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Purpose & Methods: Not all hypertensive patients respond well to ACE inhibition. Here we determined whether renin-angiotensin system (RAS) phenotyping, i.e., the measurement of renin or ACE, can predict the individual response to RAS blockade, either chronically (enalapril vs. enalapril + candesartan) or acutely (enalapril ± hydrochlorothiazide, HCT)., Results: Chronic enalapril + candesartan induced larger renin rises, but did not lower blood pressure (BP) more than enalapril. Similar observations were made for enalapril + HCT vs. enalapril when given acutely. Baseline renin predicted the peak changes in BP chronically, but not acutely. Baseline ACE levels had no predictive value. Yet, after acute drug intake, the degree of ACE inhibition, like Δrenin, did correlate with ΔBP. Only the relationship with Δrenin remained significant after chronic RAS blockade. Thus, a high degree of ACE inhibition and a steep renin rise associate with larger acute responses to enalapril. However, variation was large, ranging >50 mm Hg for a given degree of ACE inhibition or Δrenin. The same was true for the relationships between Δrenin and ΔBP, and between baseline renin and the maximum reduction in BP in the chronic study., Conclusions: Our data do not support that RAS phenotyping will help to predict the individual BP response to RAS blockade. Notably, these conclusions were reached in a carefully characterized, homogenous population, and when taking into account the known fluctuations in renin that relate to gender, age, ethnicity, salt intake and diuretic treatment, it seems unlikely that a cut-off renin level can be defined that has predictive value.

Aim: The optimal antiproteinuric dose of aliskiren is unknown. This study compared the effect of placebo and increasing doses of aliskiren on urinary albumin excretion rate (UAER)., Methods: The trial was a double-blind crossover design. Twenty-six patients with type 2 diabetes mellitus, hypertension and albuminuria were randomised to 2-month treatments with placebo or aliskiren 150 mg, 300 mg or 600 mg once daily, in random order. Primary endpoint was change in UAER; secondary endpoints included changes in 24-h BP, GFR, biomarkers and components of the renin-angiotensin-aldosterone system., Results: Placebo geometric mean UAER was 350 mg/day, mean 24-h BP was 137/81 (SD 12/9) mmHg, GFR was 85 (SD 26) ml min(-1) 1.73 m(-2). Aliskiren 150, 300 and 600 mg daily reduced UAER significantly by 36% (95% CI 17-51), 48% (33-60) and 52% (38-63) respectively (p < 0.001) compared with placebo. UAER reduction during the 600 mg dose was not significantly different from the 300 mg dose. Twenty-four-hour systolic BP was reduced by 4.5, 8.0 and 9.2 mmHg versus placebo, significant for 300 and 600 mg (p < or = 0.001). Twenty-four-hour diastolic BP was reduced by 3.0, 4.1 and 4.4 mmHg, significant versus placebo (p = 0.019, p = 0.001 and p < 0.001). GFR was reduced by 3.0, 5.1 and 6.5 ml min(-1) 1.73 m(-2). hsPRA was reduced by 63%, 70%, and 82% (p < 0.001 for all). Adverse events, most frequently dizziness and fatigue, occurred during all doses., Conclusions: In patients with type 2 diabetes mellitus, hypertension and albuminuria there is no improved antiproteinuric effect when using 600 mg aliskiren daily compared with the maximal recommended antihypertensive dose of 300 mg., Trial Registration: Clinicaltrials.gov NCT00464776, Funding: Novartis Pharma AG.

Background: Autoregulation of GFR, i.e. maintenance of relative constancy of GFR despite variations in mean arterial pressure (MAP) >80 mmHg, is impaired in diabetic kidney disease; furthermore, some antihypertensive drugs may jeopardize autoregulation. The aim of our study was to establish if spironolactone affects the ability to autoregulate GFR., Methods: Sixteen hypertensive type 1 diabetic patients with persistent normoalbuminuria (presumed normal autoregulation) completed this randomized, double-masked, crossover trial. After a 4-week wash-out period, patients received spironolactone 25 mg o.d. and matched placebo for 4 weeks in random order. After each treatment period, the ability to autoregulate GFR was determined by measuring GFR ((51)Cr-EDTA clearance) before (basal) and after acute blood pressure reduction by intravenous injection of clonidine., Results: During placebo, the mean (SE) basal GFR was 115 (5) ml/min/1.73 m(2) and the BP was 146 (4)/81 (2) mmHg corresponding to a MAP of 103 (2) mmHg. Spironolactone did not significantly reduce GFR or BP. Injection of clonidine induced a significant reduction in the MAP of 17 (2) and 19 (1) mmHg during placebo and spironolactone treatment, respectively, and an overall reduction in GFR of 11 and 15 ml/min/1.73 m(2) (both comparisons NS between treatment periods). Signs of impaired autoregulation were present in nine patients during placebo and in nine patients during spironolactone treatment. Relative changes in GFR on placebo treatment correlated with diabetes duration (R = 0.67, P < 0.01) but were not related to duration of hypertension, baseline BP, GFR, HbA1c or to changes in BP., Conclusion: Spironolactone did not change the overall ability to autoregulate GFR in 16 hypertensive type 1 diabetic patients with normoalbuminuria. Our data are suggestive that the ability to autoregulate GFR is gradually impaired with increasing diabetes duration, a phenomenon not previously described in normoalbuminuric patients.

Objective: We investigated whether the antiproteinuric effect of the direct renin inhibitor aliskiren is comparable to that of irbesartan and the effect of the combination., Research Design and Methods: This was a double-blind, randomized, crossover trial. After a 1-month washout period, 26 patients with type 2 diabetes, hypertension, and albuminuria (>100 mg/day) were randomly assigned to four 2-month treatment periods in random order with placebo, 300 mg aliskiren once daily, 300 mg irbesartan once daily, or the combination using identical doses. Patients received furosemide in a stable dose throughout the study. The primary end point was a change in albuminuria. Secondary measures included change in 24-h blood pressure and glomerular filtration rate (GFR)., Results: Placebo geometric mean albuminuria was 258 mg/day (range 84-2,361), mean +/- SD 24-h blood pressure was 140/73 +/- 15/8 mmHg, and GFR was 89 +/- 27 ml/min per 1.73 m(2). Aliskiren treatment reduced albuminuria by 48% (95% CI 27-62) compared with placebo (P < 0.001), not significantly different from the 58% (42-79) reduction with irbesartan treatment (P < 0.001 vs. placebo). Combination treatment reduced albuminuria by 71% (59-79), more than either monotherapy (P < 0.001 and P = 0.028). Fractional clearances of albumin were significantly reduced (46, 56, and 67% reduction vs. placebo). Twenty-four-hour blood pressure was reduced 3/4 mmHg by aliskiren (NS/P = 0.009), 12/5 mmHg by irbesartan (P < 0.001/P = 0.002), and 10/6 mmHg by the combination (P = 0.001/P < 0.001). GFR was significantly reduced 4.6 (95% CI 0.3-8.8) ml/min per 1.73 m(2) by aliskiren, 8.0 (3.6-12.3) ml/min per 1.73 m(2) by irbesartan, and 11.7 (7.4-15.9) ml/min per 1.73 m(2) by the combination., Conclusions: The combination of aliskiren and irbesartan is more antiproteinuric in type 2 diabetic patients with albuminuria than monotherapy.

Inhibition of renin with an active site inhibitor, aliskiren, lowers blood pressure (BP) in diabetic patients. Here, we studied the time course of the antihypertensive and antiproteinuric effect of renin inhibition in 15 patients with type 2 diabetes and elevated urinary albumin/creatinine ratios (UACRs) to check whether aliskiren can decrease proteinuria. After a 4-week washout of previous medications, patients received aliskiren and furosemide daily for 28 days followed by a 4-week withdrawal period. Twenty-four-hour BPs were measured at baseline throughout treatment and withdrawal periods. The UACR was significantly reduced after 2-4 days of treatment with another significant reduction after 28 days. Systolic blood pressure (SBP) was significantly lower after 7 days with no further reduction after 28 days. The BP returned toward baseline 3 days after withdrawal, whereas the UACR was still significantly reduced compared with baseline 12 days after withdrawal. Our study shows that aliskiren reduced 24 h SBP, and this was associated with a reduction in albuminuria in type 2 diabetic patients.

Since the introduction of the aldosterone-to-renin ratio (ARR ) as a screening tool for primary aldosteronism (PA), there has been a marked increase in the reported prevalence of this condition among hypertensive subjects. A meta-analysis from the literature shows a PA prevalence of almost 8% among hypertensive patients, with a twofold higher prevalence in referred patients as compared with primary care patients (9.0 vs 4.3%). However, the usefulness of the ARR remains subject of debate, because of doubts on its validity, and the many factors affecting the ARR , including posture, time of day of blood sampling, and use of antihypertensive medication. Furthermore, there is no clear cut-off value and it is unknown what population should be screened. Recently, The Dutch ARR AT Study was initiated. This is a multicentre, prospective trial aiming to evaluate the test characteristics of the ARR within a Dutch population of therapy-resistant hypertensive patients. The effect of antihypertensive medication on the ARR will be studied. Furthermore, from this study the prevalence of PA in this population will follow. Last, the blood pressure response to the selective aldosterone-receptor-antagonist eplerenone will be evaluated. The Dutch ARR AT Study will run until the end of 2009 and will contribute to the formulation of uniform guidelines for the screening for PA in the Netherlands.

Background: Experimental evidence suggests that in conditions associated with an activated renin-angiotensin system, unopposed activity of angiotensin II underlies the marked renal vasoconstrictor response to nitric oxide synthase inhibition. In the present study, we investigated whether this holds true in hypertensive subjects pretreated with hydrochlorothiazide (HCT)., Methods: Systemic N(G)-nitro-L-arginine methyl ester (L-NAME) infusions (12.5 microg/kg per min for 40 min) were given to eight hypertensive subjects (age 53 +/- 6 years) during placebo, and during pretreatment with HCT (25 mg once daily) or HCT and losartan (LOS) (50 mg twice daily), both for 9 days. The glomerular filtration rate (GFR) and renal plasma flow were estimated from the clearances of radiolabeled thalamate and hippuran. Renal blood flow (RBF) was calculated as renal plasma flow/1 - hematocrit and the renal vascular resistance (RVR) as mean arterial pressure (MAP) divided by RBF., Results: Compared with placebo, plasma renin increased (P < 0.001) from 15 +/- 4 mU/l during placebo to 26 +/- 7 mU/l during HCT and to 133 +/- 51 mU/l during HCT + LOS. MAP (110 +/- 3 mmHg) decreased to 102 +/- 4 mmHg during HCT and to 98 +/- 5 mmHg during HCT + LOS. RBF (579 +/- 36 ml/min), GFR (97 +/- 6 ml/min) and filtration fraction (29 +/- 2%) did not change, whereas RVR (200 +/- 15 RU) decreased to 183 +/- 13 RU during HCT and to 165 +/- 14 RU during HCT + LOS (P < 0.05). In response to L-NAME, MAP and RVR increased maximally by 10 +/- 3 and 67 +/- 9%, whereas RBF and GFR decreased maximally by 42 +/- 6 and 18 +/- 4%. Compared with these responses, the responses of MAP, RBF and RVR were not affected by pretreatment of HCT or HCT + LOS, but the L-NAME-induced decrease in GFR (26 +/- 5% during HCT and 29 +/- 5% during HCT and LOS) was enhanced (P < 0.01)., Conclusions: In hypertensive subjects with an activated renin-angiotensin system, unopposed activity of angiotensin II is not involved in L-NAME-induced pressor and renal vasoconstrictor response, whereas the L-NAME-induced decrease in GFR is enhanced, indicating greater dependency of GFR on nitric oxide-mediated vasodilator tone during sodium depletion.

Background/aim: Renal vasodilation in response to L-arginine has been reported to be diminished in hypertensive (HT) subjects. If this diminished renal vasodilator response indicates disturbance of the renal NO pathway, a diminished renal vasoconstrictor response to NO synthase inhibition may be present in HT subjects as well. The present study was conducted to compare the effects of L-arginine and N(G)-nitro-L-arginine methyl ester (L-NAME) on renal and systemic hemodynamics between HT and normotensive (NT) subjects., Methods: The responses of renal and systemic vascular resistances (RVR and SVR) and plasma noradrenaline and renin (NOR and PRA) to systemic NO stimulation and inhibition were studied in patients with grade 1 essential HT and age- and sex-matched NT subjects. On separate occasions, after baseline values were obtained, 40-min randomly administered intravenous infusions of L-arginine (12.5 mg.kg(-1).min(-1)) or L-NAME (0.0125 mg.kg(-1).min(-1)) were given., Results: Baseline values of RVR (129 +/- 21 and 162 +/- 10 resistance units) and SVR (15.1 +/- 4.3 and 21.6 +/- 5.1 resistance units) were higher (p < 0.01) in HT than in NT subjects, whereas the baseline values of NOR and PRA were similar. Infusion of L-arginine caused similar decrements in SVR (29 +/- 10 and 31 +/- 11%), but the decrease in RVR was smaller (22 +/- 8 and 35 +/- 12%, respectively; p < 0.05) in HT than in NT subjects. In response to L-NAME, the increments in RVR (66 +/- 10 and 61 +/- 25%) and SVR (36 +/- 21 and 34 +/- 18%) were similar in HT and NT subjects. In both groups, infusion of L-arginine was associated with similar increments, whereas infusion of L-NAME was associated with similar decrements in NOR and PRA., Conclusions: This study confirms the smaller renal vasodilator response to L-arginine in HT than in NT subjects. Whether this is caused by a disturbance of the renal NO pathway remains doubtful considering the observed similar L-NAME-induced increments in RVR and SVR in the two groups of subjects., (Copyright 2002 S. Karger AG, Basel)

Background: Inhibition of angiotensin-converting enzyme (ACE) reduces the risk of cardiovascular problems in patients with chronic renal failure. This effect may be due in part to a decrease in sympathetic nervous activity, but no direct evidence of such an action is available., Methods: We studied muscle sympathetic-nerve activity in 14 patients with hypertension, chronic renal failure, and increased plasma renin activity before, during, and after administration of the ACE inhibitor enalapril. Ten other patients with similar clinical characteristics were studied before and during treatment with the calcium-channel blocker amlodipine. Normal subjects matched for age and weight were included in both studies., Results: At base line, mean (+/-SD) muscle sympathetic-nerve activity was higher in the group of patients who received enalapril than in the control subjects (35+/-17 vs. 19+/-9 bursts per minute, P=0.004). The baroreflex curve, which reflects changes in muscle sympathetic-nerve activity caused by manipulations of blood pressure with sodium nitroprusside and phenylephrine, was shifted to the right in the patients, but baroreflex sensitivity was similar to that in the control subjects (-2.1+/-1.9 and -2.7+/-1.3 bursts per minute per mm Hg, respectively; P=0.36). A single dose of the sympatholytic drug clonidine caused a greater fall in blood pressure in the patients than in the control subjects. Treatment with enalapril normalized blood pressure and muscle sympathetic-nerve activity (at 23+/-10 bursts per minute) in the patients and shifted the baroreflex curve to the left, reflecting normal blood-pressure levels, without significantly changing sensitivity (-2.3+/-1.8 bursts per minute per mm Hg, P=0.96). In the patients who received amlodipine, treatment also lowered blood pressure but increased muscle sympathetic-nerve activity, from 41+/-19 to 56+/-14 bursts per minute (P=0.02)., Conclusions: Increased sympathetic activity contributes to hypertension in patients with chronic renal disease. ACE inhibition controls hypertension and decreases sympathetic hyperactivity.

We studied the hemodynamic, neurohumoral, and biochemical effects of the novel angiotensin type 1 (AT1) receptor antagonist irbesartan in 86 untreated patients with essential hypertension on a normal sodium diet. According to a double-blind parallel group trial, patients were randomized to a once-daily oral dose of the AT1 receptor antagonist (1, 25, or 100 mg) or placebo after a placebo run-in period of 3 weeks. Randomization medication was given for 1 week. Compared with placebo, 24-hour ambulatory blood pressure did not change with the 1-mg dose, and it fell (mean and 95% confidence interval) by 7.0 (4.2-9.8)/6.1 (3.9-8.1) mm Hg with the 25-mg dose and by 12.1 (8.1-16.2)/7.2 (4.9-9.4) mm Hg with the 100-mg dose. Heart rate did not change during either dose. With the 25-mg dose, the antihypertensive effect was attenuated during the second half of the recording, and with the 100-mg dose, it was maintained for 24 hours. Baseline values of renin and the antihypertensive response to the 25- and 100-mg doses were well correlated (r = .68, P < .01). Renin did not change with the 1-mg dose, but it rose threefold to fourfold with the 25-mg dose and fourfold to fivefold with the 100-mg dose 4 to 6 hours after administration. With the 100-mg dose, renin was still elevated twofold 24 hours after dosing. The changes in renin induced by the AT1 receptor antagonist were associated with parallel increments in angiotensin I and angiotensin II. Aldosterone, despite AT1 receptor blockade, did not fall.(ABSTRACT TRUNCATED AT 250 WORDS)

Intravenous (i.v.) infusion of the selective vasopressin (V2) agonist 1-desamino-8-D-arginine vasopressin (DDAVP, Desmopressin) in humans causes a fall in blood pressure, an increase in heart rate, and a rise in plasma renin and noradrenaline. The present study was designed to demonstrate the vasodilatory properties of DDAVP in the renal circulation and to describe the effect of DDAVP on renin secretion. Seven male subjects (31-63 years) with hypertension, who showed no signs of renal parenchymal disease, received an i.v. infusion of DDAVP (400 ng/kg in 10 minutes). They were studied at the time they were undergoing renal vein renin sampling and renal angiography as part of the diagnostic work-up of their hypertension. 131I-Hippurate clearance was used to measure effective renal plasma flow (ERPF). True renal plasma flow was calculated as ERPF divided by the renal extraction ratio of 131I-hippurate. 125I-Thalamate clearance was used to measure glomerular filtration rate (GFR). Measurements were made before and 15-20 minutes after administration of DDAVP. Angiography was performed in the same session after the last blood samples had been collected. In all patients the renal arteries were normal and the extraction ratios of 131I-hippurate and 125I-thalamate (Ehip, Ethal) were not different for the left and right kidney, and in all seven patients a diagnosis of essential hypertension was made. After DDAVP systolic blood pressure decreased by 14.4 mmHg (2.0-26.8) (mean, 95% confidence interval, p < 0.05). Diastolic blood pressure decreased by 12.1 mmHg (2.9-21.7, p < 0.01). Heart rate increased by 17.5 bpm (11.7-23.2, p < 0.001).(ABSTRACT TRUNCATED AT 250 WORDS)

Objective: To investigate whether the compensatory rise in renin and plasma angiotensin I in response to repeated angiotensin converting enzyme (ACE) inhibitor treatment results in a partial escape of ACE inhibition over a 24-h dosing interval., Design: A single-blind placebo-controlled study in two parallel groups of eight hypertensive subjects receiving a once-daily dose of the ACE inhibitor, spirapril, of either 12.5 or 25 mg. Detailed 24-h studies were performed at the end of 2 weeks of placebo, and after the first dose and 2 weeks administration of spirapril., Methods: Twenty-four-hour ambulatory blood pressure was measured invasively. True' angiotensins I and II were measured by radioimmunoassay after high-performance liquid chromatography separation., Results: Both for the lower and higher doses of spirapril, the time-course of changes of spiraprilat, the active metabolite of spirapril, and ACE activity was similar but the maximal rise in angiotensin I was twofold higher after 2 weeks administration than after the first dose. Angiotensin II after the first dose of spirapril fell rapidly, with lowest values 2 to 4 h after dosing. At the end of dosing interval angiotensin II had returned to values seen under placebo with the 12.5-mg dose, but at the end of the 24-h period it was still suppressed with the 25-mg dose. Compared with these first-dose responses the initial maximal degree of angiotensin II suppression after 2 weeks administration of either dose was similar, but during the subsequent hours the degree of angiotensin II suppression tended to be less with the lower and was significantly less with the higher dose of spirapril. With the lower dose of spirapril responses of 24-h ambulatory blood pressure to the first dose and to 2 weeks of administration were almost superimposable, although blood pressures in the second half of the dosing interval tended to be higher during chronic treatment. With the higher dose the response of nocturnal blood pressure after 2 weeks administration was diminished by 8.8 mmHg systolic and 6.8 mmHg diastolic., Conclusions: Repeated ACE inhibitor treatment with once-daily spirapril leads to a partial escape of ACE inhibition, as reflected by a shorter duration of angiotensin II suppression. This escape also affects the antihypertensive response in the second half of the dosing interval.

To assess the role of the sympathetic nervous system in the development of genetic hypertension, blood pressure (BP) was recorded in conscious adult Lyon hypertensive (LH) and normotensive (LN) rats that had received daily injections of saline or guanethidine at 1-13 wk of age. Guanethidine abolished the pressor response to tyramine, decreased plasma norepinephrine by greater than 70% and plasma 3,4-dihydroxyphenylglycol by approximately 90%, and did not change plasma epinephrine. Bilateral adrenalectomy further reduced plasma norepinephrine to 8 and 5% of control levels in LH and LN rats, respectively. BP was lowered (-7%) in sympathectomized rats, but the mean absolute BP difference between LH and LN rats was unaltered. Despite marked supersensitivity to alpha-adrenoreceptor stimulation, phentolamine induced only a small transient depressor response, which was abolished by adrenalectomy in sympathectomized rats. It is concluded that the sympathetic nervous system is not necessary for the development of hypertension in LH rats. After sympathectomy, circulating catecholamines, which mostly derive from the adrenal medulla, play only a minor role in BP maintenance.

The effects of different beta-adrenoceptor agonists and antagonists on plasma noradrenaline and potassium concentrations were studied in patients with borderline hypertension. Heart rate, arterial pressure and the heart rate corrected duration of total electromechanical systole (QS2I) were also measured. Infusion of the beta-adrenoceptor agonists isoprenaline (non-selective) and salbutamol (beta 2-selective), but not prenalterol (beta 1-selective) caused dose-dependent increments in plasma noradrenaline. Isoprenaline and salbutamol decreased plasma potassium dose-dependently. For a given effect on heart rate and QS2I the fall in potassium was less pronounced after prenalterol. The effects of isoprenaline were also studied after the beta-adrenoceptor antagonists propranolol, 320 mg day-1 for 1 week (non-selective) and atenolol, 100 mg day-1 for 1 week (beta1-selective). The effects of isoprenaline, when infused in equipotent chronotropic doses, on noradrenaline and potassium were not affected by atenolol, whereas they were completely abolished by propranolol. The rise in noradrenaline during beta-adrenoceptor stimulation could be explained by presynaptic facilitation of noradrenaline release. The fall in potassium probably reflects stimulation of Na-K-ATPase dependent transport of potassium into the cell. Both effects were seen after beta 2- but not after beta 1-adrenoceptor stimulation. Hypokalaemia and raised levels of noradrenaline are also known to occur under such stressful conditions as acute myocardial infarction, when circulating levels of the endogenous beta 2-adrenoceptor agonist adrenaline are high. Blockade of these effects by beta-adrenoceptor antagonists may contribute to the cardioprotective effect of these drugs. This warrants further consideration of the clinical significance of beta-blocker selectivity.

In an attempt to further clarify the mechanism of the maintenance of the antihypertensive effect of beta-adrenoceptor antagonists, the effects of four antagonists with different ancillary properties (acebutolol, atenolol, pindolol, and propranolol) on systemic and renal hemodynamics, body fluid volumes, hormones, and lymphocyte beta-adrenoceptor density were studied in four groups of 10 hypertensive patients. The patients were observed for 3 weeks during active treatment and for 2 weeks after withdrawal of treatment. At the end of the 3-week treatment period, the four drugs had an equal antihypertensive effect (fall in mean arterial pressure, 10-13%). Although renin activity was suppressed (60-70%) by all four drugs, changes in renin or pretreatment values of renin levels were not correlated with the fall in blood pressure. The drugs had no effect on plasma catecholamine concentrations or body fluid volumes. Despite similar antihypertensive effects among the four drugs, the changes in flow and resistance underlying the fall in blood pressure differed considerably. With pindolol, the fall in blood pressure was associated with a fall in vascular resistance (26 +/- 6%), whereas with propranolol, it was predominantly associated with a fall in cardiac output (11 +/- 7%). No significant changes in vascular resistance or cardiac output occurred with atenolol or acebutolol. The changes in renal blood flow and renal vascular resistance occurred in parallel with the changes in cardiac output and systemic vascular resistance. Plasma epinephrine concentration and pretreatment cardiac chronotropic responsiveness to isoproterenol appeared to be inversely correlated with lymphocyte beta-adrenoceptor density (Bmax) (r = -0.41 and -0.43, respectively). With pindolol, Bmax decreased maximally by 39 +/- 6%, and with propranolol, it increased by 51 +/- 17%. With both drugs, significant changes in Bmax were already present 24 hours after treatment. Furthermore, 1 week after withdrawal of treatment with pindolol, Bmax was still down-regulated, and cardiac chronotropic responsiveness was still decreased, whereas 1 week after withdrawal of propranolol, Bmax was still up-regulated, and cardiac chronotropic responsiveness was still increased. No changes in Bmax occurred with the beta 1-selective antagonists acebutolol and atenolol. Thus, despite an equal antihypertensive effect, the four beta-adrenoceptor antagonists appear to have dissimilar effects on cardiac output, renal blood flow, and lymphocyte beta-adrenoceptors. Changes in cardiac output, the circulating blood volume, or angiotensin-mediated vasoconstriction are factors unlikely to be crucial for the antihypertensive effect of beta-adrenoceptor antagonists. Therefore, interference with vasoconstrictor nerve activity through blockade of either central or peripheral prejunctional beta-adrenoceptors could be an alternative explanation of their blood pressure-lowering potential.

The new selective 5-HT2 receptor blocking agent ketanserin was given in a dose of 10 mg intravenously to 12 patients with essential hypertension. It caused a distinct fall in supine systemic arterial, right atrial, pulmonary artery, and pulmonary capillary "wedge" pressures. Cardiac output, renal blood flow, and glomerular filtration rate showed no persistent changes. Thus 5-HT2 receptor blockade caused dilatation of both resistance and capacitance vessels and of the renal vascular bed. Heart rate and plasma concentrations of renin and noradrenaline rose after ketanserin. These data suggest that 5-HT may have a role in maintaining high blood pressure.

Ketanserin is a serotonin antagonist with high affinity for S2-serotonergic receptors, which mediate the vasoconstrictor effects of serotonin. It does not block the vasodilator effects of this monoamine, and it is devoid of agonist activity and serious central side effects. Ketanserin, however, also binds to alpha 1-adrenoceptors. The compound (10 mg i.v.) was given to 30 patients with essential hypertension and four normotensive patients with chronic autonomic failure, owing to an efferent sympathetic lesion. Ketanserin lowered systolic and diastolic arterial pressure by about 20%. The effects on cardiac output, cardiac filling pressures, forearm blood flow, renal blood flow, and glomerular filtration rate revealed a hemodynamic pattern compatible with dilatation of both resistance and capacitance vessels. These vasodilator effects were accompanied by moderate reflex stimulation of the heart. The drug did not alter the pressor effect of bolus injections of the alpha 1-adrenoceptor agonist phenylephrine, which contrasted with the competitive antagonism exerted by the alpha 1-adrenoceptor antagonist prazosin. Baroreflex-mediated bradycardia after phenylephrine also was not affected by ketanserin. The drug had a distinct hypotensive effect in patients with autonomic failure, despite the fact that these patients did not respond to the nonselective alpha-adrenoceptor antagonist phentolamine, 20 mg i.v. Thus, ketanserin is capable of lowering arterial pressure independently of alpha 1-adrenoceptor blockade. The results are therefore indirect evidence supporting a role of serotonin in hypertension.

1. Plasma noradrenaline, active and inactive plasma renin, cardiac index and total peripheral vascular resistance were studied in 41 subjects, initially aged 10-19 years, who were followed up for at least 2 years after a blood pressure reading of 140 and/or 90 mmHg or more (initial hypertensives) and in 41 normotensive control subjects selected from the same population and matched for age, sex and body-mass index. 2. The initial hypertensive subjects had a lower mean cardiac index (3.63 +/- SD 0.83 vs 4.00 +/- 0.89 litre min-1 m-2), a higher mean total peripheral resistance (26.8 +/- 5.7 vs 22.8 +/- 5.5 peripheral resistance (26.8 +/- 5.7 vs 22.8 +/- 5.5 units) and a higher mean plasma noradrenaline units) and a higher mean plasma noradrenaline concentration (336 +/- 146 vs 281 +/- 126 pg/ml) than the control subjects. 3. Mean plasma noradrenaline concentration was higher in initial hypertensive subjects with a high active renin concentration than in those with a normal renin concentration (442 +/- 70 vs 324 +/- 100 pg/ml). 4. A weight-adjusted standardized regression coefficient of 0.77 between active plasma renin concentration and left ventricular mass was found in normotensive control subjects. 5. These findings are at variance with the existence of a hyperkinetic phase in young hypertensive subjects and suggest that sympathetic overactivity may be related to early essential hypertension through increase of peripheral vascular resistance.

The possibility that sympathetic pressor responses are modulated by adrenaline-mediated facilitation of neuronal noradrenaline release was explored in 17 subjects with borderline hypertension. Infusion of adrenaline, which raised plasma adrenaline by a factor of 8 to 9, augmented the rise in systolic and diastolic arterial pressure induced by standardized cold pressor and isometric exercise tests. The heart rate response to these tests was not affected. When a low dose of propranolol was given on top of the adrenaline infusion before the cold pressor test, the blood pressure response to cold exposure was not different from the response observed when the test was performed during saline infusion. Plasma noradrenaline was higher during adrenaline infusion then during saline infusion, both before and after the cold pressor and isometric exercise tests, and the effect of adrenaline on plasma noradrenaline was antagonized by propranolol. These observations are consistent with the hypothesis that stress levels of circulating adrenaline may amplify sympathetic pressor responses by facilitation of the release of transmitter noradrenaline.

Plasma noradrenaline (PNA) concentrations were measured in 38 subjects aged 13-23, who were followed up for two to four years after an initial blood-pressure (BP) reading of 140/90 mm Hg or over was obtained, and in 39 age-matched controls from the same open population. Subjects who were hypertensive when the PNA concentration was measured had a significantly higher concentration (351 +/- SE 26 pg/ml) compared with their controls (248 +/- 29 pg/ml). Furthermore, in those subjects in whom the mean arterial pressure decreased by under 5% during the follow-up period the mean concentration was 363 +/- 27 pg/ml, compared with 271 +/- 29 pg/ml in their controls. PNA concentrations and systolic BP were positively correlated. A positive association between PNA concentrations and age was observed in the controls but not the subjects with hypertension, owing to the higher concentrations in younger hypertensive subjects.

Adrenaline may increase noradrenaline release and enhance sympathetic pressor effects through activation of pre-synaptic beta 2-adrenoceptors. Conversely, blockade of beta 2-receptors could lead to a fall in blood pressure. To test this hypothesis we performed a double-blind placebo controlled crossover study in nine patients with mild hypertension, comparing the effects of the beta 2-selective blocker ICI 118,551, 50 mg t.i.d. with those of propranolol, 80 mg t.i.d. Two hours after the first dose of ICI 118,551 or propranolol, plasma noradrenaline and blood pressure remained unchanged while heart rate and renin were reduced. After 1 week, blood pressure was significantly reduced by both drugs. The beta 2-selectivity of ICI 118,551 was confirmed by isoprenaline infusion studies. After 1 week of treatment ICI 118,551 had no effect on the beta 1-receptor mediated shortening of electromechanical systole (QS2I), the rise in systolic pressure and rise in renin, whereas these responses were blocked by a dose factor of eight after propranolol. ICI 118,551 and propranolol equally blocked the beta 2-receptor mediated fall in diastolic pressure and the rise in noradrenaline. We conclude that beta 2-selective blockade by ICI 118,551 lowers blood pressure. This finding is compatible with a role of pre-synaptic beta 2-receptors in blood pressure control.

Bopindolol is a new long-acting, nonselective beta-adrenoceptor antagonist with partial agonist activity. Its acute (24 hours, 2 mg, administered orally) and long-term (3 weeks, 2 to 4 mg) hemodynamic and hormonal effects were studied in a single-blind placebo-controlled trial in 10 hypertensive subjects. The initial response (mean +/- SE) to bopindolol was a fall in cardiac output (-12% +/- 2%) and heart rate (-11% +/- 2%). Mean arterial pressure began to fall 3 to 4 hours after administration in parallel with a decrease in systemic vascular resistance, which had increased initially. Twenty-four hours after administration, mean arterial pressure and systemic vascular resistance were reduced by 12% +/- 2% and 12% +/- 5%, respectively. By that time heart rate and cardiac output did not differ from baseline values despite beta-blockade. After 3 weeks of treatment mean arterial pressure had fallen by 9% +/- 2% and renal blood flow and glomerular filtration rate were not changed. One week after withdrawal from treatment mean arterial pressure and heart rate were no longer reduced, but beta-blockade could still be demonstrated, establishing the long duration of action of the drug.

Comparison of the hemodynamic and hormonal effects of beta-adrenoceptor antagonists with different ancillary properties may help to clarify the antihypertensive mechanism of these drugs. Under strict basal conditions, the effects of acebutolol (400 mg b.i.d.), atenolol (100 mg b.i.d.), pindolol (10 mg b.i.d.), and propranolol (80 mg t.i.d.), were studied for the first 24 hours in 40 hypertensive patients. With pindolol, mean arterial pressure was reduced (p less than 0.05) 1 hour after administration, whereas the cardiac index and the systemic vascular resistance index did not change. With the other three drugs, the fall in mean arterial pressure was delayed 2-3 hours. With these drugs, the fall in mean arterial pressure was preceded by a rise in the resistance index, which compensated for the initial fall in cardiac index. With each drug, the decrements in mean arterial pressure were associated with parallel decrements in the resistance index, and percent changes in mean arterial pressure and the resistance index were always significantly (p less than 0.001) correlated. At the end of the 24-hour period, the four drugs shared an equal antihypertensive effect, which varied 14-17%. This was associated with a return of the cardiac index toward control values by acebutolol, atenolol, and propranolol treatment and a moderately increased cardiac index above pretreatment values (13%, p less than 0.01) with pindolol. The secondary rise in the cardiac index was inversely correlated (p less than 0.001) with the fall in mean arterial pressure with all four drugs. Plasma renin was maximally suppressed 2 hours after treatment, thus before any change in mean arterial pressure had occurred with acebutolol, atenolol, and propranolol. Pretreatment values of active renin and the reduction of mean arterial pressure 24 hours after administration were not correlated in any of the four groups. Despite the "vasodilator" action of the four drugs, plasma norepinephrine did not rise. Our data show that the main hemodynamic change that occurs at the time blood pressure falls after beta-adrenoceptor antagonism is vasodilation. Neither autoregulation of blood flow nor renin suppression can explain this vasodilator action. The absence of an increase in norepinephrine, despite vasodilation, suggests that beta-adrenoceptor antagonism interferes with sympathetic vasoconstrictor nerve activity. This effect may explain the vasodilator and antihypertensive potential of beta-adrenoceptor antagonists.

Forty young subjects, aged 18 to 28 years, with mildly elevated blood pressure participated in a double-blind randomized three-period crossover study of the effect of sodium restriction with and without potassium supplementation on blood pressure. Dietary sodium intake was restricted for 18 weeks in which the patients received in random sequence 'slow-sodium' (90 mmol/day), 'slow-potassium' (72 mmol/day), and placebo tablets, each for 6 weeks. Mean urinary sodium excretion was 129 mmol/24 h in the slow-sodium period, 57 mmol/24 h during placebo, and 69 mmol/24 h during slow-potassium. Mean supine systolic blood pressure in the sixth week of the slow-potassium period was 3.3 mmHg lower than that at the end of the slow-sodium period (P less than 0.05). There was no significant difference in systolic or diastolic blood pressure between the placebo and the slow-sodium periods. The fall in systolic blood pressure in the low sodium/high potassium period was accompanied by a fall in cardiac index of 0.4 l/min per m2 body surface area (BSA) (P = 0.03). Our observations suggest a small hypotensive effect of moderate sodium restriction combined with high potassium intake in young hypertensive subjects. Sodium restriction alone has little effect on blood pressure in this group. The combination of a low sodium/high potassium diet may lower blood pressure by affecting cardiac output. Reducing the dietary sodium:potassium ratio may therefore be useful in the management of early primary hypertension.

Both nonselective beta-blockers and beta 1-selective blockers are effective antihypertensive agents. beta 1-Blockade generally is considered to be responsible for their antihypertensive action, whereas beta 2-blockade is regarded as undesirable. These common assumptions notwithstanding, the mechanism by which beta-blockers lower blood pressure remains unknown. To examine the possibility that beta 2-blockade may contribute to the antihypertensive action of beta-blocker therapy, we studied the cardiovascular effects of compound ICI 118551, a beta 2-selective blocker. First, we showed that 50 mg t.i.d. orally is a beta 2-selective dose. In contrast to propranolol, 80 mg t.i.d., or atenolol, 100 mg once a day, 50 mg of ICI 118551 t.i.d. failed to block beta 1-mediated inotropic stimulation and stimulation of renin by isoproterenol. We then performed a double-blind, placebo-controlled trial in patients with mild essential hypertension to compare this compound with propranolol, 80 mg t.i.d., and showed that ICI 118551 significantly decreased systolic and diastolic blood pressure. This antihypertensive effect was demonstrated by direct as well as by indirect blood pressure measurements. Thus, contrary to prevailing thought, beta 2-blockade has an antihypertensive effect independent of, and distinct from, beta 1-blockade.