Effects of dietary fish oil on ventricular premature complexes.

For ethical and practical reasons, in this study the antiarrhythmic potential of fish oil was evaluated in patients free from complex ventricular arrhythmias and severe heart failure. Although subjects without overt structural heart disease had ventricular arrhythmias that were not associated with an increased risk for sudden cardiac or coronary death, recent data suggest that frequent VPCs in patients similar to our study population may reflect subclinical cardiac disease amenable to the multiple beneficial actions of n-3 fatty acids. The potential and safety of fish oil as a treatment for more complex cardiac arrhythmias or arrhythmias in higher risk patients with more severe heart disease deserve further study.

Effects of clonidine and dihydralazine on atrial natriuretic factor and cGMP in humans.

The effects of a 1-wk treatment with clonidine (75 micrograms/day twice a day) and dihydralazine (25 mg/day twice a day) on base-line levels of plasma atrial natriuretic factor (ANF) and plasma and urinary guanosine 3',5'-cyclic monophosphate (cGMP) and their changes by acute saline infusion (2 liters) in eight normal subjects were evaluated. Basal ANF was decreased to 65% in the clonidine group compared with both the control and dihydralazine groups. Volume loading increased plasma ANF levels by 30-40% of base-line values in the control and the dihydralazine groups and by 15% in the clonidine group. Basal plasma and urinary cGMP levels were raised by 30 and 90% in the dihydralazine group compared with both other groups. Volume loading increased plasma cGMP levels by 40% in the control and clonidine-treated groups and by 25% in the dihydralazine-treated group. It is concluded that ANF may contribute to hemodynamic effects of clonidine but not to those of dihydralazine. Dihydralazine increases plasma and urinary cGMP, supposedly by direct activation of the soluble guanylate cyclase.

Does hormone analysis predict the antihypertensive response of basic medical treatment?

The antihypertensive effect of 200 mg metoprolol per day was compared to 25 mg hydrochlorothiazide over a period of four weeks. Metoprolol reduced mean arterial blood pressure from 120 +/- 13 mm Hg after placebo to 109 +/- 8 at the end of the study (n = 18; 38 +/- 12 years) (p less than 0.01). The corresponding values in the hydrochlorothiazide group were 119 +/- 13 mm Hg and 107 +/- 13 (n = 20; 33 +/- 12 years) (p less than 0.01). No significant difference between the groups was found for blood pressure at the end of the study. When blood pressure responders or non-responders of the metoprolol group were compared with the respective subgroup of the hydrochlorothiazide treated patients, no difference could be found for plasma renin activity as well as for aldosterone and PGE2- and PGF2a-excretion rates. However, when blood pressure responders were compared with non-responders within the same treatment group, plasma renin activity and PGE2-excretion rates were higher in the responder group corresponding with younger age in both treatments. Therefore high PGE2-excretion rate and high plasma renin activity might reflect a favorable vascular response to antihypertensive therapy. However, the hormonal analyses do not seem to help in the selection between a beta-blocker or a diuretic as a drug of first choice.

A case of immune complex hemolytic anemia, thrombocytopenia, and acute renal failure associated with doxepin use.

A 46-year-old man suffering from neurotic depression complicated by alcohol and benzodiazepine dependence developed Coombs'-positive hemolytic anemia and thrombocytopenia with acute renal failure after 5 weeks of monotherapy with doxepin at a final dosage of 100 mg daily. The patient recovered completely after discontinuation of doxepin, blood exchange transfusion, and repeated hemodialyses. He had no history of hematologic abnormalities, exposure to other toxins, or glucose-6-phosphate dehydrogenase deficiency. Because other etiologic factors were ruled out, the short interval between the onset of the patient's hemolytic crisis and the administration of doxepin highly suggests that doxepin was associated with the complication. To the best of our knowledge, ours is the first report of this adverse effect following doxepin administration.

Lack of effect of aldosterone on intracellular sodium and potassium in mononuclear leucocytes from patients with pseudohypoaldosteronism.

In three patients with pseudohypoaldosteronism the effects of aldosterone on intracellular sodium and potassium were studied and compared with normal controls in whom aldosterone prevents the loss of sodium and potassium in vitro. Mononuclear leukocytes were incubated with or without aldosterone (1.4 nM) in RPMI-1640 for 1 h at 37 degrees C. After two washes in isotonic MgCl2 the wet cell pellets were weighted and intracellular sodium and potassium determined by flame photometry, results are expressed as mmol/kg wet cells. In the patients intracellular sodium fell from 18, 23 and 29 mmol/kg to 14, 18 and 11 mmol/kg, respectively, in the absence of aldosterone. With aldosterone added to the incubation medium sodium was not different from values obtained without aldosterone (15, 20 and 13 mmol/kg). Corresponding values for potassium were 89, 48 and 75 mmol/kg before and 68, 32 and 51 mmol/kg after incubation without and 69, 36 and 54 mmol/kg after incubation with aldosterone. Thus, incubation with aldosterone did not show an effect on intracellular sodium and potassium as seen in normals. Baseline values of sodium and potassium before the incubation were within the normal range. From these results it is concluded that in patients with pseudohypoaldosteronism the absent or decreased number of mineralocorticoid receptors in mononuclear leucocytes are accompanied by a lack of response of intracellular sodium and potassium to aldosterone in vitro. However, normal baseline intracellular electrolyte concentrations in these patients may indicate that mineralocorticoids are not involved in the maintenance of normal levels of intracellular sodium and potassium.

Effects of aldosterone on intralymphocytic sodium and potassium in patients with primary aldosteronism.

In vitro effects of aldosterone have been described with regard to the intracellular sodium and potassium concentrations of human mononuclear leukocytes. In the present paper the in vitro effect of aldosterone on the intracellular sodium and potassium of human mononuclear leukocytes in 6 patients with primary aldosteronism was investigated. Except for one patient with elevated intracellular electrolytes, sodium and potassium in mononuclear leukocytes of patients with aldosteronism without incubation were within the range for normals. In the patients, no significant change of intracellular sodium or potassium was observed during incubation with or without aldosterone (1.4 nmol/l), whereas in normals, the loss of sodium and potassium during incubation without aldosterone was prevented by 1.4 nmol/l aldosterone. This insensitivity to aldosterone indicates that intracellular electrolytes in mononuclear leukocytes of patients with primary aldosteronism are kept in normal ranges by mechanism which are independent of mineralocorticoids and may represent the cellular correlate to the renal 'escape' phenomenon in aldosteronism.

Aldosterone receptors in different types of primary hyperaldosteronism.

The number of mineralocorticoid-binding sites on mononuclear leukocytes and plasma aldosterone (aldo) concentrations were measured in patients with different types of primary hyperaldosteronism. Patients with unilateral adenoma and patients with bilateral adrenal hyperplasia had a significantly lower (P less than 0.001) mean number of binding sites for aldo [144 +/- 36 (+/- SD; n = 6) and 140 +/- 28 sites/cell (n = 4), respectively] compared with normal subjects (292 +/- 110 sites/cell; n = 25). In four patients with dexamethasone-suppressible hyperaldosteronism, mineralocorticoid-binding sites in mononuclear leukocytes were normal (291 +/- 108 sites/cell). In all patients undergoing surgery for unilateral adenoma, the receptors normalized 3 months after the operation. In two patients the reduction in receptors persisted for a short time after surgery even though the plasma aldo level had already normalized. We conclude that mineralocorticoid excess produces down-regulation of mineralocorticoid receptors, which, in turn, might contribute to the genesis of the aldo escape phenomenon.

Effects of clonidine and dihydralazine on plasma ANF and cyclic GMP levels in humans during volume loading.

Acute volume loading increases plasma atrial natriuretic factor (ANF) levels in man and animals. In the present work we have compared the effects of a 1-week oral application of clonidine (2 x 0.075 mg/day) to dihydralazine (2 x 25 mg/day) in eight healthy volunteers on changes in plasma ANF and plasma and urine cyclic GMP levels after acute volume loading with 2 I physiological saline i.v. Basal plasma ANF levels before infusion were decreased by clonidine to 65% of the untreated controls and remained unaltered with dihydralazine. Volume loading increased plasma ANF levels by about 40% in the control and 30% in the dihydralazine treated group, whereas plasma ANF remained unchanged by volume loading in the clonidine-treated group. Dihydralazine increased basal cyclic GMP levels and urinary cyclic GMP excretion by 30 and 90%, respectively. Basal cyclic GMP levels were identical without treatment and after clonidine treatment. Saline infusion increased cyclic GMP levels by 40% in the control and clonidine-treated groups, and by 25% in the dihydralazine-treated group. Urinary cyclic GMP excretion increased by 2.1-, 1.6-, and 1.2-fold, respectively, in the controls, after clonidine, or after dihydralazine. The results of this study suggest that ANF is involved in the hormonal and hemodynamic effects that are induced by clonidine, but not in those induced by dihydralazine.

Effects of potassium loading in normal man on dopaminergic control of mineralocorticoids and renin release.

The interacting effects of potassium with the dopaminergic control of mineralocorticoid release were evaluated in normal man. Sixteen male healthy volunteers [27 +/- 6 (s.d.) years] on a 200 mmol sodium (Na+) and 60 mmol potassium (K+) diet (control) received a K+ load of 200 mmol/day for 6 days (high-K+ diet). Basal plasma aldosterone and 18-OH-corticosterone (18-OH-B) levels were significantly increased after 6 days of the high-K+ diet, whereas basal levels of 18-OH-deoxycorticosterone (18-OH-DOC) and corticosterone remained unchanged. Fifteen minutes after 10 mg i.v. of the dopaminergic antagonist, metoclopramide, a significant increase was only obtained for basal plasma aldosterone and 18-OH-B levels. The absolute rise of aldosterone and 18-OH-B induced by metoclopramide was greater (P less than 0.01) after K+ supplementation. However, the relative increase of these hormones was similar before and after K+ loading. Basal plasma renin activity increased significantly under high-K+ diet. The results indicate that K+ homeostasis must be taken into account when estimating absolute response of aldosterone and 18-OH-B to dopaminergic antagonism.

The determination of mineralocorticoid receptors in human mononuclear leukocytes from patients with mineralocorticoid excess: physiological and pathological implications.

The affinity and the capacity of mineralocorticoid receptors (MR) in human mononuclear leukocytes (HML) were determined in 9 patients with Conn's syndrome (PA) and in 3 patients with pseudohypoaldosteronism (PHA). The number of binding sites per cell was 136 +/- 39 (mean +/- SD) in PA. One case with PHA had no MR, and of the other 2 patients, one had 50 and the other 55 receptors per cell. The capacity of normal controls ranged from 200 to 400 receptors per cell (n = 20). We conclude that the etiology of PHA is due to a lack of MR in the target tissues and that a down regulation of MR may exist in PA.

Rapid increase in plasma and urinary cyclic GMP after bolus injection of atrial natriuretic factor in man.

We studied the effects of a bolus injection of 50/micrograms synthetic human atrial natriuretic factor (ANF) on the cyclic GMP and cyclic AMP levels in plasma and urine of eight normal men. Administration of the hormone increased basal immunoreactive (IR-) ANF levels in plasma 2.8-fold to 110 pM three minutes after injection. Thereafter, IR-ANF levels rapidly declined to basal levels. Plasma cyclic GMP levels increased 2.6-fold to 16.6 nM within 6 minutes after ANF and decreased to near basal values within 30 minutes. Urinary cyclic GMP excretion increased 2.8-fold, whereas urinary volume and sodium excretion increased less than two-fold in the 30 minutes after ANF. Plasma cyclic AMP levels did not change. The data indicate that changes in plasma IR-ANF levels are followed by changes in plasma cyclic GMP and in urinary cyclic GMP excretion and suggest that cyclic GMP is a biological marker for circulating ANF in man.

Dopamine reduces aldosterone and 18-hydroxycorticosterone response to angiotensin II in patients with essential low-renin hypertension and idiopathic hyperaldosteronism.

Plasma aldosterone, 18-hydroxycorticosterone (18-OH-B), 18-hydroxydeoxycorticosterone (18-OH-DOC), corticosterone, cortisol and prolactin levels were determined during an angiotensin II infusion at increasing rates both with and without a simultaneous infusion of dopamine in seven normotensive subjects, in ten patients with essential hypertension, and in ten patients with primary aldosteronism. In a second set of experiments, maximum increases of these plasma levels were determined after metoclopramide (10 mg intravenously) in all subgroups. As compared with the other groups, an exaggerated angiotensin II-induced response of plasma aldosterone and 18-OH-B levels was observed in the five patients with low-renin essential hypertension (LREH) and in five patients with idiopathic hyperaldosteronism (IHA). Dopamine reduced the maximal increase of aldosterone and of 18-OH-B after angiotensin II to 259 +/- 48 (SEM) pg/ml and 511 +/- 152 pg/ml respectively in LREH (without dopamine: 515 +/- 74 and 908 +/- 201 respectively; P less than 0.05), and to 466 +/- 197 and 741 +/- 212 in IHA (without dopamine: 766 +/- 193 and 1264 +/- 337 respectively; P less than 0.05). The maximal increases of plasma aldosterone, 18-OH-B, and prolactin after metoclopramide (10 mg intravenously) were higher (P less than 0.01) in patients with LREH and in patients with primary aldosteronism. Plasma levels of 18-OH-DOC, corticosterone and cortisol were not affected by the stimuli applied. The exaggerated response to metoclopramide as well as to angiotensin II and its reversion only by pharmacological doses of dopamine are consistent with an increased but ineffective dopamine inhibition of aldosterone and 18-OH-B in LREH and IHA.

Red cell Na+ -K+ transport in various forms of human hypertension. Role of cardiovascular risk factors and plasma potassium.

Na+ -Li+ exchange, Na+ -K+ cotransport and the Na+ leak of human erythrocytes are not only governed by genetic factors but also by variables influenced by exogenous factors such as plasma lipid and K+ concentrations.

Mineralocorticoid and glucocorticoid receptors in circulating mononuclear leukocytes of patients with primary hyperaldosteronism.

Mineralocorticoid and glucocorticoid receptors were measured in circulating mononuclear leukocytes in 5 patients affected by Conn's syndrome (3 cases of bilateral adrenal hyperplasia and 2 cases of adenoma plus unilateral hyperplasia). The number of the binding sites per cell resulted significantly lower (189 +/- 114, mean +/- SD), as compared with the normal controls (298 +/- 105). The affinity of aldosterone for the receptor was found to be not different than that of healthy control subjects. The capacity and the affinity of dexamethasone for glucocorticoid receptors ranged in the normal values. These data suggest a possible down-regulation of mineralocorticoid receptors in humans.

Prostaglandin excretion after furosemide in normal and low-renin essential hypertension.

We examined the urinary excretion of prostaglandin (PG)E2 and PGF2 alpha before and 15 min after stimulation with the acutely vasodilating agent furosemide in 25 normotensive controls and 81 patients with essential hypertension (EH). After furosemide administration, PGE2 excretion was lower in patients with EH (P less than 0.02). Excretion rates of PGF2 alpha and of sodium, and urinary volume in hypertensive patients were not significantly different from the values found in normotensive controls. Patients with low-renin essential hypertension (LREH) had a significantly reduced excretion of both PGE2 and PGF2 alpha before and after administration of furosemide as compared to controls. The difference in PGF2 alpha excretion was also significant when LREH patients were compared to those with normal-renin essential hypertension (NREH). Patients with LREH were older and excreted less potassium than patients with NREH or normotensive controls. We conclude that the reduced PG excretion immediately after furosemide administration in patients with EH reflects a diminished capacity of the hypertensive kidney to generate prostaglandins which exert an overall vasodilating effect. Since renin secretion is under the control of renal PG formation, the decreased responsiveness of plasma renin activity (PRA) observed in patients with EH and predominantly in those with LREH may be the consequence of a decreased renal cortical PG generation. Alternatively, mechanisms that reduce both PRA and PG generation have to be considered.

Mineralocorticoid and prolactin response to the dopamine antagonist metoclopramide in patients with primary aldosteronism.

Plasma mineralocorticoid and prolactin levels were evaluated before and 15, 30, 60 and 120 min after the administration of 10 mg metoclopramide in seven normotensive volunteers (42 +/- 5 (SD) years), as well as in ten patients with primary aldosteronism five with aldosterone-producing adenoma (49 +/- 4), and five with bilateral hyperplasia (47 +/- 3). Significant increases of plasma aldosterone, 18-hydroxycorticosterone (18-OH-B), and prolactin levels were observed in all normal subjects and in patients with primary aldosteronism after metoclopramide, whereas plasma 18-corticosterone, corticosterone, and cortisol levels as well as plasma renin activity did not change. The absolute increases of plasma aldosterone and 18-OH-B levels after metoclopramide were considerably higher in eight of the ten patients with primary aldosteronism. Furthermore, in patients with hyperplasia the maximum increase of aldosterone and 18-OH-B was delayed, as was the subsequent decrease of plasma aldosterone. Basal prolactin levels were within the normal range in all patients with primary aldosteronism, but the increase of prolactin observed 15 and 30 min after metoclopramide, was elevated in three patients with hyperplasia and in four patients with adenoma. For patients with primary aldosteronism, a positive correlation was found when the absolute maximum increase of plasma aldosterone levels after metoclopramide was plotted against the increase of prolactin (y = 1.11x - 101, r = 0.74, P less than 0.05). Our results suggest that prolactin, aldosterone, and 18-OH-B secretion is under increased inhibitory dopaminergic control in most of the patients with primary aldosteronism. The positive correlation between the metoclopramide-induced increase of plasma aldosterone and prolactin may indicate a common inhibitory dopaminergic mechanism, working on the pituitary and adrenal level.

Rapid increase of mineralocorticoids after furosemide in low-renin essential hypertension: evidence for 18-hydroxycorticosterone to be a better marker than aldosterone.

The response of plasma renin activity (PRA), plasma aldosterone, 18-hydroxycorticosterone (18-OH-B), 18-hydroxydeoxycorticosterone (18-OH-DOC) and corticosterone to furosemide were compared in 20 normal control subjects, 16 patients with normal-renin essential hypertension (NREH) and 12 patients with low-renin essential hypertension (LREH). Analyses were performed before medication, and 15 min (supine) and 120 min (active orthostasis) after IV administration of 40 mg furosemide. In normotensive subjects PRA increased 15 min after administration of furosemide from 0.8 +/- 0.4 ng AI/ml . h (SD) to 3.4 +/- 1.4 (P less than 0.01), plasma aldosterone from 109 +/- 28 pg/ml to 139 +/- 40 (less than 0.01) and 18-OH-B from 199 +/- 90 to 279 +/- 85 (P less than 0.01). In patients with NREH, PRA increased significantly less (P less than 0.01) and no significant increase of plasma aldosterone or 18-OH-B was found. PRA of patients with LREH (0.2 +/- 0.1 ng AI/ml . h) remained practically unchanged 15 min after furosemide administration, but in contrast to NREH aldosterone increased from 111 +/- 37 to 160 +/- 66 (P less than 0.05) and 18-OH-B from 162 +/- 101 to 261 +/- 71 pg/ml (P less than 0.01). The relative increase in plasma 18-OH-B was significantly greater in patients with LREH than in patients with NREH. The plasma levels of aldosterone and 18-OH-B 120 min after furosemide administration were significantly higher in normotensive subjects than in either hypertensive group (P less than 0.01). Corticosterone and 18-OH-DOC levels were the same in all investigated groups and increased significantly (P less than 0.01) only at 120 min after furosemide erone and 18-OH-B 120 min after furosemide administration were significantly higher in normotensive subjects than in either hypertensive group (P less than 0.01). Corticosterone and 18-OH-DOC levels were the same in all investigated groups and increased significantly (P less than 0.01) only at 120 min after furosemide erone and 18-OH-B 120 min after furosemide administration were significantly higher in normotensive subjects than in either hypertensive group (P less than 0.01). Corticosterone and 18-OH-DOC levels were the same in all investigated groups and increased significantly (P less than 0.01) only at 120 min after furosemide administration combined with active orthostasis. In summary, our results support the concept that sensitivity of the mineralocorticoid-producing cells is enhanced in patients with LREH. Postfurosemide 18-OH-B seems to be a better marker of this phenomenon than aldosterone.

Acute haemodynamic and hormonal effects of captopril are diminished by indomethacin.

1. The acute haemodynamic and hormonal effects of 100 mg of captopril (SQ 14.225) orally were tested in twelve healthy men in the sodium replete state before and after indomethacin pretreatment. 2. Without indomethacin, mean arterial blood pressure was reduced at 30 and 60 min after captopril (P less than 0.02). Heart rate did not change during the whole experiment. Although plasma renin activity (PRA) increased (P less than 0.002), plasma and urinary aldosterone and plasma 18-hydroxycorticosterone (18-OH-B) decreased after captopril (P less than 0.02). Prostaglandin (PG) E2, sodium and potassium excretion rates remained constant after captopril. 3. Under indomethacin pretreatment, the fall in mean arterial blood pressure was less than without indomethacin at 30 and 60 min after captopril (P less than 0.05). Heart rate was constantly lower than without indomethacin during the whole experiment (P less than 0.05). Indomethacin pretreatment decreased basal PGE2 excretion (P less than 0.02) and baseline PRA as well as the increase in PRA after captopril (P less than 0.05). Control mineralocorticoid levels were significantly lower than without indomethacin. In indomethacin-pretreated subjects, aldosterone did not further decrease after captopril, and 18-OH-B fell only slightly. 4. Without indomethacin pretreatment a significant, positive correlation was found between PRA values before captopril and the maximum decrease of mean arterial blood pressure after captopril. Under indomethacin pretreatment this correlation was no longer demonstrable. The results suggest that prostaglandins may contribute to the haemodynamic and hormonal actions of captopril.