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Guanylyl cyclases (GC) exist as soluble and particulate, membrane-associated enzymes which catalyse the conversion of GTP to cGMP, an intracellular signalling molecule. Several membrane forms of the enzyme have been identified up to now. Some of them serve as receptors for the natriuretic peptides, a family of peptides which includes atrial natriuretic peptide (ANP), brain natriuretic peptide (BNP) and C-type natriuretic peptide (CNP), three peptides known to play important roles in renal and cardiovascular physiology. These are transmembrane proteins composed of a single transmembrane domain, a variable extracellular natriuretic peptide-binding domain, and a more conserved intracellular kinase homology domain (KHD) and catalytic domain. GC-A, the receptor for ANP and BNP, also named natriuretic peptide receptor-A or -1 (NPR-A or NPR- 1), has been studied widely. Its mode of activation by peptide ligands and mechanisms of regulation serve as prototypes for understanding the function of other particulate GC. Activation of this enzyme by its ligand is a complex process requiring oligomerization, ligand binding, KHD phosphorylation and ATP binding. Gene knockout and genetic segregation studies have provided strong evidence for the importance of GC-A in the regulation of blood pressure and heart and renal functions. GC-B is the main receptor for CNP, the latter having a more paracrine role at the vascular and venous levels. The structure and regulation of GC-B is similar to that of GC-A. This chapter reviews the structure and roles of GC-A and GC-B in blood pressure regulation and cardiac and renal pathophysiology.

Immunosuppression of humoral and cellular responses following chronic oral exposure to 1, 5, 10, and 20 ppm N-nitrosodimethylamine (NDMA) was examined in CD-1 mice. Monitoring of cumulative mortality and the incidence of peritoneal ascites in animals showed an NDMA dose-related mortality and hepatotoxicity. No visible changes in immunological parameters were noted at the 1 ppm NDMA dose. Immunosuppression of immunoglobulin M (IgM) antibody response by NDMA to sheep red blood cells (SRBC) was time-related, dose-related, and could be reversed within 30 d by removal of the chemical from the drinking water. Cellular immune response, monitored by allogeneic stimulation of cells in mixed lymphocyte reaction (MLR), was markedly suppressed by 10 and 20 ppm NDMA. Thus, chronic exposure to NDMA, except for the low-hepatotoxic doses of nitrosamine, resulted in a marked and persistent immunosuppression of cellular and humoral responses in CD-1 mice. In conclusion, chronic exposure to the hepatotoxic (ascite-inducing) doses of NDMA suppressed humoral and cellular immunity. The persistent immunosuppression could be reversed after the removal of NDMA from the drinking water. Although no direct NDMA-related cancer was reported in humans, our data point to a potential epigenetic carcinogenicity of nitrosamines due to chronic immunosuppression.

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