Transient antihypertensive drug treatment during the developmental phase of hypertension in spontaneously hypertensive rats (SHR) results in a permanent reduction of MABP following treatment withdrawal. This occurs following withdrawal of the angiotensin converting enzyme inhibitor, captopril and the angiotensin AT1-receptor blocker, L158809, but not following withdrawal of the general vasodilator, hydralazine. In addition, our preliminary data indicate that sympathetic tone is attenuated in the captopril-withdrawn SHR compared to control SHR. Thus, it appears that a reduction of sympathetic tone may contribute to the sustained reduction of MABP. Sympathetic hyperactivity and a deficiency of the inhibitory neurotransmitter, gamma-aminobutyric acid (GABA) have been implicated in the development of hypertension in SHR. Interestingly, hypothalamic GABA content is increased in SHR during chronic antihypertensive treatment with captopril. Inasmuch as GABAergic control of MABP has been reported to be defective in SHR, we are proposing that early transient inhibition of the renin-angiotensin system (RAS) partially restores GABAergic control toward normal. We anticipate that adaptations of the GABAergic system will occur at a genomic level via increased expression of the rate-limiting enzyme in GABA synthesis, glutamic acid decarboxylase, and/or GABA receptor proteins. This proposal is designed to test the hypothesis that the sustained reduction in MABP following early transient inhibition of the RAS in SHR involves a sustained increase in the activity of the GABAergic neurotransmitter system in the paraventricular nucleus (PVN), an important hypothalamic cell group involved in the control of sympathetic nervous system function. SHR will be randomized to either transient or chronic treatment with captopril, L158809, or hydralazine. MABP will be recorded by radiotelemetry, and sympathetic tone will be assessed by ganglionic blockade. PVN GABAergic function will be assessed by microinjection of pharmacological agents aimed at inhibition or stimulation of GABAergic function. In addition, immunohistochemistry and Western blotting techniques will be utilized to probe the PVN for changes in glutamic acid decarboxylase and/or GABA receptor proteins. Results from these studies will provide insight into the role of the GABAergic system in the sustained antihypertensive effect of early transient inhibition of the RAS in SHR.
| Zhou, Xiaosun; Kost Jr, Curtis K (2006) Adenosine A1 receptor antagonist blunts urinary potassium excretion, but not renal hemodynamic effects, induced by carbonic anhydrase inhibitor in rats. J Pharmacol Exp Ther 316:530-8 |
| Song, Jin; Kost Jr, Curtis K; Martin, Douglas S (2006) Androgens potentiate renal vascular responses to angiotensin II via amplification of the Rho kinase signaling pathway. Cardiovasc Res 72:456-63 |
