Adrenergic activity and peripheral hemodynamics in relation to sodium sensitivity in patients with essential hypertension.

In 25 outpatients with essential hypertension, sodium sensitivity, defined as the difference in mean arterial pressure (delta MAP) between 2 weeks of high-sodium (300 mmol per day) and 2 weeks of low-sodium (LS) intake (50-100 mmol per day), was studied in relation to the plasma norepinephrine (NE) level, NE release, and pressor response to intravenous NE. In addition, forearm blood flow (FBF) was measured by plethysmography. There were two control periods of regular sodium intake, one of 4 weeks' duration at the beginning of the study and one of 2 weeks' duration at the end. The delta MAP ranged from +18 to -8 mm Hg. The eight patients in whom delta MAP was greater than 10 mm Hg were regarded as salt-sensitive. When compared with salt-insensitive subjects, salt-sensitive patients had higher plasma NE levels in the control period (p less than 0.05) and after 2 weeks of HS intake (p less than 0.01). Sodium sensitivity was directly related to the change in plasma NE between the HS and LS periods (p less than 0.001). The NE release decreased in salt-insensitive subjects whereas it increased in salt-sensitive patients between the LS and HS periods. Changes in NE release were directly related to sodium sensitivity (p less than 0.05). The pressor response to NE was not significantly influenced by changes in sodium intake. The FBF fell in salt-sensitive patients and increased in salt-insensitive subjects between the LS and HS periods. Sodium sensitivity was directly related to the change in forearm vascular resistance (p less than 0.01).(ABSTRACT TRUNCATED AT 250 WORDS)

Acute vasodilator action of pindolol in humans.

The local hemodynamic effect of pindolol, a nonselective beta-blocker with intrinsic sympathomimetic activity, was investigated in 17 healthy volunteers. Changes in forearm blood flow (FBF) in response to infusion of drugs into the brachial artery were measured by plethysmography. Pindolol increased FBF dose dependently to a maximal value of 62 +/- 8% (mean +/- SEM, p less than 0.001) without inducing changes in heart rate or blood pressure. For a single dose of pindolol the maximal effect on FBF was seen after approximately 4 minutes of infusion, and this effect persisted for at least 12 minutes after the infusion. The pindolol-induced increase in FBF was reduced by concomitant infusion of propranolol (p less than 0.001). Intra-arterial infusion of practolol did not influence FBF. No significant influence of pindolol was found on the vasoconstriction induced by the alpha 1-adrenergic receptor agonist methoxamine, the alpha 2-adrenergic receptor agonist BHT-933, or angiotensin II. Measurement of plasma pindolol concentrations in the venous effluent of the forearm suggested that vasodilatation occurred at drug levels within the therapeutic range. These results indicate that the beta-blocker pindolol has vasodilatory properties owing to stimulation of vascular beta 2-adrenergic receptors and that this effect may be of therapeutic relevance.

Demonstration of neuronal and extraneuronal uptake of circulating norepinephrine in the forearm.

Disturbances in peripheral norepinephrine release or removal by neuronal and extraneuronal uptake may have pathogenetic significance in cardiovascular disease states. We investigated the mechanisms of removal of norepinephrine in the forearm of healthy subjects under basal conditions, using measurements of arterial and venous plasma norepinephrine concentrations, blood pressure, heart rate, and forearm blood flow. The specific inhibitor of neuronal uptake, desipramine, was infused intra-arterially into the brachial artery of five subjects. Net norepinephrine overflow from the forearm increased markedly, revealing considerable local release of norepinephrine. Six other subjects received four intra-arterial infusions of norepinephrine, 1.18 pmol/kg/min, with various doses of desipramine and the extraneuronal uptake-inhibiting drug hydrocortisone. The forearm extraction rate for circulating norepinephrine decreased with increasing doses of desipramine (from 69.4 +/- 3.0 [SEM] to 35.3 +/- 8.4%; p less than 0.001). Increasing doses of hydrocortisone during continued inhibition of neuronal uptake resulted in decreased forearm extraction of norepinephrine (from 63.3 +/- 4.9 to 40.6 +/- 4.4%; p less than 0.01). In six other subjects who received the highest dose of hydrocortisone without concomitant inhibition of neuronal uptake, forearm extraction of norepinephrine decreased from 57.1 +/- 4.9 to 51.5 +/- 4.7% (p less than 0.05). These results suggest that neuronal uptake contributes markedly to the removal of circulating and endogenously released norepinephrine in the forearm. For circulating norepinephrine, a corticosteroid-sensitive mechanism of extraneuronal uptake was also demonstrated. These results indicate that neuronal and extraneuronal uptake can be estimated separately in this vascular bed. Similar organ-specific studies in patients may reveal disturbances in mechanisms of norepinephrine removal.

Does regional norepinephrine spillover represent local sympathetic activity?

Regional spillover of norepinephrine (NE), based on isotope dilution and single-compartment steady-state kinetics, is considered one of the best parameters for estimating organ sympathetic activity. However, the effects of local changes in clearance of NE on the spillover have not yet been investigated. We studied local NE kinetics and clearance in the forearm of 10 healthy subjects using intra-arterial infusions of NE, tritiated NE, the neuronal uptake inhibitor desipramine, and tyramine, which competes with NE for the neuronal uptake carrier. Before and during complete blockade of neuronal uptake by desipramine the venous concentration-time curves for tritiated NE and for NE released by tyramine were biexponential, consistent with the presence of (at least) two compartments for circulating tritiated NE and for locally released NE. The time constants for tyramine-induced release of NE and, in the same subjects during desipramine infusion, for tritiated NE were almost equal at the same level of forearm blood flow. This argues against possible diffusion or transport differences for NE to and from the circulation and the synapse. The regional intrinsic clearance capacity (a measure of the maximal ability of an organ to irreversibly remove drug by all pathways in the absence of any flow limitations) for NE decreased in the forearm by 65% (p less than 0.01) during neuronal uptake blockade by desipramine; the forearm clearance decreased by 59% (p less than 0.001), whereas the spillover rate of NE increased from 33 +/- 5 to 63 +/- 11 pmol.min-1 (p less than 0.05). Nitroprusside-induced increments in blood flow increased the spillover of NE from 18 +/- 4 to 35 +/- 6 pmol.min-1 (p less than 0.01); the clearance of circulating NE also increased (by 58%, p less than 0.05), and the intrinsic clearance capacity remained unchanged. This demonstrates that regional spillover of NE is markedly influenced by local changes in clearance and flow. The new parameter plasma appearance rate of NE is proposed. Although also derived from isotope dilution, this parameter may better approximate the regional entry of NE into the blood pool than spillover. This is corroborated by the nonsignificant changes of plasma appearance rate of NE during our desipramine and nitroprusside infusions.

Regional vascular effects of serotonin and ketanserin in young, healthy subjects.

The local hemodynamic effects of serotonin (5-hydroxytryptamine; 5-HT) and the selective 5-HT2 antagonist ketanserin were investigated in the forearm of 20 healthy volunteers. Single doses of 5-HT (0.1-80 ng/kg/min) and ketanserin (5-125 ng/kg/min) were administered intra-arterially. The relative alpha 1-adrenergic receptor and 5-HT2 blocking potencies of ketanserin were investigated using intra-arterial infusions of cumulative doses of methoxamine (0.1, 0.3, and 0.5 microgram/kg/min), tyramine (0.25, 0.50, and 1.25 microgram/kg/min), and 5-HT (10, 30, and 80 ng/kg/min) together with a low dose (5 ng/kg/min) and a high dose (50 ng/kg/min) of ketanserin. Forearm blood flow was measured by venous occlusion plethysmography. Heart rate and intra-arterial blood pressure were recorded semicontinuously. Intra-arterial infusion of 5-HT induced an initial transient vasodilatation, followed by a steady vasodilatation for the low doses of 5-HT (0.1-10 ng/kg/min; p less than 0.05). A steady vasoconstriction was only obtained at the highest dose of 5-HT. Ketanserin induced a dose-dependent increase in forearm blood flow from 15 ng/kg/min (p less than 0.05) onward. The vasodilatation induced by 5-HT (1 ng/kg/min) was significantly enhanced by ketanserin (125 ng/kg/min; p less than 0.05), whereas the vasoconstriction elicited by 5-HT (80 ng/kg/min) was reversed by ketanserin (50 ng/kg/min; p less than 0.05), thus confirming that 5-HT2 receptors were stimulated by 5-HT.(ABSTRACT TRUNCATED AT 250 WORDS)

Norepinephrine removal and release in the forearm of healthy subjects.

The relevance of local removal and release of norepinephrine (NE) for antecubital venous plasma NE concentration was studied in 22 healthy subjects. Arterial and venous plasma NE and forearm blood flow were measured during intra-arterial infusion of two doses of NE, intra-arterial NE infusion with two doses of sodium nitroprusside, intravenous infusion of NE with intra-arterial infusion of four doses of sodium nitroprusside, and lower body negative pressure of -20 mm Hg for 15 minutes. The venous plasma NE concentration-time curves during the infusions of the two doses of NE indicated first-order kinetics for forearm extraction: forearm NE extraction rate during the low dose infusion was 67 +/- 4.1% (SEM) and correlated with basal forearm blood flow (r = -0.64, p less than 0.03, n = 12). Local sodium nitroprusside-induced vasodilatation during the intra-arterial and intravenous NE infusions was accompanied by dose-dependent decreases in forearm extraction rates for NE and epinephrine. During lower body negative pressure, taking into account the high basal forearm extraction rate for NE, local and systemic release of NE was indicated by increases in arterial and venous plasma and the venous-arterial plasma NE concentration difference (p less than 0.05 for all). These data show that removal of NE from forearm circulation is a process with a high extraction ratio obeying first-order kinetics and that this extraction process inversely relates to forearm blood flow. Thus, antecubital venous plasma NE is likely to be derived mainly from local release and not from the arterial plasma NE input.

Nifedipine kinetics and dynamics during rectal infusion to steady state with an osmotic system.

Nifedipine steady-state kinetics and dynamics were investigated in a placebo-controlled study of six healthy subjects. Nifedipine was given rectally through an osmotic system at a zero-order rate for 24 hr. Steady-state plasma concentrations of approximately 20 ng/ml were achieved within 6 to 8 hr. Nifedipine lowered diastolic blood pressure (DBP) and increased forearm blood flow (FBF) and plasma norepinephrine concentration. On the other hand, heart rate (HR) and systolic blood pressure were not affected. Changes in DBP and FBF were closely related to nifedipine plasma concentrations during and immediately after the infusion period. Our data indicate that nifedipine lowers blood pressure in subjects with normotension and that it is possible by infusing the drug at a relatively low rate to dissociate its effect on blood pressure from that on HR.

Antihypertensive and renal effects of captopril in relation to renin activity and bradykinin-induced vasodilation.

The effect of captopril on blood pressure and renal hemodynamics in relation to plasma renin activity (PRA) was assessed together with the vasodilator responses to brachial artery infusions of bradykinin (BK) and sodium nitroprusside (NP) before and after 4 wk of therapy with doses of up to 450 mg/day in patients with essential hypertension. The average blood pressure reduction of captopril was from 174.4/110.6 to 155.3/96.6 mm Hg (n = 12, P less than 0.001) without increases in heart rate or body weight. It was effective in the eight patients with normal renin, but showed little effect in the four with a low renin. There was a correlation between the changes in blood pressure after captopril and the pretreatment PRA (r = -0.82, P less than 0.01 for mean pressure). Brachial artery infusions of BK and NP induced dose-dependent rises in forearm blood flow (FBF), but this was not related to the captopril blood pressure-lowering effect. Repeat measurements during captopril therapy showed a shift to the left of the BK/FBF, but not of the NP/FBF, dose-response curve, indicating effective vascular kininase II inhibition. Captopril decreased renal vascular resistance. Our data are compatible with the view that captopril's antihypertensive action mainly involves blockade of the renin-angiotensin-aldosterone system and not cumulation of BK. The favorable effects on renal hemodynamics and the lack of tachycardia and volume retention after captopril make it a valuable drug for the treatment of hypertension.

Nifedipine: influence of renal function on pharmacokinetic/hemodynamic relationship.

The hemodynamic effects and kinetics of nifedipine were examined in four groups of five subjects with different degrees of impaired renal function. In a randomized order, each subject received nifedipine by an intravenous infusion (4.5 mg in 45 minutes) and by mouth as a sustained-release tablet (20 mg). Plasma concentrations of nifedipine and urinary metabolite excretion were measured by liquid chromatography. Heart rate, blood pressure, forearm blood flow, and plasma norepinephrine levels were examined serially. After intravenous nifedipine infusion, the elimination t1/2 was 106 +/- 24 minutes in controls and increased gradually across the groups to 230 +/- 94 minutes in the group with severe renal impairment. In these same groups, the volume of distribution at steady state was 0.78 +/- 0.23 and 1.47 +/- 0.24 L/kg, but total systemic clearance did not differ. Plasma protein binding decreased from 96.0% +/- 0.5% in controls to 93.5% +/- 0.4% in severe renal insufficiency. Except for systemic clearance, kinetics were closely related to creatinine clearance, as was the urinary excretion of the main nifedipine metabolite. Except for systemic availability, which tended to decrease, the kinetics of nifedipine tablets were not influenced by the degree of renal failure. Hemodynamic effects after intravenous nifedipine could be fit to plasma concentrations under a sigmoidal model. When compared with control values, the maximal effect on diastolic blood pressure was more than doubled in severe renal failure. The inverse correlation between maximal effect on diastolic blood pressure and creatinine clearance (r = -0.68) was independent of pretreatment values. Neither free drug levels corresponding to 50% of the maximal effect on diastolic blood pressure nor the slope of the concentration-effect curve was influenced by the degree of renal impairment. The maximal effect on forearm blood flow tended to increase in renal failure, whereas the effect on heart rate was unchanged. Blood pressure changes after oral nifedipine were of the order of those after intravenous infusion. We conclude that, although nifedipine kinetics differ in patients with renal failure, these changes do not explain the greater blood pressure lowering effect.

Single- and multiple-dose nisoldipine kinetics and effects in the young, the middle-aged, and the elderly.

Pharmacokinetics of nisoldipine and the drug's effects on blood pressure and heart rate were investigated in healthy young (20 to 23 years of age), middle-aged (49 to 57 years of age), and elderly (75 to 84 years of age) subjects after single-dose and short-term multiple-dose oral administration (10 mg twice daily). No age-dependent differences in pharmacokinetic parameters were observed. Decreases in blood pressure were comparable in the three groups, but reflex tachycardia was less pronounced in the elderly subjects. Side effects mainly occurred on the first day of drug administration. Dose adaptation of nisoldipine does not seem to be necessary in elderly subjects.

Pharmacokinetics and hemodynamic effects of nisoldipine and its interaction with cimetidine.

Pharmacokinetics, diastolic blood pressure, and heart rate after oral and intravenous nisoldipine were studied in eight healthy subjects without and with cotreatment of cimetidine in a four-way crossover design. After intravenous infusion, elimination half-life (t1/2) was 4.0 +/- 2.3 hours, systemic clearance (CL) was 0.83 +/- 0.17 L/min, and volume of distribution was 1.6 +/- 0.6 L/kg. After oral nisoldipine, t1/2 was 3.8 +/- 1.3 hours and systemic availability was 3.9% +/- 3.5%. During cimetidine, t1/2 and CL were not different. Systemic availability increased to 5.7% +/- 2.8%. After all nisoldipine treatments a significant decrease in supine diastolic blood pressure (mean 10% to 16%) and increase in heart rate (mean 22% to 44%) were observed. Hemodynamic effects until 2 hours after nisoldipine administration could be fitted to a sigmoidal Emax model. At times after 2 hours a second effect peak was observed. Cimetidine inhibits the metabolism of nisoldipine but has no significant influence on hemodynamic parameters.

Rate of increase in the plasma concentration of nifedipine as a major determinant of its hemodynamic effects in humans.

The relevance of the rate of increase in the plasma concentration of nifedipine for the drug's hemodynamic effect was investigated in healthy volunteers. Nifedipine was given intravenously according to two regimens, each designed to produce the same steady-state concentration, but attained gradually (within 5 to 7 hours) with one regimen and rapidly (within 3 minutes) with the other. The mean steady-state concentrations obtained were 31.7 +/- 5.2 (SD) ng/ml and 29.4 +/- 9.8 ng/ml, respectively (not significant). With the gradual regimen, heart rate was unchanged and diastolic blood pressure was lowered gradually by approximately 10 mm Hg. With the rapid regimen, heart rate increased immediately and remained elevated for the duration of the infusion, whereas diastolic blood pressure did not change significantly. At the end of the gradual-rise regimen, the infusion rate was increased tenfold for 10 minutes, promptly resulting in tachycardia and a paradoxical rise in diastolic blood pressure. These divergent hemodynamic responses of the gradual- and rapid-rise regimens could well be related to differences in baroreceptor activation. It is concluded that the hemodynamic response to nifedipine is influenced by the rate of increase of its concentration in plasma.

Hemodynamic changes during long-term thiazide treatment of essential hypertension in responders and nonresponders.

Blood pressure, cardiac output, plasma volume, renin, and aldosterone were measured in 13 patients with essential hypertension on placebo and after 1, 4, and 12 wk on hydrochlorothiazide 100 mg daily. In 9 patients the same variables were also measured after 24 and 36 wk. Hydrochlorothiazide lowered mean arterial pressure (p less than 0.01). Cardiac output was reduced after 4 and 12 wk of treatment, followed by a return to placebo levels. Stroke volume changed in the same way but heart rate and total peripheral resistance did not differ from placebo values. Plasma volume was reduced after 1 and 24 wk. Renin was permanently elevated (p less than 0.01), but aldosterone rose only during the first 12 wk of treatment. A comparison between responders (greater than 10% fall in mean arterial pressure) and nonresponders (less than 10% fall) revealed different hemodynamic patterns. In responders the initial fall in cardiac output was followed by a return to pretreatment levels, whereas in nonresponders it was permanently reduced. Consequently, total peripheral resistance was lowered only in responders. Nonresponders tended to show a greater degree of plasma volume depletion and greater stimulation of renin and aldosterone, which probably contributed to elevated peripheral resistance. It is concluded that changes in cardiac output are unlikely to be of decisive importance in the ultimate reduction of peripheral resistance in responders to thiazide therapy.

Nifedipine: kinetics and dynamics in healthy subjects.

Kinetics and pharmacologic effects of three formulations of nifedipine were examined in six healthy young men in a crossover design. Each subject received intravenous nifedipine, 0.015 mg/kg body weight, 20 mg in a capsule, and 20 mg in a slow-release tablet. Changes in heart rate (HR), blood pressure, heart dimensions, and plasma norepinephrine levels (PNE) were examined serially. Plasma concentrations of nifedipine (Cp) and urinary metabolite concentrations were measured by liquid chromatography. After intravenous injection the elimination t1/2 was 1.7 +/- 0.4 hr, systemic clearance was 26.7 +/- 5.4 l/hr, and volume of distribution was 0.8 +/- 0.2 l/kg. After the capsule, Cp rose rapidly, to a maximum concentration (Cmax) of 117 +/- 15 ng/ml at a maximum time (tmax) of 1.4 +/- 0.5 hr. After the sustained release tablet tmax was 4.2 +/- 0.7 hr and Cmax was 26 +/- 10 ng/ml. Nifedipine bioavailability was 56% +/- 25% for the capsule and 52% +/- 13% for the tablet, but there were large interindividual differences. Urinary excretion was 58% +/- 13% 24 hr after intravenous injection, and after 32 hr was 55% +/- 13% after capsules and 32% +/- 8% after tablets. HR increased briefly after intravenous injection and after capsules (15 to 20 bpm), but not significantly after tablets. Diastolic blood pressure (DBP) fell briefly after capsules (8 to 10 mm Hg), but there was a sustained effect after tablets. Cardiac dimensions were unchanged. PNE levels paralleled plasma drug levels in the three experiments.(ABSTRACT TRUNCATED AT 250 WORDS)

The acute and chronic antihypertensive effects of ketanserin cannot be explained by blockade of vascular serotonin, type 2, receptors or alpha 1-adrenergic receptors.

The mechanism underlying the antihypertensive effect of acute and chronic administration of ketanserin was investigated in eight hypertensive patients. Intrabrachial artery infusions of serotonin and the selective alpha 1-adrenergic receptor agonist methoxamine were given before and 1 hour after a single oral dose of 20 mg ketanserin and after 4 weeks of treatment with 20 to 40 mg twice daily. Blood pressure was reduced by ketanserin both after the initial dose (p less than 0.01) and after 4 weeks of treatment (p less than 0.01). During placebo, serotonin, 1 ng/kg/min, increased forearm blood flow by 51% +/- 9% (p less than 0.01), whereas the highest dose induced a decrease in flow (-33% +/- 6%; p less than 0.01). Methoxamine elicited a vasoconstriction (p less than 0.001). These effects of serotonin and methoxamine were not influenced by either the initial dose of ketanserin or after 4 weeks of treatment. It is concluded that serotonin cannot be considered a general endogenous pressor agent in these patients. The antihypertensive effects of ketanserin cannot be attributed to either vascular alpha 1-receptor or serotonin, type 2, receptor blockade.

Integrated pharmacokinetics and pharmacodynamics of the novel catechol-O-methyltransferase inhibitor tolcapone during first administration to humans.

OBJECTIVES: To assess the tolerability, pharmacokinetics and pharmacodynamics of single oral doses of the novel catechol-O-methyltransferase (COMT) inhibitor tolcapone in healthy volunteers. METHODS: In this double-blind, placebo-controlled, ascending-single-dose study, doses of 5 to 800 mg tolcapone were administered orally to eight sequential groups of six young healthy male volunteers. Adverse events, vital signs, and clinical laboratory variables were recorded. Pharmacokinetic parameters of tolcapone and its 3-O-methylmetabolite were determined. Pharmacodynamics were assessed by determination of COMT activity in erythrocytes. RESULTS: Tolcapone was well tolerated at all dose levels and did not exert a detectable influence on vital sign measurements. The drug was rapidly absorbed and showed dose-proportional pharmacokinetics. Its mean elimination half-life was 2.0 +/- 0.8 hours (n = 42). Plasma levels of the 3-O-methylmetabolite of tolcapone were not proportional to dose, and its formation was delayed at higher doses. Its elimination half-life was 32 +/- 7 hours (n = 29). Tolcapone caused a rapid and reversible inhibition of COMT activity in erythrocytes. At doses of 200 mg and higher, COMT activity was inhibited by more than 80%. The pharmacokinetic-pharmacodynamic relationship could be described by an inhibitory Emax model and suggested that metabolites of tolcapone did not substantially contribute to its inhibitory activity. CONCLUSIONS: The novel COMT inhibitor tolcapone was well tolerated at oral doses of 5 to 800 mg. Tolcapone concentration-dependently inhibited COMT activity in erythrocytes and exhibited dose-proportional kinetics. Further investigations into its applicability in the treatment of Parkinson's disease are warranted.

Nifedipine: kinetics and hemodynamic effects in patients with liver cirrhosis after intravenous and oral administration.

The pharmacokinetics and hemodynamic effects of nifedipine were studied in patients with liver cirrhosis and in age-matched healthy control subjects. In a randomized order each subject received nifedipine by intravenous infusion (4.5 mg in 45 minutes) and as a tablet (20 mg). After intravenous nifedipine patients had a longer elimination t1/2 (420 +/- 254 vs. 111 +/- 22 minutes; P less than 0.01), a greater volume of distribution (1.29 +/- 0.60 vs. 0.97 +/- 0.42 L/kg), and a lower systemic clearance (233 +/- 109 vs. 588 +/- 140 ml/min; P less than 0.001). Plasma protein binding of nifedipine was lower in the patients (P less than 0.001). After oral nifedipine systemic availability was much higher in patients (90.5% +/- 26.2% vs. 51.1% +/- 17.1%; P less than 0.01) and maximal in patients with a portacaval shunt. Blood pressure decreased and heart rate increased after intravenous nifedipine and these effects could be fitted to plasma concentrations by a sigmoidal model. Maximal effects on heart rate and diastolic blood pressure were not different in liver cirrhosis. When free drug levels were considered, the concentrations corresponding to half the maximal effect were also not different. Blood pressure changes with oral nifedipine were comparable with those after intravenous infusion. We conclude that in patients with liver cirrhosis the pharmacokinetics of nifedipine are considerably altered; dose reduction is recommended when such patients need oral nifedipine.

Role of alpha adrenoceptors in hypertension and in antihypertensive drug treatment.

Recent plethysmographic experiments suggest that both postsynaptic alpha 1 and alpha 2 adrenoceptors in human resistance vessels play an important role in the maintenance and regulation of vascular tone. Central alpha 2 adrenoceptors are assumed to be involved in the central regulation of blood pressure. Radioligand binding studies on the density and characteristics of alpha adrenoceptors have not revealed consistent differences between normotensive and hypertensive subjects, with the exception of pheochromocytoma, in which a consistent down regulation of alpha 2 adrenoceptors in thrombocytes has been demonstrated. The radioligand binding studies are limited, since they cannot be performed on vascular tissues. Alpha adrenoceptors are vitally important as targets of several antihypertensive drugs; the activities of these agents and the principles and clinical relevance of mechanisms involving alpha adrenoceptors are reviewed.

Clinical pharmacology of cilazapril.

In clinical pharmacology studies cilazapril, after its bioactivation to cilazaprilat, was characterized as a potent, reversible angiotensin-converting enzyme (ACE) inhibitor with a terminal half-life of 30 to 50 hours consistent with saturable binding to ACE. Despite the arterial vasodilation, only slight increases in heart rate were found. Cilazapril had no acute effect on cardiovascular reflexes. Cilazapril increased effective renal plasma flow slightly. Glomerular filtration rate remained unaltered. A close and steep correlation between cilazaprilat plasma concentration and ACE inhibition was found. The potency of cilazaprilat, defined as the concentration of cilazaprilat causing 50 percent ACE inhibition, was approximately 1 ng/ml plasma. In short-term studies in hypertensive patients, it appeared that more than 90 percent of plasma ACE inhibition is needed to obtain blood pressure reduction. The result of various dose-response studies established the indirect relationship between dose, plasma concentration of the drug, and the blood pressure response and identified the dose producing maximal effect (i.e., 5 mg). Cilazapril had relatively long-lasting effects on ACE inhibition. In patients with severe chronic renal impairment or hepatic failure, the duration of ACE inhibition of cilazapril was prolonged. In these patients a reduction of the dose and/or less frequent dosing is recommended. There was no clinically relevant interaction of cilazapril with food or furosemide. The effects of hydrochlorothiazide on sodium and chloride excretion were potentiated by cilazapril. An additive effect of propranolol and nitrendipine on the blood pressure response to cilazapril was observed. An interaction with nonsteroidal anti-inflammatory drugs and cilazapril might occur, potentially reducing the blood pressure lowering effect. In general cilazapril was well tolerated.

Sodium sensitivity in essential hypertension: role of the renin-angiotensin-aldosterone system and predictive value of an intravenous frusemide test.

In order to determine factors contributing to sodium induced changes of blood pressure, 20 patients with essential hypertension were studied when on their regular sodium intake and after two weeks of a low sodium diet (50 mmol daily) and two weeks of a high sodium diet (300 mmol daily). There were two periods of regular sodium intake, one of four weeks at the beginning and one of two weeks at the end of the study. The change in mean arterial pressure between the high and low salt diets (delta MAP) was regarded as a measure of sodium sensitivity, and was directly correlated with age and initial blood pressure. Compared with non-responders, responders (delta MAP 10 mmHg or more) showed a lesser activation of the renin-angiotensin-aldosterone system during the low salt period. The response to the administration of intravenous frusemide was not helpful in predicting sodium sensitivity. A significant but relatively small (4.2 mmHg) reduction in MAP was obtained during low salt period compared with the first period of regular sodium intake. The data suggest that moderate dietary sodium restriction can help to reduce the blood pressure of the relatively older patient with hypertension.