Normalization of plasma lipid peroxides, monocyte adhesion, and tumor necrosis factor-alpha production in NIDDM patients after gliclazide treatment.

OBJECTIVE: To evaluate the effect of gliclazide administration to NIDDM patients on 1) monocyte adhesion to cultured endothelial cells, 2) plasma cytokine and lipid peroxide levels, and 3) monocyte cytokine production. RESEARCH DESIGN AND METHODS: Poorly controlled glyburide-treated diabetic patients (n = 8) and healthy control subjects (n = 8) were recruited. At the beginning of the study, glyburide was replaced by an equivalent hypoglycemic dose of gliclazide. Serum and monocytes were isolated from blood obtained from control and diabetic subjects before and after 3 months of treatment with gliclazide. RESULTS: Plasma lipid peroxide levels and monocyte adhesion to endothelial cells are enhanced in NIDDM patients, and gliclazide administration totally reverses these abnormalities. Before gliclazide treatment, serum levels of cytokines did not differ in the control and the diabetic groups, with the exception of an enhancement of tumor necrosis factor-alpha (TNF-alpha) and interleukin-6 (IL)-6 in NIDDM subjects. Basal and lipopolysaccharide (LPS)-stimulated monocyte production of interleukin-1 beta, IL-6, and IL-8 did not differ between the two groups. Furthermore, basal monocyte production of TNF-alpha was similar in the control and the diabetic groups, whereas a marked increase in the LPS-stimulated monocyte production of TNF-alpha was observed in the NIDDM group. Gliclazide treatment lowered LPS-stimulated TNF-alpha production by diabetic monocytes to levels similar to those observed in control subjects. CONCLUSIONS: Gliclazide administration to NIDDM patients inhibits the increased adhesiveness of diabetic monocytes to endothelial cells and reduces the production of TNF-alpha by these cells. These results suggest that treatment of NIDDM subjects with gliclazide may be beneficial in the prevention of atherosclerosis associated with NIDDM.

Octreotide inhibits insulin-like growth factor-I hepatic gene expression in the hypophysectomized rat: evidence for a direct and indirect mechanism of action.

Somatostatin and somatostatin analogs are known to interact with the GH-insulin-like growth factor (IGF)-I axis by inhibiting GH secretion and consequently hepatic IGF-I production. Indirect evidence suggests that octreotide, a somatostatin analog, reduces serum IGF-I levels relatively more than expected from GH reduction, implying a GH-independent pathway of action. To study the role of octreotide in the regulation of IGF-I production, independently of endogenous GH, we used the hypophysectomized (hypox) rat to measure hepatic IGF-I expression and also employed cultured rat hepatocytes to examine whether octreotide has any direct effect on the production of IGF-I. Forty male hypox Sprague-Dawley rats were randomized into 4 groups to receive daily injections for 3 days of either saline, human GH (hGH) (100 g), octreotide (100 g twice), or both hGH (100 g) and octreotide (100 g twice). GH stimulated serum IGF-I levels to 104 +/- 10 micrograms/liter as compared to saline (26 +/- 2 micrograms/liter). Octreotide alone had no effect, but combining octreotide and hGH significantly reduced the hGH-induced rise in the IGF-I levels (52 +/- 6 micrograms/liter). The relative expression of hepatic IGF-I in the rats treated with hGH increased by 4-fold compared to that in the saline-treated rats. Octreotide administered simultaneously with hGH potently blocked the hGH-induced IGF-I expression to control levels. In cultured hepatocytes, IGF-I mRNA levels maximally stimulated by combining bGH and glucagon were significantly inhibited in the presence of octreotide at low concentrations (0.3 and 3 ng/ml) by 25% and 45%, respectively. In contrast, high concentrations of octreotide (30 and 300 ng/ml) had no significant effect on IGF-I mRNA abundance. We conclude that: 1) octreotide inhibits IGF-I serum levels and hepatic gene expression in the hypox rat; and 2) octreotide can inhibit partially the direct effects of GH and glucagon on hepatic IGF-I production.

Effects of naloxone on insulin-induced release of pituitary hormones.

To evaluate the role of endogenous opiates on the regulation of the pituitary hormonal stress response, we have studied in six normal subjects the insulin-induced secretion of PRL, GH, and ACTH with and without naloxone, a specific opiate antagonist. During hypoglycemia, naloxone infusion reduced plasma PRL levels at 90 min, lowered the overall GH response, and enhanced that of ACTH. These observations suggest that endogenous opiates have a modulatory role in the stress-induced secretion of pituitary hormones.

Sulfoconjugation of catecholamines, nutrition, and hypertension.

Sulfoconjugation is an important metabolic pathway determining the fate and potential cardiovascular action of ingested phenolic substances. Among the three catecholamines, dopamine (DA) is to the highest degree sulfoconjugated and has the highest affinity toward the phenolsulfotransferase (PST). The concentration of some sulfated catecholamines, particularly of DA sulfate, increases following ingestion of catecholamines or their precursors. This can be confounded with blood-derived increases in DA sulfate associated with BP peaks in some hypertensive patients. We mimicked, therefore, the latter condition by infusion of free DA into normotensive subjects. At low DA infusion rates, plasma DA sulfate exceeded free DA concentrations, and there were no changes in blood pressure and pulse rate. At higher DA infusion rates, blood pressure and pulse rate increased only while plasma free DA concentrations exceeded those of DA sulfate, indicating that free DA remains biologically active only prior to being conjugated. A similar increase in DA sulfate from alimentary sources (e.g., eating a banana) remains without cardiovascular response and is not associated with an overflow of free DA, since all the ingested DA is conjugated in the gut. We describe a patient with pheochromocytoma who experienced repeated hypertensive crises after ingestion of food containing some biogenic amines, (once also documented by NE increase), possibly due to a phenol sulfoconjugation defect (e.g., substrate inhibition of the PST or its genetic deficiency). Platelet PST-determinations may serve as a screening tool to detect subjects with sulfoconjugation defects since they probably reflect the PSt activity in the gut where ingested phenols are sulfoconjugated.

Differential effects of a low dose dopamine infusion on prolactin secretion in normal and hyperprolactinemic subjects.

The PRL inhibitory effect of dopamine (DA) in human in vivo studies has been previously demonstrated with DA infusions at rates generally exceeding 2 micrograms/kg . min. We report here the effects of a DA infusion administered at a rate of 0.02 microgram/kg . min for 180 min to 10 normal subjects and 25 hyperprolactinemic patients with pituitary tumors (13 microprolactinomas, 8 macroprolactinomas, and 4 expanding nonsecreting pituitary adenomas). Serum free DA concentrations during the 3-h DA infusion reached an average of 0.8 +/- 0.1 ng/ml (about an 8- to 10-fold rise from basal levels). DA produced a significant (P less than ) 0.001) decline in plasma PRL levels in both normal subjects and hyperprolactinemic patients. There was a negative linear correlation between the serum DA concentrations and the percent PRL variation from basal levels (r = -0.58; P less than 0.001). The comparison of RPL responses between the different groups revealed that the mean percent overall PRL inhibition was significantly lower in patients with microprolactinomas than in normal subjects (P less than 0.02). On the other hand, PRL inhibition was greater in patients with nonsecreting adenomas than in either patients with microprolactinomas or those with macroprolactinomas (P less than 0.001). From 90-180 min, PRL suppression was also greater in patients with nonsecreting adenomas than in normal controls (P less than 0.05). The present study shows that 1) slight elevations of plasma DA are sufficient to inhibit PRL secretion, suggesting that DA acts as major physiological PRL-inhibiting factor, 2) there is a relative PRL resistance to DA inhibition in microprolactinoma patients; and 3) PRL is hyperresponsive to DA in expanding nonsecreting pituitary tumors.

Alterations of monocyte function in patients with growth hormone (GH) deficiency: effect of substitutive GH therapy.

GH deficiency (GHD) is associated with increased prevalence of atherosclerosis and cardiovascular morbidity. Because monocytes play a crucial role in the development of atherosclerosis, we investigated in the present study the effect of GH deficiency and subsequent GH replacement on monocytic function in hypopituitary subjects. Twelve patients were randomized to receive GH replacement therapy (either 3 or 6 microg/kg x day, s.c.) for 3 months. Plasma levels and monocyte production of cytokines and monocyte adhesion to endothelium were determined in controls and patients with GHD before and after GH treatment. Before GH therapy, patients with GHD had increased basal plasma tumor necrosis factor-alpha (TNF alpha; 220% over control values; P = 0.004) and interleukin-6 (IL-6; 340% over control values; P 0.0009) levels. Basal monocyte production of both cytokines was also significantly higher in patients with GHD [484% over control values for TNF alpha (P = 0.0007); 1479% over control values for IL-6 (P = 0.035)]. GH treatment for 3 months led to a reduction in plasma TNF alpha (135% over control values; P = 0.03, pre- vs. post-GH therapy), monocyte TNF alpha production (204% over control values; P = 0.01), plasma IL-6 (219% over control values; P = 0.07), and monocyte IL-6 production (448% over control values; P = 0.01). Plasma TNF alpha levels positively correlated with monocyte TNF alpha production in patients with GHD both before and after GH therapy (P = 0.003 and P = 0.049, respectively). A positive correlation (P = 0.0003) was also observed between monocyte TNF alpha production and monocyte IL-6 production. There were no correlations between these plasma cytokine levels or monocyte cytokine production and parameters of body composition, lipid profile, or IGF-I and IGF-binding protein-3 levels. Before GH treatment, adhesiveness of monocytes to cultured aortic endothelial cells was also enhanced. This alteration was not reversed by GH administration. In conclusion, our results demonstrate that markers of monocyte activation are increased in patients with GHD and that GH replacement partly reduces these abnormalities. Reduction of cellular activation of monocytes by GH therapy could potentially contribute to reduce the risk of cardiovascular events in patients with GHD.

Acromegaly: biochemical assessment of cure after long term follow-up of transsphenoidal selective adenomectomy.

This study reports the clinical and biological follow-up 5-11 yr after transsphenoidal selective adenomectomy in 25 patients with acromegaly. Eight patients had microadenomas, and 17 had macroadenomas. Initial normalization of plasma GH levels (basal values, less than 5 ng/ml; glucose-suppressed concentrations, less than 2.5 ng/ml) was achieved in all 8 patients with microadenomas and in 13 patients with macroadenomas. Of these, 3 patients with normal GH levels and dynamics had relapse of GH hypersecretion after intervals between 1-6 yr after microadenoma removal. Recurrence of pituitary adenoma was documented by surgery in 1 patient and by computed tomographic scanning in 2 others. Normal basal and glucose-suppressed plasma GH concentrations were maintained 7.4 +/- 0.5 (+/- SEM) yr after adenomectomy in 7 patients with microadenomas and in all 10 patients with macroadenomas. Thus, 88% of the patients with microadenomas and 59% of the patients with macroadenomas were cured, and the overall cure rate was 68%. We conclude that recurrence of acromegaly after successful surgery may occur late after adenoma removal and that it cannot be predicted by normal postoperative GH levels and dynamics. However, in view of the overall cure rate, transsphenoidal adenomectomy remains a most valuable treatment for acromegaly.

Long term treatment with CV 205-502 in patients with prolactin-secreting pituitary macroadenomas.

CV 205-502, a new long-acting nonergot dopamine agonist, was given to 15 patients (6 women and 9 men) with PRL-secreting pituitary macroadenomas. The compound was administered in a single daily dose for a period of 6-12 months. The treatment resulted in normalization of plasma PRL levels (less than or equal to 20 micrograms/L) in 5 of 6 women at a mean dose of 135 micrograms (range, 75-300 micrograms) and in 6 of 9 men at a mean dose of 192 micrograms (range, 75-300 micrograms). Among patients for whom computed tomographic scans were available before and after at least 6 months of therapy, definite tumor shrinkage occurred in 6 of 7 patients. Libido was improved in 5 of 6 women and in 6 of 8 men, galactorrhea disappeared in all cases (3 women and 1 man) and menses resumed in 3 of 5 women. Plasma testosterone rose to normal levels in 3 of 6 men who were not receiving testosterone injections. The PRL response to TRH was blunted in 4 of 6 patients with normalized basal PRL. Serum total cholesterol was reduced by CV 205-502 treatment in women from 5.35 +/- 0.49 to 4.63 +/- 0.51 mmol/L (P = 0.031) and in men from 5.93 +/- 0.89 to 5.28 +/- 0.82 mmol/L (P = 0.045). Side-effects included mainly headache, nausea, and dizziness. One side-effect or more occurred transiently and with mild intensity in 14 patients. No patient discontinued the therapy because of side-effects. In conclusion, CV 205-502 appears to be a safe and valuable compound in the treatment of patients with PRL-secreting macroadenomas.

Mixed growth hormone and prolactin-secreting human pituitary adenomas: a pathologic, immunocytochemical, ultrastructural, and immunoelectron microscopic study.

A study of 30 adenomas from patients with signs of growth hormone (GH) and prolactin (PRL) hypersecretion revealed the presence of mammosomatotroph cells (MSC) containing both hormones in all cases. Although the number of immunostained cells varied from case to case, in 14 of 25 tumors, all stained cells were MSC. Nine tumors had the ultrastructural appearance of densely granulated growth hormone adenomas, while 11 cases resembled sparsely granulated growth hormone adenomas with frequent fibrous bodies. Exocytosis was present in six of these 11 cases, a feature unusual for pure growth hormone adenomas. Nine tumors consisted of a mixture of cells with the morphology of GH and PRL cells. In the four cases examined, immunoelectron microscopy using double immunolabeling with protein A-gold particles revealed the presence of secretory granules containing both hormones in some tumor cells recognized as mammosomatotroph cells.

Intervention in diabetic vascular disease by modulation of growth factors.

Several growth factors have been implicated in the derangements of cellular metabolism and proliferation that occur in diabetes, eg. kidney mesangial expansion, retinal neovascular formation, and acceleration of atherosclerosis in large vessels. These phenomena contribute to the development and progression of diabetic microvascular and macrovascular disease. Pharmacological interventions aimed at reducing growth factor alterations, among other actions in diabetic vasculopathy, include a multitude of classes of drugs, such as angiotensin-converting enzyme (ACE) inhibitors, calcium antagonists, lipid-lowering drugs, and somatostatin analogs. New potential interventions, ie, antisense oligonucleotide local delivery, are being applied in growth factor research and may prove beneficial in diabetic macrovascular disease.

Effect of dietary restriction and repeated growth hormone-releasing factor injections on growth hormone response to growth hormone-releasing factor in obese subjects.

The response of serum growth hormone (GH) to a test bolus of growth hormone-releasing factor (GRF) (1 micrograms/kg, IV) was examined in eight obese subjects (166% +/- 8% ideal body weight [IBW] during a weight-maintaining control period and after 2 weeks of hypocaloric feeding (750 kcal). During the period of hypocaloric feeding subjects received either repetitive GRF 1 micrograms/kg, IV (GRF group, n = 6) at 9 AM, 1 PM, and 5 PM three times a week, or saline injections (placebo group, n = 6) at the same intervals. Four subjects were studied twice, several months apart, each receiving GRF and placebo treatments. Nitrogen balance was determined daily throughout the study. We also examined GH response to the GRF test in seven normal-weight subjects (106% +/- 6% IBW]. During the control period, obese subjects demonstrated a blunted GH response to GRF expressed as peak height or GH area under the curve (0 to 120 minutes) compared with normal subjects (P less than .005). At the end of the hypocaloric feeding, mean GH peak height after the GRF test was unchanged in the placebo group compared with the control period. GH release was significantly increased only during the second hour of testing (P less than .025). However, the GRF group demonstrated an increase in both mean GH peak height (P less than .025) and GH release during the first and second hours of testing (P less than .025) compared with the control period. Weight loss and blood glucose, triglycerides, FFA, amino acids, insulin, and T3 changes were similar in both groups.(ABSTRACT TRUNCATED AT 250 WORDS)

Gliclazide decreases cell-mediated low-density lipoprotein (LDL) oxidation and reduces monocyte adhesion to endothelial cells induced by oxidatively modified LDL.

Low-density lipoprotein (LDL) oxidation has been suggested to play a key role in the pathogenesis of atherosclerosis, a major complication of diabetes mellitus. Gliclazide, a second-generation sulfonylurea, is widely used in the treatment of type II diabetes mellitus. Recently, a free-radical-scavenging activity of gliclazide has been reported. In the present study, we examined the effects of gliclazide on cell-mediated LDL oxidation and monocyte adhesion to endothelial cells induced by oxidatively modified LDL. Incubation of human monocytes and bovine aortic endothelial cells (BAE cells) with increasing concentrations of gliclazide (0 to 10 micrograms/mL) and native LDL (100 micrograms/mL) resulted in a dose-dependent diminution of cell-mediated LDL oxidation as assayed by measurement of thiobarbituric acid (TBA)-reactive substances (TBARS). In addition, exposure of BAE cells to gliclazide (0 to 10 micrograms/mL) and native LDL (100 micrograms/mL) induced a dose-dependent diminution of the oxidized LDL-induced monocyte adhesion to BAE cells as measured by the myeloperoxidase (MPO) assay. The effects of glyburide, another second-generation sulfonylurea, were also tested on cell-mediated oxidation of LDL and LDL-induced monocyte adhesion to the endothelium. No significant effect of this drug was observed on these two processes. These results therefore demonstrate that gliclazide is effective in vitro in reducing both cell-mediated LDL oxidation and monocyte adhesion to the endothelium. These findings suggest a potential beneficial effect of gliclazide in the prevention of atherosclerosis in diabetic patients.

Gliclazide decreases low-density lipoprotein oxidation and monocyte adhesion to the endothelium.

Increasing evidence implicates oxidized low-density lipoprotein (LDL) and advanced glycation end products (AGE) in the atherogenesis associated with diabetes mellitus. In the present study, we examined the in vitro effects of gliclazide on LDL oxidation and monocyte adhesion to endothelial cells induced by oxidized LDL and glycated albumin. To assess the clinical relevance of our in vitro findings, we also measured the effect on monocyte adhesion of gliclazide administration to type 2 diabetic patients. Incubation of human monocytes and endothelial cells with increasing concentrations of gliclazide (0 to 10 microg/mL) and native LDL (100 microg/mL) induced a dose-dependent diminution of cell-mediated LDL oxidation. Pretreatment of endothelial cells with gliclazide (0 to 10 microg/mL) before addition of native LDL (100 microg/mL) or glycated albumin (100 microg/mL) resulted in a dose-dependent diminution of oxidized LDL- and glycated albumin-induced monocyte adhesion to endothelial cells. In type 2 diabetic patients, administration of gliclazide inhibits the increased adhesiveness of monocytes to levels similar to those observed in control subjects. These results indicate that gliclazide is an antioxidant and suggest a beneficial effect of this drug in the prevention of atherosclerosis associated with type 2 diabetes.

Decreased sensitivity to insulin in women with microprolactinomas.

To determine whether there exists an altered sensitivity to insulin in hyperprolactinemia, we studied, in 15 women with microprolactinomas, the insulin effects on glucose, PRL, GH, and cortisol before and after successful adenoma removal. Our results show that in women with microprolactinomas, the sensitivity to insulin is lower in hyperprolactinemia than in normoprolactinemia achieved by selective adenomectomy.

Hyperprolactinemia associated with clinically silent adenomas: endocrinologic and pathologic studies; a report of two cases.

Pituitary adenomas containing adrenocorticotropic hormone (ACTH) in one case, and ACTH, beta-lipotropin, and beta-endorphin in the other, were demonstrated in two patients who had amenorrhea-galactorrhea and hyperprolactinemia with no manifestation of Cushing's disease. Neither adenoma contained prolactin (PRL). Initial bromocriptine therapy resulted in cessation of amenorrhea-galactorrhea and normalization of PRL levels. However, there was radiologic evidence of tumor enlargement in both patients. After pituitary adenomectomy, the two patients resumed regular menses and normal PRL dynamics. These patients illustrate the need for bromocriptine therapy for possible enlargement of their pituitary adenomas. The diagnosis of silent corticotroph adenoma should be kept in mind.

Surgical outcome after repeated transsphenoidal surgery in acromegaly.

Transsphenoidal selective adenomectomy is the most efficient primary treatment for acromegaly. However, management of persistent or recurrent disease remains controversial. The objective of the present study was to evaluate the early and long-term efficacy and safety of a second transsphenoidal surgery performed in those cases. The results of a retrospective study of 16 patients undergoing reoperation by the senior author (J.H.) between 1970 and 1991 are reported. Reoperation was performed for persistent or progressive acromegaly in 11 patients, visual impairment in four, and disease recurrence in one. Normalization of growth hormone (GH) was defined as a basal GH level of less than 5 micrograms/L and suppression to less than 2 micrograms/L during the oral glucose tolerance test. Long-term follow-up data were available in 15 patients. The second transsphenoidal surgery induced a greater than 50% decrease of GH level in 11 patients. Three (19%) of 16 patients were cured according to the authors' criteria and remained so after 2, 7, and 20 years. Two more patients had a postoperative basal GH level of less than 5 micrograms/L but incomplete suppression during the oral glucose tolerance test. Thus, a total of five patients (31%) achieved a basal GH of less than 5 micrograms/L. One other patient who had no initial improvement after the second transphenoidal surgery had spontaneous normalization of his GH level after 13 years. The following complications of the second surgery occurred in three patients: one subarachnoid hemorrhage, two new visual field defects, one cranial nerve palsy, and one meningitis. Moreover, 10 patients (62.5%) developed one or more new pituitary hormone deficiencies. In conclusion, reoperation for persistent or recurrent acromegaly has low success and high complication rates. According to the authors' experience, this procedure should be reserved for patients unresponsive to other forms of therapy or with progressive visual impairment despite medical therapy.

Effect of gliclazide on monocyte-endothelium interactions in diabetes.

Enhanced monocyte-endothelial cell interactions have been documented in diabetes. Because adherence of monocytes to the endothelium is one of the earliest events in the development of atherosclerosis, its alteration may represent one of the mechanisms leading to accelerated atherosclerosis in diabetic patients. Previous studies have suggested that lipoprotein oxidation and protein glycation may contribute to the increased monocyte binding to the diabetic vasculature. Based on the recent finding that gliclazide has free-radical scavenging activity, we examined the ex vivo and in vitro effects of this drug on human monocyte binding to endothelial cells. Our results demonstrate that short-term administration of gliclazide to patients with type 2 diabetes lowers the enhanced adhesion of diabetic monocytes observed before gliclazide treatment (163+/-24% over control values, p<0.005) to levels similar to those observed in controls. They also show that gliclazide (10 microg/ml) reduces in vitro by approximately 35% both oxidized low-density lipoprotein (LDL)- and glycated albumin-induced monocyte adhesion to endothelial cells. Based on these results, we next investigated the molecular mechanisms responsible for the inhibitory effect of gliclazide on glycated albumin-induced monocyte adhesion to endothelium. In glycated albumin-treated endothelial cells, we observed induction of cell-associated expression of E-selectin (ELAM-1; 170+/-10% over control values, p<0.005), intercellular cell adhesion molecule-1 (ICAM-1; 131+/-8% over control values, p<0.005) and vascular cell adhesion molecule-1 (VCAM-1; 134+/-8% over control values, p<0.005), augmentation in the levels of the transcripts of these molecules, and an increase in the DNA binding of NF-kappaB in the promoters of these antigens. Gliclazide markedly inhibited the induction of all these parameters. Because the oxidative stress-sensitive transcription factor NF-kappaB is implicated in endothelial cell activation, the observed inhibitory effect of gliclazide on NF-kappaB activation and glycated albumin-induced expression of DNA binding activity for the NF-kappaB site in the ELAM-1, ICAM-1 and VCAM-1 promoters seems to be due to its antioxidant properties. These results suggest that gliclazide, by its ability to reduce endothelial activation, may exert potential beneficial effects in the prevention of atherosclerosis associated with type 2 diabetes.

Growth hormone rebound after cessation of sms 201-995 treatment in acromegaly.

We studied a 42-year-old woman who had persistent active acromegaly despite conventional therapies. She was treated for 6 months with SMS 201-995. Her mean plasma growth hormone GH values decreased during treatment from 9.1 +/- 1.2 to 6.6 +/- 1.2 micrograms/L. One month after the withdrawal of SMS 201-995, the plasma GH level increased to 24.4 micrograms/L (P less than 0.001). This elevation was clinically silent and transitory, as GH levels decreased 8 months later to 6.9 +/- 1.3 micrograms/L. Furthermore, at the beginning of therapy, her intractable headache was completely relieved; however, it progressively resumed under therapy. In conclusion, cessation of SMS 201-995 may be followed in some acromegalic patients by a rebound of plasma GH levels. This rebound suggests that SMS 201-995 decreases GH levels by an inhibition of its release from the pituitary. Furthermore, SMS 201-995 may relieve intractable headache in some acromegalic patients, but tolerance to the analgesic effect may develop.

Dopamine negatively modulates its own blood pressure increasing action.

To evaluate the mechanisms of the hypertensive action of dopamine and its dependence on its metabolic patterns we infused a borderline hypertensive dose of free dopamine into healthy subjects. The moderate rise in systolic and diastolic blood pressure with an expected considerable increase of plasma free dopamine concentrations was associated within 30 minutes with an increase in plasma free norepinephrine and huge increases in plasma 3-4-dihydroxyphenylacetic acid, homovanillic acid and dopamine sulfate, the latter mostly between 60 and 180 minutes of infusion when diastolic blood pressure decreased. The overall pre-, per- and postinfusion changes in systolic blood pressure were negatively correlated with corresponding changes of free dopamine and dopamine sulfate. Reproducible patterns of blood pressure responses to the dopamine infusion made possible a subdivision into those who were blood pressure responders (who generated dopamine sulfate with delay) and non responders (who generated dopamine sulfate immediately). The data suggests that the 4 micrograms/kg/min dopamine infusion rate raises blood pressure indirectly via norepinephrine. Free dopamine and dopamine sulfate (the velocity of generation of which may be an inherited trait) are probably negative modulators of this action.

Transsphenoidal adenomectomy for microprolactinomas: 10 to 20 years of follow-up.

BACKGROUND: Transsphenoidal adenomectomy is an effective treatment fo r microprolactinomas. However, postoperative recurrence of hyperprolactinemia is not rare. This study was designed to evaluate the long-term outcome of women with microprolactinomas operated on by transsphenoidal approach. METHODS: We retrospectively studied 64 women with microprolactinomas who underwent transsphenoidal adenomectomy and were followed for 10 to 20 years. RESULTS: Postoperatively, 58 women (90%) had normal plasma prolactin concentrations (<20 microg/L). After a mean of 3.3 years, during which the women were asymptomatic with normoprolactinemia, 25 (43%) had a relapse of hyperprolactinemia (> or = 20 microg/L). However, their evolution varied. Fifteen women had symptomatic hyperprolactinemia. Computed tomography (CT) scans showed recurrent microadenomas in 2 women. The other 10 women had only hyperprolactinemia. Of these women, 5 had transient hyperprolactinemia (29 +/- 4 microg/L) for 5 years, after which prolactin declined to normal 13 +/- 3 microg/L). The remaining five patients had elevated prolactin (31 +/- 3 microg/L) throughout the follow-up period (10 to 20 years). CT scan did not show recurrent adenomas in these women. Thirty-three women remained normoprolactinemic and asymptomatic for a mean period of 12 years (range, 10 to 20 years). CONCLUSIONS: In conclusion, most of the patients with late relapse of hyperprolactinemia have slight functional hyperprolactinemia and remain asymptomatic with no evidence of tumor recurrence.