Fifteen years of losartan: what have we learned about losartan that can benefit chronic kidney disease patients?

Losartan, the first AT1 receptor blocker (ARB), was FDA approved 15 years ago. During those years, researchers and clinicians have developed a growing base of knowledge on the benefits of losartan, particularly for hypertension and renal disease. These benefits include decreasing proteinuria, slowing the progression of diabetic nephropathy, controlling hypertension, and decreasing stroke risk in patients with left ventricular hypertrophy. Although many of the benefits of losartan represent a class effect for ARBs, losartan has pharmacokinetic and pharmacodynamic characteristics and effects that are unique and are not a class effect. For example, a shorter duration of action is seen with this first ARB compared with other more recently approved ARBs. Losartan also has a uricosuric effect not seen in other ARBs and attenuates platelet aggregation, which is not seen or is seen to a lesser extent with the other ARBs. This review presents the physiological effects of losartan on the kidney and discusses relevant clinical outcomes.

Adrenomedullin stimulates somatostatin and thus inhibits histamine and acid secretion in the fundus of the stomach.

Adrenomedullin has recently been localized to enterochromaffin-like (ECL) and chief cells in the gastric fundus. It has been proposed that adrenomedullin may play a role in gastric mucosal defense and repair. In the present study, we have used the isolated, luminally perfused mouse stomach and superfused rat fundic segments to examine the effect of adrenomedullin on exocrine and endocrine secretion in this region of the stomach. Addition of adrenomedullin (1 pM to 1 microM) to the isolated mouse stomach caused a concentration-dependent decrease in acid secretion. The EC(50) value was 1.4 x 10(-9) and maximal inhibition of acid secretion was obtained at a concentration of 1 microM (31+/-4% below basal level, P<0.001). In rat fundic segments, superfusion with adrenomedullin (0.1 pM to 0.1 microM) caused a concentration-dependent increase in somatostatin secretion (EC(50), 1 x 10(-10)) that was accompanied by a reciprocal decrease in histamine secretion (EC(50), 1.2 x 10(-11)). Maximal stimulation of somatostatin secretion (60+/-5% above basal level, P<0.001) and inhibition of histamine secretion (50+/-5% below basal level, P<0.01) was obtained at a concentration of 0.1 microM. Changes in acid and histamine secretion induced by adrenomedullin reflected changes in somatostatin secretion and could be abolished by addition of somatostatin antibody. The axonal blocker, tetrodotoxin, also abolished the somatostatin and, consequently, the acid and histamine responses to adrenomedullin, implying that the effect of adrenomedullin on somatostatin secretion was mediated via activation of intramural neurons. We conclude that adrenomedullin, acting via intramural fundic neurons, stimulates somatostatin and thus inhibits histamine and acid secretion. This represents one mechanism by which adrenomedullin might enhance mucosal defense and repair.