Calcium blockade in arterial hypertension. Review.

The use of calcium blockers in arterial hypertension is based on experimental evidence for an altered role of calcium (Ca++) in hypertensive vascular smooth muscle and enhanced vasodilatatory effects of these drugs in the hypertensive organism. Both verapamil and nifedipine reduce blood pressure acutely and on chronic administration. Acute administration results in reflex-activated increments of heart rate, plasma renin activity, and plasma catecholamines after nifedipine, whereas these effects are less conspicuous after verapamil. Acute diuretic, natriuretic, and uricosuric effects can be demonstrated. On repeated administration of nifedipine, a degree of tolerance develops and on long-term administration it may be necessary to combine it with a beta-adrenoceptor blocker and a diuretic. In animal experiments, calcium blockers have shown favorable effects on hypertensive cardiovascular structural changes, but such unique beneficial effects remain to be demonstrated in the human disease.

Characteristics of 9194 patients with left ventricular hypertrophy: the LIFE study. Losartan Intervention For Endpoint Reduction in Hypertension.

-Losartan was the first available orally administered selective antagonist of the angiotensin II type 1 receptor developed for the treatment of hypertension. The Losartan Intervention For Endpoint (LIFE) Reduction in Hypertension Study is a double-blind, prospective, parallel group study designed to compare the effects of losartan with those of the beta-blocker atenolol on the reduction of cardiovascular morbidity and mortality. Patients with essential hypertension, aged between 55 and 80 years, and ECG-documented left ventricular hypertrophy (LVH) were included. Altogether, 9223 patients in Scandinavia, the United Kingdom, and the United States were randomized from June 1995 through April 1997, and 9194 remain after exclusion of a study center at which irregularities were discovered. This population of hypertensives (mean systolic/diastolic blood pressure, 174.4/97.8 mm Hg) with LVH comprises women (54.1%) and men, mostly retired from active work (mean age, 66.9 years), with a high prevalence of overweight (mean body mass index, 28.0 kg/m2), diabetes mellitus (12.3%), lipid disorders (18.0%), and symptoms or signs of coronary heart disease (15.1%). There were fewer current smokers (<17%) than in the general population, and approximately 7% were nonwhite. Almost 30% of participants had been untreated for at least 6 months when screened for the study. Only 1557 persons who entered the placebo run-in period of 14 days were excluded, predominantly because of sitting blood pressures above or below the predetermined range of 160-200/95-115 mm Hg and ECG-LVH criteria not met. By application of simple 12-lead ECG criteria for LVH (Cornell voltage QRS duration product formula plus Sokolow-Lyon voltage read by a core laboratory), hypertensive patients with LVH with an average 5-year coronary heart disease risk of 22.3% according to the Framingham score were identified. This population is now being treated (goal, <140/90 mm Hg) in adherence with the protocol for at least 4 years after final enrollment (ie, through April 2001) and until at least 1040 patients suffer myocardial infarction, stroke, or cardiovascular death.

Renal effects of acute calcium blockade with nifedipine in hypertensive patients receiving beta-adrenoceptor-blocking drugs.

The effects on blood pressure and renal function of a single 20-mg sublingual dose of nifedipine were investigated in 10 patients with mild to moderate arterial hypertension insufficiently treated on beta-blocker monotherapy. Nifedipine induced a prompt and marked reduction of both systolic and diastolic blood pressure (average maximal reduction 30/22 mm Hg, P less than 0.001). Despite the beta blockade, heart rate rose 25%. Only insignificant increments of glomerular filtration (RVR) was markedly reduced (P less than 0.001). Urinary excretion rate of albumin and beta-2 microglobulin rose after nifedipine, reflecting changes in glomerular as well as tubular function. Mean blood pressure seemed to be a major determinant of the excretion of proteins. There was a marked increase in the excretion of sodium after nifedipine and urine volume rose from a mean of 8.2 +/- 1.3 to 12.5 +/- 1.8 ml/min (P less than 0.01). The changes in sodium excretion rate correlated with the renal hemodynamic changes. Uric acid excretion rate rose remarkably after nifedipine and the magnitude of the changes seemed intimately related to the basal level of RVR. The results indicate that nifedipine therapy may be advantageous in patients whose hypertension is insufficiently controlled with beta blockers alone. Renal blood flow is maintained and there is a desirable diuretic action and enhancement of uric acid excretion.

Lowering of blood pressure and predictors of response in patients with left ventricular hypertrophy: the LIFE study. Losartan Intervention For Endpoint.

The Losartan Intervention For Endpoint (LIFE) reduction in hypertension study is a double-blind, prospective, parallel-group study comparing the effects of losartan with those of atenolol on the reduction of cardiovascular complications in patients (n = 9,194) with essential hypertension and with electrocardiographically (ECG) documented left ventricular hypertrophy (LVH). Baseline blood pressure was 174.4/97.8 mm Hg (mean), age 66.9 years, body mass index 28.0 kg/m2; 54.1% were women and 12.5% had diabetes mellitus. This population will be treated until at least 1,040 have a primary endpoint. After five scheduled visits and 12 months of follow-up, blood pressure decreased by 23.9/12.8 mm Hg to 150.5/85.1 mm Hg (target < 140/90 mm Hg). The mandatory titration level of < or = 160/95 mm Hg was reached by 72.1% of the patients. At the 12-month visit, 22.7% of all patients were taking blinded study drug alone, 44.3% were taking blinded drug plus hydrochlorothiazide (HCTZ), and 17.7% were taking blinded drugs plus HCTZ and additional drugs. Controlling for all other variables, patients in the US received more medication and had 2.4 times the odds of achieving blood pressure control than patients in the rest of the study (P < .001). Previously untreated patients (n = 2,530) had a larger initial decrease in blood pressure compared with those previously treated. Diabetics (n = 1,148) needed more medication than nondiabetics to gain blood pressure control. Only 13.9% of the patients had discontinued blinded study drug and 1.4% missed the revisit at 12 months. These data demonstrate both the successful lowering of blood pressure during 12 months of follow-up in a large cohort of patients with hypertension and LVH on ECG, but also emphasize the need for two or more drugs to control high blood pressure in most of these patients. Being previously treated and having diabetes were associated with less blood pressure response, whereas living in the US indicated better blood pressure control. It has been possible to keep most of these patients with complicated hypertension taking blinded study drug for 12 months.

The Losartan Intervention For Endpoint reduction (LIFE) in Hypertension study: rationale, design, and methods. The LIFE Study Group.

The treatment of hypertension mainly with diuretics and beta blockers reduces cardiovascular mortality and morbidity, largely due to a decreased incidence of stroke, whereas the beneficial effects of antihypertensive therapy on the occurrence of coronary events have been less than expected from epidemiological studies. Furthermore, treated hypertensive patients still have a higher cardiovascular complication rate, compared with matched normotensives. This is particularly evident in patients with left ventricular hypertrophy (LVH), a major independent risk indicator for cardiovascular disease. In addition to elevating blood pressure, angiotensin II (A-II) exerts an important influence on cardiac structure and function, stimulating cell proliferation and growth. Thus, to further reduce morbidity and mortality when treating hypertensive patients, it may be important to effectively block the effects of A-II. This can be achieved directly at the A-II receptor level by losartan, the first of a new class of antihypertensive agents. It therefore seems pertinent to investigate whether selective A-II receptor blockade with losartan not only lowers blood pressure but also reduces LVH more effectively than current therapy, and thus improves prognosis. The Losartan Intervention For Endpoint reduction (LIFE) in Hypertension study is a double-blind, prospective, parallel group study designed to compare the effects of losartan with those of the beta-blocker atenolol on the reduction of cardiovascular morbidity and mortality in approximately 8,300 hypertensive patients (initial sitting diastolic blood pressure 95 to 115 mm Hg or systolic blood pressure 160 to 200 mm Hg) with electrocardiographically documented LVH. The study, which will continue for at least 4 years and until 1,040 patients experience one primary endpoint, has been designed with a statistical power that will detect a difference of at least 15% between groups in the incidence of combined cardiovascular morbidity and mortality. It is also the first prospective study with adequate power to link reversal of LVH to reduction in major cardiovascular events. The rationale of the study, which will involve more than 800 clinical centers in Scandinavia, the United Kingdom, and the United States, is discussed, and the major features of its design and general organization are described. On April 30, 1997, when inclusion was stopped, 9,218 patients had been randomized.

Alcohol consumption and cardiovascular risk in hypertensives with left ventricular hypertrophy: the LIFE study.

The Losartan Intervention For End point reduction in hypertension (LIFE) study showed superiority of losartan over atenolol for reduction of composite risk of cardiovascular death, stroke, and myocardial infarction in hypertensives with left ventricular hypertrophy. We compared hazard ratios (HR) in 4287 and 685 participants who reported intakes of 1-7 and >8 drinks/week at baseline, respectively, with those in 4216 abstainers, adjusting for gender, age, smoking, exercise, and race. Within categories, clinical baseline characteristics, numbers randomized to losartan and atenolol, and blood pressure (BP) lowering were similar on the drug regimens. Overall BP control (<140/90 mmHg) at end of follow-up was similar in the categories. Composite end point rate was lower with 1-7 (24/1000 years; HR 0.87, P<0.05) and >8 drinks/week (26/1000 years; HR 0.80, NS) than in abstainers (27/1000 years). Myocardial infarction risk was reduced in both drinking categories (HR 0.76, P<0.05 and HR 0.29, P<0.001, respectively), while stroke risk tended to increase with >8 drinks/week (HR 1.21, NS). Composite risk was significantly reduced with losartan compared to atenolol only in abstainers (HR 0.81 95% confidence interval, CI (0.68, 0.96), P<0.05), while benefits for stroke risk reduction were similar among participants consuming 1-7 drinks/week (HR 0.73, P<0.05) and abstainers (HR 0.72, P<0.01). Despite different treatment benefits, alcohol-treatment interactions were nonsignificant. In conclusion, moderate alcohol consumption does not change the marked stroke risk reduction with losartan compared to atenolol in high-risk hypertensives. Alcohol reduces the risk of myocardial infarction, while the risk of stroke tends to increase with high intake.

Long-term experiences with minoxidil in combination treatment of severe arterial hypertension.

Thirteen patients with advanced hypertensive disease insufficiently controlled by conventional drugs were treated with minoxidil in combination with a beta-blocking agent and a thiazide in a long-term study. A reduction from 214 +/- 5/122+/3 to 166 +/- 7/95 +/- 3 mm Hg in the mean supine blood pressure was obtained. The dosage range of minoxidil was 7.5-35 mg per day (mean 18.8 mg), and in all cases beta-blockade was necessitated by the occurrence of reflex tachycardia. Only two of the patients were found to be unsatisfactorily controlled on combined therapy. In five cases, minoxidil was disontinued during the observation period, but only in three cases was the discontinuation due to side effects, v.z. sodium retention and augmented hair growth. Stable diabetes developed in one patient, and in two cases of established, dietetically treated diabetes oral antidiabetic drugs had to be administered. Five non-diabetic patients showed no significant changes in fasting plasma glucose and the K values in intravenous glucose-tolerance tests. Minoxidil seems to be a safe and potent antihypertensive drug for long-term use in severe arterial hypertension, but it cannot be recommended for routine treatment.

Role of extracellular calcium in isometric contractions of the SHR aorta. Influence of age and antihypertensive treatment.

Isometric contractions induced by noradrenaline (NA), 1.8 X 10(-5) M or by potassium (K+), 127 mM were studied in paired ring-preparations of the thoracic aortae from spontaneously hypertensive rats (SHR) and age-matched normotensive Kyoto-Wistar rats. In rats aged 8--16 weeks, NA-induced contractions were significantly more dependent on extracellular calcium in preparations from the SHR than from the NWR, whereas K+induced contractions showed no difference. Relaxation studies revealed differences between SHR and NWR also in K+-induced contractions. Comparison of responses in NWRs aged 3--4 months and 10--12 months showed a significant increment in Ca++-dependency with age. This age-related difference was less pronounced in SHRs, but the effect of blockade of Ca++-influx by nifedipine was significantly stronger in the old than in the young SHR-aorta. Treatment with propranolol or hydrochlorothiazide + timolol + minoxidil for 4--5 months caused no significant reduction of blood pressure and no change in Ca++-dependency. In contrast, treatment with verapamil (60 mg/kg/day) for 12 months resulted in a significantly lower blood pressure in the treated SHRs than in their controls. A trend towards "nomrlization" of the Ca++-dependency in verapamil treated rats was also observed. The results suggest that an increased Ca++-dependency in the SHR aortae is present already at the age of 8--16 weeks, but becomes more pronounced with age. As an age-related increment in Ca++-dependency is also found in NWRs, the results suggest that the SHR aortae are "functionally" older than the NWR vessels already in young animals. Calcium antagonists seem to be effective in lowering blood pressure in SHRs and represent a promising approach to the treatment of hypertensive vascular disease.

The experimental use of calcium antagonists in the treatment of arterial hypertension.

The role of calcium for the function of vascular smooth muscle in the spontaneously hypertensive rat (SHR) was investigated, employing calcium blockers as a pharmacological tool. In the aorta of the SHR there was evidence for an increased dependency on extracellular calcium as the diseased vessels exhibited a faster membranal turn-over of calcium than vessels from normotensive control rats. In accordance with that, the effect of nifedipine appeared to be stronger in SHR vessels than in the normotensive one. Long-term treatment of SHRs with verapamil caused significant blood pressure reductions and regression of cardiac hypertrophy. In pilot studies in man both verapamil and nifedipine proved effective in lowering blood pressure. Nifedipine appeared the better suited. Hypertensive patients responded with a dose-related drop in blood pressure 10-30 min after the sublingual administration of nifedipine whereas normotensive subjects hardly showed any change of blood pressure. Following the acute administration of nifedipine a reflex increment of sympathetic tone was seen as reflected by increase in heart rate, circulating noradrenaline and plasma renin activity. An acute diuretic and natriuretic effect was seen together with a rise in urinary uric acid excretion. During long-term therapy nifedipine was effective in lowering blood pressure but side effects were common during monotherapy. When combined with a beta-adrenoceptor blocking agent side effects were few but concomitant diuretic therapy was often necessary.

Fosinopril versus enalapril in the treatment of hypertension: a double-blind study in 195 patients.

The new angiotensin-converting enzyme (ACE) inhibitor fosinopril was compared with the ACE inhibitor enalapril in a multicenter (n = 11), multinational (Denmark, Finland, Iceland, Norway, and Sweden), double-blind, randomized, parallel-group 24-week study in 195 patients with mild to moderate essential hypertension [supine diastolic blood pressure, (SDBP) > or = 95 to < or = 110 mm Hg]. After discontinuing all previous antihypertensive medication, patients were entered into a placebo lead-in period of 4-6 weeks, followed by 24 weeks of randomized treatment with the active compounds administered with a double-dummy technique. The dose of fosinopril was 20 mg, which could be increased to 40 mg after 8 weeks (average 25.6 mg); that of enalapril was 10 mg, which could be increased to 20 mg after 8 weeks (average 12.9 mg). Hydrochlorothiazide 12.5 mg could be added after 16 weeks and was administered to 27% of the patients in the fosinopril group and to 30% in the enalapril group. All drugs were administered once daily. Supine systolic BP (SSBP) decreased from 157 to 143 mm Hg in the fosinopril group (p < 0.01), and from 159 to 147 mm Hg in the enalapril group (p < 0.01). SSDP decreased from 100 to 89 mm Hg in the fosinopril group (p < 0.01) and from 100 to 92 mm Hg in the enalapril group (p < 0.01). Throughout the study period, fosinopril reduced SSBP and SDBP numerically more than did enalapril, by 0-3 mm Hg. Adverse events (AE) caused withdrawal of study medication in 8 patients in the fosinopril group and in 14 patients in the enalapril group (NS). The number of reported AE was not statistically different in the two groups. Inhibition of the ACE was assessed in a subgroup of patients (n = 26, 13 in each group). Fosinopril caused a greater inhibition of ACE at the doses used in the present study, which was statistically significant. Both fosinopril and enalapril caused statistically significant reductions in BP of a similar magnitude, and both agents were well tolerated. However, fosinopril was consistently numerically slightly more effective than enalapril in reducing BP. There were fewer withdrawals due to AE (NS) in the fosinopril group, and the overall recorded AE were fewer in the fosinopril group (NS).

Renal effects of pinacidil in hypertensive patients on chronic beta-blocker therapy.

The acute and chronic effects of pinacidil on blood pressure (BP) and renal function were investigated in 10 patients with moderate arterial hypertension insufficiently controlled by chronic beta-blockade. Acute i.v. administration of pinacidil caused a significant fall in BP of 29.9/18.3 mm Hg and, despite beta-blockade, a concomitant rise in heart rate (HR) of 21%. Renal vascular resistance (RVR) showed a marked reduction as a consequence of the fall in BP, and a transient rise in renal plasma flow (RPF). Diuresis and renal clearance of sodium and uric acid showed a parallel fall. The excretion rates of albumin and beta 2-microglobulin were also significantly reduced. Pharmacokinetic studies indicated that glomerular filtration was responsible for elimination of the parent drug, and that proximal tubular secretion was the pathway of excretion of the main metabolite, pinacidil pyridine-N-oxide. During therapy for 4 months there was no further significant reduction in BP, despite increases in the daily dose of pinacidil. The effects on HR were less conspicuous after 4 months; renal haemodynamic parameters and body weight were not significantly changed. The initial level of RVR and the initial acute reduction in this parameter appeared to be major determinants of the long-term BP response. The drug was well tolerated apart from one patient who developed slight fluid retention. However, concomitant administration of a diuretic will probably be necessary during routine use of this therapeutic combination.

Acute natriuretic effect of nifedipine in hypertensive patients and normotensive controls--a proximal tubular effect?

The acute effects of buccal nifedipine 20 mg on blood pressure, renal haemodynamics and electrolyte excretion were compared in 16 untreated patients (HT) with uncomplicated arterial hypertension (WHO I-II), 11 normotensives (NT) and 6 normotensives given a placebo. Nifedipine caused a significant fall in the systolic and diastolic blood pressures (BP) of 25.7 +/- 12/26.5 +/- 10 mmHg in the hypertensives, and a minor but significant fall in diastolic BP in the normotensives. Renal vascular resistance fell significantly and renal plasma flow was increased non-significantly in the hypertensives. No changes in these parameters were seen in NT. Glomerular filtration rate remained constant in all groups, also in HT despite the marked haemodynamic changes. Natriuresis was significantly increased to the same degree in the HT and NT groups, in spite of their different haemodynamic responses. Uric acid excretion showed a parallel acute increase in both groups. The significant and close relationship between the acute changes in the excretion of sodium and uric acid provides evidence for a proximal tubular natriuretic effect of nifedipine.

Verapamil and nifedipine inhibition of contractions induced by potassium and noradrenaline in human mesenteric arteries and veins.

Ring preparations of human mesenteric arteries and veins were contracted by noradrenaline (1.8 x 10(-5)M) or potassium (127mM). Isometric tension was recorded. In the arterial preparations, the maximum response to noradrenaline was 97 +/- 8% (mean +/- S.E.M.) of that to potassium. In the veins, the corresponding figure was 38 +/- 4%. The calcium antagonists verapamil (2.2 x 10(-7)-2.2 x 10(-5)M) and nifedipine (2.9 x 10(-8)-2.9 x 10(-6)M) relaxed both arteries and veins contracted by noradrenaline or potassium, and reduced the responses to these agents when added 15 min. before stimulation. The time course of relaxation of potassium contracted preparations, induced by verapamil and nifedipine, was more rapid and complete than that produced by a calcium-free, high potassium solution. In contrast to verapamil, nifedipine caused a more pronounced inhibition of the potassium than of the noradrenaline evoked contractions in both arteries and veins. After exposure to a calcium-free medium for 30 min., the arterial response to noradrenaline was significantly (P less than 0.05) greater than that to potassium. However, the reverse was found in the veins. In both types of vessel, verapamil (2.2 x 10(-6)M) and nifedipine (2.9--10(-7)M) were equi-effective in reducing the noradrenaline reactivity, not only between mesenteric arteries and veins, but also between, e.g. peripheral and mesenteric vessels. The calcium antagonists nifedipine and verapamil do not have an identical mode of action. However, both agents seem to inhibit influx of extracellular calcium, and might also have an inhibitory effect on the release of intracellular calcium.

Effects of extracellular calcium on potassium and noradrenaline induced contractions in the aorta of spontaneously hypertensive rats--increased sensitivity to nifedipine.

Isolated preparations of the thoracic aorta from spontaneously hypertensive rats (SHR) and normotensive Wistar rats (NWR) were contracted by noradrenaline (NA) 1.8 X 10(-5)M, and potassium (K+) 127 mM, after 30 min. pretreatment in a Ca++-free medium. In both SHR and NWR aortae, the contractions were markedly reduced; no significant differences were found between the two types of vessels in Ca++-free medium. On addition of Ca++, the contractions were restored to a significantly greater extent in the NWR than in the SHR aortae. In the presence of nifedipine 7.2 X 10(-9)M, the response to Ca++ was significantly more reduced in the SHR than in the NWR preparations. Relaxation of NA and K+ contracted preparations was induced by wash-out of the contractile agents, by addition of nifedipine 2.9 X 10(-8)M, and by introduction of a Ca++-free medium. After wash-out of NA, relaxation was slower in SHR than in NWR vessels. Relaxation induced by nifedipine and Ca++-free medium was more complete in SHR than in NWR preparations. After wash-out of K+, relaxation was more rapid in NWR than in SHR aortae. Nifedipine and Ca++-free medium induced relaxation was more complete in SHR than in NWR preparations. The results suggest that in the SHR aortae contraction induced by NA and K+ is more dependent on extracellular Ca++ than is the response in the NWR preparations; the SHR vessels are also more sensitive to the relaxing effects of nifedipine.

Abrupt withdrawal of beta-blocking agents in patients with arterial hypertension. Effect on blood pressure, heart rate and plasma catecholamines and prolactin.

Chronic treatment with beta-blockers was interrupted abruptly in six patients with arterial hypertension. Three patients, who had experienced symptoms during a previous withdrawal, again complained of transient palpitations, tremor, sweating, headache and general malaise. A significant increase in standing blood pressure (BP) and heart rate (HR) was noted after 24 h. The standing HR reached a maximum after 48 h and had decreased significantly on the 7th day (p less than 0.005). There was a strong tendency to greater increase in standing BP and HR in the patients who experienced symptoms than in those who did not. Plasma concentrations of noradrenaline, adrenaline and prolactin did not change significantly. Thus, beta-blocker withdrawal symptoms are reproducible and are indicative of a transient sympathetic hyperresponse. The increased activity is not likely to be caused by increased production of circulating catecholamines, but rather by increased sensitivity of the beta-receptor.

Long-term therapy of arterial hypertension with nifedipine given alone or in combination with a beta-adrenoceptor blocking agent.

The antihypertensive effect of nifedipine during long-term therapy was investigated in 5 patients receiving nifedipine as the sole drug and in 10 patients who had nifedipine in combination with a beta-adrenoceptor blocking drug. Nifedipine monotherapy was problematic because of side-effects and development of resistance to therapy after a few months. In patients who received the combined therapy significant and stable blood pressure reductions were maintained during the whole observation period (12-33 months). However, the occurrence of peripheral oedema in 4 of the patients necessitated the addition of a thiazide diuretic. It is concluded that nifedipine is not a first choice drug for the long-term treatment of arterial hypertension. When given in addition to a beta-blocker it is well tolerated and powerful but fluid retention may occur and if not counteracted by a diuretic it will limit the antihypertensive potential of the drug.