Serum lipid profile determines platelet reactivity to native and modified LDL-cholesterol in humans.

The effects of thrombin (0.2 U/ml) and native (n-LDL), malondialdehyde-modified (MDA-LDL) and auto-oxidized (ox-LDL) low-density lipoproteins (20 micrograms of protein/ml) on platelet activation were evaluated in seven hyperlipidemic patients and compared to seven controls (fasting serum cholesterol 8.49 +/- 0.5 and 4.61 +/- 0.4 mM, respectively). Basal and thrombin-induced increases in platelet intracellular free calcium ion concentration ([Ca2+]i; fura-2) were similar in hyperlipidemic patients and controls (45 +/- 5 vs 42 +/- 3 and 635 +/- 51 vs 599 +/- 69 mM, respectively). n-LDL, MDA-LDL and ox-LDL increased basal [Ca2+]i (16, 36 and 81 percent, p < 0.01 between LDL-types), increases were consistently smaller in patients. There was an inverse relationship between LDL-induced responses and fasting serum LDL cholesterol as well as LDL/HDL ratio. In conclusion, modified LDL activated platelets to a greater extent than n-LDL, suggesting different types of LDL-receptors. Their agonistic effect was inversely related to the fasting serum lipid profile, suggesting that blunting of platelet responses to LDL could represent a protective mechanism in hyperlipidemic patients.

Acute renal tubular and hemodynamic effects of the calcium antagonist felodipine in healthy volunteers.

To evaluate the renal tubular effects of felodipine in a low (1.25-mg) and a high (10-mg) dose, lithium clearance was measured and related to renal hemodynamics in 10 healthy volunteers. After felodipine (1.25 mg), mean blood pressure decreased 4 mm Hg and heart rate increased 4 beats per minute. GFR and renal hemodynamics were unaltered. Natriuresis and diuresis increased and lithium clearance and fractional excretion of lithium were unchanged as compared with placebo. Felodipine (10 mg) decreased mean blood pressure 8 mm Hg; heart rate increased 16 beats per minute, and plasma catecholamines were elevated. GFR was unaltered, whereas RBF increased and renal vascular resistance decreased. Natriuresis and diuresis were further increased, and lithium clearance and fractional excretion of lithium were elevated. In conclusion, felodipine in a low dose of 1.25 mg, which did not change renal hemodynamics, had natriuretic and diuretic effects at a predominantly postproximal tubular site, whereas a high dose of 10 mg, which increased RBF and decreased renal vascular resistance, had additional natriuretic and diuretic effects in the proximal tubule.

Temperature-dependence of LDL binding and activation of human platelets.

The effect of low density lipoprotein (LDL) on intracellular free calcium ion concentration ([Ca2+]i), taken as an index of the degree of platelet activation, was investigated in normal volunteers. At 37 degrees C LDL, in a dose of 20 micrograms of protein/ml, increased [Ca2+]i in all subjects tested (basal 57 +/- 11 to 113 +/- 19 nM). In contrast, when measurements were performed at 20 degrees C, no effect on [Ca2+]i was seen following LDL. Thrombin (0.2 U/ml) increased [Ca2+]i to 455 +/- 98 nM. When platelets had been exposed to LDL before thrombin stimulation, this increase was less pronounced (to 301 +/- 43 nM). Our finding of a temperature dependence of LDL induced increase in platelet [Ca2+]i supports the concept of a platelet-LDL receptor mediated mechanism. Furthermore, the lower thrombin response following LDL exposure suggests a LDL-thrombin interaction, possibly at the thrombin receptor level and/or calcium recruitment from the same stores.

Carotid artery surgery. Local versus general anaesthesia as related to sympathetic activity and cardiovascular effects.

Arterial plasma catecholamines, blood pressure and heart rate were determined in 75 patients before, during and after carotid endarterectomy. Local anaesthesia given as a cervical block with skin infiltration containing 200 micrograms adrenaline was used in 28 patients (LA-group), general anaesthesia (nitrous oxide, fentanyl, isoflurane) with skin infiltration containing 200 micrograms adrenaline in 32 patients (GAs-group) and general anaesthesia without skin infiltration in 15 patients (GAo-group). In the LA-Group plasma noradrenaline (P-NA) levels were significantly higher during anaesthesia and surgery, with an increase from preanaesthesia levels (P less than 0.05). P-NA decreased from a preanaesthesia level in the GAo-group (P less than 0.01) but remained unaltered in the GAs-group. P-NA values in the GAo-group were lower than those of the GAs-group (P less than 0.001) following anaesthesia and surgery. Plasma adrenaline (P-A) increased in the LA- and the GAs-group and decreased in the GAo-group (P less than 0.001) following anaesthesia and surgery. In the LA-group P-A was similar before the skin incision and clamping but higher after declamping as compared to the GAs-group. Before the skin incision and thereafter P-A was lower in the GAo-group as compared to the other groups. There was a positive correlation between plasma catecholamines, on the one hand, and mean blood pressure and heart rate on the other. Two patients in the LA-, eight in the GAs- and seven in the GAo-group showed a hypotensive blood pressure reaction (SBP less than 100 mmHg; LA vs. GAo, P less than 0.01).(ABSTRACT TRUNCATED AT 250 WORDS)

Use of anabolic-androgenic steroids among body builders--frequency and attitudes.

A total of 138 male body builders who regularly attended a gym participated anonymously in a study of the use of anabolic-androgenic steroids in relation to side-effects, blood pressure, body mass index (BMI; kg m-2), training frequency, social background, occupation, knowledge and attitudes to steroid use. Fifty-three of the 138 body builders had used anabolic-androgenic steroids for a median duration of 2 years. Steroid use was linked to a higher BMI and more frequent training. Seventy-five per cent (n = 18) of those attending body building for competition, and 24% (n = 11) of those attending to improve their sense of well-being, used anabolic-androgenic steroids. Of all body builders, 94% considered anabolic-androgenic steroids to be dangerous. Of the users, 81% experienced side-effects, but 74% still intended to continue steroid medication.

Renal and endocrine effects of long-term converting enzyme inhibition as compared with calcium antagonism in essential hypertension.

In a double-blind, double-dummy, placebo-controlled crossover design, the renal hemodynamic and tubular effects of 2-month specific vasodilation with a converting enzyme inhibitor (enalapril, 40 mg once daily) was compared with that of a calcium antagonist (verapamil slow release, 240 mg twice daily) in 15 patients with established essential hypertension. Enalapril and verapamil treatment induced a 9% reduction in mean blood pressure (BP). Heart rate (HR) was similar after placebo (66 beats/min), enalapril (63 beats/min), and verapamil (63 beats/min). Plasma norepinephrine (P-NE) was unaltered after enalapril and verapamil as compared with placebo (0.92, 0.88, and 1.33 nM, respectively). Plasma angiotensin II and aldosterone decreased and plasma renin activity (PRA) increased after enalapril but were unaltered after verapamil. Glomerular filtration rate (51Cr-EDTA) was not altered by either enalapril or verapamil, whereas renal blood flow (125I-hippurate) was reduced 9% by verapamil. Renal vascular resistance (RVR) was unchanged after enalapril as well as verapamil. Fractional excretion of electrolytes and diuresis were unaltered and body weight was similar after enalapril, verapamil, and placebo (81.0, 82.5, and 80.2 kg, respectively). Long-term treatment with enalapril and verapamil had a comparable antihypertensive effect. Neither enalapril nor verapamil appeared to induce reflex activation of the sympathetic nervous system. Renal hemodynamic and tubular function was well preserved with both drugs without signs of sodium and water retention.

Serum gonadotropins in postmenopausal women after long-term verapamil treatment.

The effect of long-term verapamil treatment on serum gonadotropin levels was studied in 13 postmenopausal women aged 48-73 years given verapamil 160-320 mg daily for 2-8 months. Serum luteinizing hormone and follicle stimulating hormone concentrations were unchanged during verapamil treatment [7.1 (5.8:11.0) and 24 (21:26) micrograms/L before and 8.8 (5.1:9.1) and 25 (19:31) micrograms/L following verapamil]. This suggests that chronic calcium influx inhibition has no major influence on the release of gonadotropins from pituitary cells.

Amiloride compared with nitrendipine in treatment of essential hypertension.

The antihypertensive effect of amiloride was compared to that of the calcium antagonist nitrendipine in 12 patients (8 males), aged 34-62 years, with essential hypertension WHO grade I-II (mean supine blood pressure 158/103, standing 155/106 mmHg) in a double-blind placebo-controlled cross-over study design. Amiloride was given 5 mg once daily for one month followed by 20 mg twice daily for another month. Amiloride 5 mg once daily significantly reduced supine and standing DBP but not SBP (supine 151/94, standing 149/97 mmHg), whereas 10 mg once daily decreased SBP as well as DBP (supine 145/98, standing 145/101 mmHg). Nitrendipine 20 mg once daily significantly reduced supine and standing SBP and standing DBP (supine 150/97, standing 148/98 mmHg), but on 20 mg twice daily only supine SBP was significantly reduced (supine 150/99, standing 151/106 mmHg). Heart rate was transiently increased by nitrendipine 20 mg once daily and unchanged following amiloride. Plasma noradrenaline was unaltered following amiloride 10 mg once daily as well as nitrendipine 20 mg twice daily, whereas plasma renin activity and aldosterone were elevated following amiloride. Serum electrolytes, blood glucose, plasma lipids and body weight were not altered by any of the drugs. Amiloride 5-10 mg daily has a mild to moderate BP lowering effect in patients with essential hypertension. The BP reduction following nitrendipine 20 mg once daily was comparable to that of amiloride 5 mg daily. Nitrendipine 20 mg twice daily gave no additional BP decrease.

Renal effects of acute and long-term treatment with felodipine in essential hypertension.

Enhanced renal vasoconstriction and renal tubular sodium reabsorption mediated by noradrenaline and angiotensin II (Ang II) have been implicated in the pathogenesis of essential hypertension. Since these effects seem to be calcium-dependent, renal haemodynamic and tubular function were studied following acute and long-term treatment with the calcium antagonist felodipine in 10 patients with essential hypertension. After acute felodipine administration mean blood pressure (MBP) decreased (from 111 to 95 mmHg; P less than 0.01), renal blood flow (RBF), estimated from hippurate clearance, increased (from 1030 to 1175 ml/min; P less than 0.01) and glomerular filtration rate (GFR) was unchanged (109 versus 112 ml/min). Fractional excretion (FE) of sodium, potassium, calcium, magnesium, chloride, bicarbonate and urate increased for 12 h. Following long-term felodipine treatment, mean blood pressure was reduced (97 mmHg; P less than 0.01) and RBF and GFR were unchanged (1032 and 114 ml/min, respectively). Fractional excretion of urate and calcium was increased for 24 h (from 5.9 to 6.9%; P less than 0.05 and from 1.1 to 1.3%; P less than 0.05, respectively). Serum urate decreased (from 377 to 347 mumol/l; P less than 0.01) whereas serum calcium was unchanged. Fractional excretion of sodium, potassium and chloride was increased between 3 and 6 h after felodipine. The renal haemodynamic findings after acute felodipine administration are indicative of a direct renal vasodilator action of felodipine which augments the autoregulatory renal vasodilation to produce an overall increase in RBF. Since GFR was unchanged, the increased renal excretion of electrolytes and urate reflects an action at the tubular level. Following long-term felodipine administration autoregulatory adjustment of RBF predominated.

Effects of the calcium antagonist felodipine on the sympathetic and renin-angiotensin-aldosterone systems in essential hypertension.

Studies were performed in 10 male patients with untreated essential hypertension, WHO grade I-II, aged 25-62 years, to explore the acute (single dose) and long-term (8 weeks) effects of felodipine on sympathetic activity--evaluated by plasma and urinary catecholamines--as related to blood pressure, heart rate and the activity in the renin-angiotensin-aldosterone system. The patients were hospitalized for 8 (acute) and 6 (long-term) days and were maintained on a standardized daily intake of sodium (150 mmol), potassium (75 mmol) and water (2,500 ml). Acute felodipine administration (10 mg) significantly reduced blood pressure and increased heart rate. Plasma and urinary noradrenaline, plasma renin activity and angiotensin II increased, whereas plasma and urinary adrenaline, dopamine, aldosterone and plasma vasopressin were unaltered. Long-term felodipine treatment, 10 mg twice daily, reduced blood pressure to a similar extent as acute felodipine administration, but heart rate was not significantly changed. Plasma noradrenaline 3 and 12 hours after the last dose and urinary noradrenaline were increased, whereas plasma and urinary adrenaline and dopamine were unchanged. Plasma renin activity and angiotensin II were increased 3 hours, but unchanged 12 hours after the last dose. Plasma aldosterone was unchanged but urinary aldosterone increased. Plasma vasopressin was unchanged. The changes in plasma noradrenaline as related to blood pressure, heart rate, plasma renin activity and angiotensin II during long-term felodipine treatment may reflect decreased cardiac and renal beta-adrenoceptor-mediated responses. Increased renal clearance of aldosterone could partly explain the unaltered plasma aldosterone level in spite of increased plasma angiotensin II following long-term felodipine treatment.

Review of long-term trials with nitrendipine.

The dihydropyridine calcium antagonist nitrendipine offers a pathophysiologically based antihypertensive treatment with a potent dilation of resistance vessels, increased arterial compliance, and an acute natriuretic/diuretic response. Prolonged nitrendipine treatment in essential hypertension is not associated with stimulation of the sympathetic nervous and the renin-angiotensin systems or accumulation of sodium and water. The antihypertensive effectiveness is similar to that of diuretics and beta-blockers, and the responsiveness appears to be greater in elderly and black patients. During long-term (approximately 1 year) nitrendipine treatment in mild to moderate hypertension, the blood pressure reduction is well sustained in "short-term" nitrendipine responders. In patients with severe hypertension, nitrendipine has a potent antihypertensive effect in combination with beta-blockers and/or diuretics. In mild-moderate hypertension, a single daily dose (10-40 mg) may be sufficient, whereas two daily doses (20-80 mg/day) seem necessary in severe hypertension. Common side effects are headache, flush, and palpitations (approximately 20-30%), but these are generally mild and transient. Dizziness and malaise occur in approximately 5%, often later during treatment. Peripheral edema in 5-20% of the patients is generally mild but persistent. Nitrendipine has no adverse effects on glucose and lipid metabolism or on plasma levels of electrolytes and urate. The ultimate aim of antihypertensive treatment is to prevent cardiovascular complications. As for other calcium antagonists, no study on primary prevention of cardiovascular complications in hypertension has been published. With regard to regression of left ventricular hypertrophy accompanying essential hypertension, conflicting results have been found with nitrendipine.

Glucoregulatory hormone response to insulin-induced hypoglycaemia following long-term calcium antagonism with felodipine in patients with essential hypertension.

The effect of 8 weeks' treatment with the dihydropyridine calcium antagonist felodipine on glucoregulatory hormone response following insulin-induced hypoglycaemia was evaluated in 7 patients with essential hypertension, WHO grade I-II. After an iv insulin injection (0.1 IU/kg), blood glucose decrement and nadir were similar before and during felodipine treatment. Basal glucagon, noradrenaline, adrenaline, GH and cortisol levels were unchanged, and the response to insulin-induced hypoglycaemia was similar before and during felodipine treatment. Basal plasma dopamine levels were similar and did not change during insulin-induced hypoglycaemia before and during felodipine treatment. Basal serum levels of TSH, T3 and T4 were unaltered following felodipine. In conclusion, long-term treatment with felodipine did not alter the hypoglycaemic effect of exogenous insulin, or the recovery from hypoglycaemia or the glucoregulatory hormone response to insulin-induced hypoglycaemia in patients with essential hypertension.

Catecholamines, renin-angiotensin-aldosterone, and cardiovascular response during exercise following acute and long-term calcium antagonism with felodipine in essential hypertension.

Studies were performed in nine patients with essential hypertension to explore the effect of the calcium antagonist felodipine on the exercise-induced responses of the sympathetic and renin-angiotensin-aldosterone systems as well as of blood pressure and heart rate. The patients were subjected to an individually graded submaximal work test (bicycling) after administration of placebo and a single dose of felodipine (10 mg) in a double-blind design and following long-term (8 weeks) felodipine treatment (10 mg twice daily). After a single dose of felodipine sitting preexercise blood pressure was decreased, whereas heart rate, plasma noradrenaline, adrenaline, renin activity, and angiotensin II increased. After long-term felodipine treatment blood pressure was reduced, heart rate was unchanged, and plasma noradrenaline and renin activity increased. The exercise-induced increases in plasma catecholamines, renin activity, angiotensin II, aldosterone, blood pressure, and heart rate were similar after acute and long-term felodipine administration as compared with placebo. In conclusion, acute and long-term felodipine treatment influences neither reflex activation of the sympathetic nervous system and the renin-angiotensin-aldosterone system nor the cardiovascular responses to physical exercise in patients with essential hypertension.

Unchanged insulin secretion and glucose tolerance but increased insulin clearance during long-term calcium antagonism with felodipine in essential hypertension.

Studies were performed to explore the effect of calcium antagonism with felodipine for 8 weeks on glucose homeostasis and serum lipids in 8 patients with essential hypertension. Fasting levels of blood glucose as well as serum C-peptide, insulin, glucagon and free fatty acids were unchanged following felodipine. During an intravenous glucose tolerance test, the incremental area under the curve for C-peptide and glucose was unchanged, but decreased for insulin, after felodipine. The decremental area over the curve for glucagon and free fatty acids remained unchanged. Fasting serum total cholesterol and high density lipoprotein cholesterol were unaltered, whereas triglycerides decreased following felodipine. The findings indicate that calcium antagonism with felodipine does not affect glucose-induced insulin release in vivo. The increased insulin clearance could be expected to be coupled to a change in glucose tolerance, but this was unaltered during long-term calcium antagonism.

The effect of 8 weeks treatment with the calcium antagonist felodipine on blood pressure, heart rate, working capacity, plasma renin activity, plasma angiotensin II, urinary catecholamines and aldosterone in patients with essential hypertension.

The effect of 8 weeks treatment with the calcium antagonist felodipine--a new long-acting dihydropyridine derivative--in a dose of 10 mg twice daily was studied in 10 male patients with essential hypertension, WHO grade I-II, aged 25-62 years. Diastolic blood pressure was reduced in supine and upright position. Systolic blood pressure was reduced only in the upright position. Heart rate was unchanged in the supine and decreased in the upright position. During dynamic exercise blood pressure was reduced. The maximal working capacity decreased, whereas the maximal heart rate attained was unchanged. Twenty-four hour urinary noradrenaline excretion, plasma renin activity and 24 h urinary aldosterone excretion were increased. Plasma angiotensin II and 24 h urinary adrenaline excretion were unchanged. In conclusion, felodipine is an effective long-acting blood pressure lowering drug with minor side effects. After 8 weeks on felodipine treatment heart rate was not increased, although the activity of the sympathetic nervous system and the renin-aldosterone system seemed enhanced.