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Biomedical subjects

J M Ritter

Publications and source records attributed to J M Ritter.

At least 55 records · Page 3Linked to original sources
PubMed1996

Prostacyclin biosynthesis in essential hypertension before and during treatment.

Protacyclin biosynthesis was investigated in 133 untreated newly diagnosed patients with uncomplicated essential hypertension. Urinary excretion of 6-oxo-prostaglandin F1 alpha and of 2,3-dinor-6-oxo-prostaglandin F1 alpha, stable breakdown products of prostacyclin, was measured following a 1 month run-in period. To determine whether lowering blood pressure (BP) influenced prostacyclin biosynthesis, 106 consenting patients with diastolic pressure 90-120 mm Hg were allocated randomly to treatment with bendrofluazide, metoprolol, quinapril or amlodipine in an open parallel group design. Dose was increased to reduce diastolic arterial pressure to <90 mm Hg. Terazosin was added if this target BP was not achieved, and its dose increased if necessary. Urinary excretion rates of prostaglandins were measured after 1 year in patients in whom the target diastolic pressure was achieved. Mean arterial pressure varied from 106-168 mm Hg in untreated patients and excretion of both prostacyclin-derived products varied from <5 to >350 ng/g creatinine. Arterial pressure and prostaglandin excretion were not significantly correlated. In 57 patients in whom target pressure was achieved, BP before treatment was 166 +/- 2/100 +/- 1 at baseline and 144 +/- 2/86 +/- 1 mm Hg at 1 year. Excretion rates of each prostacyclin-derived product were similar before treatment and at 1 year, with no significant differences between the drugs. These findings do not support the hypothesis that deficient prostacyclin biosynthesis contributes to the pathogenesis of essential hypertension, or that increased prostacyclin biosynthesis plays a part in the response to treatment with antihypertensive medication.

6-Ketoprostaglandin F1 alpha↗
PubMed1996

Angiotensin II-receptor (AT1) blockade in the human forearm.

Phase I human studies can be used to differentiate a novel agent from existing drugs that influence the same pathway (eg, angiotensin-converting enzyme [ACE] inhibitors). Human forearm vasculature provides a useful experimental model for such studies because antagonism of local effects of agonists on resistance vasculature can be quantified, unconfounded by reflex cardiovascular responses to systemically applied agonists. In this model, inhibition of ACE with enalapril (given orally) or its active metabolite enalaprilat (given into the brachial artery) influences responses to some, but not all, vasoactive peptides that are substrates of ACE in vitro. Vasoconstrictor responses to angiotensin I (A I) are antagonized, while vasodilator responses to bradykinin are potentiated. Responses to vasoactive intestinal peptide (VIP), substance P (SP), and atrial natriuretic peptide (ANP) are unaltered by ACE inhibition. Vasodilator responses to bradykinin are antagonized by the B2-receptor icatibant and are blunted (but not abolished) by inhibition of the L-arginine/NO pathway with L-NG-monomethyl arginine. In contrast to inhibition of ACE with enalapril, blockade of the AT1 receptor with losartan results in similar inhibition of vasoconstrictor responses to both A I and angiotensin II but has no significant effect on the vasodilator action of bradykinin. The implication is that losartan provides more specific blockade of the renin-angiotensin pathway than does inhibition of ACE. The in vivo methods described in the study confirm the mechanistically relevant differentiation between AT1-receptor antagonism and ACE inhibition in humans.

Angiotensin Receptor Antagonists↗
PubMed1995

Control of vascular resistance in the maternal and feto-placental arterial beds.

This review aims to provide a comprehensive summary of the mechanisms involved in the physiological adaptation of the vasculature to pregnancy. Profound changes occur both systemically and in discrete circulations in the mother, but it is debatable which factors are responsible. Similarly, whilst the feto-placental circulation must be substantially controlled by humoral mechanisms, the exact role of each potential contributor is not known. In view of the hitherto unappreciated and very important role of the endothelium-derived vasodilator, nitric oxide, in the control of peripheral vascular resistance, considerable emphasis will be placed on the many recent investigations in this area.

Animals↗
PubMed1995

Inhibition of acetylcholinesterase selectively potentiates NG-monomethyl-L-arginine-resistant actions of acetylcholine in human forearm vasculature.

1. NG-monomethyl-L-arginine (L-NMMA, a nitric oxide synthase inhibitor) inhibits vasodilator responses to acetylcholine but not methacholine in human forearm vasculature. To investigate whether this difference results from the relative susceptibility of these agonists to hydrolysis by acetylcholinesterase, we studied vasodilator responses to brachial artery administration of acetylcholine alone and in the presence of the acetylcholinesterase inhibitor edrophonium. 2. Vasodilator responses to constant-rate brachial artery infusions of acetylcholine were biphasic, with an initial peak response fading over 2 min to a plateau. Fade [(peak-plateau)/peak x 100%] was dose dependent (P < 0.02), ranging from 43 +/- 7% (mean +/- SEM) at low dose (16 nmol/min) to 9 +/- 8% at high dose (83 nmol/min). 3. Edrophonium (0.5 mumol/min intra-arterially) alone produced no change in forearm blood flow but increased blood flow responses to acetylcholine (P < 0.01), causing an approximately 10-fold reduction in the dose required to increase plateau blood flow by 10 ml min-1 100 ml-1. 4. Responses to low doses of acetylcholine alone (16 and 41 nmol/min) faded more (P < 0.01) than those to doses of acetylcholine with edrophonium chosen to produce similar plateau blood flows. Responses to acetylcholine (41 nmol/min) also faded more (P < 0.01) than those to methacholine (5 nmol/min), producing matched plateau flows. 5. Peak and plateau responses to acetylcholine (41 nmol/min) were reduced (P < 0.01) by similar amounts (47 +/- 15%, and 37 +/- 13% respectively, P = 0.39) by coinfusion of L/NMMA (4 mumol/min).(ABSTRACT TRUNCATED AT 250 WORDS)

Acetylcholine↗
PubMed1995

The effect of HN-65021 on responses to angiotensin II in human forearm vasculature.

We studied the effect of (2-butyl-4-chloro-1[[2'-(1H-tetrazol-5-yl) [1,1'-biphenyl]methyl]-1H-imadazole-5-carboxylic acid,-1-(ethoxycarbonyloxy) ethyl-ester (HN-65021), on angiotensin II induced vasoconstriction in forearm vasculature of eight healthy men. Placebo and HN-65021 (5, 10 and 100 mg) were administered orally. Forearm blood flow was measured by venous occlusion plethysmography during rising dose brachial artery infusions of angiotensin II (0.3-1000 pmol min-1) 2 h after dosing. HN-65021 inhibited angiotensin II, causing a shift to the right of the dose-response curve. Angiotensin II (100 pmol min-1) decreased mean blood flow in the infused arm by 63.1 +/- 3.2% when infused following placebo and by 49.9 +/- 4.3%, 50.7 +/- 3.5% and 36.4 +/- 2.8% following HN-65021 doses of 5.10 and 100 mg respectively. These results demonstrate that HN-65021 antagonises angiotensin II receptor mediated vasoconstriction in human forearm resistance vessels.

Adult↗
PubMed1995

Antiphospholipid syndrome in a patient with rapidly progressive fibrosing alveolitis.

The antiphospholipid syndrome is a thrombotic disorder which can occur in a primary form or more classically in systemic lupus erythematosus. An association between cryptogenic fibrosing alveolitis and the antiphospholipid syndrome has not previously been reported. We describe a patient with severe cryptogenic fibrosing alveolitis who developed pulmonary embolism and myocardial infarction in the presence of antiphospholipid antibody. The case also illustrates that worsening respiratory function may represent superimposition of one lung pathology on another, and may not simply be a deterioration of the pre-existing disease.

Antiphospholipid Syndrome↗
PubMed1995

Surgical cure of hypertension in a patient with brainstem capillary haemangioblastoma containing neuropeptide Y.

We describe a 29-year-old woman with persistent arterial hypertension which resolved following complete excision of a capillary haemangioblastoma from within the spinal cord at the cervico-medullary junction. Immunohistochemical staining was positive for neuropeptide Y in capillary walls and nerves in the tumour. This raises the possibility of an association between neuropeptide Y and the central control of blood pressure in man.

Adult↗
PubMed1995

The haemodynamic effects of the thromboxane A2 receptor antagonist GR32191B during cardiopulmonary bypass in the dog.

This study examined whether treatment with the specific thromboxane (TX) A2 receptor antagonist GR32191B would result in an improvement in peripheral haemodynamics during and after cardiopulmonary bypass (CPB) in anaesthetized dogs compared with animals given either saline (control) or aspirin. Following thoracotomy, heparinization and aortic cannulation, and 35 minutes before CPB, dogs received intravenously either GR32191B (15 micrograms/kg/min), saline (50 ml bolus) or aspirin (225 mg bolus) (n = 6 per group). Cardiac output (dye dilution), femoral artery blood flow (electromagnetic flowmeter), gastrocnemius muscle tissue perfusion (133Xe clearance), retinal blood flow (fluorescein angiography), and thromboxane biosynthesis (urinary excretion rates of TXB2 and the metabolite 2,3-dinor-TXB2) were measured before, during and after a standard 90 minute period of CPB at 2.4 l/min/m2 and 28 degrees C. The aspirin-treated group manifested an eightfold reduction in TXB2 excretion compared with controls, indicating a decrease in TXA2 biosynthesis. There were few haemodynamic differences between the groups, though the aspirin-treated group had better maintained muscle tissue perfusion post-CPB and significantly fewer retinal microcirculatory occlusions than GR32191B-treated animals. We conclude that specific TXA2 receptor antagonism provides no significant improvement in peripheral haemodynamics; rather aspirin provides a modest haemodynamic benefit.

Animals↗
PubMed1995

Nebivolol vasodilates human forearm vasculature: evidence for an L-arginine/NO-dependent mechanism.

Nebivolol, a beta 1 selective adrenergic receptor antagonist with additional properties, is a racemic mixture of (S,R,R,R)- and (R,S,S,S)-enantiomers. We investigated its effects on human forearm vasculature. Blood flow was measured using venous occlusion plethysmography during brachial artery infusion of drugs. Interaction between nebivolol and the L-arginine/nitric oxide pathway was investigated via comparison with carbachol (an endothelium-dependent agonist) and nitroprusside, and by coinfusion of a competitive inhibitor of nitric oxide synthase, NG-monomethyl L-arginine (LNMMA) +/- L-arginine. Nebivolol (354 micrograms/min) increased blood flow by 91 +/- 18% (mean +/- SEM, n = 8, P < .01) whereas an equimolar dose of atenolol had no significant effect. L-NMMA (1 mg/min) inhibited vasodilation to nebivolol (by 65 +/- 10%) and carbachol (by 49 +/- 8%) to a significantly greater extent than it reduced responses to nitroprusside. Inhibition of nebivolol response by L-NMMA was abolished by L-arginine (62 +/- 11% inhibition by L-NMMA, 15 +/- 17% inhibition by L-NMMA with L-arginine, 10 mg/min, n = 8). Vasodilation caused by the (S,R,R,R)- and (R,S,S,S)-enantiomers was similar. We conclude that nebivolol vasodilates human forearm vasculature via the L-arginine/nitric oxide pathway.

Adrenergic beta-1 Receptor Antagonists↗
PubMed1994

Sex differences in endothelial function in normal and hypercholesterolaemic subjects.

Acetylcholine stimulates endothelial synthesis of nitric oxide from L-arginine. To investigate the influence of sex on endothelial function, we measured vasodilator responses to brachial artery administration of acetylcholine in hypercholesterolaemic and control men and women. Mean response to acetylcholine was impaired (55% of that in controls at 15 micrograms/min) in hypercholesterolaemic men but not in hypercholesterolaemic women. L-arginine normalised responses to acetylcholine in hypercholesterolaemic men, but had similar effects in hypercholesterolaemic and control women. These results suggest that women are protected against adverse effects of hypercholesterolaemia on the L-arginine/nitric-oxide pathway.

Acetylcholine↗
PubMed1994

Preserved endothelium-dependent vasodilatation in patients with essential hypertension.

BACKGROUND: Previous studies suggest that vascular endothelial function may be impaired in essential hypertension. Although muscarinic agonists dilate blood vessels by releasing an endothelium-derived relaxing factor closely related to nitric oxide, nitroprusside dilates vessels by a mechanism that is independent of the endothelium. The finding of an impaired response to muscarinic agonists but a normal response to nitroprusside in patients with hypertension has suggested that endothelial function is abnormal in hypertension. METHODS: We reassessed this issue by measuring forearm blood flow by plethysmography during the infusion of vasodilators into the brachial arteries of 95 subjects: 37 normotensive controls (mean [+/- SE] arterial blood pressure, 92 +/- 1 mm Hg) and 58 patients with essential hypertension (mean arterial blood pressure, 121 +/- 1 mm Hg). RESULTS: In an initial study, vascular responses to the vasodilators carbachol and nitroprusside were similar in normotensive controls (n = 19) and hypertensive patients (n = 17). We wondered whether this might be attributable to the use of previously untreated patients or to the choice of carbachol as the muscarinic agonist. However, we found that the vasodilator responses to nitroprusside, acetylcholine, carbachol, and isoproterenol were also similar in separate groups of normotensive controls (n = 18) and hypertensive subjects, whether the subjects had never been treated for hypertension (n = 24) or had had therapy withheld for two weeks (n = 17). The 95 percent confidence intervals for the difference between the controls and hypertensive patients in the ratio of endothelium-dependent vasodilatation induced by acetylcholine or carbachol to endothelium-independent vasodilatation induced by nitroprusside were -14 to +23 percent for acetylcholine and -13 to +12 percent for carbachol. CONCLUSIONS: In contrast to previous studies, our findings suggest that selective impairment of the responsiveness of the forearm vasculature to muscarinic agonists is not universal in patients with essential hypertension.

Acetylcholine↗
PubMed1994

Blood flow responses to intra-arterial acetylcholine in man: effects of basal flow and conduit vessel length.

1. Acetylcholine relaxes human resistance vessels and releases nitric oxide and other factors from the endothelium. Comparison of responses to acetylcholine with those to an endothelium-independent vasodilator (such as nitroprusside) forms the basis of the so-called acetylcholine test of endothelial function. However, when this test is applied in vivo by intraarterial infusion, the metabolic instability of acetylcholine may result in differential responses to these drugs arising from anatomical rather than functional differences. 2. Vasodilator responses to brachial artery infusions of acetylcholine (41 and 83 nmol/min) and sodium nitroprusside (11 and 38 nmol/min) were measured in 30 healthy human subjects using venous occlusion plethysmography. 3. Responses to acetylcholine showed a greater dependence on resting blood flow (P < 0.05) and on forearm length (P < 0.05) than those to sodium nitroprusside (results predicted by a simple blood flow model). 4. Correction for forearm length abolished an apparent difference of 59% between responses to acetylcholine in men and women. Conduit vessel geometry and resting blood flow influence the acetylcholine test of endothelial function.

Acetylcholine↗
PubMed1994

Time-dependent inhibition by glyceryl trinitrate of platelet aggregation caused by U46619 (a thromboxane/endoperoxide receptor agonist).

Glyceryl trinitrate is a weak inhibitor of platelet aggregation in vitro. Its effect on platelet aggregation in response to U46619 (a thromboxane/endoperoxide receptor agonist) was studied turbidometrically in platelet-rich plasma from healthy volunteers. The object was to determine whether inhibition was influenced by a period of preincubation between preparation of platelet-rich plasma and addition of glyceryl trinitrate. Incubation was performed at 37 degrees C and 22 degrees C. Samples were removed at intervals and transferred to an aggregometer cuvette at 37 degrees C. Glyceryl trinitrate (100 microM) or an equal volume of distilled water was added 5 min before U46619 (2 microM), and aggregation recorded as change in light transmission. Inhibition by glyceryl trinitrate was markedly time and temperature dependent, with a progressive increase in inhibitory potency between 120 and 300 min preincubation at 37 degrees C but not at 22 degrees C. The explanation of this is unknown but the effect was not influenced by lipopolysaccharide or by cycloheximide, so it does not appear to be due to exposure to endotoxin or to enzyme induction in vitro.

15-Hydroxy-11 alpha,9 alpha-(epoxymethano)prosta-5↗
PubMed1994

Effect of NG-monomethyl-L-arginine on kinin-induced vasodilation in the human forearm.

1. We compared effects of NG-monomethyl-L-arginine (L-NMMA), an NO synthase inhibitor, on vasodilator responses to intra-arterial infusion of bradykinin and substance P in the human forearm. 2. Bradykinin (100 pmol min-1) increased forearm blood flow when infused into the brachial artery of eight healthy male volunteers, from 2.8 +/- 0.2 (mean +/- s.e. mean) to 9.3 +/- 1.0 ml min-1 per 100 ml forearm volume. 3. Co-infusion of L-NMMA (2 mumol min-1 and 4 mumol min-1) with bradykinin (100 pmol min-1) for 6 min produced respectively a 9 +/- 14% and 42 +/- 14% inhibition (compared with L-NMMA vehicle) in the response to bradykinin. 4. Substance P (1 pmol min-1) when infused into the brachial artery of a further eight male subjects increased forearm blood flow from 3.4 +/- 0.2 to 6.3 +/- 0.7 ml min-1 100 ml-1. 5. Co-infusion of L-NMMA (2 mumol min-1 and 4 mumol min-1) with substance P (1 pmol min-1) for 6 min produced respectively a 27 +/- 8% and 70 +/- 13% inhibition (compared with L-NMMA vehicle) in the response to substance P. 6. These results demonstrate that vasodilator responses to both bradykinin and substance P are mediated in part via the L-arginine/NO pathway. Bradykinin and substance P may be useful agonists with which to study endothelial function in this vascular bed.

Adult↗
PubMed1994

Inhibition of bradykinin-induced vasodilation in human forearm vasculature by icatibant, a potent B2-receptor antagonist.

1. The effect of icatibant (D-Arg-[Hyp3, Thi5, D-Tic7, Oic8] bradykinin) a potent B2-kinin receptor antagonist, was studied on bradykinin-induced vasodilation in the human forearm. 2. Eight healthy normotensive men were studied in a rising dose random-placebo controlled study. Placebo and icatibant (20, 50 and 100 micrograms kg-1 i.v.) were administered double-blind. Forearm blood flow was measured by venous occlusion plethysmography during rising dose brachial artery infusions of bradykinin (10-3,000 ng min-1) 60-90 min after placebo or icatibant. 3. Plasma concentrations of icatibant fell exponentially following each of three doses, up to the final measurement. Elimination half-lives calculated from linear regression of the mean data were 25, 27 and 29 min after 20, 50 and 100 micrograms kg-1 doses respectively. 4. Icatibant inhibited the effect of bradykinin (P < 0.001 at each dose of icatibant) in a dose-dependent manner. Bradykinin (100 ng min-1) increased mean blood flow in the infused arm by 238 +/- 31% when infused following placebo, by 112 +/- 21% after icatibant 20 micrograms kg-1, by 71 +/- 14% after icatibant 50 micrograms kg-1 and by 48 +/- 9% after icatibant 100 micrograms kg-1. 5. These results demonstrate that icatibant antagonises B2-receptor mediated vasodilation in human forearm resistance vessels. The findings provide a quantitative basis for future studies of the role of bradykinin in the response to angiotensin converting enzyme inhibitors and in circulatory disease.

Adrenergic beta-2 Receptor Antagonists↗
PubMed1994

Effect of cytoplasmic pH on Ca(2+)-stimulated eicosanoid biosynthesis in human platelets.

1. We have investigated the effect of cytoplasmic pH (pHi) on the relationship between platelet cytoplasmic Ca2+ concentration ([Ca2+]i) and eicosanoid biosynthesis. Stirred gel-filtered human platelets loaded with fluorescent indicators of Ca2+ and H+ were suspended in balanced salt solutions at 37 degrees C. [Ca2+]i was controlled by calcium ionophore (ionomycin). Increased [Ca2+]i was associated with increased production of thromboxane A2 (TXA2) as determined by radioimmunoassay of its stable hydrolysis product TXB2, and of 12-hydroxy eicosatetraenoic acid (12-HETE) measured by high performance liquid chromatography. 2. Varying pHi with a K+/H+ ionophore (nigericin) in platelets suspended in K+ rich solutions of pH 6.8, 7.4 or 7.8 with subsequent resuspension in solution of pH 7.4 containing albumin (1 g l-1) and Ca2+ (1 mM) resulted in pHi of 6.72 +/- 0.05, 7.31 +/- 0.02 and 7.71 +/- 0.04 (mean +/- s.e. mean, n = 5). Ionomycin (1.2 microM) increased [Ca2+]i by 97.1 +/- 17.6, 191.9 +/- 48.7 and 322.8 +/- 55.7 nM at the different values of pHi respectively; TXB2 production was 0.7 +/- 0.2, 2.1 +/- 0.4 and 10.7 +/- 3.3 ng micrograms-1 protein, and 12-HETE production was 150.9 +/- 68.2, 184.4 +/- 77.9 and 302.3 +/- 62.8 ng micrograms-1 protein. 3. Ammonium chloride (50 mM) caused a small reduction in pHo while increasing pHi from 7.32 +/- 0.04 to 7.89 +/- 0.05 and increasing ionomycin (1.2 microM)-induced [Ca2+]i responses from 94.1 +/- 67.3 to 721.6 +/- 288.3 nM. TXB2 production increased from 3.1 +/- 2.1 to 17.3 +/- 8.2 and 12-HETE production increased from 100.5 +/- 26.7 to 203.2 +/- 36.4 ng microg-1 protein. Responses of [Ca2+]i and TXB2 production to epoxymethano prostaglandin H2 (U46619, an endoperoxide-thromboxane receptor agonist) increased significantly in the presence of NH4C1.4. Alterations of pHi (such as may occur under pathological conditions) influence [Ca2+]i responses and eicosanoid synthesis in human platelets.

12-Hydroxy-5,8,10,14-eicosatetraenoic Acid↗