25-unsaturation in the D-ring side chain of 17 has conferred an inhibitory effect on cholesterol biosynthesis in CHO cells. In summary, the observed LDL receptor promoter activity of 17 is related to its ability to prevent 25-hydroxycholesterol from exerting the repressing effect via an undetermined mechanism and, in part, to inhibit the cholesterol biosynthesis.

Animals↗
PubMed1999

Chiari network entanglement and herniation into the left atrium by an atrial septal defect occluder device.

The Chiari network is a fenestrated membrane consisting of threads and strands in the right atrium. First described in 1897 by anatomist Hans Chiari, it is a congenital remnant of embryonic development resulting from incomplete resorption of the right valve of the sinus venosus. Found in 2% to 3% of the population, it is generally not of clinical importance. Rarely, however, the network may be associated with serious complications such as thrombus formation, embolus entrapment, arrhythmia, tumor development, and catheter entrapment. We report the entanglement of an Amplatzer septal occluder device catheter in a prominent Chiari network that was herniated into the left atrium. Transesophageal echocardiographic recognition of this before deployment and guidance during disentanglement is described below.

Aged↗
PubMed1999

Relative contribution of vasodilator prostanoids and NO to metabolic vasodilation in the human forearm.

Although many factors are thought to contribute to the regulation of metabolic vasodilation in skeletal muscle vasculature, recent interest has focused on the role of the endothelium. We examined the relative roles of nitric oxide (NO) and of vasodilator prostanoids in the control of metabolically induced functional hyperemia in the forearm of humans. In 43 healthy volunteers [24 +/- 5 (SD) yr] we assessed resting and functional hyperemic blood flow (FHBF) in response to 2 min of isotonic forearm exercise before and after inhibition of NO and/or vasodilator prostanoid production with intra-arterial NG-monomethyl-L-arginine (L-NMMA, 2 mg/min) and aspirin (ASA, 3 mg/min), respectively. Blood flow was measured using venous occlusion plethysmography. L-NMMA and ASA decreased resting forearm blood flow by 42% (P < 0.0001) and 23% (P < 0.0001), respectively, whereas infusion of ASA followed by L-NMMA reduced flow by a further 24% (P < 0.05). L-NMMA reduced peak FHBF by 18% [from 13.9 +/- 1.0 to 11.4 +/- 1.1 (SE) ml. 100 ml forearm-1. min-1, P = 0.003] and the volume "repaid" after 1 and 5 min by 25% (8.9 +/- 0.7 vs. 6.7 +/- 0.7 ml/100 ml, P < 0.0001) and 37% (26.6 +/- 1.8 vs. 16.8 +/- 1.6 ml/100 ml, P < 0.0001). ASA similarly reduced peak FHBF by 19% (from 14.5 +/- 1.1 to 11.8 +/- 0.9. 100 ml forearm-1. min-1, P < 0.001) and the volume repaid after 1 and 5 min by 14% (7.5 +/- 0. 6 vs. 6.4 +/- 0.6 ml/100 ml, P = 0.0001) and 20% (21.2 +/- 1.5 vs. 16.9 +/- 1.5 ml/100 ml, P < 0.0001), respectively. The coinfusion of ASA and L-NMMA did not decrease FHBF to a greater extent than either agent alone. These data suggest that endothelium-derived NO and vasodilator prostanoids contribute to resting blood flow and metabolic vasodilation in skeletal muscle vasculature in healthy humans. Although these vasodilator mechanisms operate in parallel in exercise-induced hyperemia, they appear not to be additive. Other mechanisms must also be operative in metabolic vasodilation.

Adult↗
PubMed1999

Estrogen improves acetylcholine-induced but not metabolic vasodilation in biological males.

We have previously shown that chronic estrogen therapy improves endothelium-dependent vasodilation in the resistance vessels of biological males. Whether this is nitric oxide (NO) mediated and whether estrogen improves metabolic vasodilation is unknown. Resting forearm blood flow (FBF), ACh-induced vasodilation, and functional hyperemic blood flow (exercise) were assessed before and after the inhibition of NO with N(G)-monomethyl-L-arginine (L-NMMA) in 15 male-to-female transsexuals prescribed estrogen and in 14 age-matched males. Resting FBF was similar in the two groups and was similarly (P = 0.44) but significantly reduced by 48% after infusion of L-NMMA (P < 0.0001). The ACh dose-response relationship was shifted upward and to the left in the transsexual compared with the male group (P < 0.01). After the inhibition of NO, however, the difference in the ACh dose-response curve between the two groups was abolished (P = 0.15). Peak functional hyperemic blood flow was similar for the two groups (P = 0.94). L-NMMA produced a significant (P < 0.01) but similar (P = 0.64) reduction in peak hyperemia in the two groups. The volume of blood repaid to the forearm 1 and 5 min after exercise was also reduced by L-NMMA (P < 0.0001); however, there were no differences between the two groups. This suggests that ACh-mediated NO-dependent vasodilation may be more sensitive to the effects of chronic estrogen than exercise-induced vasodilation. Long-term estrogen does not appear to improve exercise-induced metabolic vasodilation in biological males, despite the fact that NO contributes to this process.

Acetylcholine↗
PubMed1999

Recurrent pulmonary embolism associated with Klippel-Trenaunay-Weber syndrome.

Klippel-Trenaunay-Weber syndrome (KTWS) is a rare, congenital disorder characterized by the triad of varicose veins, cutaneous hemangiomas, and hypertrophy of soft tissue and bone. We present the case of a woman with KTWS, cor pulmonale, and death due to recurrent pulmonary embolism (PE). The risk of deep venous thrombosis and PE in patients with KTWS is evaluated, and treatment recommendations are made with emphasis on the role of early, aggressive management in the subset of patients with KTWS known to have thromboembolic disease.

Female↗
PubMed1999

Acute administration of 17beta-oestradiol does not improve endothelium-dependent vasodilatation in young men.

Studies have recently demonstrated that long-term oestrogen therapy improves endothelium-dependent and endothelium-independent vasodilatation in the conductance vessels of biological males. We sought to determine if an acute single dose of oestrogen might similarly improve vasodilator function in young males. In a randomized, double-blind, placebo-controlled, crossover study, we compared the effects of 1 mg of sublingual 17beta-oestradiol (E(2)) and placebo on endothelium-dependent and endothelium-independent vasodilatation in the brachial artery using a non-invasive ultrasound technique. We recruited 30 young males based on a power calculation. Neither acute sublingual oestrogen nor placebo affected flow-mediated vasodilatation [5.32+/-0.78% and 5.28+/-0.60% respectively (mean+/-S.E.M.), P=0.94]. Responses to nitroglycerine were similar after oestrogen or placebo (16.01+/-0.86% and 15.29+/-1. 19%, P=0.47). Basal blood flow and flow during reactive hyperaemia did not differ after oestrogen or placebo. Heart rate and blood pressure were similar during both treatment phases of the study. The absolute change in serum oestradiol levels was greater after the oestrogen treatment phase than after placebo (1509+/-87 versus -13+/-4 pmol/l, P<0.0001). Despite achieving supra-physiological oestradiol levels, the acute administration of sublingual E(2) does not appear to improve endothelium-dependent or endothelium-independent vasodilatation, at least acutely, in the brachial artery of young males. In keeping with our previous study, these data suggest that a period of oestrogen 'priming' (possibly to induce receptor-mediated nitric oxide synthesis) may be required to yield an improvement in vascular function in males.

Adult↗
PubMed1998

Towards an improved and more cost effective health system for Australia.

A new health system is proposed, based on the best aspects of the current system but with built-in incentives for containing costs. Universal cover is retained and access to the hospital system is improved. The division of health responsibilities between Federal and State governments is greatly simplified and the proposed system could be readily implemented.

Australia↗
PubMed1998

Bifuration coronary angioplasty using a new side branch accessible stent.

Two cases of successful angioplasty of bifurcational left anterior descending and diagonal lesions treated with a new side branch accessible Jomed stent in the LAD are discussed. A balloon dilatation of the side branch using kissing balloon technique in the first case and stenting the side branch followed by kissing balloon dilatation in the second case are described.

Angioplasty, Balloon, Coronary↗
PubMed1998

Continuous release of vasodilator prostanoids contributes to regulation of resting forearm blood flow in humans.

Continuous release of nitric oxide contributes to the maintenance of resting tone in the human forearm and coronary circulations; however, evidence for a similar role of vasodilator prostanoids such as prostacyclin is lacking. We examined whether continuous release of prostacyclin contributes to basal forearm blood flow. Flow was measured using venous occlusion plethysmography in 38 healthy volunteers [mean age 21.3 +/- 2.5 yr (+/- SD); 13 female, 25 male] at rest, after administration of three incremental intra-arterial infusions of either the cyclooxygenase inhibitor aspirin or placebo, and before and after administration of the endothelium-dependent and -independent dilators acetylcholine (30 micrograms/min) and nitroprusside (1 microgram/min). To assess the effect of aspirin on the production of prostacyclin, plasma 6-keto prostaglandin F1 alpha (6-keto-PGF1 alpha; the stable metabolite of prostacyclin) was measured by simultaneous arterial and venous sampling. Aspirin produced a time- and dose-dependent reduction in forearm blood flow, resulting in a 32% decrease at the highest dose. The effect was maximal after 10 min. Flow at rest and after aspirin doses of 1, 3, and 10 mg/min was 2.6 +/- 0.2, 2.3 +/- 0.2, 2.1 +/- 0.2, and 1.8 +/- 0.2 ml.100 ml forearm tissue-1.min-1, respectively (means +/- SE, P < 0.001). Commensurate with these data, the net forearm production of 6-keto-PGF1 alpha was 52.9 +/- 16.4, 11.7 +/- 8.6, 18.7 +/- 8.5, and 12.0 +/- 12.5 pg.100 ml forearm tissue-1.min-1 for the respective doses (P = 0.04). No time-dependent reduction in flow was seen in subjects with vehicle infusion. Aspirin did not affect the responses to acetylcholine or nitroprusside. These data suggest that continuous release of prostacyclin plays a role in the maintenance of resting forearm blood flow. There appears to be a direct link between the reduction in flow with aspirin and inhibition of prostacyclin production.

6-Ketoprostaglandin F1 alpha↗