New Myosin-Blocking Drug Reopens Blocked Capillaries After Heart Attacks and Kidney Injury

One of the most frustrating paradoxes in modern medicine is that reopening a blocked artery does not always save the tissue it supplies. Cardiologists can thread a catheter through a coronary occlusion and restore flow in the large vessel, yet blood still fails to reach the microscopic vessels where oxygen exchange actually happens. This phenomenon, known as capillary no-reflow, has been recognized for more than fifty years, first described in dog hearts in 1974, and it remains one of the strongest predictors of death and reinfarction after acute myocardial infarction. Despite its clinical importance, no targeted therapy has ever existed. Now, a study published in Nature reports that a rationally designed small molecule, R(+)2501, can selectively relax the contractile cells that clamp capillaries shut during ischaemia, rapidly restoring microvascular flow and dramatically improving survival in animal models of heart attack and acute kidney injury.

The culprit behind no-reflow, according to the research team led by Máté Pénzes, Máté Winternitz and Ádám I. Horváth of Motorpharma and Eötvös Loránd University in Budapest, is not the endothelium lining the vessel wall but a population of contractile cells called pericytes that wrap around capillaries. Pericytes have long been known to regulate capillary diameter in the brain, and earlier work by David Attwell’s group and others showed that ischaemia triggers them to hypercontract, squeezing the capillary lumen closed. Crucially, once constricted, pericytes do not simply relax when the artery is reopened; they remain locked in a contracted state, keeping blood flow at a standstill even as pressure builds behind them. The Hungarian-led team, working with structural biologist Anne Houdusse at Institut Curie in Paris and cardiologist C. Michael Gibson at the Baim Institute in Boston, reasoned that the molecular motor driving this hypercontraction, smooth muscle myosin, could be drugged directly.

Myosin is the ATP-fuelled motor protein that generates force in muscle cells, and inhibiting it systemically would be catastrophic, since cardiac and skeletal muscle depend on their own myosin isoforms. The challenge was therefore one of exquisite selectivity. The team screened matched pairs of enantiomers, mirror-image versions of candidate compounds, across smooth muscle myosin and cardiac muscle myosin, and found that R(+) derivatives consistently showed selective inhibition of the smooth muscle isoform. The lead compound, R(+)2501, belongs to a family of CLN derivatives and binds an allosteric site that only exists in the pre-hydrolytic state of the smooth muscle myosin motor domain, a conformation the motor adopts before it commits to its power stroke. By trapping the motor in this state, the drug prevents the pericyte from generating contractile force.

The structural basis of this selectivity was nailed down by X-ray crystallography. The researchers solved the structures of smooth muscle myosin bound to both R(+)2501 and its mirror-image counterpart S(−)2501, depositing the coordinates in the Protein Data Bank under accession codes 29ZY and 29ZZ. Electron density maps, including polder maps contoured at high sigma levels, showed unambiguous density for the entire compounds, including their chiral hydroxyl groups. Comparison with the previously characterized inhibitor CK-571 revealed that R(+)2501 occupies a related but distinct pocket, with specific residues exclusive to its binding. A structure–activity analysis across more than a hundred CLN derivatives confirmed that the R(+) configuration at the bridgehead chiral position was the decisive determinant of smooth muscle myosin selectivity over cardiac myosin, providing a molecular explanation for why the drug can paralyse pericyte contraction without weakening the heart.

Selectivity in a dish is one thing; selectivity in a living body is another. Using two-photon microscopy, a technique that allows researchers to watch individual red blood cells moving through capillaries in real time, the team directly visualized what happened when R(+)2501 was injected intravenously. In rat models of acute kidney injury induced by renal artery occlusion, peritubular capillaries that had been completely stalled after an hour of ischaemia sprang back to life within seconds to minutes of drug administration. Red blood cell velocity and flux returned to the healthy range, and in some cases exceeded it, within six minutes of treatment. The effect was strikingly durable: even after the drug itself had been rapidly cleared from the circulation, capillary flow remained restored, suggesting that the compound breaks the pathological hypercontracted state rather than merely holding the vessel open pharmacologically.

Ex vivo experiments confirmed the mechanism directly. In a supplementary video that is likely to become a teaching classic, a capillary segment ensheathed by a fluorescently labelled pericyte constricts sharply when the vasoconstrictor endothelin-1 is applied, and then relaxes almost immediately when R(+)2501 is added, restoring the lumen diameter. In isolated Langendorff-perfused hearts, ventricular capillaries dilated in response to the drug and returned to baseline after washout. The kinetics were equally telling: capillary relaxation had a half-life of roughly 0.4 minutes, far faster than the relaxation observed in larger arteries such as the basilar, femoral or common carotid arteries, which responded weakly or not at all. This vessel-size dependence is what makes the compound capillary-selective, acting where it is needed while sparing the resistance vessels that maintain systemic blood pressure.

The functional consequences in disease models were dramatic. In a pig model of acute myocardial infarction, in which the left anterior descending coronary artery was occluded and then reperfused, vehicle-treated animals showed persistent capillary stalling, pathological Q-waves on the electrocardiogram and progressive cardiac decline. Animals receiving an intravenous bolus of R(+)2501 maintained near-normal ECG patterns at two hours of reperfusion, and red blood cell velocity and flux in myocardial capillaries rose significantly above both reperfusion and vehicle levels. Survival after the reperfusion phase was markedly improved in a dose-dependent manner. Importantly, the drug preserved coronary autoregulation and systemic haemodynamics: measurements of left ventricular pressure–flow loops, heart rate, stroke volume and contractility indices in healthy rats showed no marked changes at therapeutic doses, indicating that the heart’s own pumping machinery was untouched.

The kidney results carried an equally important message about a broader clinical problem. The team found that acute myocardial infarction itself induced capillary no-reflow in the kidneys, and that R(+)2501 reversed it. This observation links capillary no-reflow to cardiorenal syndrome type I, the condition in which acute heart failure precipitates kidney injury, a syndrome with high mortality and no effective targeted treatment. The timing data from the kidney experiments also revealed a sobering therapeutic window: kidneys tolerated only about ten minutes of occlusion before significant no-reflow developed, and beyond twenty to thirty minutes the capillary flow deficit became increasingly refractory to reperfusion alone. After sixty minutes of occlusion, untreated capillaries were completely blocked. R(+)2501 could reopen even these refractory vessels, and the degree of capillary flow restoration correlated closely with measured kidney function, as assessed by estimated glomerular filtration rate, twenty-four hours later.

Why does restoring capillary flow matter so much beyond simply delivering oxygen? The study provides a mechanistic answer: neutrophils. During no-reflow, white blood cells become physically trapped in the constricted capillaries, and their accumulation is an early driver of reperfusion injury, the paradoxical damage inflicted when blood supply returns. By reopening the capillaries, R(+)2501 cleared the trapped neutrophils, linking the resolution of no-reflow to the attenuation of this inflammatory cascade at its source. This positions pericyte-targeted myosin inhibition not merely as a plumbing fix but as an intervention that interrupts the ischaemic cascade itself, potentially limiting the downstream tissue death that current reperfusion strategies cannot prevent.

Safety data presented in the study are encouraging for a compound intended for acute, high-stakes use. Genotoxicity assessments, including in vivo micronucleus tests at intravenous doses up to 100 milligrams per kilogram and Ames reverse mutagenicity tests with and without human liver fractions, showed no chromosome aberrations or mutations. Tissue concentrations of the drug remained below approximately 0.3 micromolar across all examined organs two hours after injection, and cage-side observations at very high doses did not reveal marked adverse effects. The work, funded by the Hungarian National Research Development and Innovation Office, the British Heart Foundation, CNRS and the French National Research Agency, establishes smooth muscle myosin inhibition in pericytes as a new therapeutic principle: that the capillary, long treated as a passive tube, is in fact an actively regulated and pharmacologically targetable segment of the circulation, and that unlocking it may be the key to making reperfusion therapy finally deliver on its promise across the heart, kidney and beyond.

Subject of Research: Capillary-selective vasodilation via smooth muscle myosin inhibition to reverse no-reflow after myocardial infarction and acute kidney injury

Article Title: Capillary-selective vasodilation through myosin inhibition halts ischaemic cascades

Article References: Capillary-selective vasodilation through myosin inhibition halts ischaemic cascades. (n.d.). https://doi.org/10.1038/s41586-026-11171-6

Image Credits: AI Generated

DOI: 10.1038/s41586-026-11171-6

Keywords: capillary no-reflow, pericytes, smooth muscle myosin, R(+)2501, myocardial infarction, acute kidney injury, reperfusion injury, vasodilation, microcirculation, cardiorenal syndrome, X-ray crystallography, two-photon microscopy