Hypertension renin-dependent

Potent peptide antagonists of the action of Ang II are available. The best-known of these is the partial agonist, saralasin. Saralasin lowers blood pressure in hypertensive patients but may elicit pressor responses, particularly when circulating Ang II levels are low. Because it must be administered intravenously, saralasin is used only for investigation of renin-dependent hypertension and other hyperreninemic states. 

The normative approach to the practice of medicine, based on the definition of thresholds, is a different paradigm from the continuous distribution of most biological parameters and their associated risks, as described by physiologists and epidemiologists (360-362). Blood pressure, cholesterol, and renin have a logarithmic gaussian distribution in populations. Renin dependency, for instance, may be considered as a constant feature of all humans except when they have a positive sodium balance, which more or less mimics schematic animal models such as DOCA hypertension (349). In this extreme situation, cardiac, renal, and vascular damages may be direcdy induced by the excess of salt itself, in the absence of any functional RAS (363). 

Bohlender, J., Hildenbrand, U., Wagner, K.D., Gunther, J., Hempel, P., Schlegel, W.P., Luft, F.C., Krause, E.G., and Bartel, S. 2001. Myocardial adrenergic dysfunction in rats with transgenic, human renin-dependent hypertension. J. Hypertens. 19 1453-1463. 

ACE inhibitors and AT -receptor blockers are most useful in hypertension when the raised blood pressure results from excess renin production (e.g. renovascular hypertension), or where concurrent use of another drug (diuretic or calcium blocker) renders the blood pressure renin-dependent. The fall in blood pressure can be rapid, especially with short-acting ACE inhibitors, and low initial doses of these should be used in patients at risk those with impaired renal function, or suspected cerebrovascular disease. These patients may be advised to omit any concurrent diuretic treatment for a few days before the first dose. The antihypertensive effect increases progressively over weeks with continued adminis-... 

If the blood pressure is still not controlled, a second agent should be added, using the opposite pair to the first drug e.g. if the patient is on an ACE inhibitor add a Calcium channel blocker or thiazide Diuretic (A+C or A+D), since both vasodilatation or diuresis will stimulate the renin-angiotensin system and turns nonrenin-dependent hypertension into renin-dependent hypertension). The combination B+D is associated with increased risk of diabetes and should be avoided in at-risk patients (obesity, family history). The combinations A+B or C+D usually produce a less than additive effect on blood pressure, but should be tried in patients still uncontrolled on more standard combinations. 

Interpretation Responses must be defined for the assay technique used. Patients with renin-dependent forms of hypertension (e.g., renovascular hypertension) show values that are approximately five times normal. Stimulated responses are also seen in patients with high-renin essential hypertension, pheochromocytoma, and Barttei s syndrome. Patients with hypertension firom mineralocorticoid excess (e.g., primary aldosteronism) usually have PRA below the concentration of assay sensitivity. Patients with hyporeninemic hypoaldosteronism usually have low concentrations of plasma renin and low aldosterone concentrations. Figure 51-17 shows typical responses. 

ACE inhibitors alone normahze blood pressure in -50% of patients with mild-to-moderate hypertension. Ninety percent of patients with mild-to-moderate hypertension will be controlled by the combination of an ACE inhibitor and either a Ca + channel blocker, a p adrenergic receptor blocker, or a diuretic. Diuretics in particular augment the antihypertensive response to ACE inhibitors by rendering the blood pressure renin-dependent. 

In patients with essential hypertension, indomethacin, given by in intramuscular injection at 1 mgkg increases blood pressure and total peripheral vascular resistance associated with diminution of cardiac output". However, reports that indomethacin, given orally at 75-200 mg day for 4-7 days, increases blood pressure in patients with untreated, uncomplicated, essential hypertension contrasts with reports that it does not . Cyclo-oxygenase inhibitors, indomethacin and ibuprofen, were also without effect on blood pressure in patients with renovascular hypertension . Yet, in two siblings with renin-dependent hypertension and aldosteronism, the administration of indomethacin at 250 mg day for 16 days was found to lower blood pressure and plasma renin activity, despite promoting slight retention of salt and water ... 

Aliskiren is the most advanced of these and the first to be approved for the treatment of hypertension. In healthy subjects, aliskiren produces a dose-dependent reduction in plasma renin activity and Ang I and II and aldosterone concentrations. In patients with hypertension, many of whom have elevated plasma renin levels, aliskiren suppresses plasma renin activity and causes dose-related reductions in blood pressure similar to those produced by ACE inhibitors (Figure 17-3). The safety and tolerability of aliskiren appear to be comparable to angiotensin antagonists and placebo. 

A test dose should be given to patients who are in cardiac failure (or who are already taking a diuretic for another reason, e.g. hypertension). Maintenance of blood pressure in such individuals may depend greatly on an activated renin-angiotensin-aldosterone system and a standard dose of an ACE inhibitor can cause a catastrophic fall in blood pressure. Except for captopril, most ACE inhibitors (including enalapril) are prodrugs, which are inactive for several hours after dosing. This has favoured the use of captopril... 

Mogensen CE, Neidam S, Tikkanen I, Oren S, Viskoper R, Watts RW, et al. Randomised controlled trial of dual blockade of renin-angiotensin system in patients with hypertension, microalbuminuria, and non-insulin dependent diabetes the candesartan and lisinopril microalbuminuria (CALM) study. BMJ 2000 321 1440-4,... 

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