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F C Luft

Publications and source records attributed to F C Luft.

At least 343 records · Page 19Linked to original sources
PubMed1995

Effects of human renin in the vasculature of rats transgenic for human angiotensinogen.

Transgenic rats, which express the human angiotensinogen gene, provide a unique model for studying local vascular effects of human renin. We examined the cleavage of human angiotensinogen to angiotensin I (Ang I) by human renin and its inhibition by a human renin inhibitor in an isolated perfused hindlimb preparation from such rats. Perfusion resulted in the sustained release of human angiotensinogen, which decreased from 19.4 to 11.8 pmol/mL over 45 minutes. Active human renin at doses of 3, 10, and 30 ng/mL perfusate for 15 minutes increased Ang I release from undetectable levels (mean +/- SEM) to 31.9 +/- 3.3, 147.1 +/- 26.2, and 206.4 +/- 17.1 fmol/mL, respectively, by 9 minutes. In separate experiments aimed at the quantification of renin-induced vasoconstriction, captopril decreased the perfusion pressure and lowered Ang II concentrations to nondetectable levels, whereas Ang I values increased sharply. When renin (30 ng/mL) was infused for 15 minutes, renin values in the perfusate decreased to barely detectable levels within minutes after termination of the infusion. However, Ang I values remained high for at least 30 minutes thereafter. The addition of a human renin inhibitor during renin infusion caused Ang I values to promptly decrease within minutes to undetectable levels. Hindlimbs from non-transgenic control rats released no detectable amounts of Ang I, with or without human renin. Finally, by in situ hybridization we documented the presence of human angiotensinogen message in the vessels of the hindlimb. We conclude that renin acts on angiotensinogen at a site in the vascular wall. The cleavage depends on renin and not on other lysosomal proteases.(ABSTRACT TRUNCATED AT 250 WORDS)

Angiotensin I↗
PubMed1995

Effect of captopril and angiotensin II receptor blockade on pressure natriuresis in transgenic TGR(mRen-2)27 rats.

The pressure-natriuresis curve of transgenic rats harboring an extra mouse renin gene [TGR(mRen-2)27] is shifted rightward compared with controls; however, whether intrarenal angiotensin II effects are responsible for the rightward shift is unknown. To clarify this issue we infused the converting enzyme inhibitor captopril or the angiotensin II receptor blocker CV 11974 into transgenic and normotensive Sprague-Dawley Hannover control rats. We eliminated any other neural or endocrine regulatory differences between transgenic and control rats by renal denervation and infusion of vasopressin, aldosterone, corticosterone, and norepinephrine in sufficient quantities to occupy all receptors. Sodium excretion increased from 3.4 +/- 1.2 to 10.1 +/- 0.5 mumol/min per gram kidney weight in transgenic rats when renal perfusion pressure was increased from 158 to 201 mm Hg. Captopril (4 mg/kg) and CV 11974 (0.1 mg/kg) shifted the pressure-natriuresis curve of transgenic rats leftward, so that sodium excretion was threefold higher at similar renal perfusion pressures (150 to 160 mm Hg). Similarly, fractional sodium and water excretion curves were shifted leftward, so that values for transgenic and control rats were no longer different. Over the pressure range, renal blood flow in transgenic rats ranged from 3.1 +/- 0.7 to 4.4 +/- 0.5 mL/min per gram kidney weight and increased (P < .05) with both captopril and CV 11974 to ranges from 4.8 +/- 0.9 to 6.8 +/- 0.6 or from 4.5 +/- 0.7 to 6.9 +/- 1.0 mL/min per gram kidney weight, respectively. Glomerular filtration rate in transgenic rats, on the other hand, was not increased. Transgenic kidneys showed severe hypertension-induced nephrosclerosis.(ABSTRACT TRUNCATED AT 250 WORDS)

Angiotensin II↗
PubMed1995

Differentiation of vascular smooth muscle cells and the regulation of protein kinase C-alpha.

Dedifferentiation and proliferation of vascular smooth muscle cells (VSMCs) are important features of atherosclerosis. The molecular mechanisms are largely unclear; however, protein kinase C (PKC) is a key enzyme in the intracellular signaling pathways that mediate this process. We studied the activity and immunoreactivity of PKC-alpha in primary cultures of VSMCs from rat aortas under different conditions of growth and differentiation. PKC-alpha was determined under the following conditions: (1) during the growth phase and after confluence of cultured (passages 1 through 3) VSMCs, (2) before and after induction of differentiation in VSMCs by retinoic acid, and (3) in primary cultures of VSMCs from spontaneously hypertensive rats (SHR) and Wistar-Kyoto (WKY) rats during early passages. PKC activity was measured by in vitro substrate phosphorylation. PKC-alpha immunoreactivity was assessed by Western blot using specific polyclonal antibodies and by immunostaining with confocal microscopy. Cell proliferation was measured by direct count. The cell phenotype was characterized by immunostaining and Western blot for alpha-actin and desmin. PKC-alpha expression and PKC activity during VSMC growth showed a decrease during rapid growth and an increase in confluent cells. This pattern was associated with the respective changes in cell differentiation. Retinoic acid induced an increase in PKC-alpha expression together with a more differentiated phenotype. Subcultured, rapidly growing VSMCs from SHR showed a decreased PKC-alpha expression compared with cells from WKY rats. To establish cause and effect, we next microinjected either PKC-alpha or inactivated material directly into dedifferentiated cells. We found that cells injected with active PKC-alpha expressed increased amounts of actin compared with control cells.(ABSTRACT TRUNCATED AT 250 WORDS)

Actins↗
PubMed1995

Pharmacodynamics of atrial natriuretic peptide in isolated perfused Dahl rat kidneys.

Atrial natriuretic peptide (ANP) has been implicated in the development of hypertension in Dahl R and S rats. To test the responses of DR and DS kidneys in the absence of the influence of neural and humoral mechanisms, we investigated the pharmacokinetics and pharmacodynamics of ANP in isolated perfused DR and DS kidneys, obtained from rats given a high or low sodium diet, after a bolus injection of ANP (1 microgram) or after a bolus injection plus infusion of ANP to maintain the perfusate concentration at 1000 pg/ml. The elimination rate constant was not different between the groups (DR, 0.044 min-1 vs. DS, 0.050 min-1). Clearance of ANP was 4 times greater than the glomerular filtration rate, indicating that a receptor-mediated peritubular clearance is probably the primary route of elimination. DS kidneys excreted 50% less sodium than DR kidneys. However, ANP caused a 5-fold increase in fractional sodium excretion in both DR and DS. ANP also increased sodium excretion, creatinine clearance, and urine flow. No alteration in ANP kinetics occurred to account for the reportedly increased circulating concentrations of ANP seen in DS rats. We conclude that isolated DR and DS kidneys respond differently to ANP after bolus ANP administration to concentrations of 10,000 pg/ml. This difference in response is due to the sodium excretory defect inherent in the DS kidney and not to an alteration in the DS kidney's ANP responsiveness.

Animals↗
PubMed1995

Angiotensin II-induced hypertension: effects on central and peripheral atrial natriuretic peptide.

Angiotensin (Ang) II and atrial natriuretic peptide (ANP) have opposing effects on blood pressure, sympathetic activity, vasopressin and ACTH secretion, salt appetite, and drinking. We observed their interaction by infusing Ang II (7.2 nmol/h) into the peritoneum (i.p.) or into the lateral ventricle (i.c.v.) of rats with osmotic minipumps for seven days. At sacrifice, rats receiving Ang II-i.c.v. had a systolic blood pressure of 184 +/- 3 (SEM) mmHg, those receiving Ang II-i.p. had 159 +/- 5 mmHg (p < 0.05), while controls had 109 +/- 2 and 110 +/- 2 mmHg, respectively (p < 0.05). Drinking and urine volume increased similarly in rats receiving Ang II by either route, while Uosm decreased. Renin (PRA) values were lower (p < 0.05) in rats receiving Ang II-i.c.v. (0.7 +/- 0.2 ng Ang l/ml/h) or Ang II-i.p. (0.9 +/- 0.2) than in the respective controls (2.3 +/- 0.7 and 2.0 +/- 0.3). Plasma ANP values with Ang II-i.c.v. (18 +/- 1.6 pg/ml) or with Ang II-i.p. (49 +/- 6) were also lower (p < 0.05) than respective controls (89 +/- 12, 76 +/- 4). Vasopressin (AVP) concentrations in the plasma were not influenced by the regimens. In the brain, the ANP contents in areas of the so-called AV3V-region (organum vasculosum laminae terminalis, preoptic periventricular nucleus, medial preoptic nucleus) were similarly and significantly reduced by both Ang II-i.c.v. and Ang II-i.p.. ANP values were also reduced in the median eminence by both types of Ang II-treatment, while ANP concentrations in the supraoptic nucleus were increased. The data show that Ang II infusions producing a chronic rise in blood pressure exert similar effects on drinking behavior, PRA, and ANP concentrations in blood and brain. The AV3V area may be pivotal to both models.

Angiotensin II↗
PubMed1995

Pinacidil relaxes porcine and human coronary arteries by activating ATP-dependent potassium channels in smooth muscle cells.

We investigated the effect of the potassium channel opener pinacidil on ATP-dependent K+ channels (KATP) in the relaxation of porcine and human coronary arteries by means of isometric contraction experiments in arterial rings. We also measured whole cell currents in freshly isolated porcine and human coronary artery vascular smooth muscle cells with patch clamp. We first characterized serotonin-induced precontractions in our vessels and proved that the contractions were mediated by Ca2+ influx through voltage-dependent Ca2+ channels. Similarly, we observed that serotonin-induced contractions were strongly enhanced by small K(+)-induced depolarizations. Pinacidil completely relaxed rings preconstricted with 5 microM serotonin and produced dose-dependent relaxations of 5 microM serotonin-preconstricted rings, with an IC50 of 1.26 microM. Similar results were observed (IC50 = 1.15 microM) when the endothelium was removed. The KATP blocker glibenclamide (3 microM), inhibited pinacidil-induced relaxations (5-10 microM) by approximately 25% although the KATP blocker tetrapentylammonium (10 microM), inhibited pinacidil-induced (5-10 microM) relaxations completely. Pinacidil 10 microM had only a minimal effect on rings precontracted with a 50 mM external K+ concentration (IC50 = 60 microM). Porcine and human arterial rings did not differ qualitatively in their responses. Moreover, in the patch clamp experiments pinacidil (1 microM and 20 microM) induced a large, nonrectifying, outward current in both human and porcine cells. The reversal potential was close to the K+ equilibrium potential, suggesting an induction of pinacidil-activated K+ current. The pinacidil-induced (1 microM) current was strongly inhibited by glibenclamide (3 microM). These data show that the relaxation of porcine and human coronary arteries by pinacidil is primarily induced by an opening of KATP in smooth muscle cells. Furthermore, the vasorelaxant effect of pinacidil is not endothelium dependent.

Animals↗
PubMed1995

Effect of exogenous mineralocorticoid on platelet cytosolic calcium in normal humans.

We tested the hypothesis that the fludrocortisone in doses sufficient to elevate blood pressure (BP) in normal subjects would increase platelet cytosolic calcium. Eight normal volunteers were given 0.8 mg fludrocortisone daily for 7 days (short protocol). Eight other normal volunteers ingested the drug for 6 weeks (long protocol). In the short protocol, fludrocortisone increased platelet cytosolic calcium and body weight by day 3, while BP was increased by day 7. In the long protocol, platelet cytosolic calcium was increased after 1 week, returned to basal values by 3 weeks and remained at that level for the rest of the study. Stimulation of the subjects' platelets ex vivo with thrombin and vasopressin led to a significant increase in intracellular free calcium concentration; however, fludrocortisone treatment did not alter the calcium response to either agonist. Fludrocortisone decreased serum potassium, plasma renin activity, plasma noradrenaline concentration and serum ionised calcium. These changes, as well as the BP increase, reverted to basal values when the drug was discontinued. We next incubated human platelets with fludrocortisone (1.4 nmol/l) and found a significant increase in cytosolic calcium by 30 min. The data suggest that a blood pressure-raising dose of mineralocorticoid leads to a transient (days to weeks) increase in platelet cytosolic calcium. Platelet cytosolic calcium and blood pressure are dissociated in that cytosolic calcium increases before the BP increase and later decreases to lower values, while the BP increase is sustained. Mineralocorticoid also has a direct effect on platelet cytosolic calcium in vitro.(ABSTRACT TRUNCATED AT 250 WORDS)

Adult↗
PubMed1995

Light-chain-induced renal tubular acidosis: effect of sodium bicarbonate on sodium-proton exchange.

We measured sodium-proton (Na+/H+) exchange in lymphocytes and platelets of a 46-year-old woman with the adult Fanconi syndrome before, during, and after treatment with NaHCO3. Kappa light chains in her urine and unique but rarely observed crystalline structures confirmed the presence of light-chain nephropathy. Her glomerular filtration rate was only moderately impaired at 72 ml/min. NaHCO3 at 1, 3, and 5 mmol/kg/day for 5 days increased her serum HCO3 and pH from 17 to 21 mmol/l and 7.28 to 7.39 respectively. Plasma renin and aldosterone values were decreased by NaHCO3. Na+/H+ exchange (delta Hi/min) was measured with the fluorescent marker BCECF after acidification of lymphocytes and platelets with sodium propionate at five (10-50 mM) doses. Na+/H+ exchange was accelerated in this patient compared to normal controls. NaHCO3 treatment significantly decreased Na+/H+ exchange in lymphocytes, but not in platelets. These findings suggest that Na+/H+ exchange can be influenced by NaHCO3 ingestion at doses that only modestly affect systemic pH. Since Na+/H+ exchange is involved in stimulus response coupling, cell growth regulation, cell differentiation, and perhaps the progression of nephrosclerosis, these observations may have clinical relevance.

Acidosis, Renal Tubular↗
PubMed1995

[Legal liability in clinical trials from the viewpoint of the clinician].

After a long-term work in the U.S., the liability for clinical trials is explained. The researching physician carries the responsibility for new drugs. He has to apply for the license for the study by the appropriate authority and he carries the responsibility for the consent of the volunteers which have to be informed before the trial. The studies initiated by the pharmaceutical companies relieve the researching physician from some of the responsibilities. They exert a strong control during the drug tests. The researching physician has the responsibility as a "scholarly mediator". The ethic commission inspects all stages of the study.

Attitude of Health Personnel↗
PubMed1995

'Treasure your exceptions': what we can learn from autosomal-dominant inherited forms of hypertension.

OBJECTIVE: To discuss the relevance of rare monogenic forms of hypertension to the diagnosis, pathogenesis and treatment of essential hypertension. STUDY SELECTION: Three monogenic forms of hypertension have been identified that are inherited as a simple autosomal-dominant trait. The genetic defects and the pathophysiology of two, namely glucocorticoid-remediable aldosteronism and Liddle's syndrome, have been elucidated in great detail. The third form of monogenic hypertension, which cosegregates with a second phenotype, brachydactyly, is being investigated. RESULTS: Glucocorticoid-remediable aldosteronism is caused by the presence of a chimeric gene, which incorporates the regulatory region of the 11-beta-hydroxylase gene and the structural portion of the aldosterone synthase gene. The enzyme aldosterone synthase is not only expressed in the zona fasiculata but is also regulated by adrenocorticotrophic hormone in this condition. Liddle's syndrome is caused by mutations in the beta subunit of the epithelial sodium channel. The mutations result in inappropriate channel patency and increased distal sodium reabsorption. Both of these forms of inherited hypertension are low-renin forms of hypertension. Glucocorticoid-remediable aldosteronism resembles primary aldosteronism, whereas Liddle's syndrome resembles low-renin essential hypertension. An autosomal-dominant genetic form of hypertension has been described in northeastern Turkey. The hypertension cosegregates 100% with brachydactyly. This form resembles essential hypertension, because levels of renin, aldosterone, catecholamines and other regulators are normal. Furthermore, in contrast to glucocorticoid-remediable aldosteronism and Liddle's syndrome, the patients are not salt-sensitive. CONCLUSIONS: Mechanisms of mineralcorticoid hypertension, renally induced salt-sensitive hypertension, and possibly essential hypertension, may be elucidated by studying exceptional families.

Humans↗
PubMed1994

Posterior fossa neurovascular anomalies in essential hypertension.

Intraoperative observations, necropsy, and angiographic studies support the presumption that neurovascular compression of the left ventrolateral medulla may cause neurogenic hypertension. Pulsatile irritation of the ventrolateral medulla at the root-entry zone of cranial nerves IX and X increases blood pressure in animals. To identify and assess the distribution of neurovascular compression at the ventrolateral medulla in human beings, we did a prospective single-blind study in 24 patients with essential hypertension, in 14 patients with renal hypertension, and in 14 normal subjects. To detect neurovascular compression, we used axial and coronal double-echo and magnetic-resonance angiography sequences. Blood pressure control and duration of hypertension were not different in the two groups of patients. 20 patients with essential hypertension had magnetic tomographic evidence of left-sided neurovascular compression at the ventrolateral medulla; 2 patients with renal hypertension and 1 of the normal subjects had a positive finding on the left. On the right side, we found signs of neurovascular compression in 4 patients with essential hypertension, in 4 with renal hypertension, and in 2 of the normal subjects. With magnetic resonance tomography, it is possible to evaluate the neurovascular relations in the posterior fossa and detect neurovascular compression at the ventrolateral medulla. These data in living subjects give further evidence of an association between neurovascular compression at the left ventrolateral medulla and essential hypertension.

Adult↗
PubMed1994

Medical compared with surgical treatment for massive pulmonary embolism.

We compared embolectomy (when available) with thrombolysis in patients with shock and massive pulmonary embolism. 13 patients were operated on, 10 (77%) of whom survived. The inferior vena cava was routinely clipped. The 24 medically treated patients were given alteplase until systemic and pulmonary artery pressures stabilised and heparin thereafter; 16 (67%) survived. Major haemorrhage occurred in 28% of medically treated patients, but was not fatal. 1 patient had a small cerebral haemorrhage that resolved without drainage. One-fifth of the medical group had a re-embolism, which suggests that temporary caval umbrellas are indicated in medically treated patients. Thrombolysis may provide a life-saving option and a randomised trial is warranted.

Adult↗