PHARMACOLOGY

NITRIC OXIDE ::

Nitric oxide is one of the many substances released in vascular endothelium it acts as key signalling mechanism in the cardiovascular and nervous systems and has a role in host defence 

    The physiological function of NO was first discovered in the vasculature when it was shown that the endothelium -derived relaxing factor described by furchgott and Zawadzki in 1980 could be quantitatively accounted for by the formation of NO by endothelial cells it was discovered independently that NO is the endogenous activator of soluble guanylate cyclase leading to the formation of cyclic GMP (cGMP) which functions as a second messenger in many cells including nerves smooth muscle monocytes and platelets 

Biosynthesis of Nitric Oxide 

Bacteria generate NO from nitric or oxidation of ammonia NO is biosynthesized in mammals by a modified urea cycle that has two important functions a secretory role to regenerate L-arginine for NO synthesis and an excretory role to eliminate excess nitrogen created by cell metabolism The initial step in the biosynthesis of NO is catalyzed by nitric oxide synthase (NOS) NOS are NADPH-dependent oxygenases which require tetrahydrobiopterine FAD and FMN as cofactors The normal level of L-arginine in the body is sufficient for a continuous secretory NO biosynthesis and at present two distinct types of enzymes that catalyse NO Production are known :a) Ca2+ dependent constitutive enzyme or cNOS and b) Ca2+ independent inducible enzymes or iNOS AT least two isoforms of cNOS exist -eNOS present in endothelial cells and nNOS present in neuronal cells There is however some evidence that iNOS from different cell types (macrophages versus liver cells ) demonstrate variable Ca2+ sensitivity Some of the established properties of NOS isoforms are summarized in 

NOS is one of the most regulated enzymes in biology and the structure of NOS reveals numerous regulatory mechanisms