Lisinopril versus lisinopril plus hydrochlorothiazide in essential hypertension

The efficacy of a new angiotensin converting enzyme inhibitor, lisinopril, used alone (group A) was compared with lisinopril plus hydrochlorothiazide (group B) in 26 patients with essential hypertension. Therapy with both regimens was equally effective in lowering blood pressure compared to placebo. Mean antihypertensive dose of lisinopril was lower when given in combination with hydrochlorothiazide than when given alone (48 +/- 6 vs 68 +/- 12 mg daily). Plasma renin activity increased in both groups of patients, but more in group B (p less than 0.05). Plasma aldosterone concentrations and serum uric acid levels were also higher in the group receiving lisinopril plus hydrochlorothiazide (p less than 0.05). Serum potassium concentrations were unaffected in either group. The incidence of side effects was similar in groups A and B (44% and 38%, respectively). This study suggests that lisinopril alone or in combination with hydrochlorothiazide effectively lowers blood pressure in patients with essential hypertension without any major side effects.     

Acute and long-term hemodynamic effects of tiapamil at rest and during exercise in essential hypertension

Summary The first dose and long-term hemodynamic responses to tiapamil—an aralkylamide calcium- channel blocker—were studied both at rest and during exercise in 18 male patients (mean age, 45 years) with essential hypertension (EH). Blood pressure (BP) was measured intra-arterially, cardiac output (CO) was measured by dye dilution and heart rate (JR) was measured by electrocardiogram. One hour after the first oral dose of 600 mg tiapamil, mean arterial pressure (MAP) fell 14%. Total peripheral resistance (TPR) fell 21%, while HR and CO increased 7% and 11%, respectively. There-after the effects leveled off. After 11 months of chronic tiapamil therapy (mean dose 980 mg per day), MAP was reduced 11% at rest sitting. The reduction in BP was associated with a modest reduction in TPR. Similar responses were seen at rest supine and during 100-W bicycle exercise. A small reduction was seen in HR while CO was preserved. In conclusion, tiapamil exerts a moderate antihypertensive effect, both at rest and during exercise, through reduction of TPR without a fall in heart pump function. The long-term hemodynamic changes are rather similar to those of verapamil.     

Is sodium restriction effective treatment of borderline and mild essential hypertension? A long-term haemodynamic study at rest and during exercise

Blood pressure (BP) may fall during moderate sodium restriction in patients with essential hypertension (EH). Few data are available on the haemodynamic changes associated with sodium restriction and exercise data are lacking. We studied the long-term haemodynamic effect of reduced sodium intake in 19 men aged 16-51 years with mild and borderline EH. Cardiac output (CO; by Cardiogreen) and intra-arterial BP were measured at rest and during exercise before and after 9 months therapy. Sodium excretion was reduced by 75 mmol/24 h (36%) from a mean of 209 mmol/24 h and the sodium:potassium (Na:K) ratio fell by 0.75 from 2.17. Intra-arterial pressures fell by 3-5% (P less than 0.05) at rest, both supine and sitting, and during 50, 100 and 150 W bicycle exercise. Body weight and body fluid volumes (isotope dilution) remained unchanged. Haemodynamically, the fall in BP was due to reduction in CO ranging from 7-12% at rest and during exercise, while total peripheral resistance (TPR) rose by 4-10%. Stroke volume and heart rate fell by 2-9%. We conclude that moderate sodium restriction was not an efficient treatment in our patients with borderline and mild EH. The slight reduction in BP was associated with a fall in CO but without reduction of TPR. Thus, the main haemodynamic disturbance of established EH, that is an increase in TPR, was not normalized by 9 months sodium restriction.     

Acute haemodynamic effects of carvedilol in essential hypertension at rest and during exercise

The acute haemodynamic effect of carvedilol, a new non-selective beta-receptor blocker with vasodilating effect, was examined at rest supine and sitting and during 100 W bicycle exercise in 18 patients (mean age 44 years) with essential hypertension. Intra-arterial blood pressure and heart rate were recorded continuously. Cardiac output was measured by dye dilution (Cardiogreen). Two h after the first oral dose (12.5-25 mg) of carvedilol, blood pressure was reduced in all patients sitting at rest, from 176/110 to 153/101 mmHg (P less than 0.001), associated with a reduction in cardiac index (16%; P less than 0.001) while total peripheral resistance remained unchanged or was slightly reduced. When sitting up after 2 h supine rest two patients had hypotensive reactions (excessive blood pressure drop; cold, pale, sweating skin) which disappeared after lying down with elevation of the legs and light physical exercise. The fall in cardiac index was due to reduction both in heart rate (8%, P less than 0.001) and stroke index (9%; P less than 0.01). During exercise the reduction in cardiac output was less (6%; P less than 0.05) while a clear reduction (6%; P less than 0.01) was seen in total peripheral resistance. This acute haemodynamic response is different from that seen immediately after conventional beta-blockers when total peripheral resistance always increases.     

Acute haemodynamic effects of perindoprilat in essential hypertension at rest and during exercise

The acute haemodynamic effect of perindoprilat was examined at rest, supine and sitting, and during 100 W bicycle exercise in 12 patients (mean age 42 years) with essential hypertension. Intra-arterial blood pressure and the heart rate were recorded continuously. Cardiac output was measured by dye dilution (Cardiogreen) and blood volume was determined by radio-iodinated (125I) human serum albumin. Two hours after a slow (3 min) intravenous injection of perindoprilat, blood pressure was reduced in all patients (P less than 0.01)--at rest sitting from 175/108 to 153/97 mmHg (11%)--because of reduction in total peripheral resistance index (f = 2.63; P less than 0.05). Only minor changes were seen in the heart rate, stroke index and cardiac output. The fall in blood pressure was significantly (P less than 0.05) correlated with blood volume (r = 0.65) and pretreatment total peripheral resistance index (r = 0.59).     

Long-term haemodynamic effects of amlodipine at rest and during exercise in essential hypertension

The long-term haemodynamic responses to amlodipine, a new long-acting calcium antagonist, were studied both at rest and during exercise in 18 patients (mean age 43 years) with essential hypertension. Blood pressure was measured intra-arterially, cardiac output by dye dilution and heart rate by electrocardiogram. After 11 months of treatment with 5-10 mg amlodipine once daily (mean dose 9 mg/day), mean arterial pressure was reduced by 14% sitting at rest. The reduction in blood pressure was associated with a marked reduction in the total peripheral resistance index (TPRI) of 19% (P less than 0.001). Similar responses were seen supine at rest and during 50W, 100W and 150W bicycle exercise. No significant changes were seen in heart rate. There was a slight increase in stroke index, and cardiac index was preserved at rest and during exercise with a slight trend towards an increase. In 10 of the patients, blood pressure was monitored by a portable blood pressure recorder (Accutracker II, Suntech Medical instruments, Raleigh, North Carolina, USA). Blood pressure was well controlled throughout the full 24 h period after one daily dose. In conclusion, amlodipine exerts a clear antihypertensive effect, both at rest and during exercise, through reduction in the TPRI and without a fall in cardiac pump function. No changes in heart rate were seen and there was no tendency for a reduction in the stroke index during 8 min of exercise at 150 W; on the contrary there was a trend towards an increase. The incidence of side-effects was low (ankle oedema in two patients).     

Combined captopril and hydrochlorothiazide therapy in severe hypertension: long-term haemodynamic changes at rest and during exercise

Captopril is an orally active converting enzyme inhibitor lowering blood pressure (BP) in different types of hypertension. A combination of captopril and a diuretic is often used in the treatment of severe hypertension. We have examined the chronic haemodynamic effect of combined captopril and hydrochlorothiazide treatment at rest and during 50 and 100 W dynamic exercise in 12 patients with severe therapy resistant essential hypertension. Blood pressure was measured intra-arterially before and after a mean treatment period of 8.7 months. Cardiac index (CI) was measured by dye dilution (Cardiogreen) and body fluid volumes by radioisotope dilution techniques. During rest sitting BP was reduced by 31/17 mmHg (15%) from a pretreatment value of 205/119 mmHg. Total peripheral resistance index (TPRI) fell 17% whereas CI, heart rate (HR) and stroke index (SI) did not show any significant changes. The fall in mean arterial pressure (MAP) was slightly less during exercise (12%) and the BP reduction was associated with a fall in CI and SI of 15 and 17%, respectively and no fall in TPRI. No significant changes were observed in body fluid volumes.     

Chronic haemodynamic effects of carvedilol in essential hypertension at rest and during exercise.

Nineteen men (mean age 44 years) with essential hypertension, WHO stage I, were studied invasively at rest and during exercise. Blood pressure was recorded intra-arterially (brachial artery), cardiac output by dye dilution method and heart rate by electrocardiography. After initial pre-drug recordings, the patients received 25 mg carvedilol orally and central haemodynamics at rest and during exercise were recorded 1 and 2 h after tablet intake to evaluate the immediate effects of carvedilol. The results indicated a combined beta-blocking and vasodilating effect. After 6-9 months of treatment, supine haemodynamics were recorded 12-24 h after the last dose and then 1 and 2 h after an additional 25 mg dose. During chronic treatment (2 h after last dose at rest supine) mean arterial pressure was reduced by 17% (P less than 0.001) and total peripheral resistance index by 6% (NS) while heart rate and cardiac index were reduced by 12%. Exercise haemodynamics demonstrated a fall in blood pressure of 17% (P less than 0.001). Exercise stroke index increased by 5% (NS), partly compensating for the reduction in heart rate of 17%. Total peripheral resistance index was reduced by 5% (NS). It is concluded that carvedilol is an effective anti-hypertensive agent in a large proportion of patients with essential hypertension. The haemodynamic mode of action reflects an alpha 1-blocking activity, particularly in situations with low sympathetic tone. During exercise the beta 1-blocking activity (demonstrated by the reduction in heart rate) is more prominent.     

Subacute hemodynamic effects of nebivolol in man at rest and during exercise

In a subacute experiment 7 apparently healthy volunteers received a daily oral dose of 5 mg nebivolol for seven days, followed by a seven-day washout period with placebo. From the first day during treatment with nebivolol, peak exercise heart rate and systolic blood pressure, as measured during a standardized submaximal treadmill exercise, significantly decreased by 15% and 19% respectively. A prolonged treatment for one week did not further increase the response of exercise heart rate and systolic blood pressure to nebivolol. However, the ratio of preejection period (PEPc) to left ventricular ejection time (LVETc), an indirect and valuable measure of left ventricular performance, progressively and significantly decreased during the seven-day treatment period with nebivolol from a mean value of 0.37 +/- 0.012 to 0.31 +/- 0.009. The improvement of systolic time intervals resulted from a shortening of the PEPc and a lengthening of the LVETc. At rest, heart rate did not change significantly with nebivolol, whereas both systolic and diastolic blood pressure gradually and significantly lowered. The postexercise LVETc significantly shortened during treatment with nebivolol, and this shortening was more pronounced after seven days of treatment. After discontinuation of treatment with nebivolol, all these effects persisted for more than thirty hours after the last intake and gradually returned to pretreatment values thereafter. From these data it appears that nebivolol effectively reduces blood pressure at rest and during exercise in healthy volunteers, beneficially influencing preload and afterload, as measured by systolic time intervals.(ABSTRACT TRUNCATED AT 250 WORDS)     

Long-term hemodynamic effects at rest and during exercise of newer antihypertensive agents and salt restriction in essential hypertension: Review of epanolol,doxazosin, amlodipine,felodipine, diltiazem,lisinopril, dilevalol,carvedilol, and ketanserin

Summary Hypertension is due to disturbance of the complex interplay between numerous known and unknown mechanisms that normally control blood pressure. Antihypertensive agents may, therefore, reduce blood pressure through widely different actions and, at the same time, elicit counterregulatory responses. This is a review of the long-term hemodynamic effects at rest as well as during exercise of nine relatively new antihypertensive compounds: a beta-blocker (epanolol), an alpha-receptor blocker (doxazosin), two double-acting compounds (dilevalol and carvedilol), three calcium antagonists (amlodipine, felodipine, and diltiazem), an angiotensin-converting enzyme inhibitor (lisinopril), a serotonin antagonist (ketanserin), and low-salt diet as a nonpharmacological treatment in 171 patients with mild to moderate essential hypertension. The results in the treatment groups are compared to the hemodynamic changes seen in 28 hypertensive patients left untreated for 10 years. The patient populations of the different groups were comparable. The invasive hemodynamic technique, including intraarterial blood pressure recording and measurements of cardiac output by Cardigreen, was the same in all studies. While blood pressure remained nearly unchanged in the untreated group, all antihypertensive compounds induced significant and sustained blood pressure reduction both at rest and during exercise. The modest reduction (3–5%) in blood pressure during a low-salt diet was also statistically significant. This review shows the multiplicity of the long-term hemodynamic changes, ranging from a reduction in cardiac output to peripheral vasodilatation, during chronic antihypertensive therapy. In untreated hypertensives, the cardiac output is reduced by 1–2% per year and total peripheral resistance is increased by 2–3% per year. The review also focuses on counterregulatory responses that modify the initial reduction in blood pressure after drug treatment for hypertension. It is concluded that proper understanding of the hemodynamic effects of antihypertensive agents is useful in the selection of the right treatment for specific groups of hypertensive patients.     

In-vivo intracellular pH at rest and during exercise in patients with essential hypertension

BACKGROUND : Several studies in isolated cells have reported that intracellular pH (pHi) in individuals with essential hypertension may be relatively alkaline compared to normotensive individuals. Such an abnormality of pHi in hypertension would be consistent with enhanced sodium-hydrogen exchanger activity and may provide potential mechanisms by which hypertension and its complications could develop. OBJECTIVES : To determine in-vivo intracellular pH of skeletal muscle at rest and during recovery from exercise-induced acidosis in hypertensive and normotensive subjects. METHODS : Using 31-phosphorus magnetic resonance spectroscopy, pHi of the dominant flexor digitorum superficialis was measured in 20 Caucasian subjects (14 male) with essential hypertension and 20 normotensive controls matched for gender, age, race and body mass index. Measurements were made at rest and during the exercise and recovery periods of a stepped incremental maximal exercise protocol. The rate of pHi recovery from exercise-induced acidosis was calculated by linear regression over the first 210 s of recovery from the pHi time plots of respective subjects. RESULTS : Mean resting pHi in the hypertensive (7.05 +/- 0.04) and normotensive groups (7.06 +/- 0.04) were not significantly different. There was a significant effect of gender on pHi: mean pHi was 7.07 +/- 0.03 in males and 7.02 +/- 0.03 in females, respectively (P < 0.0005). The mean intracellular pH achieved by exercise was 6.74 +/- 0.31 in hypertensive individuals and not significantly different in normotensive individuals (6.68 +/- 0.19; P = 0.4). The mean rate of pHi recovery in the hypertensives was 0.08 +/- 0.03 pH units/min and not significantly different in normotensives (0.08 +/- 0.02; P = 0.4). CONCLUSIONS : These results contrast with previously documented abnormalities in the control of pHi in hypertension and demonstrate the absence of major in-vivo disturbances of pHi in skeletal muscle, both at rest and during recovery from exercise-induced acidosis, in essential hypertension. Therefore, it is possible that previously documented abnormalities of pHi and activity of the exchanger may be either specific to cell type or not present under in-vivo conditions.     

Relation of cardiac output at rest and during exercise to age in essential hypertension

It has been suggested that the decline of cardiac output with age is due to increased prevalence of disease, particularly occult coronary artery disease. Therefore, the relation of cardiac output (direct oxygen Fick method) to age was analyzed in 110 sixteen- to 64-year-old men with World Health Organization stage I or II essential hypertension at the time of the hemodynamic study, who were alive and free of cardiovascular complications 7 years later. At supine and seated rest, during upright bicycle exercise at 50 W and and at peak work load, cardiac output was inversely (p less than 0.01) related to age. These relations were independent of weight and mean intraarterial pressure. Stroke volume decreased with advancing age at supine rest, but not at rest and during exercise in the seated position. Heart rate was not affected by age in the supine position, but was slower in older patients during upright rest and at peak exercise. In conclusion, in patients with essential hypertension who remained free of cardiovascular complications for 7 years, cardiac output was independently and inversely related to age at various levels of activity. These findings suggest that occult cardiovascular disease does not explain the decline in cardiac output with age in patients with essential hypertension.     

Diltiazem versus propranolol in essential hypertension: responses of rest and exercise blood pressure and effects on exercise capacity

Both beta-blocking and calcium channel-blocking drugs are being used with increasing frequency as initial therapy for essential hypertension. The present study was designed to compare the antihypertensive effects of a beta-blocking drug, propranolol, with a calcium channel-blocking drug, diltiazem, at rest and during upright bicycle exercise and to determine whether exercise capacity is altered by these therapies. Twenty-one patients with uncomplicated systemic hypertension and a diastolic blood pressure (BP) of 95 to 110 mm Hg without medication were randomly assigned to propranolol or diltiazem therapy in a double-blind manner. The total daily dosages were titrated as needed, from 160 to 480 mg of propranolol (mean 371 mg) and 120 to 360 mg of diltiazem (mean 307 mg) over 12 weeks, and the titrated dose was maintained for 4 additional weeks. Both drugs significantly reduced supine BP (from 149 +/- 14/101 +/- 4 to 136 +/- 17/89 +/- 10 mm Hg with propranolol and from 157 +/- 14/103 +/- 4 to 144 +/- 13/93 +/- 8 with diltiazem. Only diltiazem reduced BP during submaximal exercise, but both agents produced significant responses during maximal exercise. Diltiazem had no effect on maximal heart rate, exercise duration or O2 uptake, whereas propranolol reduced maximal VO2 from 27 +/- 6 to 22 +/- 6 ml/min/kg (p less than 0.01) and also shortened duration of exercise. Propranolol, despite its effects on heart rate, maintained the workload VO2 relation at submaximal loads, suggesting an increased oxygen delivery. However, these adaptive mechanisms appear to be insufficient during maximal effort.     

Hemodynamic effects of aerosolized iloprost in pulmonary hypertension at rest and during exercise

STUDY OBJECTIVES: Aerosolized iloprost, a stable prostacyclin analog, improves functional capacity even in patients with pulmonary hypertension who did not show a vigorous hemodynamic response after iloprost inhalation at rest. We therefore speculated that aerosolized iloprost elicits more beneficial effects on pulmonary hemodynamics during exercise than at rest. DESIGN AND SETTING: A prospective, open, uncontrolled study at a university hospital. PATIENTS: Sixteen patients with primary or secondary pulmonary hypertension. INTERVENTIONS: Right-heart catheterization at rest and during exercise before and after the inhalation iloprost, 14 to 28 microg. RESULTS: Before iloprost treatment, exercise increased mean (+/- SD) pulmonary artery pressure (PAPm) from 45 +/- 8 to 70 +/- 13 mm Hg, cardiac output from 3.7 +/- 1.0 to 5.8 +/- 2.4 L/min, and pulmonary vascular resistance (PVR) from 904 +/- 322 to 1,013 +/- 432 dyne.s.cm(-5) (each p < 0.05). After recovery, iloprost reduced PAPm from 44 +/- 8 to 41 +/- 6 mm Hg, increased cardiac output from 3.7 +/- 1.0 to 4.9 +/- 1.4 L/min, and lowered PVR from 902 +/- 350 to 636 +/- 248 dyne x s x cm(-5) (each p < 0.05). During exercise after iloprost, PAPm increased to 57 +/- 8 mm Hg, cardiac output to 7.0 +/- 3.0 L/min, and PVR to 673 +/- 279 dyne x s x cm(-5) (each p < 0.05 vs first exercise test). Systemic BP was not altered significantly by iloprost treatment during exercise. CONCLUSIONS: Aerosolized iloprost treatment exerts more favorable effects on pulmonary hemodynamics during exercise than at rest. These findings explain the functional improvement observed in patients with pulmonary hypertension who show only a moderate pulmonary vasodilatory response during iloprost inhalation at rest. Whether these beneficial effects have prognostic significance needs to be elucidated by further study.     

Hemodynamic effects of nifedipine at rest and during exercise in primary pulmonary hypertension

The potential short-term pulmonary vasodilator effect of a calcium-channel blocker, nifedipine, was tested in seven patients with primary pulmonary hypertension. Nifedipine (20 mg) produced a significant (p less than 0.01) and persistent decrease in mean pulmonary arterial pressure (58.1 +/- 14.3 to 48.6 +/- 16.3 mm Hg) and pulmonary vascular resistance (1,070 +/- 260 to 695 +/- 266 dynes X sec X cm-5). Cardiac index increased from 2.5 +/- 0.6 to 3.3 +/- 0.8 L/min/m2 (p less than 0.01), and heart rate was unchanged despite a fall in systemic pressure. In three patients tested during exercise on a bicycle, nifedipine resulted in an increase in the duration of exercise in two and a blunting of the exercise-induced increase in pulmonary pressure in all three. Long-term treatment was initiated in five of the seven patients and in two additional patients who did not receive nifedipine in the short-term study; all but one experienced symptomatic improvement. A persistent hemodynamic improvement was observed in three of the four patients restudied after long-term therapy. In conclusion, this study demonstrated the short-term beneficial hemodynamic effects of nifedipine, both at rest and during exercise. A more extensive long-term follow-up is necessary to establish the usefulness of this drug in the treatment of primary pulmonary hypertension.     

Comparison of lisinopril versus atenolol for mild to moderate essential hypertension.

The antihypertensive effects and safety profiles of lisinopril (10 to 40 mg) and atenolol (50 to 100 mg) were compared in a randomized, double-blind, parallel group trial in 144 patients with essential hypertension. After 8 weeks of therapy, seated blood pressure (BP) decreased by 26/15 mm Hg with lisinopril and by 19/14 mm Hg with atenolol. Lisinopril produced a greater reduction (p less than 0.05) in sitting systolic BP than did atenolol. Standing BP decreased by 25/15 mm Hg with lisinopril and by 19/14 mm Hg with atenolol. No important changes in hematologic and biochemical profiles were seen with either drug. Eleven patients, 7 receiving lisinopril and 4 receiving atenolol, were withdrawn because of adverse experiences; another 3 patients defaulted during treatment, 1 in the lisinopril group and 2 in the atenolol group. Both drugs were well-tolerated and are therefore suitable for first-line therapy in essential hypertension.     

Effect of timolol plus hydrochlorothiazide plus hydralazine on essential hypertension.

The effect on hypertension of hydrochlorothiazide 100 mg daily plus timolol 20-60 mg daily versus hydrochlorothiazide plus placebo and of hydrochlorothiazide plus timolol plus hydralazine 40-200 mg daily versus hydrochlorothiazide plus placebo plus hydralazine was evaluated in a double-blind, randomized, crossover study in 38 patients with hypertension. Hydrochlorothiazide plus timolol was more effective than hydrochlorothiazide plus placebo in lowering both supine and standing systolic and diastolic blood pressures. Hydrochlorothiazide plus timolol plus hydralazine was a very effective regimen in lowering both supine and standing systolic and diastolic blood pressure. The patients tolerated this regimen well with greater hypotensive activity and a lower incidence of side effects than on hydrochlorothiazide plus placebo plus hydralazine.