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Biomedical subjects

F C Luft

Publications and source records attributed to F C Luft.

At least 379 records · Page 21Linked to original sources
PubMed1993

Effect of ACE inhibitors on atrial natriuretic factor in the brains of rats with reduced renal mass.

We tested the effect of renal insufficiency, with and without angiotensin (Ang) converting enzyme (ACE) inhibition, on blood and brain atrial natriuretic factor (ANF) in rats. Two ACEs, one which penetrates into the CNS and one which does not, were used to distinguish between peripheral and central ACE effects. Rats underwent 5/6 nephrectomy (5/6-NPX) by ligation of renal arterial branches. After seven days, 28 5/6-NPX rats received lisinopril 20 mg/kg/day and 28 5/6-NPX rats received quinapril 30 mg/kg/day orally for five days, while 28 5/6-NPX control rats and 28 sham rats did not. Body weight, blood pressure, drinking and urine volume were monitored. At sacrifice, urine, plasma, and brain tissue was collected. ANF in 16 brain areas was measured by radioimmunoassay. 5/6-NPX resulted in increased blood pressure, increased urine volume, proteinuria, and increased drinking. Both ACEs lowered blood pressure to sham values and decreased proteinuria. Both ACEs increased plasma renin activity and decreased plasma ANF. However, only lisinopril decreased drinking and urine volume. 5/6-NPX increased ANF values in six brain areas, namely the periventricular preoptic nucleus, the arcuate nucleus, the perifornical nucleus, the periventricular hypothalamic nucleus, the paraventricular nucleus, and the dorsal raphe nucleus compared to sham rats. These same increases in brain ANF were also observed in 5/6-NPX rats given quinapril, compared to shams. However, lisinopril lowered ANF to sham levels in the periventricular preoptic nucleus, the arcuate nucleus, and the perifornical nucleus. In the three additional brain areas, namely the periventricular hypothalamic nucleus, the paraventricular nucleus, and the dorsal raphe nucleus, lisinopril did not effect the elevated ANF concentrations.(ABSTRACT TRUNCATED AT 250 WORDS)

Angiotensin-Converting Enzyme Inhibitors↗
PubMed1993

Vascular conversion of angiotensin I in stroke-prone spontaneously hypertensive and Wistar-Kyoto rats.

OBJECTIVE: Linkage studies have shown that the gene locus for angiotensin converting enzyme (ACE) is associated with the expression of hypertension in stroke-prone spontaneously hypertensive rats (SHRSP). We tested the hypothesis that the conversion of angiotensin I (Ang I) to angiotensin II (Ang II) in blood vessels is elevated in SHRSP. DESIGN: We measured the conversion rate of Ang I to Ang II during one pass through an isolated resistance vessel bed. We used the same substrains of SHRSP and Wistar-Kyoto control rats (WKY) that had been employed in the earlier linkage studies. METHODS: Isolated hindquarters from young and adult (10- to 12- and 36- to 38-week-old) rats were perfused with an artificial medium and then infused with Ang I at 0.5 and 2 pmol/ml. Ang I and II were measured with high-performance liquid chromatography and radioimmunoassay in hindquarter effluent and in blank control channels. Conversion and extraction rates were calculated from angiotensin levels in hindquarter and blank perfusion channels, respectively. RESULTS: The conversion rates of Ang I to Ang II did not differ between SHRSP and WKY in young or in adult rats. Captopril completely abolished the formation of Ang II in all groups of rats. During infusion at the higher dose of Ang I, the extraction of Ang I was significantly decreased in SHRSP compared with WKY. CONCLUSIONS: Our results are consistent with the notion that the metabolism of angiotensin is decreased in spontaneously hypertensive rats. However, we found no support for the hypothesis that vascular ACE is responsible for high blood pressure in SHRSP. These findings suggest that other genes close to the ACE locus or the hyperexpression of the enzyme in other areas may contribute to hypertension in these rats.

Aging↗
PubMed1993

Torasemide in the treatment of arterial hypertension.

An important role for diuretics in the treatment of hypertension is assured on the basis of the latest randomized, prospective trials. Although thiazide diuretics have been the mainstay of treatment thus far, they continue to engender debate because of putative, undesirable side effects. Older loop diuretics, such as furosemide, did not establish themselves in the treatment of essential hypertension because of an inferior efficacy profile compared with that of thiazides. Torasemide is a new loop diuretic that is efficacious at low once-daily doses in the treatment of essential hypertension. The drug compares favorably with hydrochlorothiazide and indapamide. Its mechanism of action may not be entirely based on elimination of salt and water from the body. Torasemide exhibits a favorable side-effect profile, particularly because it does not engender hypokalemia, increases in blood sugar, or serum lipid values. When the additional costs of potassium supplements or potassium-retaining medication are considered, torasemide treatment also compares favorably in terms of health-care economics. Torasemide represents a reasonable alternative to conventional diuretic management in patients with essential hypertension.

Diuretics↗
PubMed1993

A highly selective cardiorenal serotonergic 5-HT3-mediated reflex in rats.

To elucidate whether prolonged stimulation of cardiopulmonary serotonergic (5-HT3) receptors could play a role in the control of renal sympathetic nerve activity (RSNA), we compared 15-min intravenous infusions to bolus administrations of the 5-HT3 receptor agonist phenyl biguanide (PBG) and to a 0.9% saline load (5% body wt) in rats. Short-term and prolonged stimulation of 5-HT3-sensitive cardiopulmonary reflexes caused dose-related decreases in RSNA but not in lumbar sympathetic nerve activity (LSNA); only short-term stimulation caused decreases in blood pressure (BP) and heart rate (HR). Saline loading lowered RSNA but not LSNA, BP, or HR. Baroreceptor denervation did not influence any of these responses. Scopolamine attenuated BP and HR but not RSNA responses to bolus PBG. Pretreatment with a 5-HT3 receptor antagonist inhibited responses to PBG but not to saline. Vagotomy abolished all responses to all interventions. Thus 1) the prolonged stimulation of cardiopulmonary 5-HT3 receptors caused sustained suppression of RSNA, 2) decreased BP and HR were manifest only during short-term stimulation (3 min), and 3) blockade of 5-HT3 receptors did not influence responses to cardiopulmonary mechanoreceptor stimulation.

Animals↗
PubMed1993

Angiotensin II facilitates sympathetic transmission in rat hind limb circulation.

We developed a novel method to stimulate the sympathetic innervation of the isolated, perfused rat hind limb to investigate whether a subpressor concentration of angiotensin II (Ang II) facilitates noradrenergic transmission in the vascular bed to skeletal muscle. We electrically stimulated the lumbar sympathetic trunk while perfusing the preparation with artificial medium. Seventy-five percent of the resulting frequency-dependent increases in perfusion pressure were mediated by alpha 1-adrenergic receptors. Ang II (10 nM) significantly enhanced the effects of nerve stimulation at 1 and 10 Hz (by 42% and 35%, respectively). At a supramaximal stimulation frequency (20 Hz), Ang II prolonged the duration of the response without changing the peak increase in pressure. The reuptake inhibitor cocaine did not influence the effects of Ang II at 1 and 10 Hz but blocked the effect at 20 Hz. To control for nonspecific synergism with norepinephrine, we compared Ang II with vasopressin. Both peptides potentiated the pressor response to exogenous norepinephrine; however, vasopressin did not change the pressor response to nerve stimulation at any frequency. We conclude that Ang II, but not vasopressin, facilitates noradrenergic transmission in skeletal muscle resistance vessels, independent of its direct vasoconstrictor activity. The neurovascular preparation we describe may be useful in addressing other hypotheses concerning sympathetic transmission in skeletal muscle resistance vessels.

Angiotensin II↗
PubMed1993

Angiotensinogen is cleaved to angiotensin in isolated rat blood vessels.

The cleavage of synthetic tetradecapeptide renin substrate has been used to infer the presence of renin in the walls of isolated blood vessels; however, the conversion of natural angiotensinogen to angiotensin in isolated blood vessels has not been reported. We studied the release of angiotensinogen and the formation of angiotensins in a bloodless, perfused, isolated hind limb preparation of the rat. Perfusion with a modified Tyrode's solution resulted in spontaneous release of 4.7 +/- 1.5 pmol per 30 minutes of angiotensinogen as measured directly by radioimmunoassay. Western blot further identified the released material as angiotensinogen. Spontaneous release of angiotensins I and II was demonstrated by high performance liquid chromatography and radioimmunoassay. When highly purified rat angiotensinogen was added to the perfusate, release of angiotensin II was increased 14-fold compared with saline infusion. Captopril (10 mumol/L) inhibited angiotensinogen-induced angiotensin II release by 67% and led to an increase in angiotensin I release by 301%. Bilateral nephrectomy 24 hours before the experiments reduced basal angiotensin release below the detection limit and blunted angiotensinogen-induced angiotensin II formation by 95%. We conclude that active renin is present in the vessel wall and interacts with its natural substrate to form angiotensin peptides. Our data support the notion that the bulk of vascular renin is taken up from the circulation.

Angiotensin I↗
PubMed1993

Early interstitial changes in hypertension-induced renal injury.

To elucidate the mechanisms of hypertensive renal injury, we investigated the time course and extent of changes in matrix composition, as well as cell proliferation and infiltration in two-kidney, one clip rats. The nonclipped kidneys from hypertensive and sham-operated control rats (n = 5 to 10 in each group) were studied at 7, 14, 21, and 28 days after clipping. Systolic blood pressure was elevated by day 7 (154 +/- 3 versus 111 +/- 4 mm Hg in sham group, P < .001, n = 10 each). Hypertension resulted in an early expansion of the interstitial volume by 37%, whereas hypertensive vascular changes and glomerular injury did not become evident until day 21. Immunofluorescence studies revealed an early interstitial accumulation of collagens I, III, IV, V, VI, and fibronectin by day 7. In contrast, the glomeruli showed a mild to moderate increase in collagens I, III, IV, V, laminin, and fibronectin but not collagen VI later in the established phase of hypertension. Staining for proliferating cell nuclear antigen as a marker of cell replication was increased in tubular epithelial but not interstitial or glomerular cells. A progressive infiltration of macrophages (16 +/- 2 versus 9 +/- 1 ED1+ cells/mm2, P < .05, n = 6) and T lymphocytes (93 +/- 15 versus 74 +/- 7 CD4+ cells/mm2, n = 8) in the cortical interstitium had already occurred by day 7. On the other hand, only macrophages increased in number within the glomeruli. Thus, renovascular hypertension leads to an early tubular cell proliferation, mononuclear cell recruitment, and deposition of matrix proteins primarily within the interstitium. We conclude that the injury producing nephrosclerosis in this model extends far beyond the glomeruli. Both the tubules and the interstitium are actively involved and may be the more important initial sites of injury.

Animals↗
PubMed1993

Na+/H+ exchange in human lymphocytes and platelets in chronic and subacute metabolic acidosis.

The effect of acid-base disturbances on sodium/proton (Na+/H+) exchange has been examined in animal models; however, few data are available from human studies. To test the effect of metabolic acidosis on Na+/H+ exchange in man, as well as to examine the relationship between Na+/H+ exchange and cytosolic calcium ([Ca2+]i), we measured both variables in patients with decreased renal function with mild metabolic acidosis (pH 7.34 +/- 0.06), in normal control subjects (pH 7.41 +/- 0.02), and in subjects before (pH 7.40 +/- 0.01), and after (pH 7.26 +/- 0.04) ammonium chloride (NH4Cl) 15 g for 5 d. Lymphocytes and platelets were loaded with the cytosolic pH (pHi) indicator 2'-7'-bis(carboxyethyl)-5,6-carboxyfluorescein and acidified to pH approximately 6.6 with propionic acid. To quantitate Na+/H+ exchange, dpHi/dt was determined at 1 min. [Ca2+]i was measured with fura-2. Na+/H+ exchange was significantly increased only in lymphocytes of patients with renal insufficiency. Neither intracellular pH (pHi) nor [Ca2+]i was different from controls. NH4Cl resulted in a significant increase in Na+/H+ exchange in lymphocytes, but not in platelets of normal subjects. Values of pHi and [Ca2+]i in either cell type remained unaffected. Since metabolic acidosis influenced Na+/H+ only in lymphocytes, but not in platelets, it is possible that protein synthesis may be involved in increasing Na+/H+ exchange.

Acidosis↗
PubMed1993

Calcium antagonists and renal protection.

A growing body of evidence supports the notion that calcium antagonists exert a renal protective effect. Calcium antagonists may play an important future role in renal hemodynamics related to their reversal of renal vasoconstrictors. Calcium antagonists are also capable of blocking intracellular calcium overload induced by various types of ischemia or toxic stimuli. Features such as these may be of substantial value in ameliorating acute renal insufficiency secondary to renal ischemia, iodinated radiographic contrast media, or the administration of various nephrotoxic drugs. The latter includes agents such as the aminoglycoside antibiotics, cyclosporine A, and the cancer chemotherapeutic agent cisplatin. Recent prospective, controlled studies from our group indicate that calcium antagonists protected against postischemic acute renal failure in the setting of cadaveric renal transplantation. Moreover, in a prospective, randomized, controlled clinical trial, we were able to demonstrate that the prophylactic use of nitrendipine reduced the decrease in GFR in patients receiving radiographic contrast agents. Such protection may extend to favorably influencing the course of chronic renal insufficiency, particularly when the latter is complicated by hypertension. Seven putative mechanisms have been proposed by which calcium antagonists may ameliorate the decline in GFR associated with renal insufficiency. These are: (a) reduction in blood pressure per se, (b) reduction in renal hypertrophy, (c) modulation of mesangial traffic of macromolecules, (d) reduction in metabolic activity in remnant renal tissue, (e) amelioration of uremic nephrocalcinosis, (f) reduction of pressure-induced calcium entry into vessel walls, and (g) reduction of free radical formation. Experimental investigations in rats with reduced renal mass, desoxycorticosterone-induced hypertension, or chronic angiotensin II infusion, and in spontaneously hypertensive rats support such a view.

Animals↗
PubMed1993

Calcium channel blockers in current medical practice: an update for 1993.

Calcium channel blocking drugs (CCB) have been used to lower blood pressure since 1970. Three classes are currently available, the phenylalkylamines, the benzothiazepines, and the dihydropyridines. The structure of the L-type, voltage dependent calcium channel has been elucidated with molecular techniques and the different binding sites of the various CCB described. CCB have specific effects at the site of target organs. In the kidney, all classes produce natriuresis. Their action appears independent of the level of salt intake. CCB may favorably influence the course of chronic renal disease; the results of a trial comparing nifedipine to the converting enzyme inhibitor captopril showed no difference between the two drugs. CCB may impede the progression of atherosclerosis in the coronary arteries; a prospective study of nifedipine on coronary artery morphology supports this view. In the brain, nimodipine improves the outcome of patients with stroke from subarachnoid hemorrhage. Positive effects on patients with ischemic stroke have not been corroborated. CCB are approved primary treatment for patients with hypertension and are readily combined with other antihypertensive agents. They are well tolerated and have no adverse metabolic side effects. The advent of molecular pharmacology will advance current efforts to develop new CCB, which are highly selective in their site and mode of action.

Brain↗
PubMed1993

Angiotensinogen mRNA and pressor reactions to angiotensin in brain stem areas of spontaneously hypertensive rats.

The role of angiotensin (ANG II) at the tissue level, particularly in the brain, remains imperfectly defined. We measured angiotensinogen (A degrees) mRNA in the brain stems, sensory and sympathetic ganglia, and blood vessels of Wistar-Kyoto (WKY) and stroke-prone spontaneously hypertensive rats (SHR-SP) by quantitative, liquid hybridization. We micro-injected ANG II and glutamate into the brain stems of these rats to gain insight into the functional significance of our findings. A. mRNA was found in the dorsolateral, dorsomedial, and ventrolateral pons, as well as in the dorsolateral, dorsomedial, and ventrolateral medulla of both strains. A degrees mRNA was 8-10 pg/micrograms total mRNA higher (p < 0.05) in the dorsomedial medulla (nucleus tractus solitarii) in WKY and SHR-SP (28.27 +/- 1.26 and 33.50 +/- 1.42 pg/micrograms RNA respectively) than in the other areas. SHR-SP had higher values (27.22 +/- 1.77 vs. 21.53 +/- 0.57 pg/micrograms mRNA) than WKY (p < 0.05) in the dorsolateral pons (locus coeruleus). A. mRNA was also identified in the optic nerves and chiasm, trigeminal and coeliac ganglia, arteries and veins. Injections of glutamate and ANG II into the dorsomedial, dorsolateral, and ventrolateral medulla increased blood pressure, while ANG II in the dorsal medial pons did not. We conclude that A degrees mRNA is produced to different degrees in brain stem areas which participate in blood pressure regulation. Medullary structures show more response to local ANG II than pontine structures. A degrees mRNA is located in sensory neural tissues as well as sympathetic ganglia. A degrees mRNA is present in both arteries and veins. These findings underscore the scope and complexity of ANG production in tissues.

Angiotensin II↗
PubMed1993

Ibuprofen as an over-the-counter drug: is there a risk for renal injury?

Ibuprofen has recently been introduced as over-the-counter drug in several countries. The question has been raised whether or not the increased availability and use of ibuprofen as over-the-counter drug will be associated with an increased incidence of nephrotoxic side-effects. It is unquestionable that ibuprofen can cause renal damage, including functional acute renal failure, water and electrolyte disorders, and interstitial nephritis. Analgesic nephropathy is not a documented consequence of ibuprofen therapy. Renal side-effects of ibuprofen appear to be dose-dependent, and were not reported at the recommended dosage as over-the-counter drug (0.2-0.8 g/d) except for a single child. Even at anti-inflammatory doses (> 1.6 g/d), renal side-effects are almost exclusively encountered in patients with low intravascular volume and low cardiac output particularly in old age. Alternative analgesic and antipyretic agents display no less risk for renal injury than ibuprofen.

Acute Kidney Injury↗
PubMed1993

Body fluid alterations during head-down bed rest in men at moderate altitude.

To determine the effects of hypoxia on fluid balance responses to simulated zero-gravity, measurements were made in six subjects (acclimatized to 5,400 ft; 1,646 m) before and during -5 degrees continuous head-down bed rest (HDBR) over 8 d at 10,678 ft. The same subjects were studied again at this altitude without HDBR as a control (CON) using a cross-over design. During this time, they maintained normal upright day-time activities, sleeping in the horizontal position at night. Fluid balance changes during HDBR in hypoxia were more pronounced than similar measurements previously reported from HDBR studies at sea level. Plasma volume loss (-19% on day 6) was slightly greater and the diuresis and natriuresis were doubled in magnitude as compared to previous studies in normoxia and sustained for 4 d during hypoxia. These changes were associated with an immediate, but transient rise in plasma atrial natriuretic peptide (ANP) to day 4 of 140% in HDBR and 41% in CON (p < 0.005), followed by a decline towards baseline. Differences were less striking between HDBR and CON for plasma antidiuretic hormone and aldosterone, which were transiently reduced by HDBR. Plasma catecholamines showed a similar pattern to ANP (+122%) in both HDBR and CON, suggesting that elevated ANP and catecholamines together accounted for the enhanced fluid shifts with HDBR during hypoxia.

Adult↗
PubMed1993

Twenty-five years of renal transplantation from a single center: a risk factor analysis for short- and long-term outcomes.

Between 1966 and 1991 a total of 1000 renal transplants were performed in Erlangen-Nuremberg. Patients were operated upon in Erlangen and transferred immediately 25 km to Nuremberg for their postoperative and immunosuppressive care. Despite these considerable logistical obstacles, the 10-year graft survival rate in 785 consecutive transplants performed between 1980 and 1990 was 44%, while patient survival was 84%. Mismatch at the HLA-DR locus, preformed antibodies, multiple transplants, and kidneys from donors aged 10 years or younger or over 60 years were risk factors for decreased graft survival. An immunosuppressive regimen of cyclosporine and methylprednisolone resulted in better graft survival than did azathioprine and methylprednisolone, or reduced-dose cyclosporine, azathioprine, and methylprednisolone. The cyclosporine and methylprednisolone regimen had a better patient survival than azathioprine and methylprednisolone. A hazard analysis demonstrated a particular risk of late rejection between the 70th and 90th months, after transplantation. Our data indicate that favorable transplant results can be obtained despite major logistical disadvantages. Very close cooperation between referring centers, transplant surgeons, and nephrologists is indispensable for success.

Adolescent↗