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Biomedical subjects

Mias Pretorius

Publications and source records attributed to Mias Pretorius.

11 recordsLinked to original sources
PubMed2006

Bradykinin and its metabolite bradykinin 1-5 inhibit thrombin-induced platelet aggregation in humans.

Bradykinin 1-5 is a major stable metabolite of bradykinin, formed by the proteolytic action of angiotensin-converting enzyme. In vitro and animal studies suggest that bradykinin 1-5 possesses biological activity. This study tests the hypothesis that bradykinin 1-5 affects vasodilation, fibrinolysis, or platelet aggregation in humans. Graded doses of bradykinin (47-377 pmol/min) and bradykinin 1-5 (47-18,850 pmol/min) were infused in the brachial artery in random order in 36 healthy subjects. Forearm blood flow (FBF) was measured, and simultaneously obtained venous and arterial plasma samples were analyzed for tissue plasminogen activator (t-PA) antigen. In seven subjects each, alpha- and gamma-thrombin-induced platelet aggregation was measured in platelet-rich plasma obtained from antecubital venous blood at baseline and during peptide infusions. Bradykinin caused dose-dependent increases in FBF and net t-PA release (P < 0.001 for both). Bradykinin 1-5 did not affect FBF (P = 0.13) or net t-PA release (P = 0.46) at concentrations >1500 times physiologic. In contrast, both bradykinin and bradykinin 1-5 inhibited alpha-and gamma-thrombin-induced platelet aggregation (P < 0.01 versus baseline). Bradykinin 1-5 inhibited gamma-thrombin-induced platelet aggregation 50% at a calculated dose of 183 +/- 3 pmol/min. Neither bradykinin nor bradykinin 1-5 affected thrombin receptor-activating peptide-induced platelet aggregation, consistent with the hypothesis that bradykinin and bradykinin 1-5 inhibit thrombin-induced platelet aggregation by preventing cleavage of the thrombin receptor and liberation of thrombin receptor-activating peptide. This study is the first to demonstrate biological activity of bradykinin 1-5 following in vivo administration to humans. By inhibiting thrombin-induced platelet aggregation without causing vasodilation, bradykinin 1-5 may provide a model for small molecule substrate-selective thrombin inhibitors.

Adult↗
PubMed2005

Angiotensin-converting enzyme inhibition increases basal vascular tissue plasminogen activator release in women but not in men.

OBJECTIVE: Angiotensin-converting enzyme inhibition (ACEI) increases vascular tissue plasminogen activator (t-PA) release through endogenous bradykinin (BK). We tested the hypothesis that gender influences the effect of ACEI on t-PA release. METHODS AND RESULTS: We measured the effect of intra-arterial enalaprilat (0.33 microg/min per 100 mL forearm volume) on forearm blood flow (FBF) and net t-PA release before and during BK (25 to 400 ng/min) and methacholine (3.2 to 12.8 microg/min) in premenopausal women, postmenopausal women not using hormone replacement, young men, and older men. Baseline net t-PA release was similar among groups. Enalaprilat increased basal t-PA release in premenopausal (from 0.9+/-1.0 to 5.1+/-1.7 ng/min per 100 mL, P=0.023) and postmenopausal women (from -3.9+/-2.2 to 3.9+/-1.1 ng/min per 100 mL, P=0.010) but not in young or older men (P=0.028 men versus women). Enalaprilat potentiated the effect of exogenous BK on FBF similarly in all groups. However, during enalaprilat, BK-stimulated t-PA release was greatest in premenopausal women (339.9+/-86.4 ng/min per 100 mL at the 100 ng/min dose, P<0.05 versus any other group), intermediate in postmenopausal women (243.8+/-51.1 ng/min per 100 mL, P<0.05 versus either male group), and least in young (111.9+/-19.2 ng/min/100 mL) and older men (103.4+/-27.6 ng/min/100 mL). CONCLUSIONS: ACEI enhances basal t-PA release in women, independent of menopausal status, but not in men. During ACEI, both gender and menopausal status affect BK stimulated t-PA release.

Adult↗
PubMed2005

A pilot study indicating that bradykinin B2 receptor antagonism attenuates protamine-related hypotension after cardiopulmonary bypass.

BACKGROUND: The administration of protamine to patients who received heparin during cardiopulmonary bypass (CPB) induces hypotension. Protamine inhibits the carboxypeptidase N-mediated degradation of bradykinin, a peptide that causes vasodilation and tissue-type plasminogen activator (t-PA) release. This study tests the primary hypothesis that blocking the bradykinin B(2) receptor would attenuate protamine-related hypotension. METHODS: We conducted a prospective, double-blind, randomized study in 16 adult male patients undergoing elective cardiac surgery requiring CPB and taking an angiotensin-converting enzyme (ACE) inhibitor preoperatively, because ACE inhibition increases bradykinin concentrations during CPB. Subjects were randomized to receive either saline solution (N = 8) or the bradykinin B(2) receptor antagonist HOE 140 (100 mug/kg, N = 8) before the administration of protamine. Mean arterial pressure (MAP) and t-PA activity were measured intraoperatively and before and after protamine administration. RESULTS: Protamine administration caused a significant increase in bradykinin concentrations in the saline solution group (from 6.0 +/- 1.3 to 10.0 +/- 1.6 fmol/mL, P = .043), as well as the HOE 140 group (from 6.5 +/- 1.8 to 14.3 +/- 4.6 fmol/mL, P = .042). Protamine significantly decreased MAP in the saline solution group (from 69.8 +/- 4.4 mm Hg to a mean individual nadir of 56.1 +/- 2.6 mm Hg, P = .031), but bradykinin receptor antagonism blunted this effect (from 74.3 +/- 3.7 mm Hg to a mean individual nadir of 69.6 +/- 1.2 mm Hg in the HOE 140 group, P = .545). Hence, during protamine infusion, MAP was significantly lower in the saline solution group compared with the HOE 140 group (P = .002). t-PA activity decreased significantly during administration of HOE 140 (from 3.59 +/- 0.31 to 1.67 +/- 0.42 IU/mL, P = .001) but not during saline solution (from 2.12 +/- 0.48 to 1.44 +/- 0.36 IU/mL, P = .214). Similarly, t-PA activity decreased significantly during protamine administration in the HOE 140 group (from 1.67 +/- 0.42 to 0.77 +/- 0.26 IU/mL, P = .038) but not in the saline solution group (from 1.44 +/- 0.36 to 0.99 +/- 0.26 IU/mL, P = .132). CONCLUSION: Increased bradykinin contributes to protamine-related hypotension through its B(2) receptor in ACE inhibitor-treated patients.

Aged↗
PubMed2004

Relationship between carbamoyl-phosphate synthetase genotype and systemic vascular function.

Endothelial cells can convert l-citrulline to l-arginine, the precursor of nitric oxide. The present study tests the hypothesis that a C-to-A nucleotide transversion (T1405N) in the gene-encoding carbamoyl-phosphate synthetase 1, the enzyme catalyzing the rate-limiting step in l-citrulline formation, influences nitric oxide metabolite concentrations or nitric oxide-mediated vasodilation in humans. Bradykinin (100, 200, and 400 ng/min) was infused via brachial artery in 106 (CC:AC:AA=40:54:12) healthy subjects. Sodium nitroprusside (1.6, 3.2, and 6.4 microg/min) was also infused in 87 (CC:AC:AA=31:46:10) subjects. Forearm blood flow was measured by plethysmography and blood samples were collected for tissue-type plasminogen activator antigen, nitric oxide metabolites, and cyclic GMP. There was a significant relationship between carbamoyl-phosphate synthetase 1 genotype and nitric oxide metabolites, such that nitric oxide metabolite concentrations were highest in individuals homozygous for the C allele (mean+/-SD, 14.0+/-8.5 micromol/L), lowest in individuals homozygous for the A allele (9.1+/-3.1 micromol/L), and intermediate (11.8+/-6.6 micromol/L) in heterozygotes (P=0.036). There was a significant effect of carbamoyl-phosphate synthetase 1 genotype on forearm blood flow during bradykinin (P=0.028), such that the vasodilator response was greatest in C allele homozygotes (22.2+/-9.1 mL/min/100 mL at 400 ng/min), least in A allele homozygotes (13.6+/-6.2 mL/min/100 mL), and intermediate (19.4+/-10.7 mL/min/100 mL) in heterozygotes. Similarly, carbamoyl-phosphate synthetase 1 genotype influenced forearm blood flow during nitroprusside (maximal flow 19.2+/-8.3, 18.1+/-8.3, and 11.5+/-4.9 mL/min/100 mL in the CC:AC:AA groups, respectively; P=0.022). In contrast, there was no effect of carbamoyl-phosphate synthetase 1 genotype on the nitric oxide-independent tissue-type plasminogen activator response to bradykinin (P=0.943). These data indicate that a polymorphism in the gene encoding carbamoyl-phosphate synthetase 1 influences nitric oxide production as well as vascular smooth muscle reactivity.

Adult↗
PubMed2004

Angiotensin-converting enzyme inhibition and smoking potentiate the kinin response to cardiopulmonary bypass.

BACKGROUND: This study tested the hypothesis that angiotensin-converting enzyme (ACE) inhibitors potentiate activation of the kallikrein-kinin system during cardiopulmonary bypass (CPB). METHODS: The effects of CPB on concentrations of bradykinin and its metabolite bradykinin 1-5 (BK1-5) were determined in 31 patients taking an ACE inhibitor who were randomized to continue ACE inhibitors until coronary artery bypass surgery (ACE inhibitor group, N = 19) or to discontinue them 48 hours before surgery (no ACE inhibitor group, N = 12). Arterial and venous blood was sampled before CPB, at 30 minutes of CPB, at 60 minutes of CPB, after separation from CPB, and on postoperative day 1. RESULTS: Arterial bradykinin ( P < .001 [from 22.4 +/- 24.1 fmol/mL to 86.2 +/- 98.7 fmol/mL in the no ACE inhibitor group]) and arterial ( P < .001) and venous ( P = .016) BK1-5 concentrations increased significantly during CPB. Arterial bradykinin concentrations were significantly higher ( P = .017), whereas BK1-5 concentrations ( P = .024) and the molar ratio of BK1-5/bradykinin ( P = .008) were significantly lower in the ACE inhibitor group compared with the no ACE inhibitor group. In addition, arterial bradykinin concentrations were significantly increased in smokers compared with nonsmokers ( P = .015), when we controlled for the ACE inhibitor group. There was no effect of smoking on ACE activity ( P = .597 overall). There was a significant inverse correlation between arterial bradykinin and mean arterial pressure ( r 2 = 0.2137, P = .010) and a significant correlation between arterial bradykinin and tissue-type plasminogen activator antigen concentrations ( r 2 = 0.174, P = .022) during CPB. Tissue-type plasminogen activator antigen was significantly higher in the ACE inhibitor group than in the no ACE inhibitor group (18.0 +/- 7.8 ng/mL versus 12.4 +/- 4.5 ng/mL, P = .016) but not in smokers compared with nonsmokers ( P = .451). CONCLUSION: Preoperative ACE inhibitors and smoking potentiate the kinin response to CPB and may contribute to the hemodynamic and fibrinolytic response observed during CPB.

Angiotensin-Converting Enzyme Inhibitors↗
PubMed2003

Angiotensin-converting enzyme inhibition alters the fibrinolytic response to cardiopulmonary bypass.

BACKGROUND: Increased plasminogen activator inhibitor-1 (PAI-1) concentrations after coronary artery bypass grafting (CABG) are associated with increased risk of vein graft occlusion. Because angiotensin II stimulates PAI-1 expression, we tested the hypothesis that preoperative angiotensin-converting enzyme (ACE) inhibition decreases PAI-1 expression after CABG. METHODS AND RESULTS: We measured the effects of cardiopulmonary bypass (CPB) on PAI-1 antigen and tissue-type plasminogen activator (tPA) antigen and activity in 31 patients taking an ACE inhibitor (ACEI) who were randomized to continue ACEI until the morning of surgery (ACEI group, n=19) or to discontinue it 48 hours before surgery (No-ACEI group, n=12). Arterial blood samples were taken at baseline before CPB, twice during CPB, after separation from CPB, and on postoperative day 1 (POD1). CPB caused an early decrease in PAI-1 antigen, followed by an increase in PAI-1 antigen on POD1 (P<0.001 for effect of time). ACE inhibition attenuated the increase in PAI-1 antigen such that both PAI-1 antigen on POD1 (P=0.013) and the change in PAI-1 antigen from baseline to POD1 (P=0.009) were higher in the No-ACEI group (from 17.0+/-5.0 to 48.7+/-8.8 ng/mL) versus the ACEI group (from 19.9+/-3.4 to 33.1+/-6.2 ng/mL). There was no significant difference between the 2 groups in intraoperative tPA activity (P=0.259); however, the increase in tPA activity was significantly greater in the ACEI group than in the No-ACEI group (P=0.030). CONCLUSIONS: Preoperative ACEI attenuates the increase in PAI-1 after CABG, suggesting a role for ACE inhibition in reducing the risk of acute graft thrombosis.

Angiotensin-Converting Enzyme Inhibitors↗
PubMed2003

Angiotensin-converting enzyme inhibition increases human vascular tissue-type plasminogen activator release through endogenous bradykinin.

BACKGROUND: Angiotensin-converting enzyme (ACE) inhibition potentiates the tissue-type plasminogen activator (t-PA) response to exogenous bradykinin. This study tested the hypothesis that ACE inhibition increases endothelial t-PA release through endogenous bradykinin. METHODS AND RESULTS: We measured the effect of intra-arterial enalaprilat (5 micro g/min) on forearm blood flow (FBF) and net t-PA release before and during intra-arterial infusion of bradykinin (25 to 400 ng/min) and methacholine (3.2 to 12.8 microg/min) in 24 smokers pretreated with bradykinin receptor antagonist HOE 140 (100 microg/kg intravenously) or vehicle. There was no specific effect of HOE 140 on FBF or forearm vascular resistance (FVR, 29.9+/-3.6 versus 29.7+/-3.6 mm Hg x mL(-1) x min(-1) x 100 mL(-1) after vehicle and HOE 140, respectively, P=0.956 between groups). Resting FVR decreased during enalaprilat compared with vehicle or HOE 140, but not compared with baseline, and the effect was similar in the 2 groups (22.0+/-2.7 and 24.1+/-2.9 mm Hg x mL(-1) x min(-1) x 100 mL(-1), respectively, P=0.610). In contrast, enalaprilat significantly increased resting net t-PA release (from 0.6+/-0.4 to 1.7+/-0.6 ng. min(-1) x 100 mL(-1), P=0.002); this effect was abolished by HOE 140 (0.1+/-0.3 ng x min(-1) x 100 mL(-1), P=0.036 versus enalaprilat alone). Enalaprilat increased the effect of exogenous bradykinin on FBF 60% (from 17.5+/-2.5 to 28.1+/-4.0 mL. min(-1) x 100 mL(-1) during 100 ng/min bradykinin, P=0.001) and on t-PA release 14-fold (from 21.2+/-7.9 to 317.4+/-118.9 ng x min(-1) x 100 mL(-1), P=0.024). Enalaprilat increased the t-PA response to bradykinin to a greater extent than the FBF response, shifting the relationship between net t-PA release and FBF (P=0.005). HOE 140 blocked these effects. There was no effect of enalaprilat or HOE 140 on the FBF or t-PA response to methacholine. CONCLUSION: ACE inhibition increases constitutive endothelial t-PA release through endogenous bradykinin.

Adult↗
PubMed2002

Water warming garment versus forced air warming system in prevention of intraoperative hypothermia during liver transplantation: a randomized controlled trial [ISRCTN32154832].

BACKGROUND: The authors compared two strategies for the maintenance of intraoperative normothermia during orthotopic liver transplantation (OLT): the routine forced-air warming system and the newly developed, whole body water garment. METHODS: In this prospective, randomized and open-labelled study, 24 adult patients were enrolled in one of two intraoperative temperature management groups during OLT. The water-garment group (N = 12) received warming with a body temperature (esophageal) set point of 36.8 degrees C. The forced air-warmer group (N = 12) received routine warming therapy using upper- and lower-body forced-air warming system. Body core temperature (primary outcome) was recorded intraoperatively and during the two hours after surgery in both groups. RESULTS: The mean core temperatures during incision, one hour after incision and during the skin closing were significantly higher (p < 0.05, t test with Bonferroni corrections for the individual tests) in the water warmer group compared to the control group (36.7 PlusMinus; 0.1, 36.7 PlusMinus; 0.2, 36.8 PlusMinus; 0.1 vs 36.1 PlusMinus; 0.4, 36.1 PlusMinus; 0.4, 36.07 PlusMinus; 0.4 degrees C, respectively). Moreover, significantly higher core temperatures were observed in the water warmer group than in the control group during the placement of cold liver allograft (36.75 PlusMinus; 0.17 vs 36.09 PlusMinus; 0.38 degrees C, respectively) and during the allograft reperfusion period (36.3 PlusMinus; 0.26 vs 35.52 PlusMinus; 0.42 degrees C, respectively). In addition, the core temperatures immediately after admission to the SICU (36.75 PlusMinus; 0.13 vs 36.22 PlusMinus; 0.3 degrees C, respectively) and at one hr (36.95 PlusMinus; 0.13 vs 36.46 PlusMinus; 0.2 degrees C, respectively) were significantly higher in the water warmer group, compared to the control group, whereas the core temperature did not differ significantly afte two hours in ICU in both groups. CONCLUSIONS: The investigated water warming system results in better maintenance of intraoperative normothermia than routine air forced warming applied to upper- and lower body.

Journal Article↗
PubMed2002

Ethnicity affects vasodilation, but not endothelial tissue plasminogen activator release, in response to bradykinin.

Previous studies indicate that the vasodilator response to bradykinin (BK) and other endothelium-dependent and -independent agonists is decreased in black Americans compared with white Americans. The purpose of the present study was to determine the effect of ethnicity on fibrinolytic function in humans. Graded doses of BK (100, 200, and 400 ng/min), acetylcholine (15, 30, and 60 microg/min; N=20), or methacholine (3.2, 6.4, 12.8 microg/min; N=20), and sodium nitroprusside (0.8, 1.6, and 3.2 microg/min) were infused via brachial artery in 19 white and 21 black age-matched normotensive subjects. Forearm blood flow (FBF) was measured by plethysmography, and venous and arterial samples were collected for tissue plasminogen activator (tPA) antigen. Compared with whites (increase in FBF from 3.7+/-0.5 to 23.9+/-2.5 mL x min(-1) x 100 mL(-1)), blacks (increase in FBF from 2.8+/-0.3 to 15.2+/-1.9 mL x 100 mL(-1) x min(-1)) exhibited a blunted FBF response to BK (P=0.035). Responses to sodium nitroprusside and methacholine or acetylcholine were similarly decreased. In contrast, there was no effect of ethnicity on net tPA antigen release in response to BK (increase from -0.2+/-0.4 to 67.3+/-15.2 ng x min(-1) x 100 mL(-1) in blacks; from 0.04+/-0.9 to 65.9+/-13.6 ng x min(-1) x 100 mL(-1) in whites). Thus, ethnicity significantly influenced the relationship between the flow and tPA release responses to BK (P=0.037). These data suggest that the BK-dependent alterations in vascular fibrinolytic function are preserved in black Americans compared with white Americans.

Adult↗
PubMed2002

Smoking impairs bradykinin-stimulated t-PA release.

Bradykinin stimulates tissue plasminogen activator release from human endothelium through a flow-independent, B2 receptor-dependent mechanism. The present study tests the hypothesis that smoking impairs bradykinin-stimulated tissue plasminogen activator release. Graded doses of nitroprusside (1.6 to 6.4 microg/min), methacholine (3.2 to 12.8 microg/min), and bradykinin (100 to 400 ng/min) were infused in the brachial artery in random order in 20 smokers and 12 nonsmokers matched for age, gender, and body mass index. Forearm blood flow was measured by strain-gauge plethysmography. All 3 drugs caused a dose-dependent increase in forearm blood flow, with no significant difference between smokers and nonsmokers. Bradykinin (P=0.001) and methacholine (P=0.001) caused significant dose-dependent increases in net tissue plasminogen activator release. The tissue plasminogen activator response to bradykinin was significantly greater than the tissue plasminogen activator response to methacholine in the nonsmokers (maximal net tissue plasminogen activator release, 73.2+/-21.5 versus 27.6+/-7.2 ng/min per 100 mL; P=0.001) but not in the smokers (maximal net tissue plasminogen activator release, 44.5+/-10.7 versus 24.8+/-9.3 ng/min per 100 mL; P=0.154). The effect of bradykinin (P=0.037), but not methacholine (P=0.978), on net tissue plasminogen activator release was significantly reduced in smokers compared with nonsmokers. The vascular tissue plasminogen activator response to bradykinin, but not methacholine, is impaired in smokers. Stimulated tissue plasminogen activator release may be a more sensitive measure of endothelial function than vasodilation.

Adult↗