pituitrin and nipecotic-acid

Previous studies in this laboratory have shown that GABAergic neurotransmission in the nucleus tractus solitarius contributes to the maintenance of blood pressure. Increasing the synaptic action of GABA in the nucleus tractus solitarius by injection of the blocker of the uptake of GABA, nipecotic acid elevated blood pressure. The current studies examined the subtype of GABA receptor involved in mediating this response. Bilateral injections of (-)baclofen into the nucleus tractus solitarius (1-100 pmol in 100 nl) of chloralose-anesthetized, paralyzed, ventilated Sprague-Dawley rats increased blood pressure without significantly altering heart rate. This pressor response was neither attenuated nor blocked by the selective GABAA receptor antagonist bicuculline. Similarly, the pressor response elicited by the injection of nipecotic acid into the nucleus tractus solitarius was totally unaffected by the GABAA receptor blockade with bicuculline. Since nipecotic acid acts by potentiating the action of synaptic GABA, and the GABA present presumably can interact with both GABAA and GABAB receptors, the observation that bicuculline did not block or attenuate the pressor response to nipecotic acid suggests that the pressor response to the enhanced synaptic action of GABA in the nucleus tractus solitarius can be produced independently of the involvement of GABAA receptors, and presumably is mediated through an action on GABAB receptors.

Topics: Animals; Baclofen; Bicuculline; Blood Pressure; gamma-Aminobutyric Acid; Hemodynamics; Injections; Male; Medulla Oblongata; Nipecotic Acids; Proline; Rats; Rats, Inbred Strains; Receptors, GABA-A; Vasopressins

gamma-Aminobutyric acid (GABA) has been identified in axon terminals innervating neurons of the supraoptic nucleus and has been shown to inhibit the electrical activity of supraoptic neurons when applied iontophoretically. This study examines the effects of GABA and GABA antagonists on vasopressin (VP) release from organ-cultured explants of the hypothalamo-neurohypophyseal system (HNS). The GABA antagonists bicuculline and picrotoxin stimulated VP release in a concentration-dependent manner. These observations suggest that VP release by HNS explants is tonically inhibited by GABA. Exposure of HNS explants to GABA (10(-8)-10(-3) M) did not consistently alter basal VP release. This was true even when penicillin, which can block GABA-activated chloride channels, was omitted from the medium. Similarly, nipecotic acid, an agent that potentiates GABA activity by inhibiting GABA uptake, did not alter basal VP release; stimulation of VP release by acetylcholine and increases in osmolality was not diminished by the addition of 10(-5) M GABA. The failure of exogenous GABA to modify basal and stimulated VP release suggests that GABAergic inhibition of VP release is maximally activated by endogenously released GABA in cultured HNS explants. This is consistent with evidence for a local source of GABA in the supraoptic nucleus and suggests that one role of GABA in the regulation of VP release is that of a potent local inhibitory neurotransmitter.

Topics: Acetylcholine; Animals; Bacitracin; Bicuculline; Chlorides; GABA Antagonists; gamma-Aminobutyric Acid; Hypothalamus; Ion Channels; Male; Nipecotic Acids; Organ Culture Techniques; Osmolar Concentration; Penicillins; Picrotoxin; Pituitary Gland, Posterior; Proline; Rats; Rats, Inbred Strains; Vasopressins

GABAergic agents microinjected into the nucleus tractus solitarius (NTS) influence blood pressure (BP) and plasma vasopressin (VP) levels. The direct-acting GABAergic agonist muscimol (3.75-160 pmol) microinjected bilaterally into the NTS of chloralose-anesthetized, paralyzed, ventilated rats increased BP without significantly altering heart rate. Similar results were obtained using the indirect GABA agonist nipecotic acid (10 nmol), a GABA uptake blocker. In contrast, blocking the action of GABA with bicuculline (5 pmol) elicited a small but consistent decrease in BP. Injections of the vehicle (artificial cerebrospinal fluid) into the NTS or GABAergic agents in an area lateral to the NTS did not alter BP. Unilateral injection of muscimol into the NTS did not elicit immediate pressor responses as did bilateral injections; unilateral muscimol injections following destruction of the contralateral NTS produced a pressor response similar to that seen following bilateral muscimol administration. Stimulation of GABA receptors within the NTS by either muscimol or nipecotic acid resulted in an increase in plasma VP levels. The elevated levels of plasma VP contributed to the pressor response elicited by stimulation of GABAergic receptors as evidenced by the decrease in BP observed following the intravenous administration of a VP pressor antagonist during the pressor response. These studies indicate that tonically active GABAergic mechanisms within the NTS influence BP and VP release, and provide further evidence that VP can be involved in cardiovascular responses elicited from the NTS.

Topics: Animals; Bicuculline; Blood Pressure; gamma-Aminobutyric Acid; Heart Rate; Male; Medulla Oblongata; Muscimol; Nipecotic Acids; Pressoreceptors; Proline; Rats; Rats, Inbred Strains; Vasopressins

Previous studies have shown that hypotension produced by drugs facilitating gamma-aminobutyric acid (GABA) transmission was caused by a decrease in sympathetic nervous system outflow. We attempted to determine if GABA agonists and GABA uptake inhibitors could also lower arterial pressure that was elevated by increasing the secretion of endogenous vasopressin. GABA and nipecotic acid, an uptake inhibitor of GABA, were administered intraventricularly to determine the cardiovascular effects of these agents in nephrectomized rats made acutely hypertensive with hypertonic saline. A 2-hr i.v. infusion of hypertonic saline (3.0 mEq/ml) increased arterial pressure from 119 +/- 2 to 157 +/- 2 mm Hg. Intraventricular administration of artificial cerebrospinal fluid, 100 micrograms of GABA and 175 micrograms of nipecotic acid produced a peak decrease in blood pressure of 0 +/- 0, 30 +/- 4 and 22 +/- 3 mm Hg, respectively. In nephrectomized rats receiving an equal volume of isotonic saline (0.15 mEq/ml), infused i.v. arterial pressure did not change. In these animals, central infusions of artificial cerebrospinal fluid, 100 micrograms of GABA and 175 micrograms of nipecotic acid decreased blood pressure only 1 +/- 1, 13 +/- 2 and 8 +/- 3 mm Hg, respectively. Further experiments utilizing nephrectomized rats infused with hypertonic saline were designed to determine the mechanism for the augmented depressor response produced by these agents. Elimination of the contribution of vasopressin to arterial pressure with a vascular vasopressin antagonist reduced the depressor responses produced by 100 micrograms of GABA and 175 micrograms of nipecotic acid to 10 +/- 3 and 8 +/- 3 mm Hg, respectively.(ABSTRACT TRUNCATED AT 250 WORDS)

Topics: Aminobutyrates; Animals; Blood Pressure; gamma-Aminobutyric Acid; Heart Rate; Male; Nephrectomy; Nipecotic Acids; Osmolar Concentration; Proline; Rats; Rats, Inbred Strains; Saline Solution, Hypertonic; Sodium; Sympathetic Nervous System; Vasopressins