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Despite considerable advances in the treatment of hypertension, many patients fail to respond to standard drug therapy, which focuses on regulating blood volume, salt intake, and the body's renin-angiotensin system (RAS). For these patients, their condition is often due to a frequently overlooked entity—neurogenic hypertension—that requires different pharmacological intervention, according to a report by a NewYork Weill Cornell Medical Center researcher.

The review, by Dr. Samuel J. Mann, Associate Professor of Clinical Medicine at Weill Cornell Medical College and Associate Attending Physician at NewYork-Presbyterian Hospital Weill Cornell Medical Center, appears in this month's American Journal of Hypertension.

Dr. Mann's study helps to explain why such a large proportion of patients with high blood pressure do not respond to standard drug regimens. Physicians and patients have to realize that hypertension, like fever, has many causes. Those causes involve not only the kidneys and regulatory systems that control blood volume and salt retention, but also the nervous system and other so-called "stress" hormones besides those released by the kidneys. It is, for example, frequently unrecognized, that only one third of all hypertensive patients are salt-sensitive (the number is higher for African-Americans and the elderly). This is where neurogenic hypertension comes in, an overlooked disorder related to another regulatory system known as the SympathoAdrenal System (SAS).

"In any given individual, hypertension may be exquisitely responsive to one agent yet completely unresponsive to another," notes Dr. Mann. "And there remains the compelling fact that hypertension remains inadequately controlled in 40% of treated patients. This non-response to therapy indicates that we need to widen our scope of investigation and look at other mechanisms that may be causing the hypertension. Different causes require different drugs. The bottom line is that treatment really must be individualized—it's not simply a case of 'one size fits all.'"

Recent hypertension research has focused on the central role of blood volume and of the RAS in the development of hypertension. Drugs directed at them—including diuretics, angiotensin-converting enzyme inhibitors (ACEI's), and angiotensin receptor blockers (ARB's)—have played an increasingly prominent role in treatment. Patients with volume-dependent hypertension typically have salt sensitivity—their blood pressure increases as salt intake increases. These patients respond to salt restriction and diuretics. Patients with RAS-dependent hypertension, however, do not respond as well to diuretics. In these patients, the renin-angiotensin system, triggered by the release of the hormone renin by the kidneys, sustains the high blood pressure. These patients usually respond to drugs directed at this system, such as ACEI's and ARB's. Yet, a significant number of hypertensive patients fail to respond to therapy with these drugs.

Dr. Mann's report points out that, in these patients, the hypertension may be caused instead by increased activity of another important regulatory system—the sympathoadrenal system (SAS)—which comprises the sympathetic nervous system and the adrenal gland. In this form of "neurogenic" hypertension, blood pressure elevation is caused by increases in cardiac output and constriction of systemic arteries due to increased epinephrine (adrenaline) and norepinephrine production—the so-called "stress" hormones. Epinephrine stimulates cardiac beta receptors, which increase heart rate, stroke volume, and cardiac output—while norepinephrine stimulates both cardiac beta receptors and the alpha receptors that stimulate constriction of the systemic arteries.

"Patients with neurogenic hypertension do not respond well to the recently recommended first-line therapy—diuretics—because their condition is not driven by blood volume and salt. However, they do respond to other medications, such as beta blockers and alpha blockers, which only makes sense considering the involvement of alpha and beta receptors in SAS-mediated hypertension," notes Dr. Mann. Beta blockers lower blood pressure by reducing both renin secretion and cardiac output, while alpha blockers lower blood pressure by reducing peripheral resistance. Thus, identifying neurogenic forms of hypertension offers the potential to better understand hypertensive mechanisms in individual patients and to guide appropriate drug selection.

The problem remains, however, how to identify patients whose hypertension may be neurogenic in nature. A major barrier is the absence of clinically convenient techniques for assessing SAS tone in individual patients. "In this context, clinical rather than biochemical indicators may deserve more consideration as clues of possible neurogenic hypertension," points out Dr. Mann. Many patients with hypertension have coexisting conditions that are associated with both increased SAS tone and increased blood pressure. These include stroke, sleep apnea, obesity, tachycardia (rapid heart rate), and alcohol abuse. Other clinical factors also might serve as indicators of neurogenic hypertension, although this area has not been well studied. These include situations in which the onset or pattern of hypertension are clearly atypical, such as sudden onset, or severe or labile blood pressure elevation. Psychological factors also may be involved in some patients, even in individuals who appear unaffected by severe stress.

According to Dr. Mann, neurogenic hypertension should be considered when treating hypertensive patients who are unresponsive to the widely used diuretic/ACEI combination or whose clinical presentation is atypical. "It is important to recognize that neurogenic hypertension does exist, and that we need more clinical trials designed to identify patients with neurogenic hypertension and their response to different anti-hypertensive regimens. We will better serve patients by individualizing selection of anti-hypertensive drugs rather than prescribing the same medication for all patients."

The NewYork Weill Cornell Medical Center, located in Manhattan on the Upper East Side at York Avenue and 68th Street, comprises NewYork-Presbyterian Hospital and Weill Cornell Medical College.