Neuroendocrine Factors
Role of Sympathetic Nervous and Renin Angiotensin Systems
Both the renin-angiotensin systemand the sympathetic nervous system (sympathetic nervous system) are frequently overactive in patients with hypertension. Whereas the activation of the renin-angiotensin system can be relatively easily assessed by relating plasma renin to urinary sodium levels, there are no reliable routine measurements to assess the sympathetic activity. Consequently, the elevation of renin in hypertension is a matter of record, whereas the more indirect evidence for sympathetic overactivity merits a short review.
Each measurement of sympathetic overactivity has its limitations. Plasma catecholamine levels are too variable whereas the measurement of urinary catecholamines is rather insensitive. In spite of these limitations, it has been shown that norepinephrine and epinephrine are elevated in a substantial proportion of patients with hypertension. More complex measurements have also confirmed an elevation of sympathetic tone in hypertension, but, of necessity, these observations are limited to a small number of patients. The simplest and therefore best documented evidence for sympathetic overactivity stems from measurements of heart rate in hypertension. The evidence that tachycardia is important in hypertension can be summarized as follows. In large population studies, heart rate is invariably positively correlated with blood pressure (blood pressure). Fast heart rate in normotensive subjects is a predictor of future hypertension, and in most studies and at all ages hypertensive subjects have faster heart rate than normotensive subjects, and the distribution of the heart rate in these populations is bimodal. The bimodal distribution and the fact that the group with tachycardia also has higher blood pressure suggest that the “hyperkinetic neurogenic” hypertension may be a separate, pathophysiologically distinctive entity. Data indicate that about 30% of patients with hypertension have tachycardia.
The tachycardia in hypertensive patients can be abolished by a pharmacologic denervation of cardiac sympathetic and parasympathetic receptors, which, in turn, suggests that the tachycardia is neurogenic.
Changing phenotype of sympathetic overactivity in hypertension
An increased sympathetic tone in patients with the hyperkinetic state who have mild hypertension, tachycardia, and increased cardiac output has been demonstrated by measurements of catecholamine turnover, and by direct microneurography of sympathetic activity in peroneal nerves. The evolution from mild hyperkinetic to treatment requiring established hypertension has been confirmed in an important longitudinal cohort study. However, as hypertension advances tachycardia is less pronounced, and cross-sectional studies have suggested that with passage of time plasma norepinephrine levels and turnover cease to be elevated.
The absence of telltale signs of sympathetic overactivity in advanced hypertension has been used to challenge the significance of the sympathetic nervous system in hypertension. If sympathetic overactivity is indeed important in early phases of hypertension, why is it so hard to find signs of enhanced sympathetic tone among the “garden variety” patients with more advanced forms of hypertension?
The answer to this question lies in the changing responsiveness of cardiovascular organs to sympathetic stimulation. Prolonged sympathetic stimulation elicits a downregulation of the β-adrenergic responsiveness. A decreased chronotropic and inotropic responsiveness to infusions of isoproterenol has been demonstrated in hypertension. As the exemplary and unique study by Lund-Johanasson et al. demonstrates, the gradual decrease in heart rate in hypertension is associated with a similarly gradual decrease in the stroke volume and cardiac output. Blood pressure in these patients slowly increased, and after 20 yr their underlying hemodynamic pattern changed from a state of high cardiac output and tachycardia to a typical high-resistance type of established hypertension.
The increase in vascular resistance in later phases of hypertension can be best explained by vascular hypertrophy. As arterioles become hypertrophic, the thicker muscular (medial) layer protrudes into the lumen of the blood vessel. This is of little hemodynamic significance as long as the vessels are dilated. However, during vasoconstriction, the wall of such hypertrophic vessels abnormally and excessively encroaches on the lumen and thereby elicits a steep increase in vascular resistance. Infusion of norepinephrine or angiotensin into the brachial artery causes a substantially higher increase in forearm vascular resistance in hypertensive than in normotensive subjects.
The excessive responsiveness of arterioles to vasoconstriction also provides an explanation for the gradual decrease in plasma norepinephrine values in the course of hypertension. In hypertension the brain seems to seek and maintain a constant elevation of the baseline blood pressure levels. As peripheral vascular responsiveness to sympathetic stimulation increases, less sympathetic outflow is needed to maintain the same blood pressure elevation. Under these circumstances, the plasma norepinephrine values in hypertensive patients are nominally similar to the ones in normoten-sive patients. However, in spite of the diminished tone, the central nervous system continues to maintain the blood pressure at hypertensive levels. Details supporting this hypothesis are given elsewhere.
Interaction of sympathetic nervous system AND renin-angiotensin system
As is the case with many systems that regulate important functions in the body, the sympathetic nervous system and renin-angiotensin system interact and mutually reinforce each other’s actions. Sympathetic stimulation via renal β-adrenergic receptors elicits the release of renin from the kidneys. Renin, in turn, releases angiotensin from its substrate. Angiotensin increases the sympathetic discharge from the brain and, peripherally, potentiates the sympathetic cardiovascular responses. In view of this, it is not surprising that patients with elevated plasma renin activity also have increased norepinephrine values.
In addition to a direct mutual potentiation, the renin-angiotensin system and sympathetic nervous system potentiate each other’s physiologic actions. A good example is fluid and sodium balance in which both systems induce retention but through very different mechanisms: angiotensin via aldosterone, sympathetics through a direct renal action. Similar potentiation of physiologic outcomes through different mechanisms occurs regarding the trophic effect of both systems on smooth muscle hypertrophy and regarding the enhancement of coagulation. In the pathophysiologic setting of hypertension, these physiologic interactions promote cardiovascular complications.
Sympathetic overactivity and coronary risk in hypertension
Implications for practice
The understanding that hypertension is associated with multiple coronary risk factors and that both the renin-angiotensin system and sympathetic nervous system overactivity contribute to pressure-independent cardiovascular morbidity in hypertension ought to affect clinical practice. It is logical that antihypertensive drugs, which centrally decrease the sympathetic outflow or peripherally interfere with angiotensin’ s action, may be particularly useful in patients with multiple cardiovascular risk factors. However, currently a clinician’s enthusiasm for sympatholytic agents is restrained by the awareness that drugs such as reserpine, aldomet, and clonidine can cause considerable side effects. The new imidazoline agonists appear to be equally effective as clonidine while causing fewer side effects, but they are not available in the United States. Problems with the clinical diagnosis of neurogenic hypertension are another impediment to the use of sympatholytic agents. How is a physician to know which patient has a neurogenic form of hypertension? The answer is reasonably simple. In the absence of other causes (hyperthyroidism, anemia, pulmonary disease), a resting sitting heart rate of 75 beats/min or higher is a good indicator of sympathetic overactivity in hypertension.
Whereas on conceptual grounds the use of drugs that antagonize the renin angiotensin system appears to offer additional benefits, physicians will not change their prescribing habits until there is some demonstration that these theoretical properties can be translated into practical advantage. Several comparative trials of old vs new antihypertensive drugs are under way. Should these trials prove the superiority of new agents, physicians will use them more frequently.
Currently, decreasing blood pressure by any of the available drugs remains the primary clinical objective. It is, however, reasonable to tailor the treatment to an individual patient’s clinical condition. Personally, in a patient who has signs of sympathetic overactivity, I prefer to start with an angiotensin-converting enzyme inhibitor, an angiotensin receptor blocking agent, or possibly with an a-adrenergic blocking agent. β-blockers decrease blood pressure but aggravate both the dyslipidemia and insulin resistance and should not be the primary drug for patients with a metabolic syndrome.
This post has been viewed 278 times.
Comments are closed.
