I. Drugs to reduce intrahepatic resistance endothelin Endothelin (ET) is one of the most potent vasoconstrictor substances, and there are three isoforms (ET-1, ET-2, and ET-3).ET-1 is synthesized mainly in the liver, and its receptor is most abundant in the hepatic stellate cells (HSCs), which is closely related to the contractile effect of HSCs.ET-1 inhibits the hepatic sinusoidal endothelial cell window Ca2+-Mg2+-ATPase activity and the ET-1 inhibits Ca2+-Mg2+-ATPase activity and Ca2+ pump activity, which ultimately leads to contraction of hepatic sinusoidal endothelial cell window and increase of hepatic sinusoidal pressure.ET synthesis inhibitors and ET-1 receptor antagonists theoretically can reduce portal pressure, and the drugs are currently in the research stage. Yuan Gang, Department of Hepatology, Ningbo Second Hospital, Ningbo, China Nitric oxide (NO) and nitric oxide synthase (NOS) system NO is a vasodilator substance, and cirrhotic liver sinusoidal endothelial cell injury leads to a decrease in NO, which leads to vasoconstriction of the hepatic sinusoidal blood vessels and an increase in intrahepatic resistance. Two classes of drugs are included: 1) Nitrate vasodilators. Nitroglycerin, isosorbide mononitrate, etc. exert vasodilatory effects by releasing NO, and because they lead to adverse effects such as insufficient circulating blood volume, severe hypotension, and even renal insufficiency, the use of nitrates alone to prevent first-time bleeding is not recommended. (2) NOS and related drugs. NOS causes vasodilation mainly through two mechanisms: ① directly increase the concentration of NO; ② cause myosin light chain phosphodiesterase content increase, activity enhancement, leading to myosin light chain dephosphorylation, cross-bridge and actin dissociation, causing smooth muscle cell diastole. Animal experiments showed that all 3 subtypes of NOS (iNOS, nNOS, and eNOS) significantly reduced portal pressure. However, the feasibility of this method for human application still needs to be demonstrated by a large number of experiments. Renin-angiotensin-aldosterone system Both angiotensin II inhibitors (ACEIs) and angiotensin II receptor antagonists (ARBs) can reduce intrahepatic vascular resistance. However, ACEIs have a greater effect on peripheral hemodynamics, especially renal blood flow. Thromboxane A2/prostaglandin-peroxide (TXA2/PGH2) receptor antagonists In cirrhosis, NO bioactivity is diminished and prostaglandin-like products (e.g., thromboxane A2) are increased, which in turn may modulate hepatic vascular tension.TXA2/PGH2 receptor blockade corrects endogenous dysfunction in cirrhosis and increases intrahepatic NO activity. Terutroban, a TXA2/PGH2 receptor antagonist, improves intrahepatic vascular resistance, increases NO bioactivity, and decreases portal pressure.Rosado et al. demonstrated that, compared with placebo, the terutroban-treated group significantly attenuated portal pressure ([15.2±2.0 vs. 17.3±2.0] mm Hg) and intrahepatic vascular resistance ([17.8±5.2 vs. 22.3±7.5] mm Hg/mL-1・min-1), both P < 0.05.JAK2 inhibitor Cirrhotic portal hypertension is partly due to HSC contraction mediating intrahepatic vasoconstriction. Angiotensin II type 1 receptor (AT1R) activation mediates HSC contraction through JAK2/Arhgef1 and ultimately by Rho-kinase. Thus, JAK2/Arhgef1 is associated with AT1R activation, and JAK2 inhibitors reduce portal pressure.AG490, a JAK2 inhibitor, reduces portal pressure by decreasing intrahepatic resistance in a dose-dependent manner. Other factors Vasoactive substances related to the contractile effect of HSC also include cyclooxygenase-2 (COX-2), 5-hydroxytryptamine (5-HX), etc. Theoretically, receptor antagonists of these substances can reduce portal pressure by inhibiting the contractile effect of HSC, but there are few relevant experimental studies. Second, drugs to reduce portal blood flow β-blockers reduce cardiac output by inhibiting β1 receptor, reduce portal blood flow by inhibiting β2 receptor constriction of visceral blood vessels, thus reducing portal pressure, mainly used for esophagogastric fundal varices rupture rebleeding and prevention of the first hemorrhage.NOS inhibitors NOS inhibitors can inhibit peripheral NO production, increase peripheral vascular tension, and play a role in inhibiting the hyperdynamic circulation. Growth inhibitors and their analogs Mainly by inhibiting the secretion of endogenous vasodilating substances, such as glucagon, vasoactive intestinal peptide, and NO, thereby blocking visceral vasodilatation, decreasing portal blood flow, and lowering portal pressure. Vasopressin and its analogs By constricting systemic and visceral blood vessels, it reduces portal blood flow and lowers varicose vein pressure, and is mainly used in the treatment of ruptured varicose vein hemorrhage in esophagogastric fundus of liver cirrhosis. Its derivative terlipressin can significantly slow down the portal venous flow rate, reduce blood flow and cardiac output, and effectively reduce the pressure within the varicose veins. Calcium antagonists Three studies have confirmed the long-term efficacy of the calcium antagonist carvedilol in lowering portal pressure.Bruha and Stanley et al. gave carvedilol (25 mg/d) to 36 and 10 patients, respectively, with a mean HVPG decrease of 16%; Banares gave carvedilol (31 mg/d) to 24 patients with a mean HVPG decrease of 19%. was 19%. Third, combination therapy and other drug studies have confirmed that the efficacy of combination therapy is better than monotherapy, for example, nitrates + vasopressin or nitrates + β-blockers. Chinese herbs and vascular endothelial growth factor inhibitors (sorafenib) have also been used to treat portal hypertension, but sorafenib is not definitively effective in treating portal hypertension, is expensive, and has low clinical utility. The pathophysiologic mechanism of portal hypertension remains unclear, and there are no safe and effective drugs. Ideal drugs should have the characteristics of selectively acting on the visceral vascular bed, lowering portal pressure, maintaining effective hepatic perfusion, and improving hepatic function, which may be the focus of future research.