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1.
Am J Med Genet ; 77(4): 261-7, 1998 May 26.
Article in English | MEDLINE | ID: mdl-9600732

ABSTRACT

While loss-of-function mutations in Gsalpha are invariably associated with the short stature and brachydactyly of Albright hereditary osteodystrophy (AHO), the association with hormone resistance (to parathyroid hormone and thyrotropin) typical of pseudohypoparathyroidism type Ia (PHP-Ia) is much more variable. Observational studies and DNA polymorphism analysis suggest that maternal transmission of the Gsalpha mutation may be required for full expression of clinical hormone resistance. To test this hypothesis, we studied transmission of a frameshift mutation in Gsalpha through three generations of a pedigree affected by AHO and PHP-Ia. While all family members carrying this loss-of-function mutation in one Gsalpha allele had AHO, neither the presence of the mutation nor the degree of reduction of erythrocyte Gsalpha bioactivity allowed prediction of phenotype (AHO alone versus AHO and PHP-Ia). Paternal transmission of the mutation (from the patriarch of the first generation to three members of the second generation) was not associated with concurrent PHP-Ia, but maternal transmission (from two women in the second generation to four children in the third generation) was invariably associated with PHP-Ia. No expansion of an upstream short CCG nucleotide repeat region was detected, nor was there evidence of uniparental disomy by polymorphism analysis. This report, the first to document the effects across three generations of both paternal and maternal transmission of a specific Gsalpha mutation, strongly supports the hypothesis that a maternal factor determines full expression of Gsalpha dysfunction as PHP-Ia.


Subject(s)
Fibrous Dysplasia, Polyostotic/genetics , Frameshift Mutation , GTP-Binding Protein alpha Subunits, Gs/genetics , Pseudohypoparathyroidism/genetics , DNA Probes , Electrophoresis, Polyacrylamide Gel , Erythrocyte Membrane/metabolism , Female , Fibrous Dysplasia, Polyostotic/metabolism , GTP-Binding Protein alpha Subunits, Gs/metabolism , Genes, Recessive , Humans , Isotope Labeling , Male , Nucleic Acid Hybridization , Pedigree , Polymerase Chain Reaction , Polymorphism, Genetic , Pseudohypoparathyroidism/metabolism , Sequence Analysis, DNA
2.
J Pharmacol Exp Ther ; 278(2): 503-9, 1996 Aug.
Article in English | MEDLINE | ID: mdl-8768697

ABSTRACT

Platelets metabolize arachidonic acid via cyclooxygenase and lipoxygenase (LO) enzymatic pathways. Although platelets produce large amounts of arachidonic acid metabolites via the LO pathway, little is known regarding the physiological significance of these products. We used three structurally dissimilar LO inhibitors, 5,8,11-eicosatriynoic acid (ETI), baicalein and phenidone, and found that LO inhibition attenuated thrombin- and U46619 (a thromboxane mimetic)-induced increases of platelet intracellular calcium ([Ca++]i) in washed human platelets. LO inhibitors also reduced platelet aggregation induced by thrombin and U46619. The effect of ETI on reducing the thrombin-induced [Ca++]i elevation persisted even when cation channels were blocked, suggesting that LO inhibitors modify release of Ca from intracellular stores. Stimulating endogenous LO product formation potentiated thrombin-induced [Ca++]i responses and aggregation, and these effects were eliminated by ETI. ETI did not alter inositol 1,4,5-trisphosphate production in stimulated platelets, but increased platelet cyclic AMP production in thrombin- or forskolin-stimulated platelets. These results suggest that LO products are regulators of platelet [Ca++]i mobilization and aggregation in response to some agonists, and that LO inhibitors may work in part by modifying platelet cyclic AMP metabolism.


Subject(s)
Calcium/metabolism , Flavanones , Lipoxygenase Inhibitors/pharmacology , Lipoxygenase/drug effects , Platelet Aggregation Inhibitors/pharmacology , Platelet Aggregation/drug effects , Thrombin/pharmacology , Thromboxanes/pharmacology , 12-Hydroxy-5,8,10,14-eicosatetraenoic Acid , Dose-Response Relationship, Drug , Enzyme Inhibitors , Flavonoids/pharmacology , Humans , Hydroxyeicosatetraenoic Acids/pharmacology
3.
Biochem Mol Med ; 58(1): 18-24, 1996 Jun.
Article in English | MEDLINE | ID: mdl-8809352

ABSTRACT

Defects in the G (guanine nucleotide-binding)-protein subunit (G alpha s) which stimulates adenylyl cyclase may result in either loss or gain of endocrine function. Reduced G alpha s activity is found in the hormone resistance syndrome, pseudohypoparathyroidism type Ia (PHP-Ia), while constitutive activation of G alpha s is associated with endocrine organ overactivity, including the gonadotropin-independent sexual precocity seen in patients with McCune-Albright syndrome. We identified two unrelated boys presenting with concurrent PHP-Ia and gonadotropin-independent sexual precocity (testotoxicosis). Mutational screening by denaturing gradient gel electrophoresis and sequencing of PCR-amplified exons of the G alpha s gene revealed a point mutation which generates an alanine-to-serine substitution in codon 366 of one G alpha s allele (A366S), an alanine present at the homologous position in all G-proteins. We have previously shown in transfected testis cells that the A366S mutation activates G alpha s by decreasing affinity for GDP, thereby increasing the rate of nucleotide exchange in a receptor-independent fashion. In contrast to differential stability of the activated mutant G alpha s protein in Leydig cells, with stability at 32 degrees C but not at 37 degrees C, skin fibroblasts with the mutation had the same reduced G alpha s levels at both temperatures. Our findings explain the limitation of clinical manifestations of G alpha s overactivity to testis, without involvement of other body appendages which are generally at lower than core body temperature. This unique mutation at a critically conserved residue of G alpha s is the first mutant G-protein which affects guanine nucleotide affinity and is associated with human disease, producing widely divergent and tissue-specific effects.


Subject(s)
GTP-Binding Proteins/genetics , Pseudohypoparathyroidism/genetics , Puberty, Precocious/genetics , Blotting, Northern , Blotting, Western , Codon , Electrophoresis, Polyacrylamide Gel , Exons , Humans , Infant , Male , Pedigree , Polymerase Chain Reaction , Restriction Mapping
4.
Endocrinology ; 136(6): 2497-504, 1995 Jun.
Article in English | MEDLINE | ID: mdl-7750471

ABSTRACT

Although PTH and PTH-related protein (PTHrP) are vasodilators, prolonged exposure to elevated levels of PTH is often associated with hypertension. We investigated the effects of prolonged incubation with PTH or PTHrP on arterial segments and cultured vascular smooth muscle cells (VSMC). PTH or PTHrP transiently relaxed precontracted arterial segments within 10 min. Additional PTH or PTHrP added after 40-min exposure to these peptides had little effect on vascular tone, whereas forskolin, isoproterenol, isobutylmethyl-xanthine, or acetylcholine were still potent. In fura 2-loaded VSMC, 5-min incubation with PTH or PTHrP attenuated angiotensin II (Ang II)-induced calcium mobilization, an effect that was reduced by preincubation of VSMC with PTH for 1.5 h. Similarly, 1.5-h preincubation with PTH or PTHrP decreased the cAMP response to these peptides but not to forskolin or NaF. Ang II potentiated the cAMP response to PTH and PTHrP but was also subject to desensitization. Nle8, 18Tyr34 bovine PTH(3-34) amide did not desensitize vascular tissue to PTH or PTHrP. Our results suggest that homologous desensitization to PTH or PTHrP in vascular tissue requires receptor stimulation, occurs proximal to G stimulatory protein, and impairs attenuation of calcium mobilization by PTH or PTHrP. This may be a mechanism by which vasodilator effects of these peptides are decreased with prolonged elevation of PTH levels.


Subject(s)
Blood Vessels/drug effects , Parathyroid Hormone/pharmacology , Proteins/pharmacology , Angiotensin II/pharmacology , Animals , Blood Vessels/physiology , Calcium/metabolism , Cattle , Cells, Cultured , Cyclic AMP/biosynthesis , Femoral Artery/drug effects , Femoral Artery/physiology , Humans , Hypertension/etiology , In Vitro Techniques , Male , Muscle, Smooth, Vascular/drug effects , Muscle, Smooth, Vascular/metabolism , Parathyroid Hormone-Related Protein , Rats , Vasodilator Agents/pharmacology
5.
Hypertension ; 23(3): 402-8, 1994 Mar.
Article in English | MEDLINE | ID: mdl-8125568

ABSTRACT

Parathyroid hormone and parathyroid hormone-related protein lower blood pressure and relax contracted arteries. Parathyroid hormone also attenuates angiotensin II-induced vasoconstriction. To determine the cellular mechanism or mechanisms by which parathyroid hormone analogues antagonize pressor effects, we examined the effect of these peptides on angiotensin II-induced calcium mobilization in fura 2-AM-loaded cultured rat vascular smooth muscle cells. Either 100 nmol/L parathyroid hormone or parathyroid hormone-related protein significantly reduced the amount of calcium mobilized by 100 nmol/L angiotensin II. The attenuating effect of these peptides was mimicked by 10 mmol/L forskolin and 10 mmol/L isobutylmethylxanthine and was not dependent on the presence of extracellular calcium. This effect of the parathyroid hormone analogues was reduced when cells were pretreated with 100 mmol/L 2',5'-dideoxyadenosine, an adenylate cyclase inhibitor. Combined inhibition of cyclic nucleotide-dependent protein kinases eliminated the inhibitory effect of parathyroid hormone, whereas protein kinase C inhibition had no effect. Parathyroid hormone analogues decreased the amount of calcium released by inositol 1,4,5-trisphosphate in digitonin-permeabilized vascular smooth muscle cells. This effect was inhibited by treatment with 2',5'-dideoxyadenosine. These results suggest that these peptides attenuate inositol 1,4,5-trisphosphate-sensitive calcium mobilized by angiotensin II via an adenylate cyclase-dependent mechanism. This may be a mechanism by which acute administration of parathyroid hormone or parathyroid hormone-related peptide antagonizes vasoconstriction.


Subject(s)
Calcium/metabolism , Muscle, Smooth, Vascular/drug effects , Parathyroid Hormone-Related Protein , Parathyroid Hormone/pharmacology , Animals , Cells, Cultured , Cyclic AMP/physiology , Male , Muscle, Smooth, Vascular/metabolism , Peptide Fragments/pharmacology , Proteins/pharmacology , Rats , Rats, Sprague-Dawley , Teriparatide
6.
Am J Hypertens ; 6(1): 46-51, 1993 Jan.
Article in English | MEDLINE | ID: mdl-8427661

ABSTRACT

Elevated levels of serum parathyroid hormone (PTH) and platelet cytosolic free calcium ([Ca2+]i) have been reported in subjects with essential hypertension. In addition, there is a positive correlation between serum PTH and platelet [Ca2+]i in white subjects with essential hypertension. Black normotensive subjects have relatively higher levels of serum PTH when compared to white normotensive subjects. To investigate the possibility that elevated serum PTH levels in black normotensives may contribute to elevated platelet [Ca2+]i, calcitropic hormone profiles and platelet [Ca2+]i were determined in 31 black normotensive subjects and 34 age-matched white normotensive subjects. There was no difference between the two groups in total serum calcium, plasma ionized calcium, or creatinine clearance. However, serum PTH was significantly elevated (P < .02) in the black normotensive group. Serum 1,25(OH)2 vitamin D levels were similar between the two groups whereas serum 25(OH) vitamin D levels were significantly lower (P < .001) in the blacks. The 24 h urinary excretion of Ca was also lower (P < .05) in the black normotensive group. Basal platelet [Ca2+]i was significantly lower (P < .05) in black normotensive than in white normotensive subjects. Serum PTH levels did not correlate with platelet [Ca2+]i in either group, or in the groups combined. These results demonstrate that the higher serum PTH concentrations in black normotensives is not associated with higher platelet [Ca2+]i, as is the case in white hypertensive patients.


Subject(s)
Black People , Blood Platelets/metabolism , Calcium/blood , Cytosol/metabolism , Parathyroid Hormone/blood , White People , Adult , Aged , Blood Pressure , Calcium/urine , Female , Humans , Hydroxycholecalciferols/blood , Male , Middle Aged , Osmolar Concentration , Reference Values
7.
Biochem Biophys Res Commun ; 189(1): 343-9, 1992 Nov 30.
Article in English | MEDLINE | ID: mdl-1449489

ABSTRACT

Pseudohypoparathyroidism type Ia (PHP-Ia), an inherited multi-hormone resistance syndrome, is associated with deficient cellular activity of the alpha-subunit of the guanine nucleotide-binding protein (Gs alpha) that stimulates adenylyl cyclase. We determined prevalence of three recently described mutations in exons 1 and 10 of the Gs alpha gene among 24 unrelated patients with PHP-Ia. Restriction analysis was used to detect two mutations that produce unique RFLPs, and allele-specific oligonucleotide hybridization was used to detect the other mutation. As none of these mutations were not found, genomic DNA was analyzed with denaturing gradient gel electrophoresis to screen for other mutations in exon 10. Mutations of the initiation codon and exon 10 in the Gs alpha gene thus rarely (< or = 4% each) cause PHP-Ia and the Gs alpha gene mutations causing PHP-Ia are heterogeneous and unique to each pedigree.


Subject(s)
GTP-Binding Proteins/genetics , Mutation , Pseudohypoparathyroidism/genetics , Adenylyl Cyclases/metabolism , Base Sequence , Ethnicity , Exons , GTP-Binding Proteins/metabolism , Humans , Macromolecular Substances , Molecular Sequence Data , Oligodeoxyribonucleotides , Oligonucleotides, Antisense , Pseudohypoparathyroidism/classification , Restriction Mapping
8.
J Pharmacol Exp Ther ; 263(1): 78-83, 1992 Oct.
Article in English | MEDLINE | ID: mdl-1403805

ABSTRACT

Certain bioflavonoids and phenolic compounds have long been known to enhance catecholamine responses, in vivo and in vitro. In the present studies the flavone, baicalein, potentiated nerve-stimulated contractions in vitro in rat tail and femoral artery isometric ring preparations. Inhibition of catecholamine reuptake with cocaine or catecholamine metabolism with tropolone and parglyine (monoamine oxidase and catecholamine-O-methyl transferase inhibitors, respectively) did not alter baicalein's ability to potentiate contractile responses to nerve stimulation. Baicalein (10(-5) M), the prototype flavone, also increased sensitivity to exogenous norepinephrine, serotonin, arginine vasopressin and to the noncatecholamine alpha-1 and alpha-2 adrenergic agonists, cirazoline and tramazoline. Structure-function studies indicated that flavone potentiation required three contiguous A or B ring hydroxylations. Several nonflavone phenol derivatives with three contiguous hydroxyls also potentiated nerve stimulation responses. As baicalein is a potent lipoxygenase inhibitor, comparisons were made between potentiating ability and lipoxygenase inhibitory activity in a series of flavonoids. There was no direct correlation between inhibition of 12-hydroxy-5,8,10,14-eicosatetraenoic acid levels in thrombin stimulated human platelets and potentiation of contractile responses in the femoral artery. Additionally, the specific substrate analog lipoxygenase inhibitor, 5,8,11-eicosatriynoic acid, and the cyclooxygenase inhibitor, ibuprofen, were nonpotentiating. Ibuprofen pretreatment did not alter the potentiating action of baicalein. It is concluded that flavonoids with three contiguous hydroxyls on either the A or B ring increase in vitro vascular responsiveness via a post-synaptic process, independent of cyclooxygenase, lipoxygenase, monoamine oxidase or catecholamine-O-methyl transferase activity.


Subject(s)
Flavanones , Flavonoids/pharmacology , Muscle, Smooth, Vascular/drug effects , 12-Hydroxy-5,8,10,14-eicosatetraenoic Acid , Animals , Blood Platelets/drug effects , Blood Platelets/metabolism , Drug Synergism , Hydroxyeicosatetraenoic Acids/biosynthesis , Male , Muscle Contraction/drug effects , Rats , Rats, Sprague-Dawley
9.
J Pers Assess ; 59(1): 176-84, 1992 Aug.
Article in English | MEDLINE | ID: mdl-1512675

ABSTRACT

A discussion is presented of five Rorschach protocols that appear to meet the criteria proposed by Exner and Weiner (1982, p. 31) for "brief and barren" Rorschach protocols. The protocols were obtained from a social service agency treating abused, neglected, disturbed, and delinquent youths. An attempt is made to bring to bear a conceptual approach to these Rorschachs, so that they may be seen as clinically valuable and revealing, hence not "invalid" diagnostic protocols. Emphasis is placed on the subjects' approach to the task, the subject-examiner interaction, and the meaning of the subjects' ostensibly peripheral comments. Recommendations are offered regarding ways to maximize the clinical utility of such protocols.


Subject(s)
Child Abuse/psychology , Juvenile Delinquency/psychology , Rorschach Test/statistics & numerical data , Adolescent , Child , Community Mental Health Centers , Countertransference , Female , Foster Home Care/psychology , Humans , Male , Psychometrics , Residential Treatment , Social Environment
10.
Child Welfare ; 70(1): 69-80, 1991.
Article in English | MEDLINE | ID: mdl-1997293

ABSTRACT

A program is described that provides for transition into a relatively unstructured supervised independent-living program for adolescents with a history of behavioral and emotional disturbance, often including delinquency and/or psychiatric hospitalization. Contracts used to define expectations, logistics, and conflicts experienced by the youths are discussed. Developmental issues are highlighted, focusing on the rapprochement subphase.


Subject(s)
Community Mental Health Services , Mental Disorders/rehabilitation , Activities of Daily Living , Adolescent , Community Mental Health Services/economics , Community Mental Health Services/organization & administration , Humans , Male , Michigan
11.
Hypertension ; 16(5): 515-22, 1990 Nov.
Article in English | MEDLINE | ID: mdl-2228152

ABSTRACT

Plasma ionized calcium, platelet cytosolic calcium (using the fura-2 method in gel-filtered platelets), parathyroid hormone (both the intact hormone and a midmolecule portion), calcitriol, and calcidiol were measured in 19 untreated male patients with essential hypertension and 19 age-matched normotensive male research subjects. Mean levels of platelet cytosolic calcium, parathyroid hormone, calcitriol, and calcidiol were all significantly higher, whereas plasma ionized calcium was significantly lower, in the hypertensive group compared with the normotensive group. Both platelet cytosolic calcium and intact parathyroid hormone were positively correlated with mean arterial pressure (r = 0.58, p less than 0.001; r = 0.54, p less than 0.001, respectively), whereas plasma ionized calcium was inversely correlated with mean arterial pressure (r = -0.60, p less than 0.001) in the combined group of all study subjects. All three of these correlations were significant in the hypertensive group alone but not in the normotensive group alone. When analyzed with plasma ionized calcium, body mass index, serum calcitriol, and calcidiol in a multivariable regression model, the significance of the partial regressions of platelet cytosolic calcium and parathyroid hormone with mean arterial pressure persisted. Intact parathyroid hormone was positively correlated to platelet cytosolic calcium (r = 0.43, p less than 0.01) and plasma ionized calcium was inversely correlated to platelet cytosolic calcium (r = -0.44, p less than 0.01). These results confirm previous reports of disturbances of calcium metabolism in essential hypertension and suggest that the elevated platelet cytosolic calcium observed in essential hypertension may be linked to one or more of these alterations of calcium metabolism.


Subject(s)
Blood Platelets/metabolism , Blood Pressure , Calcitriol/blood , Calcium/blood , Hypertension/metabolism , Parathyroid Hormone/blood , Adult , Aged , Calcifediol/blood , Humans , Male , Middle Aged
12.
Chronobiologia ; 17(1): 37-44, 1990.
Article in English | MEDLINE | ID: mdl-2350986

ABSTRACT

The relationship between 24-h recumbent blood pressure levels and secretory patterns of catecholamines was investigated in 4 patients with pseudohypoparathyroidism (PsHP) and hypertension and in 9 patients with essential hypertension. A clear circadian rhythm of blood pressure and catecholamines was documented in both groups with lowest levels of blood pressures and catecholamines occurring during sleep. During the 24-h period of recumbency mean arterial blood pressure (MAP) was correlated (r = 0.63, p less than or equal to 0.01) with plasma norepinephrine (N) in the patients with essential hypertension, but this correlation was weaker in patients with PsHP (r = 0.38, p less than or equal to 0.05). MAP was more closely related to plasma epinephrine (E) (r = 0.62, p less than or equal to 0.01) than to plasma NE in patients with PsHP. Plasma NE and E levels were considerably lower in patients with PsHP than in patients with essential hypertension throughout the 24-h recumbent period. The sleep-related decline in blood pressure and NE was less than in patients with essential hypertension. These results suggest that while the sympathetic nervous system may have a role in hour-to-hour maintenance of blood pressure in patients with PsHP and hypertension, it does not appear to be responsible for the elevated arterial pressure in these patients. Factors other than those investigated, such as obesity, alterations in sodium homeostasis of refractoriness of the vascular smooth muscle to the vasodilatory effect of PTH may be involved in the pathogenesis of hypertension in PsHP.


Subject(s)
Catecholamines/blood , Circadian Rhythm/physiology , Hypertension/physiopathology , Pseudohypoparathyroidism/physiopathology , Adult , Blood Pressure/physiology , Epinephrine/blood , Female , Humans , Hypertension/blood , Hypertension/complications , Male , Middle Aged , Norepinephrine/blood , Pseudohypoparathyroidism/blood , Pseudohypoparathyroidism/complications
13.
Endocrinol Metab Clin North Am ; 18(3): 659-700, 1989 Sep.
Article in English | MEDLINE | ID: mdl-2673767

ABSTRACT

When available, state of the art noninvasive localization studies should be utilized routinely in previously unexplored patients for localizing parathyroid pathology, even when exceptional surgical experience exists. These studies can both minimize the 3 to 20% incidence of missed pathology and promote an approach of limited neck exploration with consequent lowering of morbidity, complications, and costs. Choice of imaging modalities for localizing these small masses is largely dependent on the level of state of the art of available equipment, the interest and experience of the performing physicians, and the attention to technical detail for each of the modalities at an individual institution. In choosing a single test, CT, and most recently cine CT with three-dimensional modeling, is favored because of higher probability of providing the kinds of information most useful to the surgeon. This includes precise anatomic localization and identification of locations likely to be missed by the surgeon (such as mediastinum, deep neck) and the capability for predicting multiple gland disease, for detecting smaller lesions, and for lower incidence of false-positive results. Ultrasound is attractive because of the low cost and noninvasiveness, and it is particularly sensitive in the thyroid region and upper neck. In difficult cases, CT, cine CT, and ultrasound may be augmented by needle aspiration of fluid for PTH assay. Thallium-technetium scanning and MRI are useful alternatives. In the previously explored patient and in patients with difficult diagnostic problems (such as ectopic adenoma, parathyroid carcinoma), the use of multiple noninvasive studies is strongly recommended, preferably CT (particularly, cine CT with three-dimensional imaging) and isotope scanning or MRI. The concurrence of two or more of these studies has a relatively high predictive value (82 to 88%) for localization. However, highly selective venous catheterization and selective magnification arteriography remain the most accurate modalities in these patients (91 to 95% sensitivity with few false-positive results) and may be combined with interventional radiologic techniques for tumor ablation in selected patients without compromising subsequent surgical alternatives. Stereotactic ablation techniques are in development.


Subject(s)
Diagnostic Imaging/methods , Parathyroid Diseases/pathology , Parathyroid Glands/pathology , Catheterization, Peripheral , Humans , Models, Anatomic , Parathyroid Diseases/surgery , Parathyroid Glands/surgery
14.
Am J Med ; 85(6): 785-92, 1988 Dec.
Article in English | MEDLINE | ID: mdl-2848415

ABSTRACT

PURPOSE: There is increasing evidence of a central role for the calcium ion in blood pressure regulation. By studying blood pressure control in disorders of calcium homeostasis, a better understanding of the role of the calcium ion and certain calcitrophic hormones in modulating arterial pressure in humans may be gained. Our goal was to examine levels of blood pressure in a group of patients with either type Ia or type Ib pseudohypoparathyroidism (PsHP), a disorder characterized by target organ resistance to parathyroid hormone. PATIENTS AND METHODS: Forty-six patients with type I PsHP were recruited for the study (28 with type Ia and 18 with type Ib). Blood pressure was measured and the degree of obesity was assessed in all patients. Detailed measurements of hormones involved in blood pressure regulation were made in nine hypertensive patients with PsHP. RESULTS: Elevated arterial pressure was present in 18 of the 46 patients with PsHP, which comprised 53 percent (18 of 34) of the adult subjects. Prevalence of hypertension was similar in PsHP type Ia (nine of 21) and type Ib (nine of 13; p not significant) and was not related to coexisting hypothyroidism or degree of hypocalcemia. However, hypertension in PsHP was strongly linked to severe obesity. Mean body weights of normotensive and hypertensive patients with PsHP were 64 +/- 2.8 (SEM) kg (125 +/- 6 percent ideal body weight) and 96 +/- 4.7 kg (172 +/- 10 percent ideal body weight), respectively. Compared with obese hypertensive non-PsHP persons, hypertensive subjects with PsHP had reduced basal and posture-stimulated renin activity (basal, 1.68 +/- 0.36 [n = 9] versus 3.97 +/- 0.61 ng/ml/hour [n = 9] [p less than 0.05]; upright posture, 2.11 +/- 0.42 versus 7.13 ng/ml/hour [p less than 0.05]; and lower basal and posture-stimulated plasma norepinephrine levels (basal, 236 +/- 52 versus 426 +/- 37 pg/ml [p less than 0.05]; upright posture, 424 +/- 62 versus 707 +/- 64 pg/ml [p less than 0.05]). CONCLUSION: Our data suggest that hypertension is common in PsHP types Ia and Ib. This newly identified form of endocrine hypertension is strongly linked to excessive body weight but is associated with alterations in the renin-aldosterone and sympathetic nervous systems that are distinct from those encountered in obesity-related hypertension in the general population. The pathophysiologic basis for hypertension in these two distinctly different forms of PsHP remains to be determined.


Subject(s)
Hypertension/etiology , Pseudohypoparathyroidism/complications , Adolescent , Adrenocorticotropic Hormone/pharmacology , Adult , Aldosterone/blood , Angiotensin II/pharmacology , Catecholamines/blood , Child , Female , Humans , Hydrocortisone/blood , Hypertension/blood , Hypertension/genetics , Male , Obesity/etiology , Parathyroid Hormone/physiology , Posture , Pseudohypoparathyroidism/blood , Pseudohypoparathyroidism/genetics , Renin/blood
16.
Am J Physiol ; 252(6 Pt 2): H1112-9, 1987 Jun.
Article in English | MEDLINE | ID: mdl-3296787

ABSTRACT

Some proposed mechanisms for the hypotensive effect of high calcium intake involve reduction in vascular responsivity. To assess the effect of dietary calcium on vascular responsivity, spontaneously hypertensive rats (SHR) were placed on normal (N-Ca; 0.4%) or high (H-Ca; 2.8%) casein-based synthetic diet for 4 wk. Intraarterial pressure, pressor response to graded intravenous infusion of norepinephrine (NE) and angiotensin II (ANG II), and in vitro vascular reactivity of tail artery segments to NE and transmural nerve stimulation (TNS) were studied. Urinary electrolyte excretion, plasma renin activity (PRA), aldosterone, NE, and epinephrine (EPI) were also determined. H-Ca SHR had a lower intraarterial systolic and diastolic pressure. However, H-Ca SHR had greater in vivo pressor response to both ANG II and NE. Maximal contractile force developed by tail artery segments in vitro in response to NE and TNS was slightly, but not significantly, higher in H-Ca SHR. In vitro dose-response curves to NE and TNS were not significantly different. Although H-Ca SHR had increased urinary excretion of sodium throughout the study period, PRA and aldosterone levels were similar in both groups. Plasma NE and EPI levels in the two groups were also not different. Despite lowered intra-arterial blood pressure, H-Ca SHR exhibited enhanced pressor response to ANG II and NE in vivo and a similar in vitro vascular reactivity to NE and TNS when compared with N-Ca SHR. Our results do not support a role for alterations in vascular reactivity to NE or ANG II in the hypotensive effect of high calcium intake in SHR.(ABSTRACT TRUNCATED AT 250 WORDS)


Subject(s)
Blood Pressure/drug effects , Calcium, Dietary/pharmacology , Hypertension/physiopathology , Aldosterone/blood , Angiotensin II/pharmacology , Animals , Calcium, Dietary/administration & dosage , Dose-Response Relationship, Drug , Electrolytes/metabolism , Epinephrine/blood , Male , Norepinephrine/blood , Norepinephrine/pharmacology , Rats , Rats, Inbred SHR , Renin/blood
17.
Life Sci ; 40(14): 1397-404, 1987 Apr 06.
Article in English | MEDLINE | ID: mdl-3561157

ABSTRACT

The effect of a hypercalcemia-producing Leydig cell tumor on vascular reactivity in Fischer rats was studied. Seven to eight days after tumor implantation, there was no difference between tumor (T) and control (C) animals in serum calcium, serum phosphate, plasma catecholamine levels, mean arterial pressure (MAP), or blood pressure responses to norepinephrine (NE) infusion. At day 12-13 of tumor growth, the serum calcium in the tumor-bearing rats was significantly higher (12.2 +/- 0.8 vs. 9.7 +/- 0.3 mg%, P less than .01) and their serum phosphate significantly lower (4.5 +/- 0.3 vs. 5.7 +/- 0.4 mg%, P less than .01) than controls. Plasma epinephrine (E) (497 +/- 154 vs. 62 +/- 13 pg/ml, P less than .05), and norepinephrine (NE) (686 +/- 85 vs. 329 +/- 75 pg/ml, P less than .01) were markedly elevated in the tumor rats. MAP and the blood pressure responses to graded NE infusions were significantly lower in tumor animals at Day 12-13, whereas there was no change in sensitivity to angiotensin II (AII) infusions. In vitro contractile responses of tail artery segments to transmural nerve stimulation (TNS) in animals with tumors were lower than in controls but there were no differences in sensitivity to exogenous NE in vitro. These results suggest that the tumor stimulates production of a circulating factor which desensitizes NE receptors and that this tumor also decreases neurovascular function by an undefined mechanism.


Subject(s)
Blood Vessels/drug effects , Hypercalcemia/physiopathology , Leydig Cell Tumor/physiopathology , Norepinephrine/pharmacology , Animals , Blood Pressure/drug effects , Catecholamines/blood , Hypercalcemia/etiology , In Vitro Techniques , Leydig Cell Tumor/blood , Male , Rats , Rats, Inbred F344 , Vasoconstriction/drug effects
18.
J Clin Endocrinol Metab ; 64(2): 297-303, 1987 Feb.
Article in English | MEDLINE | ID: mdl-3025245

ABSTRACT

ACTH-, angiotensin II (AII)-, and K+-mediated aldosterone responses in vitro are dependent on extracellular and intracellular Ca concentrations. This study examined in vivo the relationship of changes in ambient serum calcium (serum Ca) to ACTH- and AII-mediated aldosterone release in hypoparathyroid subjects. Plasma aldosterone (PA) responses to graded dose infusions of ACTH and AII were examined in hypoparathyroid (HypoPTH) patients before (n = 8) and after correction of hypocalcemia (n = 6) and compared to responses in 20 normotensive normocalcemic subjects. ACTH and AII were infused for 90 min at rates increasing from 12.5 to 50 mIU/30 min and 0.5 to 2.0 ng/kg X min, respectively. Pretreatment mean serum Ca was 6.8 +/- 0.2 (+/- SEM) mg/dl, and it rose to 9.3 +/- 0.2 mg/dl after 3-8 weeks of vitamin D administration. In the untreated HypoPTH patients, basal mean PA (5.4 +/- 1.3 ng/dl) was lower (P less than 0.01) than in the normal subjects (10.6 +/- 0.6 ng/dl) or treated HypoPTH patients (9.5 +/- 1.8 ng/dl). There was a marked reduction in PA responses to ACTH at all doses in the untreated HypoPTH patients compared to the normal subjects. With normalization of serum Ca in four patients, the mean peak PA response to ACTH (25.1 +/- 6.0 ng/dl) was not significantly different from normal (28.9 +/- 1.7 ng/dl). During graded dose AII infusion in five untreated HypoPTH patients, mean PA levels increased from 6.9 +/- 1.2 to 11.6 +/- 2.2 ng/dl; when the serum Ca was normal, the corresponding values were 8.7 +/- 1.8 and 20.2 +/- 3.61 ng/dl. There was a positive correlation (r = 0.475; P less than 0.05) between basal PA and serum Ca levels. In addition, maximum changes in mean arterial pressure in response to AII infusions were significantly greater after correction of hypocalcemia. These observations indicate that in HypoPTH patients, extracellular Ca concentrations can influence humoral aldosterone response to ACTH and AII and pressor responses to AII.


Subject(s)
Adrenocorticotropic Hormone/pharmacology , Aldosterone/blood , Angiotensin II/pharmacology , Hypocalcemia/blood , Adult , Blood Pressure/drug effects , Calcium/therapeutic use , Female , Humans , Hypocalcemia/drug therapy , Hypoparathyroidism/blood , Hypoparathyroidism/drug therapy , Male , Middle Aged , Sodium/administration & dosage , Vitamin D/therapeutic use
19.
Clin Otolaryngol Allied Sci ; 11(6): 435-41, 1986 Dec.
Article in English | MEDLINE | ID: mdl-3815869

ABSTRACT

In the last 8 years 33 patients with hyperparathyroidism have been surgically treated by the authors. Thirty patients had primary, 2 secondary and 1 tertiary hyperparathyroidism. In the 30 patients with the primary disorder, 26 had a single adenoma and 28 of these patients had normal calcium levels postoperatively. Two patients were hypocalcaemic following surgery and required calcium supplements for 3 months and 9 months respectively. It is recommended that when a single adenoma is found its removal will render the patient normocalcaemic. When all 4 glands are hyperplastic the surgery should be subtotal (3 1/2 glands) parathyroidectomy except in the case of secondary hyperparathyroidism when total parathyroidectomy with autotransplantation and cryopreservation of the remainder should be performed.


Subject(s)
Hyperparathyroidism/surgery , Adenoma/etiology , Adult , Aged , Aged, 80 and over , Calcium/therapeutic use , Female , Humans , Hyperparathyroidism/blood , Hyperparathyroidism/complications , Hyperparathyroidism/drug therapy , Kidney Diseases/etiology , Male , Middle Aged , Parathyroid Neoplasms/etiology
20.
J Clin Endocrinol Metab ; 63(6): 1354-60, 1986 Dec.
Article in English | MEDLINE | ID: mdl-3023420

ABSTRACT

Single or graded doses of glucagon (Eli Lilly) were given to patients with pseudohypoparathyroidism (PsHP) type I to examine the possible presence of hormone resistance. The doses of glucagon ranged from 0.25-15 micrograms/kg. The following individuals were studied: 13 normal subjects, 5 patients with low erythrocyte N-protein activity (PsHP type Ia), and 7 patients with normal erythrocyte N-protein activity (PsHP type Ib). Two additional patients with treated primary hypothyroidism who were relatives of a patient with PsHP type Ib were also studied. The patients with PsHP type Ia had blunted plasma cAMP responses to all glucagon doses. In contrast, the patients with PsHP type Ib had normal cAMP responses to glucagon infusion. However, the 2 relatives of the patient with PsHP type Ib had clearly decreased cAMP responses to glucagon infusion; both had normal renal responses to PTH and were clinically and biochemically euthyroid at the time of study. Glucose responses to glucagon were normal in both PsHP groups; the glucose response per unit cAMP response was slightly, but not significantly, enhanced in PsHP type Ia patients. Glucagon resistance appears to be a common finding in patients with PsHP type Ia, but not in those with PsHP type Ib. However, the observation of reduced glucagon responsivity in association with familial hypothyroidism in a kindred with PsHP type Ib suggests the possibility that this disorder may also cause disturbances in several hormone systems.


Subject(s)
Glucagon , Pseudohypoparathyroidism/blood , Adolescent , Adult , Blood Glucose/metabolism , Cyclic AMP/blood , Dose-Response Relationship, Drug , Drug Resistance , Erythrocytes/metabolism , Female , GTP-Binding Proteins/blood , Glucagon/administration & dosage , Glucagon/blood , Humans , Infusions, Intravenous , Insulin/blood , Male , Middle Aged
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