Responses to GABA-A receptor blockade in the hypothalamic PVN are attenuated by local AT1 receptor antagonism.
Blockade of GABA-A receptors in the hypothalamic paraventricular nucleus (PVN) has been repeatedly shown to increase arterial blood pressure (ABP), heart rate (HR), and sympathetic nerve activity (SNA), but the mechanism(s) that underlies this response has not been determined. Here, we tested whether full expression of the response requires activation of local ANG II AT1 receptors. ABP, HR, and renal SNA responses to PVN microinjection of bicuculline methobromide (BIC; 0.1 nmol) were recorded before and after microinjection of vehicle (saline); losartan (or L-158809), to block local AT1 receptors; or PD123319, to block AT2 receptors. After PVN microinjection of vehicle or PD123319 (10 nmol), BIC significantly (P < 0.05) increased mean arterial pressure (MAP), HR, and renal SNA. However, PVN microinjection of 2 and 20 nmol of losartan dose dependently reduced responses to PVN-injected BIC, with the 20-nmol dose nearly abolishing MAP (P < 0.005), HR (P < 0.05), and renal SNA (P < 0.005) responses. Another AT1 receptor antagonist, L-158809 (10 nmol), produced similar effects. Neither losartan nor L-158809 altered baseline parameters. Responses to PVN injection of BIC were unchanged by losartan (20 nmol) given intravenously or into the PVN on the opposite side. MAP, HR, and renal SNA responses to PVN microinjection of l-glutamate (10 nmol) were unaffected by PVN injection of losartan (20 nmol), indicating that effects of losartan were not due to nonspecific depression of neuronal excitability. We conclude that pressor, tachycardic, and renal sympathoexcitatory responses to acute blockade of GABA-A receptors in the PVN depend on activation of local AT1 receptors.
Chen
Qing Hui
QH
Dept. of Physiology-7756, The Univ. of Texas Health Science Center, 7703 Floyd Curl Drive, San Antonio, Texas 78229-3900, USA.
Toney
Glenn M
GM
D047228:Angiotensin II Type 1 Receptor Blockers; D057912:Angiotensin II Type 2 Receptor Blockers; D000818:Animals; D000959:Antihypertensive Agents / Q000494:pharmacology; D001640:Bicuculline / Q000031:analogs & derivatives* / Q000494:pharmacology; D001794:Blood Pressure / Q000187:drug effects; D058787:GABA-A Receptor Antagonists; D006339:Heart Rate / Q000187:drug effects; D007093:Imidazoles / Q000494:pharmacology; D007668:Kidney / Q000294:innervation; D019808:Losartan / Q000494:pharmacology; D008297:Male; D010286:Paraventricular Hypothalamic Nucleus / Q000378:metabolism*; D011725:Pyridines / Q000494:pharmacology; D051381:Rats; D017207:Rats, Sprague-Dawley; D044140:Receptor, Angiotensin, Type 1 / Q000378:metabolism; D044139:Receptor, Angiotensin, Type 2 / Q000378:metabolism; D011963:Receptors, GABA-A / Q000378:metabolism; D013564:Sympathetic Nervous System / Q000187:drug effects
D047228:Angiotensin II Type 1 Receptor Blockers; D057912:Angiotensin II Type 2 Receptor Blockers; D000959:Antihypertensive Agents; D058787:GABA-A Receptor Antagonists; D007093:Imidazoles; D011725:Pyridines; D044140:Receptor, Angiotensin, Type 1; D044139:Receptor, Angiotensin, Type 2; D011963:Receptors, GABA-A; C073402:PD 123319; C036615:bicuculline methobromide; D019808:Losartan; D001640:Bicuculline