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Biomedical subjects

T Philipp

Publications and source records attributed to T Philipp.

At least 19 recordsLinked to original sources
PubMed1992

Alpha- and beta-adrenoceptors in hypertension: molecular biology and pharmacological studies.

Recent years have witnessed astonishing progress in our understanding of the molecular basis of adrenoceptor structure, function and regulation and revealed an unexpected heterogeneity of adrenoceptors demonstrating the existence of at least 11 subtypes. This paper discusses the implications of these advances on studies regarding a specific role of adrenoceptors in the development of genetic hypertension. The available data indicate that among the alpha-adrenoceptor subtypes the alpha 2A-adrenoceptor is the most likely candidate for an alteration specifically linked to genetic hypertension in the animal model of the spontaneously hypertensive rat and possibly in some patients. Alterations of other alpha-adrenoceptor subtypes may be specific for some forms of genetic hypertension but are unlikely to play an important role for blood pressure regulation. Most beta-adrenoceptor alterations appear to occur secondary to blood pressure elevation independently of whether hypertension has occurred on a genetic basis or not. Moreover, the mechanisms regulating alpha- and beta-adrenoceptor responsiveness upon prolonged agonist exposure may be altered in hypertension and thereby contribute to the pathophysiology of this disease.

Adrenergic alpha-Antagonists↗
PubMed1992

On the role of renal alpha-adrenergic receptors in spontaneously hypertensive rats.

We tested the hypothesis that a genetically determined increase in renal alpha-adrenergic receptor density might be a pathophysiologically important factor in the spontaneously hypertensive rat model of genetic hypertension. In a first study, we compared renal alpha 1 and alpha 2-adrenergic receptor density with systolic blood pressure in 45 rats of an F2 generation of Wistar-Kyoto x spontaneously hypertensive rat hybrids but were unable to detect significant cosegregation between either receptor density or blood pressure. In a second study, we determined renal alpha 1- and alpha 2-adrenergic receptor density in Wistar-Kyoto and spontaneously hypertensive rat kidneys that were transplanted into an F1 generation of Wistar-Kyoto x spontaneously hypertensive rat hybrids. Although Wistar-Kyoto kidneys lowered blood pressure in these animals and spontaneously hypertensive rat kidneys increased blood pressure, renal alpha-adrenergic receptor densities were similar in membranes from both types of kidneys. Since rat kidney coexpresses alpha 1A- and alpha 1B-adrenergic receptors, we also investigated whether differential regulation of these two subtypes might conceal ongoing alterations. The alpha 1A/alpha 1B-adrenergic receptor ratio, however, was similar in Wistar-Kyoto rats, spontaneously hypertensive rats, and F1 rats transplanted with a kidney from either strain. Taken together these data do not support the hypothesis that genetically determined alterations of renal alpha-adrenergic receptor numbers play an important role in the development of elevated blood pressure in the spontaneously hypertensive rat.

Animals↗
PubMed1992

Lack of oral kallikrein in lowering systemic blood pressure in primary hypertension.

Primary hypertension is associated with a lack in renal kallikrein activity which might be one of the reasons for the blood pressure elevation. Some smaller and partially uncontrolled studies suggested that an oral substitution of glandular kallikrein lowers blood pressure by a kinin-mediated vasodilation and increased natriuresis. To test this hypothesis we treated in two studies over 100 patients with untreated mild to moderate primary hypertension (WHO I-II) for 5 resp. 12 weeks in a double blind randomized and placebo controlled manner with 1800 U glandular kallikrein orally. Blood pressure measurements were performed according to the two study designs after 3 and 5 resp. 8 and 12 weeks of treatment sphymomanometrically in the day time course. No significant changes in blood pressure by kallikrein treatment could be observed at any time. Neither renal kallikrein excretion, renin and ACE-activity nor blood glucose concentration in diabetics or non-diabetics was changed. Thus, we could undoubtedly demonstrate that oral applied glandular kallikrein has no effect on primary hypertension.

Administration, Oral↗
PubMed1991

[Effect of erythropoietin therapy on alpha receptor density in chronic dialysis patients].

The effect of a six months therapy with human recombinant erythropoietin (rHu-EPO) on blood pressure and on several parameters of sympathetic nervous activity was studied in chronic haemodialysis patients in a controlled and randomized trial in order to gain further insight into the mechanism of rHu-EPO-induced blood pressure elevation. Treatment was started at a dose of 3 X 80 IE/kg/week in eleven patients aiming to increase the initial hemoglobin concentration (7.0 +/- 0.3 [SEM] g%) to 10.0 g% by dose adjustments, while another untreated eleven patients served as a control group. Diastolic arterial pressure measured before and after haemodialysis increased on rHu-EPO treatment by 7 and 8 mm Hg respectively (p less than 0.05). Plasma noradrenaline concentration was increased (p less than 0.05) after the six months treatment period in the presence of unchanged dry weights. Conversely platelet alpha 2-adrenoceptor density (3H-yohimbine binding) and the fraction of high affinity binding sites for alpha 2-agonists (3H-UK 14.304) decreased (p less than 0.01) along with a decrease in reactivity to exogenous noradrenaline (p less than 0.05). None of these parameters changed in the control group compared to pretreatment values. The results obtained demonstrate that increased plasma noradrenaline concentrations may participate in rHu-EPO induced blood pressure increases. The decrease in platelet alpha 2-adrenoceptor densities and the decrease in noradrenaline reactivity in the presence of increased plasma noradrenaline concentrations suggest an intact regulation of alpha 2-adrenoceptors in chronic haemodialysis patients on chronic rHu-EPO therapy.

Blood Platelets↗
PubMed1991

Does treatment with beta-adrenoceptor antagonists in vivo alter human adenylate cyclase responsiveness in vitro?

1. Treatment with beta-adrenoceptor antagonists in vivo can alter adenylate cyclase responsiveness in the human heart. We have determined the effects of treatment with four different beta-adrenoceptor antagonists in vivo on the responsiveness of lymphocyte and platelet adenylate cyclase in vitro in healthy volunteers. 2. Propranolol (non-selective, 4 x 40 mg day), bisoprolol (beta 1-selective, 1 x 10 mg day), and ICI 118.551 (beta 2-selective, 3 x 25 mg day) were tested as drugs without and pindolol (non-selective, 2 x 5 mg day) as a drug with intrinsic sympathomimetic activity. Adenylate cyclase stimulation by GTP, prostaglandin E1 and forskolin was determined before, after a 7 day treatment period and 7 days after drug withdrawal. 3. Neither treatment with or withdrawal of any of the beta-adrenoceptor antagonists altered adenylate cyclase responsiveness. 4. We conclude that adenylate cyclase responsiveness in circulating blood cells underlies different regulatory mechanisms than that in solid tissues such as the human heart. Our data suggest that circulating blood cells do not always reflect alterations in solid tissues.

Adenylyl Cyclases↗
PubMed1991

Influence of the calcium antagonist nitrendipine on the hepatotoxic effect of cyclosporine A.

Calcium antagonists have a protective effect on different forms of nephrotoxicity due to cyclosporine A (CsA). The objective of the present study was to examine the influence of a calcium antagonist on the liver function in CsA-treated patients after kidney transplants. Different quantitative liver function tests were performed in six patients before and 3 months after administration of the calcium antagonist nitrendipine. Indocyanine green clearance (ICG-Cl) as a marker for hepatic blood flow and excretion showed a significant increase under nitrendipine. In addition, there was an improvement of the galactose elimination capacity. Although nitrendipine and lidocaine are both metabolized by the cytochrome P system, there was no reduction in lidocaine clearance. These results suggest an improvement of liver function under nitrendipine. Whether these findings alone are the expression of an improved liver blood flow or whether there is an additional hepatoprotective characteristic of the calcium antagonist nitrendipine cannot be determined.

Cyclosporine↗
PubMed1991

Hydrochlorothiazide and verapamil in the treatment of hypertension. The Verapamil Versus Diuretic (VERDI) Trial Research Group.

The efficacy and tolerability of hydrochlorothiazide, sustained-release verapamil, and their combination was compared in patients with mild to moderate hypertension. The design was a multicenter, randomized, double-blind clinical trial with a single-blind placebo baseline period of 2 weeks. Three hundred sixty-nine patients with a diastolic blood pressure of 95-120 mm Hg were included. Treatment consisted of 12.5 mg of hydrochlorothiazide once daily, then 25 mg once daily, and finally 25 mg twice daily; the other group received verapamil at a dose of 120 mg once daily, then 240 mg once daily, and finally 240 mg twice daily. Patients not achieving target blood pressure (less than 90 mm Hg diastolic) were given the combination of hydrochlorothiazide and verapamil, that is, 25 and 240 mg once daily and twice daily. During all time points during the study patients receiving verapamil achieved target blood pressure more often than patients receiving hydrochlorothiazide (after 8 weeks, 57.7 and 42.7%; after 24 weeks, 46.8 and 26.4%; and after 48 weeks, 44.8 and 24.7%, respectively). Adding verapamil to hydrochlorothiazide was more effective in lowering blood pressure than adding hydrochlorothiazide to verapamil. The number of treatment withdrawals was essentially the same with the two drugs. Therefore, in the doses currently used in antihypertensive treatment, verapamil was more effective than hydrochlorothiazide as a single agent and in combination in mild to moderate hypertension.

Adult↗
PubMed1990

[Prevalence, causes and effects of increased iron storage in patients with kidney transplantation].

Patients on chronic hemodialysis often need blood transfusions due to erythropoietin deficiency. Even after successful kidney transplantation iron overload may persist. Former histological studies have revealed siderosis of the liver in 69% of all patients whose serum ferritin was above 1100 ng/ml. The aim of the present study was to evaluate the influence of iron overload on liver function. In 146 symptom free patients with renal allografts serum ferritin was determined to detect possible iron overload. Serum ferritin between 4 and 5480 ng/ml were found (women: 358.7 +/- 105.3; men 282.4 +/- 63.3 ng/ml; x +/- SEM). Twelve patients (8.1%) had ferritin levels higher than 1100 ng/ml. These twelve patients as well as another group of eight patients with renal allografts whose serum ferritin was known to be higher than 1100 ng/ml were included for further evaluation. Their data were matched and compared with those of a control group also patients with renal allograft (same age and sex) whose serum ferritin was lower than 1100 ng/ml. Transaminases (SGPT 22.6 +/- 3.6 vs. 15.4 +/- 6.0 U/l; SGOT 14.7 +/- 2.0 vs. 13.0 +/- 4.8 U/l) and plasma glucose (90.5 +/- 7.1 vs. 76.8 +/- 3.7 mg/dl) were found to be significantly higher (p less than 0.05) in patients with serum ferritin levels above 1100 ng/ml. Elevated transaminases were significantly more frequent in patients with high serum ferritin (9 vs. 2; p less than 0.02) as compared with the control. Ferritin levels significantly correlated with the number of preceding blood transfusions (p less than 0.002). Hbs-persistence was detected in six out of 20 patients with high ferritin levels but only in one out of 20 in the control group (p less than 0.05) whereas anti-Hbs prevalence was not different in the two groups. These data indicate that chronic iron overload should be considered as a possible cause of chronic liver disease in patients with renal allografts.

Adolescent↗
PubMed1990

Effect of erythropoietin on parameters of sympathetic nervous activity in patients undergoing chronic haemodialysis.

The effect of erythropoietin (rHu-EPO) on blood pressure and on parameters of sympathetic nervous activity of patients undergoing chronic haemodialysis treatment was evaluated in a controlled and randomized 6-months study. Both groups did not differ significantly at the onset of the study in terms of dialysis protocol, haematological parameters, blood chemistry, weight, blood pressure and parameters of sympathetic nervous activity. Haemoglobin increased from 7.0 +/- 0.3 g dl-1 to 10.0 +/- 0.3 g dl-1 by 6 months on rHu-EPO (n = 11) and remained constant in the control group (n = 11). After 6 months diastolic blood pressure was higher in the treatment group compared with the control group as well as compared with pretreatment values, whereas reactivity to exogenous noradrenaline and platelet alpha 2-adrenoceptor densities ([3H]-yohimbine- and [3H]-UK 14,304-binding sites) were lower. Plasma noradrenaline concentration increased during rHu-EPO compared with pretreatment values, while dry weights were unchanged during the study. The results demonstrate alterations of some parameters of sympathetic nervous activity during rHu-EPO-therapy which were absent in the control group.

Blood Platelets↗
PubMed1990

Folate nephropathy occurring during cytotoxic chemotherapy with high-dose folinic acid and 5-fluorouracil.

High-dose folinic acid with 5-fluorouracil (5-FU) is a novel combination chemotherapy used in the treatment of metastatic gastrointestinal cancer. One of the mechanisms of action of 5-FU is its conversion into fluorodeoxyuridylate (FdUMP), which inhibits thymidilate synthetase (TS). The rate of inhibition of TS is augmented by increasing concentrations of folinic acid. On the other hand, it is well known that treatment of animals with high doses of folinic acid results in acute renal failure due to tubular obstruction. In order to find out whether there are similar findings in the clinical setting, we investigated 8 patients (pts.) with metastatic gastrointestinal cancer who were treated with this chemotherapy. We used the following parameters: 1. excretion of four urinary enzymes (LDH, LAP, GGT, NAG); 2. creatinine clearance on days 1 and 5. Therapy consisted of folinic acid 200 mg/m2 i.v. on days 1-5 and 5-fluorouracil 400 mg/m2 on days 1-5. Each treatment cycle was repeated on day 28. We found a constant decrease in the excretion of all 4 enzymes from normal to subnormal values which was statistically significant (p less than .05) during the two treatment cycles. Creatinine clearance decreased about 50% in three patients from normal initial values. In conclusion, during therapy with high-dose folinic acid and 5-fluorouracil we found signs of tubular damage which are similar to those found in folate nephropathy.

Antineoplastic Combined Chemotherapy Protocols↗
PubMed1989

Verapamil versus hydrochlorothiazide in the treatment of hypertension: results of long term double blind comparative trial. Verapamil versus Diuretic (VERDI) Trial Research Group.

OBJECTIVE: To compare the efficacy and tolerability of hydrochlorothiazide, sustained release verapamil, and their combination in patients with mild to moderate hypertension. DESIGN: Randomised multicentre trial of 48 weeks' duration with a double blind comparison of hydrochlorothiazide and verapamil followed by an open trial of combined treatment for patients not achieving the target diastolic blood pressure (less than 90 mm Hg) during treatment with a single drug. SETTING: Outpatient departments in 10 clinics and 10 private practices of general practitioners or internists. PATIENTS: 369 Hypertensive patients with a diastolic blood pressure of 95-120 mm Hg during a placebo run in period of two weeks. INTERVENTIONS: Initial treatment consisted of 12.5 mg hydrochlorothiazide (n = 187) or 120 mg sustained release verapamil (n = 182) once daily (regimen I). If the target diastolic blood pressure of less than 90 mm Hg was not achieved within four weeks doses were increased to 25 mg hydrochlorothiazide or 240 mg verapamil once (regimen II) and twice daily (regimen III). Patients not achieving target blood pressure were given the combination of hydrochlorothiazide and verapamil--that is, 25 and 240 mg once (regimen IV) and twice daily (regimen V). MAIN OUTCOME MEASURE: Blood pressure determined with a device permitting automatic repeated measurements with printouts. RESULTS: After eight weeks of treatment with a single drug 76 out of 178 (43%) and 101 out of 175 (58%) patients achieved the target blood pressure with hydrochlorothiazide and verapamil, respectively. During follow up until 48 weeks patients treated with verapamil reached the target blood pressure more often and at lower doses and were less likely to switch to combination treatment than patients randomised to hydrochlorothiazide treatment. Adding verapamil to hydrochlorothiazide was more effective than the addition of hydrochlorothiazide to verapamil. At the end of the study 42 out of 169 (25%) and 73 out of 163 (45%) patients initially randomised to hydrochlorothiazide and verapamil, respectively, were at target blood pressure without combination treatment. After adding verapamil to hydrochlorothiazide or hydrochlorothiazide to verapamil an additional 58 (34%) and 29 (18%) patients reached the target blood pressure, respectively. Altogether 92 out of 332 (28%) patients failed to achieve target blood pressure with regimen V. There were four, 10, seven, and seven withdrawals due to possible adverse effects to treatment with hydrochlorothiazide, verapamil, combining verapamil with hydrochlorothiazide, and combining hydrochlorothiazide with verapamil, respectively. CONCLUSIONS: In doses currently used in antihypertensive treatment verapamil was more effective than hydrochlorothiazide as a single agent and in combination in mild to moderate hypertension, whereas withdrawal rates caused by side effects possibly related to treatment were similar.

Adult↗
PubMed1989

Increased intracellular free calcium and sensitivity to angiotensin II in platelets of preeclamptic women.

Preeclampsia is characterized by a generalized vasoconstriction and increased vascular sensitivity to angiotensin II. Intracellular free calcium, implicated in vascular smooth muscle contraction, has been found to be elevated in platelets of other hypertensive disorders. We therefore measured intracellular free calcium concentrations by using the fluorescent probe quin-2 in platelets of six patients with preeclampsia and compared them to measurements in ten normotensive pregnant women and ten age-matched nonpregnant women. Intracellular free calcium was also determined in the preeclamptic women after delivery. We found that intracellular free calcium was slightly elevated in normal pregnancy (102 +/- 13 nmol/L v 87 +/- 17 nmol/L) but was markedly increased in preeclampsia (138 +/- 13 nmol/L, P less than .05). This increase disappeared six weeks after delivery (84 + 10 nmol/L, P less than .01). To investigate whether the increased intracellular free calcium was related to angiotensin II, the platelets were exposed to thrombin and angiotensin II in vitro. Exposure to thrombin and angiotensin II caused a dose-dependent increase in intracellular free calcium. The intracellular response to thrombin was not significantly different in the three groups. However, stimulation with angiotensin II revealed an increased response in intracellular free calcium in preeclampsia (P less than .05) that disappeared after delivery. Our findings show a sustained increase in platelet intracellular free calcium in preeclampsia and suggest a functional alteration of the angiotensin II receptor in this disease.

Adult↗
PubMed1989

Increased forskolin stimulation of lymphocyte-adenylate cyclase in normotensive subjects predisposed to essential hypertension.

Since a significant heritability has been shown for forskolin stimulation of lymphocyte adenylate cyclase activity in twins, we evaluated lymphocyte forskolin-stimulated adenylate cyclase activity with respect to a familial predisposition towards essential hypertension. Lymphocyte adenylate cyclase activity was measured in broken cell preparations of 32 male normotensive volunteers with (n = 15) and without (n = 17) a positive family history of hypertension. The maximal forskolin stimulation of adenylate cyclase activity was significantly higher in the positive compared with the negative group (maximal stimulation of activity 53.5 +/- 3.4 versus 41.2 +/- 1.9 pmol cyclic AMP (cAMP)/mg protein per min; P less than 0.01). Dose-response curves showed a significantly greater stimulation of adenylate cyclase activity in the positive group at forskolin concentrations of 10(-7) to 2 x 10(-4) mol/l. The median effective dose (ED50) and adenylate cyclase activity in the absence of forskolin were similar in both groups. We conclude that lymphocyte forskolin-stimulated adenylate cyclase activity may depend in part on hereditary factors associated with a familial predisposition to essential hypertension.

Adenylyl Cyclases↗
PubMed1989

Alpha 2- and beta 2-adrenoceptor downregulation in marathon runners.

The regulation of platelet alpha 2- and lymphocyte beta 2-adrenoceptor densities by alterations in endogenous catecholamines was examined. In order to activate the sympathetic nervous system eight trained male normotensive subjects carried out a marathon run. Adrenoceptor densities and plasma catecholamine concentrations were measured before and immediately after the run. Platelet alpha 2-adrenoceptor density and lymphocyte beta-adrenoceptor density decreased after the run (P less than 0.05), whereas both plasma noradrenaline and adrenaline concentrations increased (P less than 0.01). Mean arterial pressure decreased (P less than 0.05), and the heart rate increased (P less than 0.001). The data suggest that increases in endogenous catecholamine concentrations cause downregulation of both alpha- and beta-adrenoceptor densities on human blood cells.

Adult↗