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Our data add to the growing body of literature suggesting that erectile dysfunction correlates with the level of glycemic control. Peripheral neuropathy and hemoglobin A1c but not patient age were independent predictors of erectile dysfunction.

Previous studies from this and other laboratories have shown that angiotensin II (AII) induces [Ca2"j transients in proximal tubular epithelium independent of phospholipase C. AII also stimulates formation of 5,6-epoxyeicosatrienoic acid (5,6-EET) from arachidonic acid by a cytochrome P450 epoxygenase and decreases Na' transport in the same concentration range. Because 5,6-EET mimics AII with regard to Na' transport, its effects on calcium mobilization were evaluated. ICa2i, was measured by video microscopy with the fluorescent indicator fura-2 employing cultured rabbit proximal tubule. AII-induced ICa2+i transients were enhanced by arachidonic acid and attenuated by ketoconazole, an inhibitor of cytochrome P450 epoxygenases. Arachidonic acid also elicited a ICa2i1, transient that was attenuated by ketoconazole. 5,6-EET augmented (Ca2'], similar to that seen with AII, but was unaffected by ketoconazole. By contrast, the other regioisomers (8,9-, 11,12-, and 14,15-EET) were much less potent. ICa2+i, transients resulted from influx through verapamil-and nifedipine-sensitive channels. These results suggest a novel mechanism for AII-induced Ca mobilization in proximal tubule involving cytochrome P450-dependent arachidonic asid metabolism and Ca influx through voltage-sensitive channels. (J. Clin. Invest. 1991.

The pharmacological properties and signaling of angiotensin IV (ANG IV) receptors were studied in opossum kidney cell line OK7A. Saturation binding experiments with 125I-labeled ANG IV demonstrated the presence of high-affinity ANG IV binding sites in OK7A cell membranes with a dissociation constant (Kd) of 0.40 +/- 0.08 nM and a maximal amount of binding sites (Bmax) of 180 +/- 50 fmol/mg protein. In competition experiments, unlabeled ANG IV inhibited 125I-ANG IV binding biphasically: 20% of binding sites had high affinity [inhibition constant (Ki) = 0.44 +/- 0.04 nM] and 80% had low affinity (Ki = 130 +/- 10 nM). ANG III displaced 125I-ANG IV from binding sites with low affinity (Ki = 205 +/- 10 nM), and ANG II did not compete with 125I-ANG IV at concentrations up to 10 microM. The binding of ANG IV to OK7A cell membranes was significantly enhanced in the presence of 5 mM EDTA and completely blocked by 5 mM dithiothreitol. Guanosine 5'-O-(3-thiotriphosphate) inhibited the binding of 125I-ANG IV, indicating the G protein coupling of ANG IV receptors in OK7A cells. In signaling studies, ANG IV induced transient increase in intracellular calcium concentration ([Ca2+]i) from 49 +/- 3 to 280 +/- 45 nM. ANG IV failed to influence phosphoinositol metabolism, indicating that Ca2+ mobilization is not linked to ANG IV signaling. Ethylene glycol-bis(beta-aminoethylether)-N,N,N',N'-tetraacetic acid completely abolished ANG IV-induced increase in [Ca2+]i, consistent with Ca2+ influx. The voltage-sensitive Ca2+ channel blocking agents verapamil and nifedipine attenuated the effect of ANG IV on [Ca2+]i to 133 +/- 33 and 174 +/- 32 nM, respectively. These data suggest that ANG IV induces Ca2+ influx in OK7A cells, at least partially, through the voltage-sensitive Ca2+ channels.

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Angiotensin II (Angll) is a potent regulator of electrolyte transport with biphasic effects on salt and HCO₃-resorption in proximal tubule epithelia (PCT). In cultured PCT cells, pM to nM Angll activates a GTP-binding protein to inhibit cAMP formation and thus releases inhibition of apical Na/H exchange. Phospholipase A₂ is activated by nM to µM Angll releasing arachidonate which is metabolized by a novel P450 epoxygenase to form 5,6-epoxy-eicosatrienoic acid (5,6-EET). 5,6-EET and nM apical Angll cause dihydropyridine-sensitive Ca²⁺ influx from the extracellular space, inhibition of apical-to-basolateral Na flux, and decrease in epithelial monolayer short circuit current. 5,6-EET also inhibits Na/K-ATPase by 50%. This P450 epoxygenase is physiologically important in the AngII -signaling system because the P450 inhibitor ketoconazole blocks Angll effects while potentiating exogenous 5,6-EET effects. Finally, these AngII-mediated signaling systems are polarized in the PCT with pM basolateral Angll inhibiting adenylate cyclase and nM apical Angll activating PLA₂ and subsequent generation of 5,6-EET.

Pituitary tumor apoplexy represents a rare clinical syndrome caused by hemorrhagic infarction of an existing, often previously unrecognized, large adenoma. We present our approach and experience in the field, and we provide a summary of pertinent published literature addressing diagnosis, management, and pathophysiology of the clinical manifestations of pituitary tumor apoplexy. Although many precipitating factors are known, most episodes occur spontaneously and present clinically with relatively sudden onset of severe headache, visual field defects, and ophthalmoplegia. Either computed tomography (nonenhanced and enhanced) or magnetic resonance imaging in a symptomatic patient can define pertinent anatomical changes and aid in establishing diagnosis. Immediate treatment with corticosteroids is necessary. Patients with the mild form of the syndrome respond quickly to steroids and can be managed conservatively with continued glucocorticoid therapy. Most patients with persistent neural deficits require urgent transsphenoidal decompression. Unless surgery is delayed, results of transsphenoidal decompression are usually very good, and improvements in neurological symptoms and endocrine function are noted within hours to days of the procedure. Patients need to be closely followed up after the episode because a large number continue to have residual tumor requiring additional therapy, or they have pituitary hormone abnormalities that need treatment. Close interaction between neurosurgeons and endocrinologists in the management of patients with pituitary tumor apoplexy is essential for optimal outcome.

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