In this proposal the applicant will test the hypotheses that the presence of a hypertension genetic permissive factor must be present for this background alone is not sufficient for expression and that the major antihypertensive mechanisms of action of ACE inhibitors is related to an alteration in brain All stores and/or metabolism or to an alteration in the brain All receptor. Breeding pairs of SHR and WKY will be treated with CAP and offspring will either be maintained on CAP until experimentation or taken off CAP (OFFCAP) at 2 months of age and kept off CAP (OFFCAP) until experimentation (5 and 9 months of age). The project is divided Into the following specific aims:
Aim 1 : to determine whether or not lack of expression of the morbid phenotype persists in subsequent generations.
Aim 2 : to determine whether a reduction in blood pressure in SHR dams leads to lack of expression of the morbid phenotype in offspring.
Aim 3 : to determine whether or not the postnatal environment, through chemical mediators secreted in the milk or psychobehavioral factors (nursing) lead to lack of expression of the morbid phenotype in offspring. For these studies, the applicant will breed SHR who received short term CAP treatment (in utero to 2 mo of age) and their progeny out to F4-F5 generations; they will also treat SHR dams with hydralazine, an antihypertensive agent different from CAP and rear offspring from in utero CAP- treated with untreated SHR females and vice versa, respectively.
Aim 4 : to determine whether or not the antihypertensive effect of captopril related to or accompanied by alterations in brain All content and/or metabolism and/or decreased number, affinity or subtype of brain All receptors.
Aim 5 : to determine whether or not the antihypertensive effect of CAP is related to alterations in vasopressin (AVP) synthesis, content, release and/or AVP binding in the brain. Brain All and AVP will be characterized biochemically (RIA and HPLC), via molecular biology techniques (Northern and slot blot analyses of mRNA for components of the RAS and All receptor subtypes and AVP), immunocytochemically, and functionally (drinking and pressor responses to Al and All and AVP). Radioligand binding and autoradiographical studies will be performed to characterize All and AVP binding in brains from control and CAP-treated SHR and WKY and progeny. Findings from this proposal should lead to new information concerning the role of brain RAS in the pathophysiology of hypertension and the factors important in the antihypertensive action of ACE inhibitors.
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