Neuropeptide Y (NPY) with its multiple receptor subtypes is emerging as an important sympathetic regulator of cardiovascular and metabolic functions. Very potent vasoconstrictor and appetite stimulating activities of NPY suggest the physiological importance of this peptide and its involvement in the pathogenesis of hypertension and obesity. Antagonizing specific NPY activities may offer new avenues for treatment these diseases. This project tests the hypothesis that endogenous NPY by activating its own receptor increases vascular tone directly or indirectly by modulating adrenergic transmission to the blood vessels and that an increased chronic expression of the NPY gene will cause the development of hypertension. To test this hypothesis the NPY transgenic of Sprague Dawley rats were generated in which endogenous NPY is overexpressed under its natural promoter allowing for physiological regulation in the constitutive sites. These animals develop persistent hypertension with mildly elevated body weight. Using this model, the role of NPY and its newly discovered receptors in the long-term regulation of cardiovascular functions will be determined.
Four Specific Aims are proposed: (1) Analyze the pattern of NPY overexpression at the protein and mRNA levels in the NPY transgenic male and female rats with particular emphasis on the constitutive sites of endogenous NPY production involved in the cardiovascular regulation; (2a) Determine the effect of NPY overexpression on arterial blood pressure and vascular resistance in male and female rats; and (2b) using available specific NPY receptor antagonists, identify the NPY receptor(s) involved in the development of the hypertension in the NPY transgenic rats; (3) Determine the effect of NPY overexpression on the adrenergic transmission to blood vessels by measuring a) pressor responsiveness to an adrenergic agonist norepinephrine (alpha1/alpha2); and b) (alpha1/ alpha2) responsiveness of the submandibular gland blood flow to supramaximal nerve stimulation; (4) Evaluate the contribution of increased food consumption and body weight to the development of the hypertension in the NPY transgenic rats using a pair feeding approach. This studies will determine the role of endogenous NPY and its receptors in a long-term regulation of blood pressure and the mechanisms of the cooperation between the sympathetic neurotransmitters. The NPY overexpressing rats with well defined mutation of the NPY gene will provide a new transgenic animal model of hypertension; such a model should also be very useful for development of new therapies for treating this diseases.
