Hermann Saxenhofer

Serum Lipoproteins During Treatment with Antihypertensive Drugs

SummaryHypertension and certain alterations in serum lipoproteins such as a decrease in high density lipoprotein-cholesterol (HDL-C), an increase in low density lipoprotein-cholesterol (LDL-C) and perhaps also elevated triglycerides (Tg), are complementary coronary risk factors. Moreover, it has become evident that several of the drugs used for standard anti-hypertensive therapy may also interact with lipoprotein metabolism. The following has been observed after 1 to 12 months of treatment.Various diuretics can significantly increase LDL- C and/or very LDL-C and total C/ HDL-C ratio, while HDL-C is often largely unchanged; Tg also are often elevated. LDL-C increased in diuretic-treated men and in chlorthalidone-treatedpostmenopausal women, but not in chlorthalidone-treated premenopausal women. The latter may be protected from this side effect. Drug dosages were usually high in these studies. Indapamide, given at a dose of 2.5 mg/day, seems to exert no relevant effect on the lipoproteins. It is not established whether this difference is related to the nature of the drugs or the doses used. There is little doubt that the dose of chlorthalidone used was greater than that required for a full antihypertensive effect of this drug.Several β-blockers given as monotherapy induce significant increases in Tg and a tendency for decreases in HDL-C. These changes are most prominent on non-selective β1+2− blockers without partial intrinsic sympathomimetic activity (ISA), less pronounced on highly selective β1blockers without ISA, and even more discrete or absent on β-blockers with distinct ISA.Other sympatholytics such as reserpine, methyldopa, debrisoquine, urapidil, clonidine, labetalol, or postsynaptic α-blockers (prazosin, trimazosin, doxazosin etc.) did not affect or, postsynaptic α-blockers in particular, sometimes even slightly decreased Tg or LDL-C and very LDL-C values.During combination therapy, diuretic-induced increases in LDL-C were at short term prevented or reversed by the concomitant administration of certain β-blockers, but not by sympatholytics such as reserpine, methyldopa or clonidine. With combined diureticpra-zosin treatment, a tendency for slightly higher HDL-C was reported.Angiotensin converting enzmye inhibitors (captopril, enalapril) and calcium channel blockers (verapamil, nifedipine, nitrendipine, diltiazem) seem to be largely devoid of undesirable effects on serum lipoproteins.Monotherapy with the potent direct vasodilator carprazidil improved blood pressure and significantly increased HDL-C.Whether and to what extent the observed variations in lipoproteins may persist beyond 1 year of treatment is as yet unclear. Therefore, at present these lipoprotein effects should be categorised as associated biochemical effects and no more. Long term studies are needed to clarify the pathogenic and prognostic relevance oflipoprotein changes induced by certain diuretics and/or β-blockers. In the meantime, it is of clinical interest that several of the generally available antihypertensive drugs seem to be ‘neutral’ or sometimes perhaps even potentially beneficial with regard to lipoprotein metabolism.

Atrial Natriuretic Peptide in Man

The history of the atrial natriuretic peptides (ANP) begins with the observation of electron dense granules in atrial myocytes of guinea pigs (1). Similar granules were later demonstrated in human and other species (2–4), and it was noted that the granularity varies inversely with the state of hydration (5–6). This prompted the landmark study of De-Bold, showing a natriuretic and diuretic effect of extract from rat atrial tissue (7). Several groups have subsequently identified and synthesized ANPs with 21 to 28 amino acid residues (8–12), which in addition to their natriuretic effect, exhibit vasorelaxant and adrenal steroidogenesis-inhibiting (13,14) properties. Although investigations in humans began only recently, information is rapidly expanding. The following summarizes some observations on blood levels and effects of ANP in man.

Atrial natriuretic peptide in man

The heart is the major source of atrial natriuretic peptides (ANP). A propeptide is stored in atrial myocytes. In normal humans, atrial distension secondary to volume overload and/or increased atrial pressures are thought to stimulate the secretion of biologically active alpha-ANP (ANF-[99-126], 28 amino residues) into the circulation. Plasma immunoreactive ANP (irANP) rises in response to acute sodium-volume loading, the central shift of volume produced by lying down or by immersion, acute increases in blood pressure (BP), dynamic exercise, or the administration of glucocorticoids or mineralocorticoids. Plasma irANP also rises with aging. Synthetic alpha-ANP infused acutely i.v. can lower BP, reduce plasma volume by an extravascular shift, cause baroreflex-mediated sympathetic activation, directly inhibit adrenal steroidogenesis and lower plasma aldosterone and cortisol, directly inhibit renal renin release, elevate plasma insulin; diuresis, free water clearance and natriuresis increase already in response to low alpha-ANP doses that raise plasma irANP within the physiological-pathological range. It follows that in addition to direct influences on cardiovascular and renal function, the ANP system may comprise a cardio-adrenal feedback mechanism and perhaps also modulate insulin and the release of ADH. The major although yet unproven physiological role of the ANP system may be the protection of the heart against volume and/or pressure overload. The pathophysiological, diagnostic and therapeutic aspects of elevated plasma irANP values, ANP measurements, or administration of synthetic ANP, respectively, in various diseases are currently under intense study and of great potential interest.

Use of drugs with more than a twenty-four-hour duration of action.

Aim To assess compliance with a drug regimen of two doses a day compared with one a day. Patients and methods A prospective crossover study was set up in a general practice environment to compare compliance on a drug regimen of once a day versus twice a day. Data were collected by electronic monitoring in 113 patients with hypertension or angina pectoris. All patients were prescribed slow-release nifedipine twice a day during the first month and then crossed to a single daily dose of amlodipine for another month. Results Compliance, defined as the proportion of days on which the correct dose was taken, improved in 30% of patients (95% confidence interval 19–41%; P< 0.001) when the patients were switched from twice a day to once a day, but at the same time there was a 15% increase (95% confidence interval 5–25%; P<0.02) in the number of patients with one or more no-dose days. Approximately 8% of patients displayed low compliance, irrespective of the dose regimen. Actual dose intervals were used to estimate the extent and timing of periods with unsatisfactory drug activity for various hypothetical drug durations of action. Conclusions The apparent advantage of a single daily dose in terms of compliance appears to be clinically meaningful only when the duration of activity extends beyond the dose interval in all patients.

Atrial natriuretic factor in mild to moderate chronic renal failure.

The relationship between kidney function and plasma immunoreactive atrial natriuretic factor (irANF) levels as well as the effects of synthetic human ANF-(99-126) were investigated in 13 patients with mild to moderate chronic renal failure. Under basal conditions, glomerular filtration rate averaged 39 +/- 5 (SEM) ml/min/1.73 m2 and blood pressure (BP) averaged 166/107 +/- 7/2 mm Hg; 12 patients were hypertensive. Plasma irANF levels were significantly increased (98 +/- 16 vs 42 +/- 4 pg/ml in healthy control subjects; p less than 0.001) and correlated (p less than 0.05-0.005) inversely with hematocrit (r = -0.65) and positively with systolic BP (r = 0.75) or fractional sodium excretion (r = 0.75). Human ANF-(99-126) infusion for 45 minutes at 0.034 microgram/kg/min augmented (p less than 0.05-0.01) diuresis and urinary sodium, chloride, calcium, phosphate, and magnesium excretion. During the subsequent 45 minutes of human ANF-(99-126) infusion at a rate of 0.077 microgram/kg/min, diuresis and electrolyte excretion remained elevated (p less than 0.05-0.01). Glomerular filtration rate and effective renal plasma flow were not significantly modified, but filtration fraction rose progressively (p less than 0.01). Human ANF-(99-126) infusion decreased BP (p less than 0.05-0.01), produced hemoconcentration (hematocrit + 7%; p less than 0.01) without negative body fluid balance, and increased (p less than 0.01-0.001) plasma norepinephrine, insulin, and serum free fatty acids; plasma aldosterone and renin activity were unaltered during but rose after cessation of human ANF-(99-126) infusion.(ABSTRACT TRUNCATED AT 250 WORDS)

Hypotension and Renal Impairment during Infusion of Atrial Natriuretic Factor in Liver Cirrhosis with Ascites

Plasma immunoreactive atrial natriuretic factor (irANF) levels and the effects of alpha-human ANF (alpha-hANF) infusion were investigated in 7 patients with liver cirrhosis and ascites. Under basal conditions, supine blood pressure (BP) averaged 136/76 +/- 9/4 mm Hg (mean +/- SEM). Plasma irANF concentrations (124 +/- 33 pg/ml) were higher (p less than 0.01) than those in age-matched normal subjects (47 +/- 5 pg/ml). Plasma renin activity (PRA 5.9 +/- 2.2 ng/ml/h), aldosterone (18 +/- 7 ng/dl) and norepinephrine (NE, 66 +/- 5 ng/dl) levels were also elevated compared to the age-related normal range. Alpha-hANF infusion for 60 min at 0.036 micrograms/kg/min decreased the mean BP (-14%; p less than 0.05), increased PRA (+179%; p less than 0.05) and plasma NE (+24%; p less than 0.05). Glomerular filtration rate (GFR), effective renal plasma flow (ERPF), diuresis and natriuresis were not modified. A subsequent 60-min infusion of alpha-hANF at 0.067 micrograms/kg/min produced a marked fall in mean BP (-26%; p less than 0.001), hemoconcentration (hematocrit +6%; p less than 0.001) despite stable body fluid balance and a further increase in PRA (+350%, p less than 0.005). GFR and ERPF were severely reduced (-55 and -56%, respectively; p less than 0.001), while diuresis and natriuresis were not modified. Plasma aldosterone was unaltered during, but rose (+72%; p less than 0.01) after the cessation of alpha-hANF infusion. Variations in natriuresis during alpha-hANF infusion correlated positively with BP (r = 0.47; p less than 0.01), ERPF (r = 0.53; p less than 0.01) or GFR (r = 0.51; p less than 0.01).(ABSTRACT TRUNCATED AT 250 WORDS)

Antihypertensive contribution of sodium depletion and the sympathetic axis during chronic angiotensin II converting enzyme inhibition

The known physiological adaptation of cardiovascular sensitivity to variations in angiotensin II (Ang II) levels would predict that the blood pressure (BP)-lowering effect of Ang II inhibition might be at least partly counterbalanced by enhanced Ang II reactivity. Therefore, factors other than Ang II inhibition per se may contribute to the antihypertensive mechanisms of angiotensin converting enzyme (ACE) inhibitors. In order to further investigate this, the body sodium-blood volume state as well as the pressor reactivity to infused Ang II or norepinephrine (NE) were assessed in 12 normal subjects and 16 patients with essential hypertension given a placebo, and after 6 weeks of intervention with enalapril (20-40 mg/day). Enalapril produced in both groups similar falls in plasma ACE activity (P less than 0.0001) and upright plasma aldosterone (P less than 0.01), and a rise in plasma renin activity (PRA; P less than 0.05). BP decreased from 156/107 +/- 3/2 (mean +/- s.e.m.) to 142/94 +/- 5/3 mmHg (P less than 0.001) in the hypertensives and from 118/84 +/- 4/2 to 111/73 +/- 4/3 mmHg (P less than 0.01) in the normal subjects. In the hypertensive patients only, the Ang II pressor reactivity relative to Ang II plasma levels during Ang II infusion was increased (P less than 0.01), while the NE pressor reactivity relative to NE plasma levels during NE infusion (P less than 0.01) as well as the exchangeable body sodium (-5%, P less than 0.001) were reduced significantly. Blood and plasma volume, levels of plasma atrial natriuretic factor and catecholamines, and the heart rate and its response to isoproterenol were unchanged in both groups.(ABSTRACT TRUNCATED AT 250 WORDS)

Modulation of noradrenergic but not angiotensinergic blood pressure control by beta-blockade with carteolol.

Various beta-blockers possessing similar antihypertensive potency have been found to differ widely with regard to their influence on blood pressure-regulating factors such as cardiac output and plasma levels of renin or norepinephrine. Recently, beta-blocker-induced stimulation of circulating atrial natriuretic factor (ANF) was reported. Blood pressure is determined not only by levels of vasoconstrictive factors but also by tissue reactivity. To investigate these aspects, we assessed the cardiovascular responsiveness to norepinephrine and angiotensin II, plasma levels of catecholamines, angiotensin II, ANF and aldosterone and the body sodium-blood volume state of 15 patients with essential hypertension (mean age +/- s.e.m., 42 +/- 3 years) and 12 normal control subjects (41 +/- 5 years), first on placebo and then after 4 weeks of intervention with carteolol, a non-selective beta-adrenergic antagonist with intrinsic sympathomimetic activity. Compared with placebo, carteolol decreased resting plasma norepinephrine in both groups while plasma norepinephrine-blood pressure response curves were shifted to the left, their slopes increased and norepinephrine pressor doses decreased (P less than 0.05 to less than 0.001). Chronotropic responses to isoproterenol were abolished but negative chronotropic responses to a norepinephrine-induced 20 mmHg rise in diastolic blood pressure were unaltered. Plasma norepinephrine clearance in the supine position was slightly decreased in hypertensive and unchanged in normal subjects. Supine and upright blood pressure was lowered (P less than 0.05 to 0.001) in the hypertensive while upright systolic blood pressure only decreased in the normal group.(ABSTRACT TRUNCATED AT 250 WORDS)

Atrial natriuretic factor, renal failure and hemodialysis.

Atrial natriuretic factor (ANF), a biologically active peptide produced mainly in cardiomyocytes, is released into the circulation in response to atrial distension secondary to an increase in central blood volume and/or atrial pressure (1-2). In vivo and in vitro studies have shown that ANF can relax vascular smooth muscle, enhance excretion of sodium and water, inhibit the renin aldosterone system and antagonise the vasoconstrictor actions of angiotensin II and norepinephrine (3-5). This spectrum of activity has lead to suggestions that ANF may be an important element in the homeostatic regulation of extracellular fluid volume and blood pressure (6-7). In exploring regulatory mechanisms and responses of the ANF system in disease states associated with abnormal control of extracellular body fluids, renal failure has become an interesting area of focus. Patients with end-stage renal disease on chronic dialysis cannot maintain body fluid balance and extracellular fluid volume varies cyclically, gradually increasing during the interdialysis interval and decreasing rapidly during hemodialysis, often in association with impaired blood pressure control. Suggestions that release of ANF under these circumstances may represent a cardiac response to changes in preload and afterload, has lead to speculation on the existence of a link between plasma ANF levels and blood pressure in hypervolemia-prone uremic patients and to controversy concerning the potential physiological or pathological significance of the ANF system under these conditions. Seen in this context, ANF has been considered by some as a uremic toxin contributing to hypotension and hemodynamic instability following dialysis (8), yet viewed by others as a potentially beneficial agent limiting production or activity of several compounds which may otherwise exacerbate sodium retention and hasten the development of hypertension (9-13). In an attempt to resolve these differing opinions approximately nineteen papers, primarily concerned with the investigation of plasma irANF levels before and after dialysis in end-stage renal patients, have appeared over the last three years (8-27). A brief summary of these data is presented in Table I. The main aims of these studies have been to establish how and to what extent circulating irANF levels are altered during end stage renal disease and hemodialysis and to clarify whether such changes primarily reflect an appropriate response by the heart to variations in intravascular fluid load or whether other mechanisms are also involved. As shown in Table I there is consensus among all investigators that plasma irANF levels are increased prior to, and decrease to a greater or lesser extent following, either hemodialysis or ultrafiltration. In 45% of the studies, hemodialysis restored irANF levels to essentially normal values (9-13, 18-20, 23). These data clearly implicated fluid overload as the major factor responsible for elevated predialysis levels and suggested the potential usefulness of plasma irANP measurements as an index of volume expansion (10, 18). In contrasting reports, however, an inability to detect correlations with changes in weight or hematocrit (16, 26) and, in particular, the occurrence of residually high plasma levels of irANF after dialysis compared to what were considered normal values (8, 15, 16, 26), prompted suggestions that factors other than simple volume expansion may determine pre and post dialysis plasma irANF levels and questioned the physiological significance and diagnostic value of changes in irANP under these conditions. Since ANF has vasorelaxant properties it was suggested that elevated levels found in some patients after dialysis could in theory have a detrimental effect on hemodynamic stability (8). Furthermore, reductions in the rate of degradation and renal clearance have been proposed as additional plausible mechanisms which could ostensibly influence levels of irANF pre and post dialysis (27). At first sight, these suggestions may appear to necessitate a re-evaluation of initial ideas concerning underlying mechanisms, role and significance of changes in plasma irANF in end-stage renal disease;