The Story of S 9490-3
The year is 1985, and in a laboratory, a revolutionary blood pressure medication is being put to the test, not in an anesthetized animal, but in a conscious, freely moving rat. This landmark study would unlock secrets about a drug that would eventually help millions.
Hypertension, or high blood pressure, is often called the "silent killer" for its lack of symptoms and devastating consequences, including stroke, heart failure, and kidney disease. For much of medical history, treating this pervasive condition was a significant challenge. Then came the ACE inhibitors—a class of drugs that would revolutionize cardiovascular medicine. Among them was a promising new compound known as S 9490-3.
This is the story of the pioneering scientific work that uncovered how this drug worked, not in a test tube, but in a living, breathing subject. It's a tale of innovation, meticulous experimentation, and a quest to tame one of humanity's most persistent health threats.
To appreciate the breakthrough, one must first understand the biological system it was designed to correct. The body has a sophisticated system for regulating blood pressure called the Renin-Angiotensin-Aldosterone System (RAAS).
Think of it as the body's built-in blood pressure thermostat. When it senses blood pressure is too low, it produces a hormone called angiotensin II, a powerful substance that causes blood vessels to constrict, thereby increasing pressure. The key enzyme that creates this potent hormone is called Angiotensin-Converting Enzyme (ACE).
In hypertension, this system is overactive, like a thermostat stuck on "high," leading to chronically constricted blood vessels and elevated blood pressure. The logical solution? Find a way to inhibit the ACE enzyme, thus preventing the formation of angiotensin II and allowing blood vessels to relax 2 6 .
Kidneys release renin into bloodstream
Renin converts angiotensinogen to angiotensin I
Angiotensin-Converting Enzyme (ACE) converts angiotensin I to angiotensin II
Angiotensin II causes blood vessels to constrict, raising blood pressure
Drugs like S 9490-3 block ACE, preventing vessel constriction
Before S 9490-3, the first ACE inhibitors, like captopril, had already proven the value of this approach. However, scientists were on a quest to develop even better drugs—ones that were longer-lasting, more potent, and had fewer side effects.
S 9490-3, which would later be known generically as perindopril, was one of these second-generation ACE inhibitors. It belonged to a class called "prodrugs," meaning it was administered in an inactive form. Only after being absorbed by the body was it converted into its active form, perindoprilat, a process that made it more effective 9 . Biochemically, it was a powerhouse, binding to the ACE enzyme with remarkable affinity and blocking its action with high potency 6 .
The 1985 study, titled "Cardiovascular effects of S 9490-3," was groundbreaking not just for the drug it tested, but for the sophisticated way it was conducted 1 .
Earlier pharmacological studies were often performed on anesthetized animals. But anesthesia itself can interfere with the cardiovascular system, masking a drug's true effects. The researchers chose to study conscious, unrestrained rats that had been genetically bred to develop spontaneous hypertension (SHR). This model provided a more realistic and reliable picture of how the drug would behave in a living being with chronic high blood pressure.
The methodology was exceptionally rigorous for its time. Here is a step-by-step breakdown of the experimental procedure:
| Parameter | Effect | Significance |
|---|---|---|
| Systolic BP | Significant decrease | Confirmed antihypertensive action |
| Diastolic BP | Significant decrease | Effect on baseline arterial pressure |
| Duration | ~11 hours | Long-lasting effect, ideal for medicine |
| Heart Rate | No significant increase | Lack of compensatory reflex tachycardia |
Data from the 1985 study in conscious SHR rats 1
| Parameter | Effect | Clinical Implication |
|---|---|---|
| Blood Pressure | Significantly lowered | Effective long-term control |
| BP Variability | Reduced | Lowered cardiovascular risk |
| Heart Rate | Slight increase | Manageable change |
| Left Ventricle Weight | Significantly decreased | Reversal of cardiac hypertrophy |
Data from chronic oral treatment study 3
Follow-up research soon revealed even greater benefits with long-term use. When SHRs were given S 9490-3 orally for 12 days, it not only lowered blood pressure consistently but also reduced the variability of systolic pressure—a known risk factor for organ damage. Remarkably, this chronic treatment also decreased the weight of the left ventricle, reversing the harmful heart thickening (hypertrophy) that hypertension causes 3 . This was a clear sign that the drug wasn't just masking symptoms; it was protecting the heart from damage.
The study of S 9490-3 relied on several key tools and concepts that are fundamental to cardiovascular pharmacology research.
Provides data free from the distorting effects of anesthesia, offering a more truthful representation of drug effects.
Allows for continuous, precise monitoring of blood pressure and heart rate over long periods.
A genetic model that closely mimics human essential hypertension, making results more clinically relevant.
An ingenious chemical strategy where an inactive drug is converted into its active form inside the body.
Catheter implantation in spontaneously hypertensive rats (SHR)
24 hours of continuous blood pressure and heart rate monitoring
Two IV doses of S 9490-3 (0.2 mg/kg and 2 mg/kg)
Another 24 hours of continuous cardiovascular tracking
Computerized analysis of drug effects over the 48-hour period
The promising data from the rat studies was just the beginning. S 9490-3, developed into the drug perindopril, proved to be highly effective in humans. Its prodrug design provided excellent absorption when taken orally 9 . Furthermore, it possessed a unique tissue affinity, meaning it bound strongly to ACE enzymes in critical organs like the heart and blood vessels, which may contribute to its long duration of action and robust protective effects 4 9 .
Unlike earlier ACE inhibitors, perindopril demonstrated a smooth, sustained effect with a low incidence of sharp blood pressure drops after the first dose, a noteworthy safety feature 9 . Its ability to regress vascular hypertrophy—meaning it could help reverse the stiffening and thickening of blood vessels caused by chronic high blood pressure—set it apart as not just a treatment, but a medicine that could repair damage 9 .
Better absorption and conversion to active form in the body
Reverses harmful changes in heart and blood vessels
Sustained 24-hour effect with once-daily dosing
The computerized study of S 9490-3 in conscious rats was more than a successful experiment; it was a demonstration of a more refined, holistic approach to cardiovascular pharmacology. It showed that true understanding comes from observing a drug's action in a system that is as close to the natural state as possible.
The journey of S 9490-3 from a coded compound in a rat lab to the widely used perindopril underscores a profound truth in medicine: groundbreaking clinical triumphs begin with fundamental, meticulous basic science.
The researchers who meticulously tracked the blood pressure of those conscious rats over 48 hours were not just collecting data; they were charting a course toward a therapy that would ultimately safeguard the hearts of millions.
Groundbreaking study in conscious SHR rats
Development of perindopril for clinical use
Widespread clinical adoption
Ongoing research confirms cardiovascular protection