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Biomedical subjects

W H Beierwaltes

Publications and source records attributed to W H Beierwaltes.

At least 19 recordsLinked to original sources
PubMed1992

Endothelium modulates renal blood flow but not autoregulation.

Inhibition of the production of the endothelium-derived relaxing factor (EDRF) nitric oxide using N omega-nitro-L-arginine methyl ester (L-NAME) increases blood pressure (BP) and decreases renal blood flow (RBF), suggesting that basal EDRF can modulate both systemic resistance and renal perfusion. We tested whether L-NAME inhibition of EDRF could also change the autoregulation of RBF. Blood pressure and RBF were measured in Inactin-anesthetized Sprague-Dawley rats. A bolus of 10 mg/kg body wt of L-NAME produced the maximum pressor response (23 +/- 3 mmHg) and blocked acetylcholine-induced renal vasodilation. In control rats, sequential changes in renal perfusion pressure showed that RBF was well autoregulated down to 95 +/- 2 mmHg. L-NAME increased BP, decreased RBF by 33% (P less than 0.005), and increased renal vascular resistance twofold. Although RBF was decreased, the kidney was still able to autoregulate RBF, although reset around the lower flow. Acute hypertension by carotid occlusion and vagotomy increased BP by 26 +/- 6 mmHg (P less than 0.005) and slightly increased RBF, while autoregulation was maintained. The pressor response to L-NAME was amplified to 38 +/- 6 mmHg (P less than 0.001), but RBF decreased by 35% (P less than 0.01). Autoregulation of RBF was maintained, although reset around the lower flow. We conclude that, although endothelial EDRF production may help maintain RBF, it does not seem to mediate the intrinsic autoregulatory responses of the renal vasculature to altered renal perfusion pressure.

Animals↗
PubMed1992

Endothelium-derived relaxing factor regulates renin release in vivo.

Endothelium-derived relaxing factor (EDRF), through its inhibitory second messenger guanosine 3',5'-cyclic monophosphate (cGMP), inhibits renin release in vitro. To determine whether EDRF affects renin in vivo, we tested whether EDRF synthesis inhibition could stimulate renin secretion in intact rats. Because EDRF synthesis inhibition increases blood pressure and consequently withdraws sympathetic activity (both renin inhibitory signals), we also studied the effect of L-N omega-nitroarginine methyl ester (L-NAME) when renal perfusion pressure was controlled and during beta-adrenergic blockade. Mean blood pressure (BP), heart rate (HR), and plasma renin activity (PRA) were measured in anesthetized rats before and after EDRF synthesis inhibition by a 10 mg/kg body wt bolus of L-NAME. L-NAME decreased PRA by 67% [from 11.0 +/- 2.7 to 3.7 +/- 0.8 ng angiotensin I (ANG I).ml-1.h-1, n = 12; P less than 0.001], increased BP by 20 +/- 2 mmHg (P less than 0.001), and decreased HR from 332 +/- 8 to 312 +/- 9 beats/min (P less than 0.005). We repeated our experiment in rats instrumented with an intra-aortic balloon catheter to control renal perfusion pressure and pretreated with propranolol to eliminate the beta-adrenergic effect. Under these conditions, L-NAME now increased PRA by 55% (from 6.9 +/- 1.9 to 10.8 +/- 2.6 ng ANG I.ml-1.h-1, n = 12; P less than 0.02), whereas renal perfusion pressure was unchanged (91 +/- 4 vs. 90 +/- 4 mmHg). HR increased slightly from 308 +/- 5 to 315 +/- 3 beats/min (P less than 0.005).(ABSTRACT TRUNCATED AT 250 WORDS)

Animals↗
PubMed1992

Submandibular enzymatic vasoconstrictor messenger RNA in rat kidney.

Recently, we reported the isolation and identification of a potent vasoconstrictor enzyme from the rat submandibular gland, a member of the rat kallikrein gene family, which we named submandibular enzymatic vasoconstrictor (SEV). We studied whether messenger RNA (mRNA) for SEV is present in the kidney and isolated glomeruli, using the polymerase chain reaction assay with primers specific to the entire rat kallikrein family that would amplify a 430-bp fragment from their mRNA. As a probe we used a phosphorus-32-labeled oligonucleotide specific for SEV mRNA. A fragment of the predicted size was obtained on Southern blot for amplified renal RNA; however, no signal was obtained with glomerular RNA. To further confirm the presence of SEV mRNA in the kidney, polymerase chain reaction was repeated using primers specific to SEV mRNA that would amplify a 372-bp fragment from SEV mRNA alone. Again, a fragment of the predicted size was obtained on Southern blot after amplification of renal RNA but not RNA from the glomeruli. Southern blot of polymerase chain reaction-amplified RNA with primers that amplified the entire kallikrein gene family, using kallikrein complementary DNA that recognizes all members of the kallikrein gene family as a probe, revealed a 430-bp fragment for both renal and glomerular RNA, indicating that glomeruli contain mRNA for a member or members of the kallikrein family other than SEV. When the Southern blots were hybridized with a 32P-labeled oligonucleotide probe specific for glandular kallikrein, a fragment of the predicted size was obtained from amplified renal RNA but not glomerular RNA.(ABSTRACT TRUNCATED AT 250 WORDS)

Animals↗
PubMed1992

Nonprostanoid endothelium-derived factors inhibit renin release.

Although endothelium-derived prostaglandin I2 stimulates renin release, exogenous endothelium-derived relaxing factor (EDRF) can inhibit it. To characterize the role of EDRF as an endogenous regulator of renin release, we inhibited or stimulated its production in rat renal cortical slices in vitro. Renin concentration in the incubation medium was determined by radioimmunoassay for angiotensin I (Ang I) generation. NG-Monomethyl-L-arginine (LNMMA) (10(-4) M), which blocks EDRF formation, significantly enhanced basal renin release from kidney slices by more than 50% in control medium (40.0 +/- 14.3 ng Ang I/hr/mg/30 min; p less than 0.01) or in medium treated with 1.6 x 10(-5) M meclofenamate (50.8 +/- 8.4 ng Ang I; p less than 0.025). Isoproterenol (10(-5) M)-stimulated renin release (40.0 +/- 14.3 ng Ang I; p less than 0.02) was not modified by LNMMA; addition of L-arginine (10(-5) M), the precursor of EDRF, did not change basal but blocked isoproterenol stimulation of renin. Nitroprusside (10(-5) M) completely reversed melittin-stimulated renin release. Endothelin-1, an endothelium-derived vasoconstrictor, inhibits renin release and stimulates EDRF and prostaglandin synthesis. To determine whether any of the renin-inhibiting effect of endothelin-1 was due to its stimulation of EDRF, we compared the effect of endothelin-1 on cortical slices with and without EDRF inhibition. Endothelin-1 (10(-7) M) decreased renin by 36.7 +/- 10.9 ng Ang I (p less than 0.01) compared with controls, and the response was the same after either LNMMA or hemoglobin treatment.(ABSTRACT TRUNCATED AT 250 WORDS)

Animals↗
PubMed1992

Sympathetic modulation of endothelium-derived relaxing factor.

To determine whether the release of endothelium-derived relaxing factor (EDRF) is sympathetically mediated, we studied the effects of beta-blockade by propranolol, ganglionic blockade with hexamethonium, or mechanical pithing on the blood pressure response to EDRF inhibition in anesthetized rats. We inhibited EDRF with 10 mg/kg of either NG-monomethyl-L-arginine (L-NMMA) or N omega-nitro-L-arginine-methyl ester (L-NAME). In controls, L-NMMA and L-NAME increased blood pressure by 14 +/- 1 (p less than 0.01) and 22 +/- 2 mm Hg (p less than 0.01), respectively. Propranolol lowered blood pressure from 98 +/- 3 to 72 +/- 4 mm Hg without altering the response to L-NAME (delta 26 +/- 3). This response correlated with the resting blood pressure (r = 0.87; p less than 0.001). Hexamethonium (25 mg/kg) lowered blood pressure from 118 +/- 6 to 85 +/- 4 mm Hg but did not change the response to L-NMMA (delta 15 +/- 1). In pithed rats, blood pressure was lowered, but the pressor response to L-NAME was unchanged. When blood pressure was returned to normotensive levels by angiotensin II, norepinephrine, or phenylephrine, L-NAME increased blood pressure by 50 +/- 2, 68 +/- 8, and 109 +/- 7 mm Hg, respectively (p less than 0.001). We conclude that an intact autonomic nervous system is not needed for the pressor response to EDRF inhibition. The enhanced response in pithed rats treated with vasoconstrictors may be due to removal of the buffering effect of the baroreceptors and the absence of EDRF, which would oppose vasoconstriction.(ABSTRACT TRUNCATED AT 250 WORDS)

Adrenergic beta-Antagonists↗
PubMed1992

Angiotensin dependence of endothelium-mediated renal hemodynamics.

Endothelium-derived relaxing factor has been shown to regulate renal blood flow, and inhibition of its synthesis increases blood pressure and renal vascular resistance and decreases renal blood flow. Using the substrate antagonist NW-nitro-L-arginine methyl ester (L-NAME), we tested whether renal vasoconstriction induced by endothelium-derived relaxing factor synthesis inhibition could be mediated in part by angiotensin II. In 14 control rats, 10 mg/kg body wt L-NAME increased blood pressure from 106 +/- 6 to 126 +/- 6 mm Hg (p < 0.001), increased renal vascular resistance by 74% (from 19.3 +/- 2.6 to 33.6 +/- 2.9 resistance units), and decreased renal blood flow by 34% (from 5.9 +/- 0.5 to 3.9 +/- 0.3 ml.min-1.g kidney wt-1, p < 0.005). When six rats were treated with 10 mg/kg body wt of the angiotensin receptor antagonist DuP 753, L-NAME increased blood pressure from 84 +/- 4 to 106 +/- 4 mm Hg (p < 0.001); however, renal vascular resistance increased by only 27% (from 13 +/- 2 to 17 +/- 3 resistance units, p < 0.01; p < 0.05 different from control value) and renal blood flow was unchanged. Likewise, after pretreatment of six rats with 32 micrograms/100 g body wt of the angiotensin converting enzyme inhibitor enalaprilat, L-NAME increased blood pressure from 88 +/- 5 to 124 +/- 6 mm Hg (p < 0.001) and renal vascular resistance by 54% (from 12 +/- 1 to 18 +/- 3 resistance units, p < 0.01; p < 0.05 different from control value) but renal blood flow was unchanged.(ABSTRACT TRUNCATED AT 250 WORDS)

Angiotensin II↗
PubMed1992

Plasma renin activity and the renal response to nitric oxide synthesis inhibition.

Inhibition of systemic endothelium-derived relaxing factor (EDRF) synthesis with L-Nw-nitroarginine (L-NAME) results in decreased RBF, which can be reversed by acute blockade of angiotensin II (AII). Because AII is particularly elevated in the renal circulation, it was hypothesized that the degree of renal vasoconstriction produced by L-NAME in Inactin-anesthetized rats is related to PRA. To test this, PRA was chronically increased or suppressed by the manipulation of dietary sodium (eating 0.03% sodium chow or deoxycorticosterone acetate plus drinking 1% NaCl, respectively). After 10 days, rats were anesthetized for determination of blood pressure (BP) and RBF before and after L-NAME (10 mg/kg body wt). In rats with high PRA (61.6 +/- 10.4 ng of angiotensin I [Al]/mL/h; N = 8), L-NAME increased BP by 29 +/- 2 mm Hg (from 110 +/- 4 to 139 +/- 5 mm Hg; P < 0.001), decreased RBF by 27% (from 7.9 +/- 0.3 to 5.8 +/- 0.3 mL/min/g kidney wt; P < 0.001), and increased renal vascular resistance (RVR) by 67% (from 14.5 +/- 0.9 to 24.2 +/- 1.1 resistance units [RU]; P < 0.001). When rats with high PRA (N = 8) were treated with 10 mg/kg body wt of DuP 753, on AII receptor antagonist, L-NAME similarly increased BP by 30 +/- 5 mm Hg (from 81 +/- 3 to 111 +/- 5; P < 0.001) but RBF did not change and RVR increased by only 31% (from 10.9 +/- 0.8 to 13.3 +/- 0.7 RU; P < 0.005).(ABSTRACT TRUNCATED AT 250 WORDS)

Animals↗
PubMed1991

Phaeochromocytoma and functioning paraganglioma in childhood and adolescence: role of iodine 131 metaiodobenzylguanidine.

Phaeochromocytomas and functioning paragangliomas are rare tumours in childhood and adolescence. We review our experience of 43 cases (24 men, 19 women) who were first diagnosed at the age of less than or equal to 18 years. All patients were evaluated at some point in their illness with iodine 131 metaiodobenzylguanidine (131I-mIBG) scintigraphy. Eight patients (19%) had bilateral adrenal tumours, 12 (28%) had solitary extra-adrenal tumours, and 8 (19%) had multiple tumours. In 10 patients (23%), the tumours were associated with a familial neurocristopathic syndrome. Thirteen of 24 (54%) unifocal tumours which were initially considered to be benign ultimately proved to be multi-focal and/or malignant. The final prevalence of malignancy was 60%--26 patients, of whom only 15 (57%) had obviously malignant tumours at the time of diagnosis. Primary tumour size greater than or equal to 5 cm was more commonly associated with a malignant course in adrenal but not extra-adrenal tumours. No other clinical, biochemical or morphological characteristic was significantly associated with malignancy. Although the high prevalence of malignancy in this series at least partly reflects referral bias, the need for lifelong follow-up of these patients is underscored. 131I-mIBG scintigraphy was positive in 36 patients (84%), with a somewhat lower false-negative rate (12%) than X-ray computed tomography (20%). Eight patients with malignant tumours received therapeutic doses of 131I-mIBG, with partial tumour responses in 3. Thus, 131I-mIBG is an efficacious, non-invasive, localising agent and may be considered as a palliative therapeutic agent when alternatives have failed.

3-Iodobenzylguanidine↗
PubMed1990

Possible endothelial modulation of prostaglandin-stimulated renin release.

Studies were run to determine whether the renal microvascular endothelium influences renin release. Blood-free rat renal cortical slices were incubated in a bicarbonate buffer for 60 min and sampled at 30 and 60 min to determine renin concentration and at 60 min for prostaglandin (PG) E2 and I2 (6-keto-PGF1 alpha) synthesis. Stimulation by 10(-6) M melittin of endogenous PGs simultaneously increased renin release, PGE2, and PGI2 synthesis, and all were inhibited by 1.6 x 10(-6) M meclofenamate. Renin release was stimulated with isoproterenol [26.2 +/- 2.4 ng angiotensin I (ANG I) .h-1.mg-1.30 min-1; P less than 0.001], PGI2 (32.3 +/- 7.4 ng ANG I.h-1.mg-1.mg-1.30 min-1; P less than 0.005), and PGE2 (25.7 +/- 2.8 ng ANG I.h-1.mg-1.30 min-1, P less than 0.001). Acetylcholine did not affect basal renin but potentiated the response to PGE2 by 80% (46.0 +/- 5.8 ng ANG I.h-1.mg-1.30 min-1; P less than 0.001). Atropine (10(-7) M) reversed this potentiation. Deendothelialization of renal microvessels with H2O2 eliminated PGI2, but neither PGE2 nor renin release, and reversed acetylcholine-potentiation of PGE2-stimulated renin release as did meclofenamate. Hemoglobin increased PGE2-stimulated renin similarly to acetylcholine. These studies suggest that stimulating the endothelium with acetylcholine results in selective potentiation of PGE2-stimulated renin release, which may be mediated through some cyclooxygenase product and is independent of endothelium-derived relaxing factor. Thus the renal endothelium may influence or modulate renin release.

Acetylcholine↗
PubMed1990

Products of cells from gliomas: VIII. Multiple-well immunoperoxidase assay of immunoreactivity of primary hybridoma supernatants with human glioma and brain tissue and cultured glioma cells.

To test the feasibility of primary screening of hybridoma supernatants against human glioma tissue, over 5000 combinations of hybridoma supernatants with glioma tissue, cultured glioma cells, and normal central neural tissue were screened with a new multiple-well (M-well) screening system. This is an immunoperoxidase assay system with visual endpoints for screening 20-30 hybridoma supernatants per single microscope slide. There were extensive differences between specificities to tissue and to cultured glioma cells when both were screened with M-wells and when cultured cells were screened with standard semi-automated fluorescence. Primary M-well screening with glioma tissue detected seven hybridoma supernatants that specifically identified parenchymal cells of glioma tissue and that were not detected with cultured cells. Immunoreactivities of individual supernatants for vascular components (nine supernatants), necrosis (five supernatants), and nuclei (three supernatants) were detected. Other supernatants bound multiple sites on glioma tissue and/or subpopulations of neurons and glia of normal tissue. The results show that primary screening with glioma tissue detects a number of different specificities of hybridoma supernatants to gliomas not detected by conventional screening with cultured cells. These are potentially applicable to diagnosis and therapy.

Antibody Specificity↗
PubMed1990

Direct stereotactic intracerebral injection of monoclonal antibodies and their fragments: a potential approach to brain tumor immunotherapy.

Delivery of monoclonal antibodies (Mab) to brain tumors is restricted by the blood:brain barrier. To circumvent this problem, we studied direct stereotactic injection of the Mab into the brain. An anti-melanoma intact Mab and its Fab fragments, which do not react with normal rat brain, were radioiodinated and injected either intracerebrally (IC) or intravenously (IV) into rats. At 5 days after injection, IC delivery of intact antibody was 101 times higher than IV delivery. The ratio of radioantibody in injected cerebrum:blood was 14:1. With IC delivered Fab fragments, the radioantibody ratio in injected cerebrum:blood was 242:1 at 5 days after IC injection, with a 680-fold delivery advantage over IV injection. These data demonstrate a dramatic regional delivery advantage for intact Mab and especially for Fab fragments injected directly into the brain. This route of Mab delivery may have therapeutic potential for brain tumors.

Animals↗
PubMed1989

Effect of prostanoids on renin release from rabbit afferent arterioles with and without macula densa.

There is evidence that cyclooxygenase products of arachidonic acid participate in the control of renin release. In this study we tested the hypothesis that prostaglandin (PG) I2 and/or its metabolite(s), which are synthesized in the afferent arteriole (AF), stimulate renin release by acting directly on the AF while PGE2 stimulates renin release indirectly via the macula densa. AF alone and AF with macula densa attached (AF-MD) were microdissected from rabbit kidneys and incubated in vitro. The renin release rate from a single AF (or an AF-MD) was calculated and expressed as ng AI.hr-1. AF-1/hr (where AI is angiotensin I). When arachidonic acid (0.12 mM) or PGI2 (10 microM) was added to AF, renin release increased significantly (P less than 0.0001) from 1.04 +/- 0.21 to 3.12 +/- 0.86 (x +/- SEM, N = 7), and from 0.45 +/- 0.14 to 1.48 +/- 0.53 (N = 9), respectively. During the recovery period, renin release increased even further, reaching 9.53 +/- 1.76 and 4.50 +/- 1.24, respectively. A PGI2 synthetase inhibitor, 9, 11-azoprosta-5,13-dienoic acid blocked the effect of arachidonic acid. To examine whether the increases in renin release during the recovery period were due to metabolite(s) of PGI2, we tested the effect of both 6-keto-PGE1 (an active metabolite of PGI2) and carba-PGI2 (a synthetic analog that is metabolized differently from PGI2). Six-keto-PGE1 and carba-PGI2 increased renin release only during the experimental period with no further increase during the recovery period.(ABSTRACT TRUNCATED AT 250 WORDS)

Alprostadil↗
PubMed1989

Kinin antagonist reverses converting enzyme inhibitor-stimulated vascular prostaglandin I2 synthesis.

Treatment with a converting enzyme inhibitor has been shown to stimulate aortic prostaglandin I2 synthesis. We studied whether converting enzyme inhibitor-stimulated prostaglandin I2 synthesis might be mediated by kinins. Anesthetized male Sprague-Dawley rats were given a continuous 70-minute infusion of either saline or a kinin analogue antagonist, [DArg0-Hyp3-Thi5-DPhe7-Thi8]bradykinin, 8 micrograms/kg/min. After 10 minutes, rats were given an intravenous bolus of either vehicle or the converting enzyme inhibitor enalaprilat (30 micrograms/100 g body wt). After 70 minutes, aorta and renal cortical slices were harvested and incubated in vitro in buffer without drugs at pH 7.4, 37 degrees C for 60 minutes. The buffer was then sampled for measurement of 6-keto prostaglandin F1 alpha (an index of prostaglandin I2), prostaglandin E2, and renin release (angiotensin I generation) by radioimmunoassay. The aortic prostaglandin I2 from rats treated with converting enzyme inhibitor was significantly elevated (36.7 +/- 5.0 ng/mg dry wt/hr) compared with aorta from rats treated with either vehicle (25.6 +/- 2.2 ng/mg/hr), kinin antagonist (25.1 +/- 2.4 ng/mg/hr), or kinin antagonist plus converting enzyme inhibitor (23.0 +/- 2.0 ng/mg/hr), p less than 0.02. There were no differences in aortic prostaglandin E2, renin release, or prostaglandin E2 from renal cortical slices. Direct in vitro incubation of aorta with molar concentrations of converting enzyme inhibitor from 10(-9) to 10(-4) had no effect on prostaglandin I2. These results suggest that kinins may mediate the effect of converting enzyme inhibition on aortic prostaglandin I2 synthesis and thereby may account for part of the hemodynamic responses resulting from treatment using converting enzyme inhibitors.

Angiotensin-Converting Enzyme Inhibitors↗
PubMed1989

Unusual complications of antithyroid drug therapy: four case reports and review of literature.

Two cases of propylthiouracil-associated acute hepatitis, one case of fatal methimazole-associated hepatocellular necrosis and one case of propylthiouracil-associated lupus-like syndrome are described. The literature related to antithyroid drug side effects and the mechanisms for their occurrence are reviewed and the efficacy and complications of thyroidectomy and radioiodine compared to those of antithyroid drugs. It is concluded that in most circumstances 131I is the therapy of choice for hyperthyroidism.

Adult↗