Albert van 't Laar

Circulatory effects of coffee in relation to the pharmacokinetics of caffeine

Drinking coffee results in an increase in blood pressure (BP) after an interval of caffeine abstinence. During chronic caffeine intake this pressor response disappears and adaptation to the circulatory effects of caffeine develops. This study was designed to determine whether a pressor response to coffee occurs during chronic caffeine intake if low basal plasma caffeine levels are achieved by a period of caffeine abstinence, defined by individual plasma caffeine half-life. In 8 normotensive subjects, circulatory measurements were studied after ingestion of coffee in 2 strengths, decaffeinated coffee and hot water after a caffeine abstinence of 4.5 times individual caffeine half-life. These measurements were compared to the same protocol without intervention. Coffee of both strengths resulted in a similar increase in BP (diastolic BP +/- 15%). The coffee-induced increase in forearm blood flow and plasma epinephrine levels were less pronounced. Decaffeinated coffee induced a smaller increase of diastolic BP, and after water, no changes were observed. Additionally, a negative correlation was found between the coffee-induced BP increase and basal plasma caffeine level in a group of 30 normotensive subjects (r = -0.71, p less than 0.001). During chronic caffeine intake, subjects with short plasma caffeine half-life are exposed to a pressor response after drinking coffee, despite the phenomenon of adaptation.

Hemodynamic and humoral effects of coffee after β1-selective and nonselective β-blockade

Several studies report a substantial rise in plasma catecholamines after caffeine. Epinephrine infusion induces a pressor response after nonselective β‐blockade. We studied the hemodynamic and humoral effects of drinking coffee after placebo and after both nonselective (propranolol) and β1‐selective (metoprolol) blockade in 12 normotensive subjects. After placebo, coffee induced a rise in systolic and diastolic blood pressure and a fall in heart rate, whereas forearm blood flow did not change. Plasma catecholamines, especially epinephrine (+150%), rose and plasma renin activity, fell after drinking coffee. The effects of coffee on blood pressure, forearm blood flow, and all humoral parameters were not altered by pretreatment with propranolol or metoprolol. The fall in heart rate after coffee, however, seemed to be greater during propranolol. We conclude that the rise in plasma epinephrine after coffee was too small to reveal differences in reaction in propranolol‐ and metoprolol‐pretreated subjects.

Effect of low‐dose epinephrine infusion on hemodynamics after selective and nonselective β‐blockade in hypertension

We studied hemodynamic effects of low doses of epinephrine in five hypertensive patients receiving long‐term treatment with propranolol and metoprolol. Epinephrine was infused at graded rates of 0.5, 1.0, 2.0, and 4.0 µg/min. During propranolol treatment epinephrine induced a marked pressor effect at all rates. There was a considerable rise in systolic as well as in diastolic blood pressure and heart rate fell. During metoprolol treatment there was only a slight rise in blood pressure and heart rate rose. Forearm blood flow was decreased by epinephrine during propranolol. Calculated forearm vascular resistance showed opposite effects. We conclude that infusion of small doses of epinephrine results in a marked difference in reaction in propranolol‐ and metoprolol‐treated patients and that this may have relevance in the choice of beta blocker to be used in the treatment of hypertension.

Intrapatient comparison of treatment with chlorthalidone, spironolactone and propranolol in normoreninemic essential hypertension

The effects of chlorthalidone, spironolactone and propranolol in reducing blood pressure were compared in the same 11 normoreninemic hypertensive patients. All three drugs decreased the blood pressure significantly and no agent had a superior blood pressure-lowering effect. The blood pressure did not normalize. The data suggest that no one variable--volume factors, relative hyperactivity of the renin-aldosterone system or beta-adrenergic hyperactivity--is the prime mover in normoreninemic hypertension. Long-term treatment with chlorthalidone resulted in slight hyperreninism (26.3 +/- 4.9 ng-ml-1-3 hours-1) (mean +/- standard error) with concomitant changes in plasma aldosterone (23.0 +/- 3.2 ng-100 ml-1). The body weight decreased significantly (--1.8 kg, P less than 0.005). Plasma potassium concentrations were low (3.2 +/- 0.1 mEq-liter -1). Creatinine clearance was unimpaired (117 +/- 6 ml-min-1). Treatment with spironolactone resulted in more marked hyperreninism (47.0 +/- 14.3 ng-ml-1-3 hours-1) and hyperaldosteronism (61.9 +/-11.8 ng-100 ml-1). The body weight decreased significantly (--1.9 kg, P less than 0.004). Significant hyperkalemia occurred (4.4 +/- 0.1 mEq-liter-1). The glomerular filtration rate decreased significantly to 93 +/- 3 ml-min-1 (P less than 0.004). Treatment with propranolol resulted in marked suppression of the plasma renin activity (1.8 +/- 0.2 ng-ml-1-3 hours-1) and plasma aldosterone levels (8.9 +/- 1.3 ng-100 ml-1). A significant increase in body weight occurred (+2.3 kg, P less than 0.013). The plasma potassium concentration increased to a level not significantly different from the value found after treatment with spironolactone (4.2 +/- 0.1 mEq-liter-1). The creatinine clearance decreased significantly to 99 +/- 5 ml-min-1 (P less than 0.008). Hyperreninemia (by spironolactone and chlorthalidone), effective hyperaldosteronism (by chlorthalidone) and volume retention (by propranolol) are considered to represent expressions of mechanisms counteracting the depressor effects of these different pharmacologic maneuvers, leading to the maintenance of supranormal blood pressure.

Double-blind, placebo-controlled study of prazosin in Raynaud's phenomenon

We performed a randomized, double‐blind, placebo‐controlled, crossover study of the therapeutic efficacy of prazosin (1 mg t.i.d.) in 24 patients with Raynauds phenomenon. Comparison of prazosin vs. placebo showed a moderate subjective improvement with a reduction of the daily number (P = 0.003) and duration (P = 0.02) of attacks. Patients showed a marked preference (P = 0.0002) for prazosin. Finger skin temperature and laser Doppler estimated finger skin blood flow, assessed during a standard finger cooling test, revealed a beneficial effect of prazosin (P = 0.0001 and P = 0.003, respectively). No differences in reaction to therapy could be found between patients with Raynauds disease and secondary Raynauds phenomenon. We conclude that prazosin is useful in the treatment of digital vasospastic disease, with an overall good response in two thirds of patients.

Hemodynamic effects of isometric exercise and mental arithmetic in hypertension treated with selective and nonselective β‐blockade

Hypertensive patients have an unfavorable pressor response to exogenous epinephrine during nonselective β‐blockade. We studied hemodynamics during epinephrine release induced by handgrip exercise and mental arithmetic to examine the clinical relevance of this phenomenon. Twenty‐two hypertensive patients were examined in a double‐blind crossover experiment with placebo, propranolol (240 mg daily), placebo‐washout, and metoprolol (300 mg daily). Changes induced by stress tests for systolic and diastolic blood pressure, heart rate (HR), and forearm blood flow (FBF) were of the same order on both β‐blockers. Rises in HR and FBF were equally reduced by both drugs. Neither handgrip exercise nor mental arithmetic induced significant differences in reaction during selective and nonselective β‐blockade.

Some metabolic characteristics of low-density lipoprotein subfractions, LDL-1 and LDL-2: in vitro and in vivo studies

Two low-density lipoprotein subfractions, LDL-1 and LDL-2, with density ranges of respectively 1.023-1.034 and 1.036-1.041 g/ml, were isolated by aspiration after density gradient ultracentrifugation of human pooled serum. In vitro interactions of both LDL subfractions with the LDL receptor of human cultured fibroblasts, human hepatoma cell line Hep G2 and human hepatocytes were compared. No difference in association (binding and internalization) nor in degradation between LDL-1 and LDL-2 by these cells was found. However, kinetic studies in guinea pigs showed that LDL-2 disappeared faster from the circulation and accumulated to a greater extent in the liver, compared to LDL-1. Thus, we were unable to show a difference in the LDL receptor-mediated uptake of both LDL subfractions by various cells in vitro. The results obtained in vivo suggest that LDL-1 is more atherogenic than LDL-2, because its longer half-life renders the particle more susceptible to uptake by the scavenger LDL receptor on macrophages.

Studies on the function of hepatic lipase in the cat after immunological blockade of the enzyme in vivo

In order to investigate the in vivo function of hepatic lipase, cats were injected with anti-cat hepatic lipase antibodies which produced a complete and specific inhibition of heparin-releasable hepatic lipase. The cat was chosen as an animal model because it displays, like man, a relative deficiency of lipoprotein lipase compared to hepatic lipase and because the possession of two subfractions of high density lipoproteins, HDL2 and HDL3. In fasted cats no changes were observed in plasma triglycerides or phospholipids. In fed animals triglycerides increased considerably, indicating that hepatic lipase may have a function in the postprandial phase. In fat-loaded cats (6 g of fat/kg) triglycerides in the d less than 1.019 g/ml fraction increased from 4 h after the blockade due to accumulation of lipoproteins with pre-beta-mobility containing the apoproteins, apo B-100, apo E and apo A-I. Apo B-48 did not accumulate consistently. Phospholipids in the HDL2-fraction and those in the HDL3-fraction of the fat-loaded cats tended to increase and decrease from 6 and 9 h after the blockade, respectively. The absolute change in HDL2 phospholipids approximated that of HDL3-phospholipids. Overall, the density of HDL particles decreased, apparently secondary to the accumulation of apo A-I in the d less than 1.019 g/ml fraction. Our findings suggest that hepatic lipase is involved in the hydrolysis of a special class of apo A-I containing triglyceride-rich lipoproteins synthesised in the postprandial phase.

Studies on the relationship between the cholesterol content in total high density lipoprotein and its subfractions, HDL2 and HDL3 in normo- and hyperlipidemic subjects.

Total high density lipoprotein (HDL) cholesterol and cholesterol in its main subfractions, HDL2 and HDL3, were determined in 160 normo- and 90 hyperlipidemic subjects by density gradient ultracentrifugation (range of HDL-cholesterol: 0.05-2.85 mmol/l). Both in the normolipidemics and in the combined group HDL3-cholesterol (HDL3-chol) as well as HDL2-cholesterol (HDL2-chol) showed a parabolic relationship with total HDL-chol. The results indicate, that at low total HDL-chol values almost all cholesterol is present in the HDL3 fraction, which shows a linear increase with total HDL-chol from 0 to 0.75 mmol/l. At a further increase of total HDL-chol, cholesterol is increasingly isolated in the HDL2-fraction, especially when HDL3-chol has reached its maximum (about 1.25 mmol/l). Thus, the magnitude of the absolute intra-individual variation of either HDL3-chol or HDL2-chol (in mmol/l) is related to the total HDL-chol concentration. Given the strong correlation between cholesterol in both HDL-subfractions with total HDL-chol and the inverse relationship of total HDL-chol with the risk for coronary heart disease, a rise in HDL3-chol or in HDL2-chol may be equally favorable.

Treatment of Raynaud's syndrome with adrenergic alpha-blockade with or without beta-blockade.

In a double blind placebo-controlled cross-over trial of 24 weeks 31 patients with Raynauds syndrome were treated with the alpha-blocker phenoxybenzamine (10-20 mg daily) and with the combination of the alpha-blocker phenoxybenzamine (10-20 mg daily) and the beta-blocker sotalol (40-80 mg daily). A favourable effect on recovery of finger temperature after finger cooling was demonstrated after alpha-blockade as com pared to the before treatment situation. This favourable effect was not different when the group received the combined alpha- and beta-blockade. The blood pressure was not influenced by either of the 2 medications. Fluid retention appeared with alpha-blockade and was absent with combined alpha- and beta-blockade. Decrease of heart rate oc curred with alpha- plus beta-blockade and was absent with alpha-blockade alone. Clinical symptoms of Raynauds syndrome equally were alleviated by the two medica tions. Common, and equally frequent side effects of the two medications were nasal congestion, disturbed ejaculation and potence, dry mouth, exercise-induced and ortho- static dizziness. We conclude that alpha-blockade is beneficial in Raynauds syndrome and that additional beta-blockade counteracts the alpha-blocker side-effect fluid retention, re duces the heart rate and thus may prevent alpha-blocker induced tachycardia, and that it does not cause hypotension.