Drugs Inhibiting Endothelial Activation

Mycophenolate mofetil (MMF) is converted to mycophenolic acid, the active form of the drug. The active product inhibits cytosine monophosphate dehydrogenase and, secondarily, inhibits T-cell lymphocyte proliferation downstream, it interferes with leukocyte adhesion to endothelial cells through inhibition of E-selectin, P-selectin, and intercellular adhesion molecule 1. MMF s pharmacokinetics and toxicities are discussed in Chapter 55. 

Halichlorine (1) (Fig. 11.1) is an alkaloid which was isolated from the marine sponge H. okadai Kadota (Kuramoto et ah, 1996). This compound was revealed to be a novel alkaloid containing an azaspiro[4.5]decane skeleton clarified by detailed spectroscopic analyses. The absolute stereostructure was confirmed by many synthetic studies (Arimoto et ah, 1998 Clive et ah, 2005 Liu et ah, 2009 Trauner et ah, 1999). Halichlorine was shown to inhibit the induction of vascular cell adhesion molecule-1 (VCAM-1) in cultured human umbilical vein endothelial cells. Drugs that block the inflammatory stimuli-induced expression of VCAM-1 may be useful for treating atherosclerosis, coronary artery diseases, angina, and noncardiovascular inflammatory diseases (Kock et ah, 1995). We introduce here the recent aspects of the biological and physiological activities of halichlorine. 

Blood vessels receive no direct innervation from the parasympathetic nervous system. However, parasympathetic nerve stimulation dilates coronary arteries, and sympathetic cholinergic nerves cause vasodilation in the skeletal muscle vascular bed (see Chapter 6 Introduction to Autonomic Pharmacology). Atropine can block this vasodilation. Furthermore, almost all vessels contain endothelial muscarinic receptors that mediate vasodilation (see Chapter 7 Cholinoceptor-Activating Cholinesterase-Inhibiting Drugs). These receptors are readily blocked by antimuscarinic drugs. 

---