text: In 1898, the physiologist Robert Tigerstedt and his student, Per Bergman, experimented with rabbits by injecting them with kidney extracts. Their results suggested the kidneys produced a protein, which they named renin, that caused a rise in blood pressure. In the 1930s, Goldblatt conducted experiments where he constricted the renal blood flow in dogs; he found the ischaemic kidneys did in fact secrete a chemical that caused vasoconstriction. In 1939, renin was found not to cause the rise in blood pressure, but was an enzyme which catalyzed the formation of the substances that were responsible, namely, angiotensin I (Ang I) and Ang II.
  In the 1970s, scientists first observed Ang II to harm the heart and kidneys, and individuals with high levels of renin activity in plasma were at increased risk of myocardial infarction and stroke.
  With the introduction of angiotensin converting enzyme (ACE) inhibitors in the late 1970s it was confirmed that Ang II plays an important role in regulating blood pressure and electrolyte and fluid balance.
  Before that attempts had been made to develop useful Ang II receptor antagonists and initially, the main focus was on angiotensin peptide analogues. Saralasin and other Ang II analogues were potent Ang II receptor blockers but the main problem was a lack of oral bioavailability.
  In the early 1980s it was noted that a series of imidazole-5-acetic acid derivatives diminished blood pressure responses to Ang II in rats. Two compounds, S-8307 and S-8308, were later found to be highly specific and promising non-peptide Ang II receptor antagonists but using molecular modeling it was seen that their structures would have to mimic more closely the pharmacophore of Ang II. Structural modifications were made and the orally active, potent and selective nonpeptide AT receptor blocker losartan was developed. In 1995 losartan was approved for clinical use in the United States and since then six additional ARBs have been approved. These drugs are known for their excellent side-effects profiles, which clinical trials have shown to be similar to those of placebos.