Mechanism of Action

The road to statins runs through mouse experiments, Nobel Prize–winning biochemistry, thousands of fungal cultures, and a discovery that nearly never reached patients. In this episode of Mechanism of Action, we continue our cholesterol series with the story of Akira Endo, a Japanese scientist whose fascination with mushrooms and molds helped launch a new era of cholesterol treatment. Inspired by the discovery of penicillin, Endo searched the fungal world for something that could block the body’s cholesterol production. We trace the science from acetate and the cholesterol synthesis pathway to HMG-CoA reductase—the enzyme that became statins’ target. Along the way, we explore the discovery of compactin, disappointing animal experiments, safety concerns that threatened the entire field, and the eventual arrival of lovastatin. Chapters (00:00:00) - Cholesterol Synthesis and the Road to Statins(00:01:18) - Mouse Experiments Reveal Cholesterol Regulation(00:02:43) - Mapping the Cholesterol Synthesis Pathway(00:05:45) - Nobel Prizes and a Promising Drug Target(00:08:07) - Akira Endo’s Fascination with Fungi(00:09:51) - Searching Thousands of Fungal Strains(00:11:07) - Compactin and the Rat Experiment Setback(00:13:20) - Testing Compactin in Patients(00:14:15) - Safety Concerns Halt Development(00:15:45) - Merck, Lovastatin, and the First Approved Statin(00:17:13) - Proving Statins Could Save Lives(00:18:19) - The Discoveries That Changed Cholesterol Treatment

A failed schizophrenia treatment, a vitamin given in massive doses, radioactive rats, and a water-filter resin that became one of the first drugs used to lower cholesterol. In this episode, we trace the strange early history of cholesterol-lowering therapy through niacin and cholestyramine. We begin in a Saskatchewan psychiatric hospital, where researchers experimenting with high-dose niacin as a treatment for schizophrenia stumbled onto an unexpected effect: cholesterol levels fell. That observation helped launch niacin into cardiovascular medicine and eventually contributed to some of the earliest evidence that lowering cholesterol could reduce the risk of heart attack. From there, we follow radioactive cholesterol through laboratory rats as scientists worked out how the body eliminates—and then reabsorbs—cholesterol through the liver, bile, and intestines. That discovery opened the door to an entirely different approach: preventing bile acids from being recycled. The solution came from an unlikely place: ion-exchange resins already used in water treatment. Cholestyramine could trap bile acids inside the intestine and force the body to use more cholesterol to replace them. Together, niacin and cholestyramine helped establish a revolutionary idea that cholesterol wasn't just associated with heart disease, but could be deliberately lowered to reduce cardiovascular risk—setting the stage for the statin era that followed. Chapters (00:00:00) - Niacin, Cholestyramine, and a Saskatchewan Schizophrenia Case(00:03:26) - What Is Niacin? The Story of Pellagra(00:06:51) - Black Tongue Reveals Niacin(00:07:36) - Why Niacin Was Tried for Schizophrenia(00:08:59) - Altschul’s Cholesterol Experiments(00:10:42) - The Coronary Drug Project(00:12:51) - Following Radioactive Cholesterol(00:14:11) - Siperstein and Chaikoff’s Rat Experiments(00:16:36) - Discovering Cholesterol Recycling(00:18:09) - How Cholestyramine Traps Bile Acids(00:19:37) - The First Human Cholestyramine Study(00:20:23) - A Trial Tests Heart Attack Prevention(00:21:31) - Why Cholestyramine Was Hard to Take(00:22:53) - When Doctors Began Treating Cholesterol(00:24:47) - Next: Statins

An eleven-year-old girl, cholesterol-fed rabbits, a wartime centrifuge, and the receptors that transformed our understanding of heart disease. In this episode, we trace how scientists uncovered the connection between cholesterol and atherosclerosis. We begin with an 1889 case involving a young girl covered in xanthomas, then follow cholesterol from its discovery in bile to the fatty plaques found inside diseased arteries. From there, we explore the experiments that showed cholesterol could cause atherosclerosis, the technology that separated HDL from LDL, and the families whose early heart disease revealed the genetics of familial hypercholesterolemia. Finally, we examine the discovery of the LDL receptor and how it transformed our understanding of cholesterol metabolism laying the foundation for modern cholesterol-lowering therapies. Chapters (00:00:00) - Cholesterol: Xanthomas, Blood, and Bile(00:01:07) - The First Case of Familial Hypercholesterolemia(00:02:49) - What Is Cholesterol?(00:03:54) - From Hardening Arteries to Atherosclerosis(00:04:47) - Cholesterol’s Discovery in Bile(00:08:04) - Finding Cholesterol in Arterial Plaques(00:11:12) - Proving the Connection with Rabbits(00:14:25) - High Cholesterol Runs in Families(00:15:47) - Cholesterol Is More Than One Thing(00:17:37) - Discovering HDL and LDL(00:19:01) - Connecting LDL to Heart Disease(00:21:41) - The Discovery of the LDL Receptor

A blood transfusion, a horse-drawn carriage, fish scales, and a rare cancer that transformed our understanding of allergies. In this episode, Dr. Adam J. Brown concludes the asthma series by telling the remarkable story of IgE—the antibody at the center of allergic disease. We begin with a mysterious 1919 case in which a man seemingly developed a horse allergy after a blood transfusion, then follow the pioneering experiments that revealed allergic sensitivity could be transferred through plasma. From there, we piece together the puzzle of allergy by connecting IgE, mast cells, and histamine. You'll discover how allergen-specific IgE triggers the release of histamine, why this pathway is responsible for many allergic reactions and asthma attacks, and how these discoveries paved the way for anti-IgE therapies like omalizumab—changing the treatment of allergic asthma, chronic hives, food allergies, and more. Chapters (00:00:00) - Introduction: The Story of IgE(00:01:09) - The Man Who Acquired a Horse Allergy(00:05:22) - The Fish-Scale Allergy Experiment(00:07:00) - The Search for the Mystery Antibody(00:09:02) - The Discovery of IgE(00:10:36) - A Rare Cancer and Peter Shackford’s Donation(00:12:13) - Histamine, Mast Cells, and Paul Ehrlich(00:16:18) - Connecting IgE, Mast Cells, and Histamine(00:18:23) - How Allergens Trigger Histamine Release(00:20:09) - From IgE Receptors to Omalizumab(00:22:37) - Why Do We Have IgE and Mast Cells?(00:24:33) - Closing Thoughts

Medieval peasants, poisonous rye fungus, racing hearts, and one of the most important inhalers ever invented. In this episode, Dr. Adam J. Brown continues the asthma series with the strange history of beta-2 agonists and albuterol. We begin with ephedra, ephedrine, and early plant-based asthma treatments, then follow the trail through ergot-contaminated rye, Henry Dale’s experiments with ergotamine and adrenaline, and the discovery that the sympathetic nervous system was working through more than one receptor. From there, we trace Raymond Ahlquist’s alpha/beta receptor breakthrough, the rise of epinephrine and isoproterenol as asthma therapies, the asthma death epidemic of the 1960s, and the leap that separated beta-1 from beta-2 receptors. That discovery opened the door to albuterol—an inhaler designed to target the lungs more than the heart, and still one of the most important rescue treatments in asthma. Chapters (00:00:00) - Introduction(00:00:58) - Ephedrine: The Mongolian Asthma Remedy(00:02:26) - Ergot: Medieval Pregnant Cows(00:04:50) - Henry Dale and the Ergot Mystery(00:06:43) - Adrenaline and the Sympathetic System(00:08:24) - The Ergotamine-Adrenaline Paradox(00:11:10) - Ahlquist Discovers Alpha and Beta Receptors(00:12:34) - Early Modern Asthma Treatments(00:13:36) - Isoproterenol and the Asthma Death Epidemic(00:15:16) - Beta-1 vs Beta-2 Receptors(00:15:17) - Albuterol: Modern Rescue Inhaler

Asthma treatment wasn’t always built around inhalers. It once came from poisonous plants, smoke, and a mysterious dream. In this episode, we explore the strange history of anticholinergics, tracing the path from Jimsonweed and belladonna to atropine, acetylcholine, and Otto Loewi’s discovery of “Vagusstoff.” We follow how Loewi’s frog-heart experiment helped prove that nerves communicate through chemical messengers, and how Henry Dale’s work connected those discoveries to the vagus nerve and airway constriction. We examine why early plant-based asthma remedies could open the airways while also causing dangerous side effects, and how that understanding eventually led to modern anticholinergic therapy. This episode reveals how a dream, a frog heart, and a toxic smoke helped shape the pharmacology of asthma. Chapters (00:00:00) - The Dream That Changed Asthma Medicine(00:00:58) - Types of Neurotransmitters(00:02:41) - Dr. Otto Loewi’s Has a Dream(00:04:22) - Smoking Plants for Asthma(00:06:02) - Jimsonweed(00:08:27) - Belladonna(00:11:36) - Atropine Isolated(00:13:26) - The Autonomic Nervous System(00:14:44) - The Vagus Nerve(00:17:36) - The Frog Heart Experiment(00:18:54) - Vagusstoff Becomes Acetylcholine(00:19:42) - Henry Dale and Anticholinergic(00:21:49) - The Problem With Inhaled Atropine(00:22:15) - Modern Anticholinergic Therapy(00:23:56) - Outro

Asthma wasn’t always a diagnosis—it was once just a word for breathlessness. In this episode, we explore how asthma evolved from a nonspecific symptom into a defined disease of the small airways. From early descriptions in Greek medicine to the pathologic insights of Morgagni and the mechanistic thinking of Henry Hyde Salter, we follow the key discoveries that shaped our understanding of asthma. We examine how airway inflammation, bronchospasm, mucus plugging, and allergic responses were gradually identified as central features of the disease. This episode sets the stage for understanding the modern pathophysiology of asthma and the therapies that followed. Chapters (00:00:00) - Opening: Episode Setup(00:01:29) - Story: A Sickly Child in the 1800s(00:05:57) - What Is Asthma? (Modern Definition)(00:06:40) - Asthma Symptoms & Triggers(00:08:55) - Origins of the Word “Asthma”(00:09:55) - Muscle Contractions: Early Clinical Observations(00:13:39) - Allergy & Inflammation: 20th Century Shift(00:14:46) - Animal Models of Asthma(00:18:51) - Human Trials with Histamine(00:20:21) - Closing

From the discovery of a mysterious blood-pressure–lowering effect in the venom of a Brazilian pit viper to the development of the first ACE inhibitor, we trace how scientists transformed a deadly toxin into lifesaving medicine. We follow the work that identified bradykinin-potentiating peptides in snake venom and revealed that angiotensin-converting enzyme could be blocked—leading to the creation of captopril and later drugs such as enalapril and lisinopril. Along the way, landmark experiments and clinical trials showed that ACE inhibitors do far more than lower blood pressure, reshaping the treatment of heart failure and chronic kidney disease by targeting maladaptive activation of the renin–angiotensin–aldosterone system. Chapters (00:00:00) - ACE Inhibitor Story Continues: Shutting off RAAS(00:01:00) - Recap: The RAAS Refresher(00:02:36) - Venom Mystery : Why Pit Viper Bites Cause Hypotension(00:05:02) - Venom and the ACE Connection: John Vane's Lab(00:06:20) - Interview With a Pit Viper: Snake’s Take on Pharma(00:09:18) - Venom Into Medicine: Turning Raw Venom into a Drug(00:10:04) - Captopril: The First ACE Inhibitor(00:11:04) - Better ACE Inhibitors: Captopril to Enalapril to Lisinopril(00:12:35) - Maladaptive RAAS Activation: Heart Failure Activates Renin(00:19:36) - Maladaptive RAAS Activation: Kidney Failure Activates Renin(00:24:24) - Episode Conclusion: ACE Inhibitors Transform Cardiorenal Medicine

From grinding up kidneys and injecting the extracts into animals to the famous Goldblatt clamp experiment, we trace decades of bold science that uncovered the body's most elaborate blood pressure system piece by piece. In part one of a two-part story, we follow the kidney's rise from simple filter to master regulator — through the discovery of renin, the bitter 17-year naming rivalry between Buenos Aires and Cleveland, and the identification of the enzyme that activates it all. Along the way, we encounter a Brazilian pit viper whose venom holds a molecular clue to one of modern medicine's greatest breakthroughs. Chapters (00:00:00) - ACE Inhibitors: A Two-Part Story Begins(00:01:00) - Catching Up: Hypertension, Early Treatments, and Accidental Drugs(00:02:35) - What Is an ACE Inhibitor?(00:03:27) - Step-by-Step RAAS: Renin → Angiotensin → Aldosterone(00:05:43) - Enter the Brazilian Pit Viper: Venom and Hypotension(00:07:45) - Dr. Richard Bright and the Kidney–Heart Connection(00:09:13) - Tigerstedt and the Discovery of Renin(00:10:27) - Wild Inspiration: Brown-Séquard’s Influence(00:11:36) - Rabbit Kidney Extracts and a Pressor Substance(00:13:52) - Goldblatt’s Clip: Renal Ischemia Causes Hypertension(00:16:45) - Buenos Aires Group: What Is the Kidney Secreting?(00:19:00) - Hypertensin vs. Angiotonin: Two Names, One Substance(00:22:09) - Dr. Skeggs: Angiotensin I vs II(00:23:30) - Sodium Chloride and the Hint of ACE(00:24:05) - Recap and Tease for Part Two

From mercury injections in early syphilis and heart failure patients to the discovery of carbonic anhydrase and the rise of sulfa drugs, we follow how physicians first learned to manipulate fluid balance. We also explore the development of acetazolamide and the eventual breakthrough of thiazide diuretics—revealing how observation and experimentation reshaped the treatment of heart failure and high blood pressure. Chapters (00:01:18) - What are diuretics?(00:02:28) - Mercury for congenital syphilis & surprise diuresis(00:08:46) - Mercury’s problems & the need for safer diuretics(00:10:26) - Sulfa drugs & penicillin’s first patient(00:12:24) - Sulfanilamide, acidosis, and the first kidney clues(00:15:01) - Discovery of carbonic anhydrase and its significance(00:17:36) - Designing better carbonic anhydrase inhibitors (Acetazolamide)(00:19:55) - Chlorthiazide and the thiazide era(00:21:26) - Wrap-up