Reduction Of Elevated Blood Pressure Research Articles

Modulation of sympathetic outflow by centrally acting antihypertensive drugs.

The modulation of peripheral sympathetic activity by the central nervous system (CNS) has been intensely investigated as a potential target of antihypertensive drugs. In particular, clonidine, guanfacine, and alpha-methyl-DOPA (acting via its metabolite alpha-methylnoradrenaline) have been developed as antihypertensives with a predominantly CNS site of action. Initially these drugs have been assumed to reduce elevated blood pressure via the stimulation of central alpha2-adrenoceptors in the brain stem, thus leading to peripheral sympathoinhibition and a reduction of elevated blood pressure, heart rate, and plasma catecholamines. In a later stage it has been recognized that central imidazoline (I1) receptors, probably located in the nucleus reticularis lateralis in the medullary region, may also be the target of centrally acting antihypertensives. Moxonidine and rilmenidine are the prototypes of such agents. Accordingly, the receptor profile of the various types of centrally acting antihypertensives may be characterized as follows: alpha-methyl-DOPA, alpha2 (through alpha-methylnoradrenaline); clonidine alpha2 + I1 (mixed agonist); and moxonidine, rilmenidine, I1 > alpha2. The various compounds mentioned will thus cause peripheral sympathoinhibition, initiated by different receptor targets in the CNS. Finally, the peripheral alpha1-blocker, urapidil, has been demonstrated to possess an additional central mechanism, mediated by the stimulation of serotonergic 5HT1A-receptors located in the rostral ventrolateral medulla. The stimulation of these 5HT1A-receptors appears to suppress, via the autonomic nervous system, the reflex tachycardia triggered by vasodilation.

From α and β to I1

There is no doubt that the sympathetic nervous system (SNS) plays an important role in the pathogenesis and maintenance of hypertensive disease, although many details concerning this association remain to be clarified. Over the years, several types of antihypertensive drugs have been developed that can impair SNS activity at virtually all levels of the system. Alpha and beta-adrenoceptor antagonists, postganglionic sympathetic neuron blockers and ganglioplegic agents are well-known examples of drugs with a predominantly peripheral activity. The CNS regulation of peripheral sympathetic activity offers a further possibility to counteract the influence of SNS activity. In particular, central catecholaminergic neurons and alpha-adrenoceptors have been analyzed in detail and are recognized as important targets for the classic centrally acting antihypertensives clonidine, guanfacine, and alpha-methyldopa. Initially, these drugs were assumed to reduce elevated blood pressure via the stimulation of central alpha-adrenoceptors in the brainstem, thus leading to peripheral sympathoinhibition and a reduction of elevated blood pressure, heart rate, and plasma catecholamines. In a later stage it has been recognized that central imidazoline (I1) receptors may also be involved in the central regulation of peripheral sympathetic activity and that they act as a target for centrally acting antihypertensives. Moxonidine and rilmenidine are the prototypes of such agents. Accordingly, the receptor profile of the various types of centrally acting antihypertensives can be characterized as follows: alpha-methyl-DOPA (through alpha-methyl-norepinephrine) alpha 2; clonidine (mixed agonist), alpha 2 + I1; moxonidine, rilmenidine, I1 > alpha 2. The various compounds mentioned will thus cause peripheral sympathoinhibition, initiated by different receptor targets in the CNS. Because most of the adverse reactions to clonidine and related drugs are mediated by central alpha-adrenoceptors, is is hoped that the imidazoline receptor agonists (moxonidine, rilmenidine) will show a more favorable pattern of side effects.

New central mediators as targets of centrally acting antihypertensive drugs.

The modulation of peripheral sympathetic activity by the central nervous system may involve various pathways, neurotransmitters and receptors. In particular central catecholaminergic neurones and alpha-adrenoceptors have been analysed in detail, and they are recognized as important targets of the classic centrally acting antihypertensives clonidine, guanfacine and alpha-methyl-DOPA. Initially these drugs have been assumed to reduce elevated blood pressure via the stimulation of central alpha 2-adrenoceptors in the brain stem, thus leading to peripheral sympathoinhibition and a reduction of elevated blood pressure, heart rate and plasma catecholamines. In a later stage it has been recognized that central imidazoline (I1) receptors, probably located in the nucleus reticularis lateralis in the medullary region may also be involved in the central regulation of peripheral sympathetic activity, and for that matter as a target of centrally acting antihypertensives. Moxonidine and rilmenidine are the prototypes of such agents. Accordingly, the receptor profile of the various types of centrally acting antihypertensives may be characterized as follows: [formula: see text] The various compounds mentioned will thus cause peripheral sympathoinhibition, initiated by different receptor targets in the CNS. Finally, the peripheral alpha 1-blocker urapidil has been demonstrated to possess an additional central mechanism, mediated by the stimulation of serotonergic 5HT1A-receptors located in the rostral ventrolateral medulla.

Hypertension and Risk of Stroke: The Influence of Associated Risk Factors in the Framingham Study

Hypertension is the pre-eminent risk factor for stroke with incidence of both ischemic stroke and hemorrhage increasing with level of blood pressure. However, at any blood pressure level, risk of stroke varies widely according to the presence and intensity of other risk factors. These include: age; antihypertensive therapy; presence of cardiovascular disease; cigarette smoking; diabetes; LVH by ECG; and atrial fibrillation. Without risk factor abnormalities, a hypertensive individual may actually have a lower probability of stroke than a normotensive with multiple elevated risk factor levels. The person with multiple borderline risk factor levels is particularly difficult to categorize. To determine probability of stroke, taking the risk factor and blood pressure levels into account, a stroke risk profile was developed using Framingham Study data. Key to the usefulness of the risk profile is the knowledge, derived from observational studies and controlled clinical trials, that modification of a number of these risk factors can reduce the incidence of stroke. These include: reduction of elevated blood pressure, systolic as well as diastolic; cessation of cigarette smoking; improved control of blood sugar level in diabetics; and treatment of persons with atrial fibrillation with low intensity warfarin. Thus, the Framinghan stroke risk profile may guide the physician in identifying patients at heightened risk, and provide guidance in measures that can reduce the likelihood of stroke. (Hypertens Res1994; 17 Suppl. I: S83-S88)

In Reply

I thank Dr. Neurath for his comments on blood pressure measurement in the elderly. The term “pseudohypertension” has indeed become a diagnostic term that refers to artifactual hypertension in patients with Mönckeberg's medical calcification of large arteries.1 This process can be diagnosed by radiographic examination of the arms; vascular calcification will be evident. Pseudohypertension may be superimposed on existing hypertension, normotension, or even hypotension and must be diagnosed correctly in order to prevent potentially dangerous overtreatment. Unfortunately, the true prevalence of pseudohypertension remains unknown although it is relatively uncommon. The Osler maneuver has not proved to be reliable, and a high index of clinical suspicion remains the best screening measure.2 There are many other causes of erroneous blood pressure readings, several of which are listed by Dr. Neurath. One of the most common is use of a blood pressure cuff that is too small for the patient's arm. The need for correct blood pressure measuring technique cannot be overemphasized. This includes the palpation of the peripheral pulse (radial or brachial) to avoid the error of the “silent zone” with consequent underestimation of the true intraarterial pressure. The diagnosis of ISH clearly requires multiple measurements on separate visits. The physical examination, chest X-ray, and ECG greatly underestimate the true prevalence of left ventricular hypertrophy. Nevertheless, cardiac ultrasound should be reserved for patients for whom the results are expected to be critical for diagnostic and therapeutic decision making. It is not a routine test. I could not agree more regarding the dangers of too rapid reduction of elevated blood pressure, especially in elderly patients. Rapid reduction is rarely necessary and potentially dangerous. Patients who are anxious and/or in pain may have blood pressure levels truly elevated above their usual baseline. Often the best treatment is relief of the anxiety and/or pain and not direct treatment of the blood pressure numbers. Semantics aside, the most important point of my editorial was that there are now data on which to base the treatment of patients with ISH.3 It is, of course, crucial to determine that the patient does, in fact, have ISH in order to avoid the risks of treatment, however small, for an entity that the patient does not actually have.

Practical considerations in treating the elderly hypertensive patient

More than half of all older Americans die of cardiovascular diseases. Hypertension is a major risk factor for cardiovascular diseases, and its prevalence increases with age. Older patients are both at higher risk for end-organ complications and less likely than younger ones to survive such complications as myocardial infarction and stroke. Clinical studies have shown that reduction of elevated blood pressure is beneficial in many older persons. Optimal selection of antihypertensive therapy requires consideration of the special characteristics of the elderly, who differ from their younger counterparts in physiology, response to therapy and frequency of concomitant illnesses and medications. Calcium antagonists are particularly effective in these patients; other agents are useful in selected situations. Drugs that are likely to cause central nervous system side effects or orthostatic hypotension generally should be avoided in this patient population. Therapy should begin with a low dose and be titrated upward slowly, thus avoiding excessive reduction of blood pressure and the development of orthostatic hypotension. Treatment should be altered as necessary to minimize side effects that may impair quality of life or lead to poor compliance.

Vascular effects of calcium antagonists: Implications for hypertension and other risk factors for coronary heart disease

All calcium antagonists (CAs) so far developed are vasodilators, and this property is a most important component of their therapeutic potency in hypertension and angina pectoris. At a cellular level, the specific interaction of CAs with transmembranous calcium fluxes involves both potential and receptor-operated channels, respectively. Both α 2 and α 1 adrenoceptors when activated with an appropriate agonist can trigger the calcium influx through receptor-operated CA channels, α 2 adrenoceptors probably more readily so than α 1. More recently, angiotensin II receptors have also been demonstrated to be involved, although moderately, in the influx of calcium ions from the extracellular space. The hemodynamic profile of CAs is characterized by a particular specificity for the resistance vessels and for the coronary arterial system, as a useful basis for their therapeutic effect in hypertension and in angina pectoris. The weak natriuretic activity of CAs, probably the result of a tubular effect in the kidney, counteracts the fluid retention to be expected for vasodilator drugs. Interesting ancillary properties of CAs are their potentially favorable effects on the myocardial and vascular hypertrophy associated with long-standing hypertension, as well as their antiatherogenic activity that so far has only been demonstrated in animal models. Such additional properties are of potential benefit and deserve further research, since most large-scale hypertension trials have shown that vasodilation and the reduction of elevated blood pressure as such, are probably not sufficient to adequately protect hypertensive patients against coronary events.

Left ventricular hypertrophy in hypertensive patients

H ypertension has long been associatetl \vith an increased occurrence of cartliovascular diseases such as stroke, ischemic coronary, artery disease, and congestive heart failure. In addition, it has long been realized that the reduction of elevated blood pressure by effecti\:e antihypertensive therapy helps to reduce the incidence of morbidity and mortality from hypertensive cardiovascular disease in general. The therapeutic goals in the treatment of hypertension therefore include a reduction in blood pressure and attendant hypel.tension-inducetl morbidity and mortality. To accomplish the latter, prevention or reversal of hypertension-induced cardiac structural hypertroph>r is emerging as an important goal of antihypertensive therapy. HyT~ertrophic cardiovascular changes are already evident early in the natural history of hype]*tension and can be used as a prognostic indicator. Specifically, electrocardiographic evidence of left ventricular hvpertrophy is associated with an eightfold increase-in the cardiovascular mortalitv rate and a sixfold increase in the coronary mortality rate ]I]. It is important for clinicians to realize that different antihypertensive agents will have different effects on left ventricular hypertrophy, even though they may effectively reduce blood pressure. In this segment of this supplement, the issue of h:ypertensioninduced left. ventricular hypertrophy is discussed. with a focus on those agents that ina!’ prevent or reverse this serious complication of hypertension. Hypertension affects the heart in several ways. To maintain cardiac output and normal systemic perfusion in the face of a sustained work overload of sufficient magnitude and duration, the heart initially responds by increasing mass and/or volume. This state of cardiac enlargement is due to an increase in the size but not in the number of cardiac myocytes. This compensatory response occurs with the heart utilizing its systolic (Increase in contractility) and/or its diastolic (Starling’s principle) reserves in an attempt to preserve the circulation. Ventricular distention or dilatation will cause an increase in the end diastolic volume. Rut if ventricular dilatation exceeds an optimal value, this initially beneficial response may further exacerbate the load on the heart, and cardiac failure may supervene. The form of the hypertrophic response causing this initial compensatory alteration in cardiac size depends on the type and duration of the jvork load imposed 121. If the heart is burdened by pressure overload, as in hypertension, the overload will manfest as concentric hypertrophy, since the left ventricular mass will increase without chamber enlargement

Cardiovascular risk factors and antihypertensive therapy

Reduction of elevated blood pressure is effective in reducing morbidity and mortality from cardiovascular disease in general. Striking decreases in stroke, congestive heart failure, and renal impairment have been observed when blood pressure is reduced. However, the ability of traditional, diuretic-first, stepped-care therapeutic algorithms to reduce the occurrence of myocardial infarction or angina has been exceedingly difficult to demonstrate. An increased frequency of sudden death among hypertensive men with electrocardiographic abnormalities has been observed in some diuretic-based treatment trials. The failure of conventional therapy to reduce coronary artery disease and death has forced a re-appraisal of antihypertensive treatment. The risk factors for coronary disease are reviewed in detail with an emphasis on the impact of various classes of antihypertensive drugs on these factors. The emergence of effective antihypertensive agents that lower blood pressure without adversely affecting cardiovascular risk factors provides a new opportunity to further extend the benefit of treatment by reducing such risk.

Cardiovascular risk factors and antihypertensive therapy

Reduction of elevated blood pressure is effective in reducing morbidity and mortality from cardiovascular disease in general. Striking decreases in stroke, congestive heart failure, and renal impairment have been observed when blood pressure is reduced. However, the ability of traditional, diuretic-first, stepped-care therapeutic algorithms to reduce the occurrence of myocardial infarction or angina has been exceedingly difficult to demonstrate. An increased frequency of sudden death among hypertensive men with electrocardiographic abnormalities has been observed in some diuretic-based treatment trials. The failure of conventional therapy to reduce coronary artery disease and death has forced a re-appraisal of antihypertensive treatment. The risk factors for coronary disease are reviewed in detail with an emphasis on the impact of various classes of antihypertensive drugs on these factors. The emergence of effective antihypertensive agents that lower blood pressure without adversely affecting cardiovascular risk factors provides a new opportunity to further extend the benefit of treatment by reducing such risk.

Tolerability and well-being with indapamide in the treatment of mild-moderate hypertension: An Italian multicenter study

Since hypertension is an important risk factor of cardiovascular morbidity and mortality that can be at least in part decreased by pharmacologic reduction in elevated blood pressure, it is necessary that an antihypertensive agent be effective, but at the same time well tolerated and, according to some recent hypotheses, have no deleterious effect on serum electrolyte levels, as well as lipoprotein and glucose tolerance. However, due to different cultural and social backgrounds, lifestyles, and so on, the tolerability may differ from one population to another and the conclusions drawn from a population cannot be extrapolated to people of other countries. For these reasons, the well-being of patients, as well as the tolerability of indapamide, a non-thiazide diuretic, have been investigated in patients with hypertension of mild and moderate degree from different parts of Italy with a satisfactory blood-pressure response to this drug (−22.8 ± 0.6/−17.1 ± 0.5 mm Hg). Simultaneous to the significant blood-pressure reduction, the only significant change among the metabolic effects was a slight reduction in plasma potassium levels (−0.37 ± 0.03 meq/liter). The tolerability was, on the whole, very good with a tendency toward an improvement of well-being in patients, the majority of whom were already asymptomatic before starting the treatment. Since hypertension is an important risk factor of cardiovascular morbidity and mortality that can be at least in part decreased by pharmacologic reduction in elevated blood pressure, it is necessary that an antihypertensive agent be effective, but at the same time well tolerated and, according to some recent hypotheses, have no deleterious effect on serum electrolyte levels, as well as lipoprotein and glucose tolerance. However, due to different cultural and social backgrounds, lifestyles, and so on, the tolerability may differ from one population to another and the conclusions drawn from a population cannot be extrapolated to people of other countries. For these reasons, the well-being of patients, as well as the tolerability of indapamide, a non-thiazide diuretic, have been investigated in patients with hypertension of mild and moderate degree from different parts of Italy with a satisfactory blood-pressure response to this drug (−22.8 ± 0.6/−17.1 ± 0.5 mm Hg). Simultaneous to the significant blood-pressure reduction, the only significant change among the metabolic effects was a slight reduction in plasma potassium levels (−0.37 ± 0.03 meq/liter). The tolerability was, on the whole, very good with a tendency toward an improvement of well-being in patients, the majority of whom were already asymptomatic before starting the treatment.

Tolerability and well-being with indapamide in the treatment of mild-moderate hypertension: An Italian multicenter study

Since hypertension is an important risk factor of cardiovascular morbidity and mortality that can be at least in part decreased by pharamcologica reduction in elevated blood pressure, it is necessary that an antihypertensive agent be effective, but at the same time well tolerated and, according to some recent hypotheses, have no deleterious effect on serum electrolyte levels, as well as lipoprotein and glucose tolerance. However, due to different cultural and social backgrounds, lifestyles, and so on, the tolerability may differ from one population to another and the conclusions drawn from a population cannot be extrapolated to people of other countries. For these reasons, the well-being of patients, as well as the tolerability of indapamide, a non-thiazide diuretic, have been in vestigated in patients with hypertension of mild and moderate degree from different parts of Italy with a satisfactory blood-pressure response to this drug (−22.8 ± 0.6 /−17.1 ± 0.5 mm Hg). Simultaneous to the significant blood-pressure reduction, the only significant change among the metabolic effects was a slight reduction in plasma potassium levels (−0.37 ± 0.03 meq/liter). The tolerabolity was, on the whole, very good with a tendency toward an improvement of well-being in patients, the majority of whom were already asymptomatic before starting the treatment.

Diuretic Responsiveness of Blood Pressure in the Elderly

The problem of elevated blood pressure in the elderly is a common and potentially devastating one. Reduction of elevated blood pressure, whether systolic, diastolic, or both, is particularly beneficial in older hypertensive subjects in reducing morbidity and mortality. The older individual presents a unique pathophysiologic situation, one in which a variety of considerations must be given to the safest choice of antihypertensive agents. A consistent response of blood pressure in the elderly is not observed with different antihypertensive agents, and the problems of side effects and as well as life-threatening effects of antihypertensive drugs are of particular concern among older hypertensive subjects. While diuretics, on balance, appear to be more effective in lowering blood pressure in older hypertensive patients than in young individuals, the disadvantages and risks of diuretic therapy make them less than ideal agents. Calcium channel blockers and serotonin antagonists have proven, in preliminary studies, to be useful, effective, and safe alternatives to diuretic therapy in older hypertensive patients.

Antihypertensive therapy and the concept of total cardiovascular protection

Drug-induced reduction of elevated blood pressure decreases cardiovascular mortality and morbidity in patients with moderate and severe hypertension. Furthermore, antihypertensive drug studies in mild hypertensive subjects (diastolic blood pressure 90 to 104 mm Hg) have shown protection against stroke, left ventricular hypertrophy, congestive heart failure and progression of renal damage, as well as improved patient longevity. The Hypertension Detection and Follow-up Program trial, recently carried out in the U.S., documented reduced coronary artery disease events (fatal and nonfatal) in special drug-treated patients with mild hypertension. From the standpoint of practical management and considering the ubiquity of essential hypertension, a modified stepped-care regimen advocating initial drug therapy with a β blocker and addition of low-dose thiazide diuretic when necessary constitutes a judicious approach for widespread application. Although there are 8 orally active β blockers currently approved in the U.S. for clinical use in systemic hypertension, only acebutolol possesses all of the salutary pharmacologic properties of cardioselectivity, intrinsic sympathomimetic activity and hydrophilicity, thereby making this compound an effective and safe β-blocking agent for first-order management of a broad segment of the hypertensive population.

Coronary artery disease risk factor management in the hypertensive patient

Recent advances in understanding the relation of risk factors to coronary artery disease (CAD) have initiated a change in the approach to managing the hypertensive patient. Reduction of elevated blood pressure still remains a major therapeutic priority. However, the risk of cardiovascular morbidity is also related to hypercholesterolemia, hyperuricemia, hyperglycemia, hyperfibrinogenemia and obesity; all aggravate the risk of CAD in the patient with high blood pressure. Life-style is also important: cigarette smoking, high alcohol consumption and lack of physical exercise all predispose to precocious atheromatous CAD. Thus, the most favorable prognosis in terms of reducing CAD risk is accomplished by reducing elevated systemic arterial pressure while simultaneously improving all other risk factors. The method by which blood pressure is lowered is an important consideration. The ancillary metabolic activities of antihypertensive drugs now available differ widely. Diuretics and β blockers, for example, have potentially adverse metabolic effects, whereas agents such as selective α 1-adrenoceptor inhibitors appear to beneficially affect several metabolic cofactors influencing the CAD risk profile. The impact of such drug-induced metabolic changes on overall prognosis of the hypertensive patient remains to be clarified. In the absence of other contraindications, however, it is sensible to use drugs that do not increase the metabolic predilection to precocious CAD.

Kinetics and dynamics of nifedipine after oral and sublingual doses

Nifedipine is frequently administered by the sublingual route to provide rapid onset of intense effect, especially in patients in whom urgent reduction of elevated blood pressure is indicated. Previously available data, however, suggest that peak levels of nifedipine are higher and occur earlier when the drug is administered orally. Results of pharmacodynamic studies show that maximal hypotensive effects occur between 30 and 60 minutes after administration by either route, but that such effects are often achieved earlier when the drug is given orally. Recent work implies that the absorption of nifedipine through the buccal mucosa is poor, if it occurs at all, and that the appearance of nifedipine in plasma requires delivery of the drug to the stomach for active absorption. The small time lag in absorption that may be attributed to the dissolution of the nifedipine capsule may be obviated by biting through the capsule and swallowing the contents; this bite-and-swallow approach to dosing provides the most rapid rise in plasma nifedipine concentrations, and produces peak levels well above those achieved with sublingual administration.

Profile of trimazosin: An effective and safe antihypertensive agent

Trimazosin, a selective alpha-1-adrenoceptor-blocking agent, has been extensively evaluated in over 1000 patients. In hypertensive patients, reduction in elevated blood pressure in both supine and standing positions, consequent to a reduction in systemic vascular resistance, persisted in long-term therapy. Progression of hypertension target organ damage did not occur. Improvement in blood lipids with decreased total serum cholesterol was noted in long-term therapy. In long-term studies, 74% of patients responded at a trimazosin dose of 300 mg/day or less; the maximum dose was 300 mg/day or less in 52% of patients and 200 mg/day or less in 36%. Most patients received twice a day therapy. The side effect profile of trimazosin was comparable to placebo and significantly better than that of either methyldopa or propranolol. Concomitant disease or therapy did not adversely affect the trimazosin safety profile. Hematology, clinical cheistry, and urinary parameters did not indicate deleterious effects. Because of its excellent safety and toleration profile, trimazosin may be particularly suitable in first-line therapy of patients with mild or moderate hypertension.

Effect of reducing elevated blood pressure on cerebral circulation.

Circulation to the brain is protected not only by autoregulation, which maintains cerebral blood flow (CBF) in spite of a decrease in mean arterial pressure, but also by baroreflexes that tend to prevent or minimize hypotension. Hypertensive patients have impaired cerebral autoregulation and depressed baroreflex sensitivity, suggesting that the brain might be vulnerable to a reduction in blood pressure. Nevertheless, in clinical experience, studies of cerebral blood flow during drug-induced reduction of elevated blood pressure have shown that control of hypertension can usually be achieved without jeopardizing cerebral blood flow or inducing signs and symptoms of cerebral ischemia, even in patients with cerebrovascular disease. Indeed, control of hypertension reduces both the risk of stroke and the recurrence rate for second strokes.

Angiotensin Converting Enzyme (ACE) Inhibitors

Angiotensin converting enzyme inhibitors represent a new class of agents which were designed to retain only that unique property. Because of this inhibition, administration of these agents results in the significant reduction of elevated blood pressure of various etiologies and in the amelioration of symptoms associated with congestive heart failure resistant to digitalis glycosides and diuretics. The mechanism(s) of action is not entirely certain but almost certainly resides in the inhibition of ACE. Certainly, the future will see still further advances made in this therapeutic area as well as with other inhibitors of the renin-angiotensin system.

The Prevention of Hypertension

Our way to prevention is to find a list of traits known to be predictors of elevated blood pressure. This list of predictors offers means for the early identification of susceptibile persons. Years of experience in preventive work indicate that such identification is always useful for developing preventive programmes, since it gives a focus for action (5). Most of the predictors show possible ways in which action could be directed towards prevention of hypertension and reduction of elevated blood pressure. We will focus on salt, control of obesity, physical exercise, and meditation. We would like to discuss preventive aspects of hypertension and the possibility of treating with other methods than drugs.