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Biomedical subjects

P van Brummelen

Publications and source records attributed to P van Brummelen.

At least 37 records · Page 2Linked to original sources
PubMed1991

Effect of the renin response during renin inhibition: oral Ro 42-5892 in normal humans.

The effect of the new renin inhibitor Ro 42-5892 was evaluated in healthy volunteers after both intravenous and oral administration. In a preliminary study, 14 subjects received a 10-min infusion of Ro 42-5892 at doses ranging from 0.001 to 1 mg/kg. Plasma renin activity (PRA) and angiotensin (Ang) II levels were maximally suppressed in a dose-dependent manner at the end of the infusion. Plasma active renin concentration increased up to threefold. In a second study, 24 volunteers received placebo or 100, 600, or 1,200 mg of Ro 42-5892 p.o. in a single-blind, randomized fashion. Within 30 min after drug intake, PRA and plasma Ang I and Ang II levels fell to their nadir. Both Ang I and Ang II were measured specifically after extraction on phenylsilylsilica and separation by isocratic HPLC. The degree as well as the duration of inhibition were dose related. The decrease in plasma Ang lasted maximally for 2 h. Active renin increased dose dependently and remained elevated for more than 8 h after the 1,200 mg dose. A theoretical generation rate of Ang I was calculated for individual plasma samples assuming Michaelis-Menten kinetics for competitive inhibition and steady-state conditions. This calculated Ang I generation rate, based on plasma active renin concentrations and drug levels, closely correlated with actually measured Ang I and Ang II levels (r = 0.90, n = 88) over the whole 8 h time period. Thus, a sustained renin inhibition by Ro 42-5892, as indicated by increased plasma active renin levels, induces a much shorter fall in plasma Ang I and II apparently because of a rise in renin secretion.

Administration, Oral↗
PubMed1991

Diurnal variation of essential and physiological tremor.

Evaluations were made of the diurnal variations of tremor power at rest, after fatigue and after mass loading, and plasma norepinephrine in patients with familial essential tremor and normal subjects. Diurnal tremor power rhythms for both essential and physiological tremor pursued identical temporal profiles. Plasma norepinephrine levels followed a congruent diurnal pattern with later peak values than the peak values of tremor power. Sympathetic nervous system activity is unlikely to be the cause of diurnal tremor power variation. The consistent diurnal rhythm of tremor power may affect dosage schemes of tremorolytic drugs.

Adult↗
PubMed1991

Does regional norepinephrine spillover represent local sympathetic activity?

Regional spillover of norepinephrine (NE), based on isotope dilution and single-compartment steady-state kinetics, is considered one of the best parameters for estimating organ sympathetic activity. However, the effects of local changes in clearance of NE on the spillover have not yet been investigated. We studied local NE kinetics and clearance in the forearm of 10 healthy subjects using intra-arterial infusions of NE, tritiated NE, the neuronal uptake inhibitor desipramine, and tyramine, which competes with NE for the neuronal uptake carrier. Before and during complete blockade of neuronal uptake by desipramine the venous concentration-time curves for tritiated NE and for NE released by tyramine were biexponential, consistent with the presence of (at least) two compartments for circulating tritiated NE and for locally released NE. The time constants for tyramine-induced release of NE and, in the same subjects during desipramine infusion, for tritiated NE were almost equal at the same level of forearm blood flow. This argues against possible diffusion or transport differences for NE to and from the circulation and the synapse. The regional intrinsic clearance capacity (a measure of the maximal ability of an organ to irreversibly remove drug by all pathways in the absence of any flow limitations) for NE decreased in the forearm by 65% (p less than 0.01) during neuronal uptake blockade by desipramine; the forearm clearance decreased by 59% (p less than 0.001), whereas the spillover rate of NE increased from 33 +/- 5 to 63 +/- 11 pmol.min-1 (p less than 0.05). Nitroprusside-induced increments in blood flow increased the spillover of NE from 18 +/- 4 to 35 +/- 6 pmol.min-1 (p less than 0.01); the clearance of circulating NE also increased (by 58%, p less than 0.05), and the intrinsic clearance capacity remained unchanged. This demonstrates that regional spillover of NE is markedly influenced by local changes in clearance and flow. The new parameter plasma appearance rate of NE is proposed. Although also derived from isotope dilution, this parameter may better approximate the regional entry of NE into the blood pool than spillover. This is corroborated by the nonsignificant changes of plasma appearance rate of NE during our desipramine and nitroprusside infusions.

Adult↗
PubMed1991

Clinical pharmacology of cilazapril.

In clinical pharmacology studies, cilazapril, after its bioactivation to cilazaprilat, was characterised as a potent, reversible angiotensin converting enzyme (ACE) inhibitor with a terminal half-life of 30 to 50 hours, which is consistent with saturable binding to ACE. Despite the arterial vasodilatation, only slight increases in heart rate occurred during cilazapril administration. Cilazapril had no acute effect on cardiovascular reflexes, and increased effective renal plasma flow slightly. Glomerular filtration rate remained unaltered. A close positive correlation was found between the cilazaprilat plasma concentration and degree of ACE inhibition. The potency of cilazaprit, defined as the concentration of cilazaprilat causing 50% inhibition of ACE, was approximately 1 microgram/L plasma. In short term studies in patients with hypertension, it appeared that more than 90% inhibition of plasma ACE was needed to obtain blood pressure reduction. Results of various dose-response studies established the indirect relationship between dose, the plasma concentration of the drug, and the blood pressure response, and identified the dose producing the maximal effect to be 5mg. Cilazapril inhibited ACE for a relatively long period which was extended in patients with severe chronic renal impairment or hepatic failure. In these patients a reduction of the dose and/or less frequent administration is recommended. There was no clinically relevant interaction of cilazapril with food, furosemide (frusemide), digoxin or coumarins. The effects of hydrochlorothiazide on sodium and chloride excretion were potentiated by cilazapril, and an additive effect of propranolol and nitrendipine on the blood pressure response to cilazapril was observed. An interaction with indomethacin and cilazapril might occur, potentially reducing the blood pressure-lowering effect of cilazapril. In general, cilazapril was well tolerated.

Angiotensin-Converting Enzyme Inhibitors↗
PubMed1991

Intrinsic vasodilation protects Wistar Kyoto rats from progressive glomerulosclerosis after unilateral nephrectomy.

Genetically determined differences in functional and structural determinants that govern the development of progressive glomerulosclerosis (GS) were studied in aging sham-operated or unilaterally nephrectomized male rats of two strains. Wistar rats showed an increase of proteinuria and GS with age, which was enhanced by unilateral nephrectomy (UN). In contrast, intact and UN Wistar Kyoto rats did not show an increase of proteinuria with age and 7 months after UN, no GS was seen in these rats. Systemic blood pressure was comparable in both strains and was not affected by UN. Functional studies in a separate group of rats 1 month after UN showed an identical increase in glomerular filtration rate in both strains as compared with sham-operated controls. The Wistar rats did not show an effect of UN on renal plasma flow, and consequently, there was an increase in filtration fraction, in contrast to Wistar Kyoto rats, which showed an increase in renal plasma flow with an unchanged filtration fraction. Glomerular volume was increased in both strains at 1 month and 7 months after UN. Mesangial expansion was not observed at 1 month after UN in either strain, which indicates that this is not a decisive factor in the development of GS. These data indicate that the genetically determined susceptibility to the development of GS in these two rat strains may be related to the degree of vasoconstriction, whereas glomerular volume expansion per se does not lead to GS but can well be a consequence of hyperfiltration. These studies are concordant with previous studies that revealed the role of hemodynamics in the pathogenesis of GS irrespective of glomerular expansion.

Animals↗
PubMed1990

Prolonged blood pressure reduction by orally active renin inhibitor RO 42-5892 in essential hypertension.

OBJECTIVE: To investigate the effects of a novel specific renin inhibitor, RO 42-5892, with high affinity for human renin (Ki = 0.5 x 10(-9) mol/l), on plasma renin activity and angiotensin II concentration and on 24 hour ambulatory blood pressure in essential hypertension. DESIGN: Exploratory study in which active treatment was preceded by placebo. SETTING: Inpatient unit of teaching hospital. PATIENTS: Nine men with uncomplicated essential hypertension who had a normal sodium intake. INTERVENTIONS: Two single intravenous doses of RO 42-5892 (100 and 1,000 micrograms/kg in 10 minutes) given to six patients and one single oral dose (600 mg) given to the three others as well as to three of the patients who also received the two intravenous doses. RESULTS: With both intravenous and oral doses renin activity fell in 10 minutes to undetectably low values, while angiotensin II concentration fell overall by 80-90% with intravenous dosing and by 30-40% after the oral dose. Angiotensin II concentration was back to baseline four hours after the low and six hours after the high intravenous dose and remained low for at least eight hours after the oral dose. Blood pressure fell rapidly both after low and high intravenous doses and after the oral dose and remained low for hours. With the high intravenous dose the daytime (0900-2230), night time (2300-0600), and next morning (0630-0830) systolic blood pressures were significantly (p less than 0.05) lowered by 12.5 (95% confidence interval 5.6 to 19.7), 12.2 (5.4 to 19.3), and 10.7 (3.2 to 18.5) mm Hg respectively, and daytime diastolic pressure was lowered by 9.3 (2.2 to 16.8) mmHg. With the oral dose daytime, night time, and next morning systolic blood pressures were lowered by 10.3 (5.5 to 15.4), 10.5 (4.2 to 17.2), and 9.7 (4.0 to 15.6) mm Hg, and daytime and night time diastolic pressures were lowered by 5.8 (0.9 to 11.0) and 6.0 (0.3-12) mm Hg respectively. CONCLUSIONS: The effect of the inhibitor on blood pressure was maintained over a longer period than its effect on angiotensin II. RO 42-5892 is orally active and has a prolonged antihypertensive effect in patients who did not have sodium depletion. This prolonged effect seems to be independent, at least in part, of the suppression of circulating angiotensin II.

Administration, Oral↗
PubMed1990

[Renal artery reconstruction for renovascular hypertension].

Between 1959 and 1983, 172 patients were treated for hypertension by reconstruction of a renal artery. Reconstruction was preferably performed with autologous material. In a selected group of 29 patients with lesions in the distal renal artery or the hilar branches, an extracorporeal reconstruction with autotransplantation was performed. After a mean follow-up of 8.4 years the hypertension was cured or improved in 82% of the patients. In patients with an arteriosclerotic renal artery stenosis this result was favourably influenced by a short duration of hypertension before the operation. Their life expectancy after the operation was clearly favourably influenced by a beneficial blood pressure response even if arteriosclerotic lesions of coronary arteries, extracranial vessels and/or peripheral vessels were present before the renovascular operation. In selected patients, renal artery reconstruction for treatment of hypertension yields excellent short-term and long-term results, not only with regard to the blood pressure response but also with respect to the patients' life expectancy.

Adult↗
PubMed1990

Subclinical renal dysfunction in rheumatoid arthritis.

We studied renal function in 35 patients with chronic, seropositive rheumatoid arthritis (RA), of whom 7 had vasculitis, 10 had hypergammaglobulinemia, and 18 had neither of these 2 conditions. Findings included a decreased glomerular filtration rate in 8 patients, (micro)proteinuria in 11, a defective urine concentration in 10, and increased urinary tubular enzyme levels in 15. These results indicate that subclinical renal dysfunction is common in patients with chronic, seropositive RA. In addition, vasculitis and hypergammaglobulinemia were not identified as risk factors for renal dysfunction in the RA patients studied.

Arthritis, Rheumatoid↗
PubMed1990

The role of serotonin in cardiovascular diseases and their treatment.

Serotonin (5HT), discovered in the 1950s, has been the subject of renewed interest for several years, in particular due to the subdivision of 5HT receptors into various types. Concomitantly, several more or less selective agonists and antagonists for these various receptor subtypes have been developed. Although the physiologic relevance of 5HT remains largely unknown, its role in certain pathologic processes is widely accepted. Certain symptoms of the carcinoid syndrome, thromboembolic processes at the level of the microcirculation, and possibly also coronary spasm and peripheral vascular disease are likely to be associated, at least in part, with endogenous 5HT and serotonergic mechanisms. However, a primary and causative role for such mechanisms in essential hypertension seems unlikely. The blockade of peripheral 5HT2 receptors with drugs may offer advantages, in particular in those disorders where an interaction between predamaged blood vessels and platelets is involved. Such a therapeutic approach seems to be a more generally applicable principle than the lowering of blood pressure as such, which appears not to be a general phenomenon provoked by 5HT2-receptor blockade.

Animals↗
PubMed1990

Effect of propofol on peripheral vascular resistance during cardiopulmonary bypass.

Twenty-eight patients undergoing elective coronary artery bypass surgery were allocated randomly to receive either propofol 2 mg kg-1 or an equivalent volume of its vehicle during cardiopulmonary bypass with constant pump flow. Peripheral vascular resistance (PVR) was calculated from perfusion pressure and pump flow. After propofol, PVR decreased from 1767 (SD 415) dyn s cm-5 to a minimum of 1263 (283) dyn s cm-5 at 2 min, and remained significantly less than the control value until 12.5 min after administration of propofol. In the group given the vehicle, PVR did not change significantly. In a second study in 10 patients, venous blood samples were withdrawn before and 2, 4, 6, 8, 10, 20 and 30 min after injection of propofol 2 mg kg-1 during cardiopulmonary bypass, for measurement of blood concentrations of propofol. Concentrations were greater than predicted by a computer simulation based on published pharmacokinetic data. The decrease in PVR may be an important factor in the hypotension caused by propofol during induction of anaesthesia.

Aged↗
PubMed1990

The role of 5-hydroxytryptamine and 5-hydroxytryptaminergic mechanisms in hypertension.

1. The possible role of 5-hydroxytryptamine (5-HT) and 5-HT-receptors in hypertension, already suggested by Page in 1954, has been subject to a renaissance of interest owing to the development of antihypertensive drugs which interact with 5-HT-receptors. These drugs, like ketanserin, urapidil and flesinoxan are used as tools to study the role of 5-HT and its receptors in hypertension. 2. The following arguments would plead in favour of a certain role of 5-HT and 5-HT-receptors in the pathogenesis and maintenance of hypertension: hyperresponsiveness of blood vessels from hypertensive patients and animals to 5-HT-induced constriction; the antihypertensive/vasodilator activity of the 5-HT2-receptor antagonist ketanserin; enhanced sensitivity of platelets from hypertensives to 5-HT. 3. However, at least as many arguments would deny a role of peripheral 5-HT in hypertension, like for instance: the fact that 5-HT is not a generally accepted pressor agent, whereas its concentration in the circulating blood is subthreshold; the hyperresponsiveness of vessels from hypertensives is not specific for 5-HT; the elevated local concentration of 5-HT released by platelets is mainly limited to the microcirculation; the 5-HT2-receptor antagonist ketanserin is the only agent of this type which lowers blood pressure, other 5-HT2-receptor blockers like ritanserin and LY 53587 being inactive. 4. The various data and arguments available do not unequivocally support a relevant role of peripheral 5-HT and its receptors in hypertensive disease.(ABSTRACT TRUNCATED AT 250 WORDS)

Animals↗
PubMed1990

Raised plasma renin and prorenin in rheumatoid vasculitis.

The value of plasma renin and its inactive precursor, prorenin, were examined as a marker for vasculitis in rheumatoid arthritis (RA). Plasma renin and prorenin rise when the renin-angiotensin system is activated; an isolated increase of prorenin may be a marker for microvascular complications in diabetes mellitus. Renin concentrations in plasma obtained from 34 patients with RA (seven with vasculitis, 27 controls) were measured under standard conditions, before and five days after stopping non-steroidal anti-inflammatory drugs; creatinine clearance was also measured. At first the median renin concentration in the patients with vasculitis was 19 (range 12-63) mU/l (normal less than 61 mU/l) and in the controls 9 (3-43) mU/l. The median prorenin concentration in patients with vasculitis was 233 (144-428) mU/l (normal less than 358 mU/l) and in the controls 144 (25-364) mU/l. Renin and prorenin concentrations increased significantly in both groups after withdrawal of nonsteroidal anti-inflammatory drugs. The creatinine clearance was similar in both groups and did not correlate with renin concentrations. In conclusion, it was found that, unlike patients with diabetes mellitus, patients with RA with vasculitis had slightly raised concentrations of both renin and prorenin. These findings signal activation of the renin-angiotensin system and might indicate early cardiac or renal involvement by vasculitis.

Aged↗
PubMed1990

Pharmacological profile of antihypertensive drugs with serotonin receptor and alpha-adrenoceptor activity.

During the last few years, several antihypertensive drugs with multiple actions have been introduced. Most of these hybrid drugs are beta-adrenoceptor blockers with an additional vasodilator component, such as labetalol, dilevalol, carvedilol and celiprolol. A second category of antihypertensive drugs with multiple actions consists of agents which interact simultaneously with serotoninergic receptors and alpha-adrenoceptors. Urapidil, ketanserin, and a few experimental compounds related to these drugs are examples of this type of antihypertensive. They may be characterised pharmacologically as follows: (1) Ketanserin is a selective antagonist of serotonin 2 receptors with an additional much weaker alpha 1-adrenoceptor antagonistic activity. Its well documented antihypertensive activity cannot be explained by either serotonin 2-receptor blockade or alpha-adrenoceptor antagonism alone. An unknown type of interaction between serotonin 2-receptor and alpha 1-adrenoceptor blockade appears to be necessary, either in the periphery or in the CNS. (2) Urapidil is a selective alpha 1-adrenoceptor antagonist and, as such, a peripheral vasodilator. In addition, it displays central hypotensive activity, probably caused by the stimulation of serotonin 1A receptors in the CNS. This component is probably additive to the peripheral effect, and is also the background to the lack of reflex tachycardia seen with urapidil. The modes of action of both types of drugs are discussed in connection with the role of serotonin and its receptors in the cardiovascular system, both at the peripheral and the CNS levels.

Adrenergic alpha-Antagonists↗
PubMed1990

Pathophysiological and pharmacotherapeutic aspects of serotonin and serotonergic drugs.

A survey shall be given on the physiological, pathophysiological and pharmacotherapeutic backgrounds of the biogenic amine 5-hydroxytryptamine (serotonin; 5HT), to be preceded by a few historical remarks. 5HT is biosynthesized from L-tryptophan via hydroxylation and subsequent decarboxylation. 5HT is predominantly found in enterochromaffin cells, platelets and in various structures of the central nervous system. Its concentration in circulating blood is low and probably subthreshold. Whereas the physiological role of 5HT is rather unclear, 5HT appears to play a relevant role in certain psychiatric disorders, in migraine and the carcinoid syndrome. Its role in essential hypertension remains uncertain. However, 5HT appears to contribute to and to exacerbate the damage to blood vessels which were already predamaged by atherosclerosis, diabetes mellitus or possibly old age as such. A major breakthrough in the pharmacology of the serotonergic system was achieved by the discovery of several subtypes of 5HT receptors, with a corresponding collection of selective agonists and antagonists towards these receptor subtypes. This development is the basis of various drugs which interact with the serotonergic system and its receptors, like the various 5HT2 receptor antagonists (of which ketanserin is the prototype), methysergide, pizotifen, urapidil, flesinoxan and a variety of psychoactive drugs. The most important of these drugs and their potential application will be discussed with an emphasis on cardiovascular disorders.

Animals↗
PubMed1989

Variability in the pharmacokinetics of nisoldipine as caused by differences in liver blood flow response.

We investigated whether the effect of nisoldipine on liver blood flow depends on its route of administration. Ten healthy subjects took nisoldipine I.V. (infusion) and orally (without and with sotalol pretreatment). Pharmacokinetics of nisoldipine was assessed and liver blood flow (ICG clearance) was measured before dosing and at the end of the infusion or during absorption. During I.V. infusion the ICG plasma clearance increased by only 14%, whereas the increase was 60% during absorption of nisoldipine. Nisoldipine increases liver blood flow considerably only during the absorption phase. A positive correlation was found between the increase in liver blood flow during absorption and the systemic availability of nisoldipine, suggesting that the differences in liver blood flow response to nisoldipine substantially contribute to the variability in pharmacokinetics of the drug.

Administration, Oral↗
PubMed1989

Long-term results of renal artery reconstruction with autogenous artery in patients with renovascular hypertension.

Renal artery reconstruction for the treatment of renovascular hypertension is preferably performed with an autologous graft when a graft is required. Although satisfactory results with vein grafts have been reported, stenosis and dilatation are not infrequent complications which have been observed only occasionally in arterial grafts. We have analysed our long-term results obtained with autogenous arterial grafts for renal artery reconstruction to determine the functional and anatomical results with regard to these complications. The data from 57 survivors operated on from 1959 through 1983 were analysed. All patients were hypertensive and the average systolic and diastolic blood pressure was 173/109 mmHg (mean number of 2.2 drugs). The renal artery stenosis was caused by arteriosclerosis and fibrodysplasia in 24 and 33 patients, respectively. In situ repair was performed in 30 patients (arterial bypass: 17 patients; splenorenal bypass: 13 patients). Extracorporeal repair of fibrodysplastic branch lesions was performed in 27 patients using branched hypogastric artery grafts (mean number of 2.4 branch anastomoses per kidney). Results were evaluated in the short (mean 8.3 months) and long term (mean 7.5 years) and the blood pressure response classified as either beneficial (cured/improved) or failed. Anatomical results were evaluated by angiography in the short-term in 87% of the patients and the long-term in 70%. A beneficial blood pressure response was obtained in 77% and 86% of patients in the short and long-term, respectively. The average blood pressure level after an interval of several years (long term) was 144/87 mmHg (mean number of 0.9 antihypertensive drugs). After in situ reconstruction, 2 and 1 anatomical failures were observed in the short and long-term, respectively.(ABSTRACT TRUNCATED AT 250 WORDS)

Arterial Occlusive Diseases↗