Long-term Antihypertensive Therapy Research Articles

Dose optimization study of arterial changes associated with angiotensin converting enzyme inhibition in hypertension

In treating hypertension the optimal dose of angiotensin converting enzyme (ACE) inhibitor is derived from dose-response curves that relate the quantity of drug taken to the resulting fall in blood pressure; the blood pressure fall reflects a decrease in vascular resistance and hence, a degree of arteriolar vasodilation. However, ACE inhibition dilates not only the small arteries but also the larger calibre arteries, which increases compliance. Given the differences in structure and function of large and small arteries, the optimal drug dose for a given vessel may differ according to the size and structure of the vessel. DOSE-RESPONSE EFFECTS IN CLINICAL STUDIES: Clinical studies indicate that in the brachial artery territory, larger doses are required to obtain arterial dilation than to produce a decrease in vascular resistance. In the aorta, an improvement in arterial compliance and distensibility is governed both by the fall in blood pressure and the drug dose. Finally, for the femoral artery, the degree of arterial dilation is influenced markedly only by the drug dose. An understanding of the drug dose required to produce a given change in the hypertensive arterial system may have important implications for the control of blood pressure. For a given mean arterial pressure, systolic blood pressure is lower and diastolic blood pressure higher when aortic compliance is increased, a haemodynamic change commonly seen following ACE inhibition. Recent double-blind studies have shown that ACE inhibitors produced a more pronounced decrease in systolic than diastolic blood pressure. These findings indicate that the optimum doses required to improve the arterial wall in large arteries must be evaluated by long-term antihypertensive therapy.

The effects of temocapril, a new angiotensin converting enzyme inhibitor, on the quality of life in hypertensive patients

A multicenter open study was performed to evaluate the hypotensive efficacy, safety, usefulness, and influence on quality of life of temocapril administered alone for 6 months. Sixty-two patients with essential hypertension, including 33 patients age 65 or older, were enrolled in the study. Of these 62 patients, 4 withdrew from treatment because of side effects, 1 because of insufficient hypotensive effects, and 2 for personal reasons. Temocapril, given at a dosage of 1 to 8 mg/day, produced a dose-dependent reduction in blood pressure without changing the pulse rate. Sufficient blood pressure reduction was achieved at the end of the study in 87.7% of the patients. Quality of life, as assessed by the attending physicians, was rated as “improved” in 67.9% of the patients. Significant improvements in mean quality-of-life scores were noted in “general symptoms,” “work performance and satisfaction,” “physical symptoms and general well-being,” “sleep,” “emotional state,” “self-control,” and “vitality.” Side effects occurred in 7 (11.5%) patients, including cough in (4.9%) 3. In the patients age 65 and older, significant improvement was obtained in “general symptoms,” “work performance and satisfaction,” “physical symptoms and general well-being,” and “emotional state.” These results indicate that long-term antihypertensive therapy with temocapril alone is useful for treating essential hypertension, even in elderly patients. In addition, this therapy has favorable effects on the patients' quality of life.

Effects of sustained-release nicardipine on regression of left ventricular hypertrophy in systemic hypertension

The effects of a sustained-release formulation of the calcium antagonist nicardipine on left ventricular (LV) mass, Doppler transmitral velocity profiles and plasma neurohumoral studies were analyzed in patients with mild to moderate systemic hypertension. A double-blind placebo control phase in 28 patients was carried out for 6 weeks with a subgroup of 13 subsequently entering an open-label long-term phase for 1 year. Nicardipine produced a significant decrease in systolic and diastolic pressure over the 6-week phase (158 ± 15 to 142 ± 9 mm Hg, and 100 ± 5 to 89 ± 9 mm Hg, respectively, both p < 0.001). No significant differences in Doppler measures of mitral inflow or echocardiographic measures of LV function, wall thickness or mass were noted in the 6-week phase of the study. Although nicardipine increased both norepinephrine and renin values after the first dose, these levels had returned to baseline in most patients after 6 weeks. In addition, there was no evidence for stimulation of adrenomedullary activity because nicardipine had no effect on epinephrine or dopamine-B-hydroxylase levels at first dose or after 6 weeks. In the 13 patients treated for 1 year, systolic and diastolic pressure remained significantly decreased compared with pressure before therapy (135 ± 9 vs 147 ± 15 mm Hg, and 85 ± 6 vs 97 ± 9 mm Hg, both p < 0.01). Concomitantly, both septal and posterior wall thickness decreased significantly (12.4 ± 1.5 to 10.7 ± 1.7 mm, and 11.0 ± 1.4 to 9.9 ± 1.7 mm, both p < 0.02) over 1 year as did LV mass index (150 ± 28 to 127 ± 31 g/m 2, p < 0.02). Importantly, no change was noted in LV cavity size, demonstrating that LV mass reduction was due solely to regression of hypertrophy. Doppler mitral inflow patterns were minimally affected with an increase in atrial velocity time integral. These results demonstrate that regression of LV hypertrophy takes place with long-term antihypertensive therapy with nicardipine, and this may be possible, in part, because of the lack of sustained neurohumoral stimulation by this agent.

Medical Repair of Hypertensive Left Ventricular Remodeling

Hypertensive left ventricular (LV) hypertrophy leads to myocytic hypertrophy, interstitial fibrosis, and structural alterations of the coronary microcirculation. This structural remodeling of the myocardium results in an impairment of diastolic function of the left ventricle and of coronary flow reserve despite normal epicardial arteries. Consequently, an antihypertensive treatment should aim at (a) reversing myocytic hypertrophy, (b) regression of myocardial fibrosis, and (c) improvement of coronary flow reserve apart from blood pressure lowering. In recent years many clinical studies have shown that regression of hypertensive hypertrophy can be induced by long-term treatment with angiotensin-converting enzyme (ACE) inhibitors, calcium-channel blockers, beta-receptor blockers, and antisympathonic drugs. However, vasodilators and diuretics, which stimulate adrenoceptor activity and increase angiotensin II levels, were found to be less effective in reversing LV hypertrophy. The trophic influence of catecholamines and angiotensin II on the myocardium counteracts the effect of systolic wall stress reduction due to blood pressure lowering. In respect of reversal of interstitial fibrosis, ACE inhibitors seem to be effective because the growth of fibroblasts was found to be stimulated by angiotensin II. Recently, clinical studies have confirmed previous experimental data that an improvement of the impaired coronary vasodilator reserve can be realized by long-term antihypertensive therapy. An antihypertensive treatment strategy which fully restores myocardial structure and completely repairs coronary microcirculation has to be considered as a causative treatment of hypertensive heart disease.

47. Effects of discontinuation of long-term antihypertensive therapy on blood pressure and left ventricular mass

47. Effects of discontinuation of long-term antihypertensive therapy on blood pressure and left ventricular mass

EVIDENCE FOR A ROLE FOR THE CARDIOVASCULAR AMPLIFIERS IN HUMAN PRIMARY HYPERTENSION

1. Hypertrophy of vascular and cardiac smooth muscle is present in human primary hypertension. The amplifier properties associated with hypertrophy play a major role in maintaining hypertension. 2. Long-term antihypertensive drug therapy causes substantial regression of the structural changes, assessed by the non-autonomic component of vascular resistance, and by left ventricular mass. The latter occurs more slowly. 3. The more complete the reversal of left ventricular hypertrophy, the more slowly hypertension redevelops if long-term antihypertensive therapy is discontinued. 4. Subjects who redevelop hypertension more rapidly tend to have higher cardiac output, suggesting that the cardiac amplifier may play a role in the pathogenesis. 5. Studies of small arteries and of veins from patients with primary hypertension suggest that there may be a general disturbance of vascular smooth muscle function, independent of the mechanical effects of elevated systemic blood pressure.

Significance of Cardiovascular Hypertrophy in the Development and Maintenance of Hypertension

The amplifier properties associated with the structural changes in the heart and resistance vessels in chronic hypertension together play a major role in maintaining the elevated blood pressure (BP) in chronic hypertension, which is greater than that of the initiating cause. In patients with primary hypertension, long-term antihypertensive drug therapy causes substantial regression of the structural changes, as assessed by normalization of the total peripheral resistance (including the nonautonomic component) and of the left ventricular (LV) mass. Reversal of LV hypertrophy (LVH) took considerably longer than reversal of the vascular changes and the more complete the reversal of LVH, the slower the rate of redevelopment of hypertension upon cessation of treatment. We observed no change in sympathetic activity or in renin-angiotensin-aldosterone levels during the redevelopment phase and we hypothesized that the cardiovascular amplifiers played a role in pathogenesis. This hypothesis was examined in spontaneously hypertensive rats (SHRs), where the vascular amplifier properties were developed substantially by 4 weeks of age, i.e., before the development of hypertension, whereas LVH occurred pari passu the rise in BP. When young SHRs were treated with enalapril for brief periods, there was almost complete long-term regression of vascular amplifier properties, but attenuation of LVH and hypertension were both smaller and more transient. In 4-week-old SHRs, complete abolition of sympathetic activity had a minimal effect on vascular amplifier properties, but affected LVH. Our findings suggest that LVH is as important in both the development and maintenance of hypertension as the structurally determined amplifier properties of the resistance vessels.

47. Effects of discontinuation of long-term antihypertensive therapy on blood pressure and left ventricular mass

Fagerberg, Bjorn; Hartford, Marianne; Ljungman, Susanne; Berglund, Goran; Wikstrand, John Author Information

Cardiac Hypertrophy and Arterial Compliance Following Drug Treatment in Hypertension

Summary: The load of the heart in hypertension is related both to increased peripheral vascular resistance and decreased aortic compliance. From noninvasive studies involving determinations of pulse-wave velocity and systolic-diastolic variations of aortic arch diameter, it can he shown that increased aortic elastic modulus is strongly related to increased cardiac mass. The relationship is observed even after adjustment for the level of mean arterial pressure. It is suggested that decreased aortic compliance in hypertension causes a disproportionate increase in systolic pressure and end-systolic stress, thus contributing to promote cardiac hypertrophy. Such a possibility may have consequences for long-term antihypertensive therapy. Following converting enzyme inhibition and calcium blockade, important dissociations may he observed between the antihypertensive effect and the cardiac and arterial changes.

Cardiovascular effects of antihypertensive drugs — Involvement in the therapeutic choice

Hypertensive patients are at an increased risk of developing cerebrovascular and cardiovascular disease. Treatment has resulted in a substantial reduction in cerebrovascular deaths but not in cardiovascular mortality. As the number of deaths from myocardial infarction exceeds the sum of all other hypertension-related mortalities, these results are disappointing. The hypothesis that metabolic side effects of many antihypertensive drugs offset the potential benefit of decreasing blood pressure is of particular interest. In established hypertension there is an increase in total peripheral resistance. Long-term therapy with diuretics decreases vascular resistance. This is also evident with dihydropyridine calcium antagonists, vasodilators, angiotensin-converting enzyme inhibitors and α blockers. In patients with hypertension, an increased wall to lumen ratio occurs in resistance vessels where mechanisms such as smooth muscle hypertrophy and increased amounts of elastin and collagen are present. In small resistance vessels, long-term antihypertensive therapy has a positive effect, but the effect in large arteries is variable.

Efficacy of Long-Term Antihypertensive Therapy with Enalapril

We examined whether long-term antihypertensive monotherapy with enalapril decreased clinical casual blood pressure (BP) as well as BP at work and during stress, and whether this angiotensin-converting enzyme (ACE) inhibitor had an adverse effect on the physiologic hemodynamic pattern during experimental mental stress. Seventeen male patients with hitherto untreated mild-to-moderate essential hypertension (mean age: 47 +/- 8 years) had 24-hour BP monitored noninvasively with the Physioport system before and during treatment with enalapril (5-10 mg/day) for 6 months. They also had a mental stress test, physical exercise test, and the cold pressor test before and after therapy. After the diagnostic observation period, average clinical casual BP was 150 +/- 12/102 +/- 7 mg Hg. Average BP at work, stress BP during all types of stimulation in the laboratory, and clinical casual BP significantly decreased during monotherapy with enalapril. Neither the circadian rhythm nor the hemodynamic pattern during mental stress was significantly altered by enalapril. BP increases during emotional stress were not significantly attenuated by the ACE inhibitor. These results demonstrated that enalapril effectively lowers BP without altering the physiologic hemodynamic pattern during emotional stress.

Influence of antihypertensive treatment with budralazine on autoregulation of cerebral blood flow in spontaneously hypertensive rats.

We studied the effect of chronic antihypertensive treatment with budralazine on the lower blood pressure limit of cerebral blood flow autoregulation using spontaneously hypertensive rats. Cerebral blood flow in the parietal cortex and caudate nucleus was measured to determine the lower limit using the hydrogen clearance method. The lower limit in both cerebral regions was significantly higher in 10 untreated spontaneously hypertensive rats than in 10 Wistar-Kyoto rats. The upward-shifted lower limit was restored to close to normal in the caudate nucleus and was partially restored in the parietal cortex of nine rats by 9 weeks of treatment with the high dose (50-68 mg/kg/day) of budralazine, which kept blood pressure constant at approximately normotension during the treatment period; the lower limit was slightly restored in both cerebral regions of seven rats by 4 weeks of treatment with the high dose. However, 9 weeks of treatment with the low dose (19-27 mg/kg/day) of budralazine, which produced moderate continuous hypotension in nine rats, did not apparently influence the lower limit. Our results suggest that long-term antihypertensive therapy with budralazine reduces the upward-shifted lower blood pressure limit of cerebral blood flow autoregulation toward normal and that the restoration induced by budralazine depends on the degree of blood pressure reduction as well as on the duration of the therapeutic period.

Life's quality: A major consideration in health care delivery — Especially with hypertensive diseases

The purposes of this paper are severalfold: a) to avoid a cloak of product inference; b) to focus attention on the need to keep patients on long-term (antihypertensive) therapy with as few side effects as possible; c) to acknowledge certain arguments relating to side effects, some of which have engendered concern among respected authorities in the field; d) to underscore the validity of current health care preoccupations relating to cost containment and cost effectiveness; and e) to question the wisdom of certain governments around the world in suggesting that low-cost antihypertensive medications that are already available should be used in preference to newer and more costly drugs no matter what the theoretical or clinical justification.

Effects of antihypertensives on plasma lipids and lipoprotein metabolism

There is good epidemiologic evidence that hypertension is associated with a high risk of cardiovascular disease. However, primary intervention trials have failed to demonstrate that a reduction in blood pressure in hypertensive patients reduces morbidity and mortality from cardiac events. Since various antihypertensive drugs adversely affect lipoprotein metabolism, these drugs may increase associated coronary risk and offset the beneficial effects of lowering blood pressure. This article reviews the effects of various antihypertensive drugs on plasma lipids, lipoproteins, and apolipoproteins. They can be summarized as follows: thiazide-type diuretics cause a marked elevation of plasma triglycerides and very low-density lipoprotein (VLDL) and minor increases in total cholesterol and low-density lipoprotein (LDL), but have little effects on high-density lipoprotein (HDL). The nonselective β-blockers do not significantly affect total cholesterol and LDL, but increase total triglycerides and VLDL and decrease HDL. The changes in plasma lipids and lipoproteins caused by cardioselective β-blockers and β-blockers with intrinsic sympathomimetic activity are qualitatively similar but less pronounced. Calcium antagonists and angiotensin-converting enzyme inhibitors appear to have no significant effects on plasma lipids. α 1-inhibitors reduce total triglycerides, total cholesterol, VLDL, and LDL and increase HDL. The possible mechanisms by which antihypertensive drugs affect cellular lipid metabolism (e.g., LDL receptor, lipid synthesis, lipoprotein lipase, lecithin cholesteryl acyltransferase, acylcholesteryl acyltransferase, and cholesteryl ester hydrolase) are described. The clinical significance of changes in blood lipids and cellular lipid metabolism caused by antihypertensive drugs is not yet totally clear. Nevertheless, before antihypertensive drug treatment is initiated, blood lipid levels should be measured to identify preexisting hyperlipidemia. Blood lipoprotein levels should be monitored during long-term antihypertensive therapy to reconsider the therapeutic regimen if adverse lipid changes are observed.

Beyond Blood Pressure Control

Although the value of treating all degrees of hypertension has been clearly established, a substantial percentage of patients fail to comply with drug therapy and thus do not receive the long-term benefits of blood pressure reduction. Antihypertensive drugs can have a negative impact on the patient's overall quality of life, as judged by their physical state, emotional well-being, cognitive acuity, and sexual and social functioning. These effects can be quite troubling to patients with a seemingly symptomless disease. In order to examine more closely the effects of different antihypertensive agents on quality of life, a double-blind, multicenter trial was conducted in which male patients were assigned to treatment with either methyldopa, propranolol or captopril for six months. Hydrochlorothiazide was added to the primary drug in patients whose blood pressure was not adequately controlled after eight weeks. Quality of life was evaluated using a battery of validated psychological assessment scales and indexes. Captopril was favored over methyldopa and propranolol on a number of the quality of life measures, including general well-being, physical symptoms, and sexual dysfunction. Addition of a diuretic negatively affected quality of life in all three primary drug groups, but captopril was still favored over the other primary drugs even when the effect of the diuretic was considered. The study demonstrated that quality of life is relevant and assessable and can be influenced by the choice of drug therapy. Greater attention by physicians to quality of life issues can hopefully improve patient compliance and extend the benefits of long-term antihypertensive therapy to more patients.

Hemodynamic response patterns to mental stress: Diagnostic and therapeutic implications

Stress has been identified as contributing to the development of cardiovascular disease. The pathophysiologic link between stress and disease still remains unclear. Because experimental stress testing in the laboratory permits the examination of the underlying mechanism for stress-induced blood pressure, analyses of cardiovascular reactivity during emotional stress could be of particular clinical importancce. The analyses of pooled data during the past 6 years (n = 298, age from 20 to 60 years, normotensive subjects as well as patients with borderline and mild essential hypertension) reveal that stress-induced changes in stroke volume and especially in total peripheral resistance are crucial parameters to analyze the hemodynamic stress response. However, neither those simple nor complex response patterns such as “hot reactor” describe clinically distinct subgroups of persons. When physiologic testing was repeated in hypertensive patients after effective long-term antihypertensive therapy with clonidine, oxprenolol, nitrendipine, or enalapril, no attenuation of the stress-induced increase in blood pressure was found in any of these groups. However, heart rate reactivity and stress-induced changes in total peripheral resistance were altered significantly by oxprenolol and nitrendipine. The β-adrenoceptor blocker decreased heart rate reactivity and increased reactivity of peripheral resistance; the calclum antagonist decreased stress-induced changes in peripheral resistance and increased the heart rate response. The centrally acting sympatholytic regimen and the anglotensin-converting enzyme inhibitor had no impact on the hemodynamic response pattern during emotional challenge.

Mechanism of action of calcium antagonists in heart and vascular smooth muscle.

A transmembrane supply of Ca2+ ions is required for active tension development in both vascular smooth musculature and myocardial fibres. Ca2+ antagonists thus not only damp hyperkinetic myocardial dysfunction but also act against practically all vasoconstrictor or spastic responses of extramural coronary smooth muscle. Clinically important targets of Ca2+ antagonists include the pulmonary, cerebral, mesenteric and renal arteries, as well as the peripheral resistance vessels of the systemic circulation. Ca2+ antagonists are used increasingly to treat acute hypertensive crises as well as for long-term antihypertensive therapy. In physiological experiments, Ca2+ antagonists not only neutralize various vasoconstrictor agents but also greatly reduce the sensitivity of the systemic arteries and arterioles to mechanical stimuli such as extension of the vascular wall by a rise in intraluminal pressure. In human arterial walls, at an advanced age, cytotoxic degrees of Ca2+ overload probably play an important role in the pathogenesis of arteriosclerotic lesions. Severe diabetics and heavy smokers exhibit an even faster progression of age-dependent arterial calcinosis. In rats, the Ca2+ antagonist verapamil not only prevented arterial calcinosis due to overdoses of vitamin D and dihydrotachysterol but also counteracted age-dependent Ca2+ accumulation. Spontaneously hypertensive rats also exhibit progressive arterial Ca2+ overload which responds excellently to the Ca2+ antagonists nifedipine, nimodipine, nisoldipine, nitrendipine, as well as to verapamil and diltiazem. Suitable Ca2+ antagonists could possibly retard or even prevent premature arterial calcinosis in humans. Moreover, Ca2+ antagonists exert a direct cardioprotective effect on the myocardium by preventing intracellular Ca2+ overload.

Antihypertensive drug side effects in the Hypertension Detection and Follow-up Program.

The 5485 participants in the Hypertension Detection and Follow-up Program, Stepped-Care group form one of the largest groups to date on which detailed surveillance of long-term antihypertensive therapy and drug side effects has been reported. During a 5-year period, among all hypertensive persons (mild, moderate, and severe combined) who were not taking antihypertensive medications at the beginning of the study and who attended the clinic at least once during the 5-year trial, a total of 9.3% had definite or probable side effects severe enough to cause discontinuation of the drug treatment in question. Less than 1% of active participants required hospitalization for side effects. No death that could be attributed to side effects was detected. Thus, the Hypertension Detection and Follow-up Program data, which have previously demonstrated the beneficial effects of antihypertensive therapy, confirm the relative safety of such therapy.

Echocardiographic Detection of Left Ventricular Hypertrophy: Its Usefulness as a Prognostic Tool in Hypertensive Patients

There is strong evidence that in hypertensive patients, electrocardiographic findings of left ventricular hypertrophy (LVH) are associated with a poor cardiovascular prognosis. In the Framingham study, the presence of defined electrocardiographic evidence of LVH was found to be associated with an increased likelihood of major cardiovascular events, independent of blood pressure level. 1 Kannel WB Gordon T Offutt D Left ventricular hypertrophy by electrocardiogram: prevalence, incidence and mortality in the Framingham study. Ann Intern Med. 1969; 71: 89-105 Crossref PubMed Scopus (692) Google Scholar , 2 Kannel WB The Framingham study. Am J Med. 1983; 75: 4 Abstract Full Text PDF PubMed Scopus (350) Google Scholar Since the detection of such target organ damage is critical for the clinical management of hypertensive patients, an accurate identification of abnormal cardiac anatomy seems particularly important. Although the electrocardiogram (ECG) has been the conventional clinical diagnostic tool for the detection and assessment of acute ischemia, conduction abnormalities, and rhythm disturbances, it has not been highly sensitive in the detection of changes in cardiac mass such as LVH. In a large-scale study by Savage et al 3 Savage DD Drayer JIM Henry WL Mathews Jr, EC Ware JH Gardin JM et al. Echocardiographic assessment of cardiac anatomy and function in hypertensive subjects. Circulation. 1979; 59: 623-632 Crossref PubMed Scopus (342) Google Scholar of patients with mild to moderate hypertension, the ECG and the chest x-ray film each identified approximately 5 percent of the patients as having met the classic criteria for a diagnosis of LVH, whereas echocardiographic criteria for LVH were demonstrated in almost 50 percent. Echocardiography, therefore, might represent the first truly sensitive and widely available noninvasive diagnostic method for critically evaluating early evidence of cardiovascular damage in patients with mild to moderate hypertension. 4 Devereux RB Alonso DR Lutas EM Gottlieb GJ Campo E Sachs I et al. Echocardiographic assessment of left ventricular hypertrophy: comparison to necropsy findings. Am J Cardiol. 1986; 57: 450-458 Abstract Full Text PDF PubMed Scopus (5583) Google Scholar This technique may potentially be of value in determining which patients will benefit most from long-term antihypertensive therapy, as well as in evaluating the effect of long-term antihypertensive therapy on left ventricular mass in patients with essential hypertension. So far, only a few long-term follow-up clinical trials have been reported. Therefore, there has not been sufficient time nor clinical experience as yet to evaluate definitively the prognostic significance of echocardiographic evidence for LVH or the use of antihypertensive therapy to reduce LVH, especially in those patients whose ECG and chest roentgenograms are apparently normal. 5 Weber MA Drayer JIM Baird WM Echocardiographic evaluation of left ventricular hypertrophy. J Cardiovasc Pharmacol. 1986; 8: S61-S68 Crossref PubMed Scopus (15) Google Scholar

Safety Aspects of Long-Term Antihypertensive Therapy (10 Years) with Clonidine

We have treated 128 patients aged 40 ± 9 years (60 males and 68 females), all with essential hypertension (W.H.O. I and II), over a period of 10 yr. The treatment was performed with clonidine at a dose that ranged from 0.150 to 1,200 mg (twice daily). Forty-two patients also received a diuretic (HCTZ 25 mg daily). Mean blood pressure decreased significantly from 169 ± 10 mm Hg systolic, 107 ± 3 diastolic to 145 ± 6 mm Hg (p < 0.001) 90 ± 3 mm Hg diastolic (p < 0.001). Side effects occurred during the first month. These were drowsiness 28%, dry mouth 35%, constipation 13%, dizziness 9%, postural hypotension 2%, and male impotence 3.3% (2/60). Side effects still present after 120 months of treatment were drowsiness 11.7%, dry mouth 26.6%, constipation 14.1%, dizziness 4.7%, and male impotence 1.7% (1/59). The number of patients who discontinued treatment resulting from side effects were 3.34%, all of them within the first 6 months. There were no changes in renal or liver function or in serum electrolytes or lipids. Retinopathy improved in most patients. Electrocardiogram (ECG) improved in 45 patients with LVH. It is concluded that clonidine provided sustained blood pressure control with minimum side effects during 10-year therapy for hypertension.