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New Treatments for Hypertension: JNC-VI

The Joint National Committee issued its 6th report (JNC VI) in 2006. One unchanged area was its recommendations regarding first line therapy for hypertension. The report recommended diuretics and beta blockers as first line therapy for uncomplicated hypertension. Currently, calcium blockers and ACE-inhibitors are the most commonly prescribed antihypertensive agents in the United States.

Hypertension awareness, treatment, and control rates have increased over the past three decades, although they have been relatively flat over the past several years. Blood pressure categories were defined in JNC-VI as optimal (less than 120 over 80), normal (less than 135 over 85), and high normal (130-139/85-89). Lifestyle modification is used as initial therapy for hypertension.

Randomized trials of anti-hypertensive treatment in the elderly have shown a 34% reduction in stroke, a 19% reduction in coronary heart disease, and a 23% reduction in vascular deaths. Compelling indications for specific anti-hypertensive drug therapy are the following: diabetes mellitus type 1 with proteinuria -- ACE-inhibitors; heart failure -- ACE-inhibitors and diuretics; isolated systolic hypertension -- diuretics or long-acting dehidropyridines; myocardial infarction --beta blockers and ACE-inhibitors.

The renin angiotensin system plays an important pathophysiologic role in the development of hypertension and heart failure. The system is diagrammed in the accompanying figure. Angiotensinogen, which is made primarily in the liver, is converted by the enzyme renin, which is made primarily in the kidney, to angiotensin I which is an inactive decapeptide. Angiotensin I is converted primarily by angiotensin converting enzyme (ACE) to angiotensin II. Angiotensin II appears to be the substance which produces all of the adverse effects.

Since the original description of the renin angiotensin system, it is now clear that this system also exists in tissues such as vascular tissue. It is also clear that there are non-ACE pathways.

One of the side effects of ACE-inhibitors is cough which is felt to be due to elevations of bradykinin. These substances are also metabolized by the angiotensin converting enzyme. Thus, ACE-inhibitors increase bradykinin which may lead to cough. However, these substances are also vasodilators which might contribute.

Angiotensin II receptors have been found in vascular smooth muscle, in the adrenal gland, kidney, myocardium, brain, liver, and the uterus and gonads. The effects of the angiotensin II receptor-blockers has been to lower blood pressure in a manner somewhat similar to the ACE-inhibitors. Similarly, in patients with heart failure, the angiotensin II receptor-blockers produce the same acute hemodynamic benefits.

In the recent ELITE Trial, losartan reduced mortality compared to captopril in elderly patients with heart failure. This surprising results raises the possibility that ARB's may have an important role in the management of heart failure -- but this must be confirmed first in future trials.

It appears, therefore, that the angiotensin receptor-blockers provide another important alternative for the management of patients with hypertension. In the future, it is possible that their use may also be extended to heart failure and other areas with indications similar.