Frans H H Leenen

Changes in left ventricular hypertrophy and function in hypertensive patients started on continuous ambulatory peritoneal dialysis

Continuous ambulatory peritoneal dialysis (CAPD) often leads to better control of hypertension. In order to evaluate the effects of such improved blood pressure control on left ventricular (LV) hypertrophy and LV function, a group of 18 patients with a history of hypertension were followed for changes in LV anatomy and function (with M-mode echocardiography) over a 6 to 12 month period after initiation of CAPD. All patients had echocardiographic evidence of increased LV mass related to concentric and eccentric hypertrophy. On CAPD, blood pressure decreased (greater than 5 mm Hg) in 12 patients. LV mass decreased in 15 patients and increased in one. A decrease in both wall thickness and LV dimension contributed to the fall in LV mass on CAPD. Initially, LV dimension exceeded normal in 9 out of 18 patients. On CAPD, LV dimension decreased to near normal in size in six, and no patient developed LV dilation on CAPD. Four patients initially had a decreased fractional shortening and ejection fraction; three of these normalized while on CAPD and no patient deteriorated. These results indicate that CAPD improves LV hypertrophy by normalizing both volume and pressure overload. These effects may prevent deterioration in LV function in patients with still normal LV function, and may improve LV function in patients who already exhibit decreased LV performance.

Caffeine as a possible cause of ventricular arrhythmias during the healing phase of acute myocardial infarction

Caffeine (300 mg) was administered to each of 70 patients a mean (+/- standard error of the mean) of 7 +/- 1 days after the onset of acute myocardial infarction to determine its effects on ventricular arrhythmias. The study was designed as a randomized, double-blind, within-patient comparison between caffeine and placebo. Continuous Holter electrocardiographic recording for 4 hours showed no significant differences in the proportion of patients who had ventricular ectopic activity or the total number and complexity of ventricular premature complexes after caffeine vs placebo. Caffeine increased mean blood pressure from 116 +/- 2/70 +/- 1 mm Hg to a maximum of 125 +/- 3/78 +/- 2 mm Hg (p less than 0.001) at 4 hours. Plasma epinephrine increased (p less than 0.01) from 58 +/- 4 pg/ml to a maximum 88 +/- 6 pg/ml 3 hours after caffeine ingestion, whereas the plasma norepinephrine level did not change. Although caffeine caused significant hemodynamic and humoral responses in this population of relatively caffeine-naive postinfarction patients, it did not increase the occurrence or severity of ventricular arrhythmias.

Epinephrine and left ventricular function in humans: Effects of beta‐1 vs nonselective beta‐blockade

Changes in cardiac performance in response to epinephrine administered by graded infusion were assessed by M‐mode echocardiography in normotensive healthy subjects after pretreatment with placebo, the β1‐selective blocker atenolol, or the nonselective β‐blocker propranolol. Epinephrine alone increased heart rate and left ventricular end diastolic dimension and decreased left ventricular end systolic dimension. Left ventricular performance as assessed by fractional shortening and systolic blood pressure/end‐systolic volume (P/V) ratio was also increased. Atenolol pretreatment did not significantly affect the increase in heart rate by epinephrine. However, atenolol did prevent the effects of epinephrine on left ventricular dimensions and left ventricular performance at the lower infusion rates and significantly blunted these effects at the highest infusion rate. After propranolol, epinephrine significantly decreased left ventricular end diastolic dimension despite decreasing heart rate and left ventricular emptying (associated with a high afterload). P/V ratio remained unchanged. These results indicate that β2‐receptors may play a major role in the increase in heart rate caused by epinephrine. In contrast, epinephrines positive inotropic effect appears to be mediated primarily via β1‐receptors and, at higher concentrations, possibly also through β2‐receptors. The pattern of changes in left ventricular end diastolic dimension suggests that epinephrine increases venous return via both β1 and β2‐receptor stimulation and that α‐receptor stimulation (epinephrine after propranolol) may actually decrease venous return.

Pharmacokinetic and pharmacodynamic interactions between nisoldipine and propranolol

The pharmacokinetic and pharmacodynamic effects of nisoldipine, a 1,4‐dihydropyridine calcium entry blocker, and the lipophilic β‐adrenoceptor blocker propranolol were assessed alone and in combination in 12 healthy men. Oral nisoldipine, 20 mg, or placebo was followed 1 hour later by propranolol, 40 mg, or placebo using a randomized, crossover, double‐blind design. Nisoldipine significantly increased the AUC (+ 43%) and peak plasma drug concentration (Cmax) (+ 68%) of propranolol resulting in a higher degree of β‐adrenoceptor blockade (as assessed by isoproterenol). Conversely, nisoldipines AUC (+ 30%) and Cmax (+ 57%) were increased with concomitant administration of propranolol. Nisoldipine did not affect blood pressure but caused significant decreases in total peripheral resistance (TPR) and increases in plasma catecholamines and cardiac index. Forearm vascular resistance and blood flow changed more markedly than did TPR and cardiac index. In contrast, propranolol had little effect on forearm hemodynamics despite significant decreases in cardiac index and increases in TPR. The data are compatible with changes in hepatic blood flow, accounting for the pharmacokinetic interaction of nisoldipine and propranolol. Different vascular beds appear to contribute to the effects of nisoldipine vs. propranolol on peripheral resistance.

Nonselective beta-blockade enhances pressor responsiveness to epinephrine, norepinephrine, and angiotensin II in normal man

Nonselective β‐blockers increase peripheral vascular resistance and, sometimes, blood pressure (BP); increased responsiveness to circulating pressor agents could be one of the underlying mechanisms. Heart rate (HR) and BP responses to graded intravenous infusions of epinephrine, norepinephrine, and angiotensin II were recorded after placebo and then after 4 wk of β‐blocker treatment (nadolol or propranolol, 240 mg/day) in 10 healthy young men. Adequacy of β‐blockade was demonstrated by a mean 31% decrease in HR response to bicycle exercise, with no differences between the two β‐blockers. Under placebo conditions epinephrine lowered diastolic BP and raised HR; these effects were reversed during treatment with β‐blockers. β‐Blockade potentiated BP responses to norepinephrine and angiotensin II: Thirty‐five percent less norepinephrine and 52% less angiotensin II were required to increase mean BP by 15 mm Hg. A final study 2 wk after β‐blocker cessation revealed the absence of lasting effect. These results confirm the concept of unopposed α‐constriction for epinephrine and also demonstrate increased BP responses to norepinephrine and angiotensin II during chronic β‐blockade.

Diuretic and cardiovascular effects of indapamide in hypertensive subjects: a dose-response curve

In a single-blind, placebo-controlled study, the effects were evaluated of increasing doses of indapamide (1.0, 2.5 and 5.0 mg/day, each dose for 4 weeks) on volume and haemodynamic status of 10 hypertensive subjects. Body weight showed a decrease of 0.5 kg at the 1 mg dose, of 1.0 kg at the 2.5 mg dose and no further decrease at 5 mg. Plasma volume did not change. Mean arterial pressure decrease in 8 subjects by about 20 mmHg; 2 patients were classified as non-responders. The decrease in blood pressure was accompanied by a reduction in total peripheral resistance and no change in cardiac output. LV end-diastolic volume decreased by about 20 ml. These results suggest that indapamide not only has a diuretic effect, but also acts as a veno-arterial vasodilator.

Nifedipine tablet vs. hydralazine in patients with persisting hypertension who receive combined diuretic and beta‐blocker therapy

The antihypertensive effects of a 20 mg tablet of nifedipine were compared with those of hydralazine in a randomized, double‐blind, placebo‐controlled study. Nineteen patients with a diastolic blood pressure (BP) between 95 and 120 mm Hg despite combined diuretic and β‐blocker therapy completed the protocol. After 2 weeks of placebo each subject received increasing doses of nifedipine (20, 40, and 60 mg b.i.d.) and hydralazine (25, 50, and 100 mg b.i.d.) if tolerated or until goal BP (supine and standing diastolic BP <85 mm Hg) was achieved. Both nifedipine and hydralazine significantly lowered supine BP from placebo baseline (146 ± 3/96 ± 2 mm Hg) to 119 ± 3/80 ± 2 and 129 ± 2/81 ± 2 mm Hg, respectively. The decrease in systolic BP with nifedipine was significantly lower than that with hydralazine at 9 weeks. Neither drug significantly altered heart rate. Mean left ventricular ejection fractions were similar for nifedipine (67% ± 2%), hydralazine (69% ± 3%), and placebo (66% ± 2%). The nifedipine tablet appears to be an effective antihypertensive agent in patients whose BP remains high despite combined diuretic and β‐blocker therapy.

Nadolol, propranolol, and thyroid hormones: Evidence for a membrane-stabilizing action of propranolol

Ten normal subjects participated in a placebo‐controlled, randomized, parallel study to determine the effects on thyroid hormones of chronic (4 wk) propranolol or nadolol, including observation for 2 wk after their discontinuation. Subjects took placebo for 1 wk, then propranolol or nadolol doses increased weekly to 240 mg/day by 3 wk. After 1 wk of placebo, after 2 wk of the highest dose of propranolol or nadolol, and 2, 4, 6, 9, and 13 days after their discontinuation, thyroid hormone levels were measured by radioimmunoassay and heart rate responses to exercise were assessed. Both drugs induced equal and high degrees of exercise tachycardia inhibition. Propranolol decreased 3,35‐triiodothyronine (T3) levels, increased 3‐3‐5‐triiodothyronine (rT3) levels, tended to increase thyroxine levels, but did not increase thyroid‐stimulating hormone levels. After discontinuation of propranolol, rT3 levels slowly (day 6) returned to values after placebo, suggesting delayed recovery of 5‐deiodination. There was no evidence of any rebound in T3 levels after withdrawal of propranolol. Nadolol induced no significant changes in the thyroid hormones measured. The data agree with the known effects of propranolol on thyroid hormones in normal man and show that nadolol does not have these effects when given chronically at an equivalent β‐blocking dose. The likely explanation is that the membrane‐stabilizing activity of propranolol alters thyroid physiology by interfering with 5‐deiodinase.

Blood pressure and left ventricular anatomy and function after heart transplantation

To determine whether hypertension occurring after heart transplant causes the development of cardiac hypertrophy, changes in pressure load (N = 13) and left ventricular anatomy (N = 11) were evaluated up to 1 year after heart transplant in a prospective longitudinal study. Pressure load was evaluated by 24-hour ambulatory blood pressure monitoring, and left ventricular anatomy and function were assessed by M-mode echocardiography under two-dimensional guidance. Body weight increased by 11 to 12 kg. Blood pressure showed a gradual increase during the first few months after transplant: diastolic pressure by 15 to 18 mm Hg and systolic pressure by 12 to 15 mm Hg, with hypertension persisting during the night. Nearly all patients required treatment with one or two antihypertensive drugs. The increase in blood pressure was related to increased total peripheral resistance with minor decreases in cardiac output. Both septal and posterior wall thickness and left ventricular mass (by 25 to 30 gm/m2) decreased during the initial months after transplant and subsequently remained at normal levels (100 gm/m2). The persistence of normal left ventricular mass may indicate either that the increases in daily pressure load and body weight were not sufficient to induce myocardial growth or that the latter was prevented by, for example, absence of cardiac sympathetic nerve activity.

Hemodynamic interaction of nonselective vs. beta‐1‐selective beta‐blockade with hydralazine in normal humans

To assess the effects of nonselective vs. β1‐selective β‐blockade on the hyperdynamic circulation induced by hydralazine, eight healthy volunteers received placebo, propranolol, 20 and 40 mg, and atenolol, 25 and 50 mg, on 5 separate days, followed by hydralazine (range 75 to 150 mg). Hydralazine decreased afterload (end‐systolic wall stress) and increased venous return and left ventricular performance (by M‐mode echocardiography). Both β‐blockers blunted the increases in heart rate, cardiac output, and venous return similarly, although heart rate and cardiac output were not completely normalized. Atenolol did not affect the hydralazine‐induced decrease in afterload, whereas propranolol significantly opposed this change (P < 0.03). The hyperdynamic circulation seen with hydralazine is mostly β mediated, primarily β1. When given with hydralazine the two β‐blocker types differ primarily in their effects on afterload.