Polycystic ovary syndrome: lack of hypertension despite profound insulin resistance.

It has been hypothesized that insulin resistance and hyperinsulinemia contribute to the development of arterial hypertension. To further investigate this relationship, we compared arterial blood pressure in controls and women with polycystic ovary syndrome (PCO), an insulin-resistant state. Fourteen PCO women and 18 normal control women of similar age, body mass index, and race were studied. Plasma glucose and insulin levels were determined in an oral glucose tolerance test. The insulin sensitivity (SI) index was determined by the minimal model method. Systolic and diastolic blood pressure were measured by 24-h ambulatory monitoring. Left ventricular mass was assessed by echocardiography. The two groups had comparable fasting glucose levels, but the 2-h postload glucose was higher in PCO (8.0 +/- 0.5 vs. 5.6 +/- 0.3 mmol/L; P less than 0.001). Compared to controls, PCO women were significantly more insulin resistant by fasting insulin, 2-h insulin concentrations, and SI (28.3 +/- 6.7 vs. 68.3 +/- 10.0 min-1/nmol.mL; P less than 0.01). Average ambulatory systolic (121 +/- 2 vs. 118 +/- 2 mm Hg) and diastolic (76 +/- 2 vs. 73 +/- 2 mm Hg) blood pressures were similar for PCO and control women. No difference was found in left ventricular mass. Therefore, despite profound insulin resistance and hyperinsulinemia, women with PCO do not have increased arterial pressure or left ventricular mass.

Heart transplantation for end-stage cardiomyopathy caused by an occult pheochromocytoma.

Dilated cardiomyopathy has been found in patients with pheochromocytoma. The cardiomyopathy and resultant congestive heart failure can be progressive and fatal, or reversible, if the source of the excess catecholamines is removed. Histologic and autopsy studies revealed a characteristic focal myocarditis and contraction band necrosis, indicating that the circulating catecholamine excess secreted by the pheochromocytoma is the cause of the cardiomyopathy.

Activation of the human neutrophil by calcium-mobilizing ligands. II. Correlation of calcium, diacyl glycerol, and phosphatidic acid generation with superoxide anion generation.

Calcium and protein kinase C (Ca2+/phospholipid-dependent enzyme) have been proposed to act as signals in triggering superoxide anion (O2-) generation by neutrophils. We have probed the adequacy and necessity of calcium and diacylglycerol (DG), activators of protein kinase C, in eliciting O2- generation and degranulation. Activation of neutrophils by the ligand 10(-7) M fMet-Leu-Phe triggered elevation of cytosolic calcium (fura-2) and a rapid, biphasic increase in labeled DG in [14C]glycerol and [3H]arachidonate prelabeled cells. Buffering of the fMet-Leu-Phe-induced elevation of cytosolic calcium with MAPTAM (a cell permeant EGTA analogue) inhibited O2- generation by 90% and degranulation by 50%, concordant with a role of calcium in signaling. However, buffering the increase in calcium also decreased DG. Since phosphatidylinositol 4,5-bisphosphate breakdown in response to fMet-Leu-Phe was not inhibited and phosphatidic acid levels were enhanced in MAPTAM pretreated cells, the removal of calcium may enhance further DG metabolism. Thus, a requirement for calcium could not be differentiated from a requirement for DG, and the profound inhibition of O2- generation in the presence of MAPTAM may reflect removal of DG. Four stimuli, fMet-Leu-Phe, 10(-7) M leukotriene B4, 100 micrograms/ml concanavalin A, and 200 nM ionomycin elevated cytosolic calcium and triggered release of specific granules, but only fMet-Leu-Phe and concanavalin A triggered substantial O2- generation. Nevertheless, all four stimuli significantly increased labeled DG. Therefore, elevated DG and elevated calcium may be necessary but do not appear adequate to elicit O2- generation. Only fMet-Leu-Phe and concanavalin A triggered generation of phosphatidic acid (PA) together with DG. Correlation of O2- generation with PA may reflect a requirement for PA per se or for a specific pool of DG that can be further metabolized to PA.

The first seconds of neutrophil activation: phosphoinositides, protein kinase C, and calcium movements.

Activation of the neutrophil by interaction of a ligand such as f-Met-Leu-Phe with its specific receptor elicits a prompt breakdown of PIP2 and the generation of PA via diacylglycerol. There is a rapid elevation of cytosolic calcium and activation of protein kinase C. Calcium and protein kinase C act synergistically to elicit the physiological responses. Although PIP2 breakdown and PA generation are prompt responses of neutrophils to receptor occupancy by chemoattractants, these steps can be bypassed by stimuli which directly activate protein kinase C or increase cytosolic calcium. Elevation of cytosolic Ca and activation of protein kinase C did not elicit breakdown of PIP2, indicating that phosphoinositide remodeling is not caused by activation of protein kinase C or by elevation of cytosolic calcium, nor is such a breakdown or the generation of phosphatidic acid required for the subsequent responses. The evidence indicates that PIP2 breakdown is an early event in stimulus-response coupling and is correlated with receptor-initiated generation of the signal.

Stimulus response coupling in the human neutrophil. Differential requirements for receptor occupancy in neutrophil responses to a chemoattractant.

Activated neutrophils aggregate, generate superoxide (O-2), and degranulate. The role of Ca as "second messenger" in neutrophil activation was examined using as agonist the chemotactic peptide fMet-Leu-Phe and its antagonist t-butoxycarbonyl-Phe-Leu-Phe-Leu-Phe to systematically vary the time of receptor occupancy. Release of enzymes from specific and azurophil granules showed a finite requirement for receptor occupancy; the cells were committed to full degranulation after 10 s of receptor-agonist interaction. In contrast, continuous occupation of the receptor by agonist was required to initiate and maintain O-2 generation and aggregation. Cytosolic Ca ( Quin2 fluorescence) increased immediately in response to fMet-Leu-Phe, requiring less than 2 s of agonist-receptor interaction to initiate an optimal response. Mobilization of membrane-associated Ca (chlorotetracycline fluorescence) also demonstrated a finite time requirement; the cells were fully committed after 10 s of agonist-receptor interaction. Increased Ca permeability (45Ca uptake) was fully launched after 15 s of agonist-receptor interaction. The data indicate that Ca movements ( quin2 , chlorotetracycline fluorescence, 45Ca uptake) are both necessary and sufficient to account for degranulation by neutrophils activated by fMet-Leu-Phe. However, neutrophil aggregation and the generation and release of O-2 in response to the same stimulus require a further unknown factor(s) associated with receptor occupancy to maintain these responses.

Stimulus response coupling in the human neutrophil. II. Temporal analysis of changes in cytosolic calcium and calcium efflux.

The role of changes in cytosolic free calcium (Ca) in the activation sequence of the human neutrophil has been monitored by means of the fluorescent probe Quin2. "Complete" secretagogues such as the chemotactic peptide f-Met-Leu-Phe and aggregated IgG, as well as the "incomplete" secretagogue concanavalin A, elicited prompt rises in cytosolic Ca. The rise in cytosolic Ca was in all cases one of the earliest measurable events, consistent with the hypothesis that increments in cytosolic free Ca serve as a signal to activate subsequent physiological responses. The source of cytosolic Ca is principally intracellular, since removal of extracellular Ca had little effect on the rise in cytosolic Ca. Although increments in cytosolic Ca may be essential for neutrophil activation, they are evidently not sufficient; chemotactic levels of f-Met-Leu-Phe elicited optimal increments in cytosolic Ca without triggering degranulation, O-2 generation, and aggregation. Some other factor, associated with high levels of receptor occupancy, must be required for secretion. The tumor promoter phorbol myristate acetate was an exceptional stimulus, since it elicited degranulation, aggregation, and O-2 generation without triggering a rise in cytosolic Ca. Finally, an efflux of Ca is initiated which serves to maintain low intracellular levels of Ca.

Pharmacokinetics of heparin VII: Effect of pregnancy on the relationship between concentration and anticoagulant action of heparin in rats.

The effect of pregnancy on the anticoagulant action of heparin was determined by comparing the slope of the relationship between the natural logarithm of the activated partial thromboplastin time (APTT) and heparin concentration (the heparin slope) in the plasma of pregnant and nonpregnant female inbred Lewis rats. Also determined were the prothrombin time, hematocrit, and the activities of coagulation factors II, VII, VIII, X, XI, and XII. The heparin slope was significantly decreased in pregnant rats at the 20th day of gestation but not in rats at the 10th day of gestation, indicative of a decreased anticoagulant action of heparin in late pregnancy. The hematocrit and prothrombin time were decreased, and the baseline APTT (i.e., the APTT without added heparin) as well as the activities of factors II, VII, and X were increased in pregnant rats at the 20th day of gestation. Both pregnant and nonpregnant animals showed a significant negative correlation between prothrombin time and factor II activity and a significant positive correlation between the activities of factors II and X. The effects of pregnancy in rats on heparin slope, prothrombin time, hematocrit, and factors VII, VIII, X, and XII are qualitatively the same as those in pregnant women in the third trimester. The increases in factor II activity and baseline APTT found in the rats were not observed in humans. Pregnant rats, like pregnant women, are relatively resistant to the anticoagulant action of heparin.