Steven L. Bealer

Noradrenergic control of central oxytocin release during lactation in rats

Noradrenergic systems regulate the systemic release of oxytocin (OT) in lactating rats. However, a role for norepinephrine (NE) in release of OT within the magnocellular nuclei during suckling has not been established. These studies were designed to determine 1) if suckling induces NE release in the supraoptic (SON) and paraventricular (PVN) nuclei of conscious rats and 2) the role of NE in the central, intranuclear release of OT within these nuclei. Female Holtzman rats were implanted with microdialysis probes adjacent to the PVN or SON on lactation days 8- 12. The following day, the pups were isolated from the dams for 4 h. Microdialysis probes were perfused with artificial cerebrospinal fluid (ACSF) or with ACSF containing an α- or a β-adrenergic receptor antagonist. Dialysate was collected before, during, and after suckling and analyzed for NE or OT. In an additional experiment, an α- or β-adrenergic agonist was administered via the microdialysis probes into the PVN in nonsuckled, lactating rats. Extracellular NE increased in the PVN during suckling but was not detectable in the SON. OT concentrations in dialysates from the PVN and SON significantly increased during suckling. Blockade of either α- (in both PVN and SON) or β- (PVN) adrenergic receptors prevented the suckling-induced increase in central OT release. OT release was increased in nonsuckled, lactating rats by central application of either an α- or β-adrenergic agonist. These data demonstrate that intranuclear NE release is increased in the PVN by suckling and that subsequent stimulation of both α- and β-noradrenergic receptors mediates intranuclear OT release.

Hypothalamic Histamine Release, Neuroendocrine and Cardiovascular Responses during Tuberomammillary Nucleus Stimulation in the Conscious Rat

Neuronal histamine (HA) in the central nervous system (CNS) has been implicated in control of peripheral cardiovascular and neuroendocrine responses. The tuberomammillary nucleus (TMN) of the posterior hypothalamus contains all CNS HA cell bodies. In these experiments, the TMN was electrically stimulated in conscious rats and HA release in the region of the supraoptic nucleus (SON) was estimated using in vivo microdialysis. In addition, mean arterial blood pressure (MAP), heart rate (HR), and plasma concentrations of norepinephrine (NE) and vasopressin (VP) were measured before, during and following TMN stimulation. Stimulation of the TMN resulted in a significant increase in extracellular HA (110 +/- 29% control) in the region of the SON. MAP, HR and plasma NE concentration were also significantly elevated during TMN stimulation. However, plasma VP concentrations were unchanged. These results show that TMN stimulation in conscious animals releases HA in the region of the SON and is associated with a pressor response, tachycardia, and increased plasma concentration of NE, but not release of VP.

Central depressor action of nitric oxide is deficient in genetic hypertension

Inhibition of NO synthase (NOS) in the central nervous system (CNS) causes a pressor response. This observation indicates that NO is normally produced at CNS site(s) where it has a tonic blood pressure lowering effect. The current study tests the hypothesis that a deficient NOS activity in the CNS may contribute to the pressure elevation in genetically hypertensive rats. NO administered intracerebroventricularly (ICV) caused a greater fall in mean arterial pressure (MAP; femoral artery) in hypertensive (SHRSP) than in normotensive (WKY) rats, -66.1 +/- 3.4 mm Hg v -23.7 +/- 3.9 mm Hg, respectively. Yet when endogenous NO was increased by stimulating NOS with ICV calcium, the depressor response was less in SHRSP than in WKY, 13.7 +/- 1.1 mm Hg v 26.7 +/- 1.9 mm Hg. Likewise, when NOS was blocked with N omega- nitro-L-arginine methyl ester (L-NAME), the resultant pressor response was less in SHRSP than in WKY, 13.8 +/- 1.1 mm Hg v 22.2 +/- 1.1 mm Hg. Blockade of the action of cGMP, a mediator of the action of NO, caused a pressor response of 6.0 +/- 2.8 mm Hg and 22.6 +/- 8.7 mm Hg (P < .01) in the hypertensive and normotensive rats, respectively. Electrolytic ablation of the anteroventral third cerebral ventricle (AV3V) did not alter blood pressure responses to NO or to agents that alter NOS activity. We conclude that a deficit in NOS activity in some other central cardiovascular regulatory area may contribute to the elevated arterial pressure of these genetically hypertensive rats.

Histaminergic Control of Oxytocin Release in the Paraventricular Nucleus during Lactation in Rats

The central neurotransmitters regulating both systemic and central release of oxytocin (OT) during lactation are not completely defined. Although central histaminergic systems have been implicated in systemic release of OT, the role of this neurotransmitter in suckling-induced intranuclear OT secretion has not been investigated. Therefore, microdialysis of the paraventricular nucleus (PVN) was used to determine if suckling stimulates histamine release within the PVN and if nursing-induced intranuclear OT release is reduced by local blockade of either H1 or H2 histamine receptors. Female Holtzman rats were implanted with microdialysis probes adjacent to the PVN on lactation days 8-12. The next day, the pups and dam were separated for 4 h, reunited, and again separated. Histamine concentrations in dialysates were measured before, during, and following suckling. In separate animals, a similar separation/reunion paradigm was used, but the dialysate OT concentration was measured during PVN perfusion with vehicle or an H1 or H2 receptor antagonist. Suckling increased dialysate concentrations of both histamine and OT in the PVN. Furthermore, local pharmacological blockade of either H1 or H2 receptors prevented the increase in OT release in the PVN during suckling. These data demonstrate that activation of histamine receptors in the PVN is necessary for intranuclear release of OT induced by suckling and extend previous findings demonstrating a similar relationship between central histamine and systemic release of OT.

Selective antagonism of hormone-induced vasoconstriction by synthetic atrial natriuretic factor in the rat microcirculation.

Synthetic atrial natriuretic factor (ANF) was either added to suffusate solutions (30 nM) or infused into the jugular vein (0.1 nanomol/min/100 g) of anesthetized rats. Steady-state blood flow was calculated from arteriolar diameter and red blood cell velocity measurements using video microscopy in the intestinal or skeletal muscle microcirculation. Arterioles demonstrated spontaneous vasomotor tone by dilating to topical adenosine, but topical or intravenous ANF did not cause vasodilation. Either angiotensin, norepinephrine, or vasopressin was added to the suffusates in the presence or absence of a cyclooxygenase inhibitor (30 microM, meclofenamate or indomethacin) because each agonist is known to stimulate vasoactive prostanoid synthesis. In the intestine, angiotensin (500 nM) caused 40 +/- 2% blood flow decreases during intravenous saline but only 23 +/- 6% during intravenous ANF. Angiotensin (162 nM) and a cyclooxygenase inhibitor caused 19 +/- 4% blood flow decreases but only 8 +/- 5% decreases with cyclooxygenase inhibitor and topical ANF. In contrast, norepinephrine (2-5 microM) caused vasoconstriction that was not altered by topical or intravenous ANF, either alone or in combination with cyclooxygenase inhibitors. In the spinotrapezius muscle, angiotensin (1-2 nM) plus a cyclooxygenase inhibitor caused 40-60% blood flow decreases but only 20-30% decreases during intravenous or topical ANF. Topical or intravenous ANF did not alter the vasoconstriction evoked by arginine vasopressin (0.5-1.0 nM) or by norepinephrine (40-230 nM). Thus, supraphysiologic concentrations of ANF produced no direct vasodilation in the intestinal or skeletal muscle microcirculation.(ABSTRACT TRUNCATED AT 250 WORDS)

Differential responses in adrenal and renal nerves to CNS osmotic stimulation.

Hypertonic solutions act in the central nervous system (CNS) to increase mean arterial blood pressure (MAP) by activation of the sympathoadrenal axis. However, adrenal nerve activity (pre- and postganglionic nerve fibers) has not been determined during central osmotic stimulation. Therefore, these experiments evaluated adrenal (AdSNA) and renal (RSNA) sympathetic nerve activity, MAP, and heart rate (HR) following CNS administration of isotonic, hypertonic, and hypotonic sodium chloride solutions in chloralose-anesthetized rats. Injection of isotonic saline (5 microliters) did not alter MAP, HR, RSNA, or AdSNA. However, injection of hypertonic saline (5 microliters of 0.5 M) into the anteroventral portion of the third cerebral ventricle increased MAP (12 +/- 2 mmHg) and decreased HR (16 +/- 6 bpm). In addition, hypertonic saline significantly decreased RSNA (58 +/- 5% control), whereas AdSNA increased (158 +/- 10% control). Injection of hypotonic (5 microliters of 0.05 M) NaCl produced the opposite responses in RSNA (119 +/- 7% control) and AdSNA (86 +/- 5% control) and had no significant effect on MAP or HR. Furthermore, pre- and postganglionic adrenal nerve fibers responded similarly to changes in CNS osmolality. These results demonstrate that osmotic stimulation produces differential responses in RSNA and AdSNA, but not in pre- and postganglionic adrenal nerve fibers.

Preoptic recess noradrenergic receptors control modification of baroreflex sensitivity by hypertonicity

These studies examined the effects of alpha1- and alpha2-adrenoreceptor blockade in the anteroventral portion of the third cerebral ventricle (AV3V) on modification of baroreflex-induced changes in heart rate and renal sympathetic nerve activity (RSNA) induced by hyperosmolality. Local administration of hypertonic artificial cerebrospinal fluid (aCSF) in the AV3V significantly increased baroreflex-induced bradycardia during intravenous phenylephrine but did not alter changes in RSNA during the pressor response or alter tachycardia and neural responses evoked by decreased blood pressure. The enhanced cardiac response was not observed during simultaneous administration of phentolamine (alpha1- and alpha2-antagonist) or yohimbine (selective alpha2-antagonist) in the AV3V region. However, treatment with prazosin (alpha1-antagonist) did not alter the exaggerated cardiac response evoked by hypertonic aCSF to increased blood pressure. These data demonstrate that acute, local hypertonic stimulation in the AV3V region selectively enhances baroreflex-induced bradycardia by stimulation of alpha2-adrenergic receptors during acute pressor responses.These studies examined the effects of α1- and α2-adrenoreceptor blockade in the anteroventral portion of the third cerebral ventricle (AV3V) on modification of baroreflex-induced changes in heart rate and renal sympathetic nerve activity (RSNA) induced by hyperosmolality. Local administration of hypertonic artificial cerebrospinal fluid (aCSF) in the AV3V significantly increased baroreflex-induced bradycardia during intravenous phenylephrine but did not alter changes in RSNA during the pressor response or alter tachycardia and neural responses evoked by decreased blood pressure. The enhanced cardiac response was not observed during simultaneous administration of phentolamine (α1- and α2-antagonist) or yohimbine (selective α2-antagonist) in the AV3V region. However, treatment with prazosin (α1-antagonist) did not alter the exaggerated cardiac response evoked by hypertonic aCSF to increased blood pressure. These data demonstrate that acute, local hypertonic stimulation in the AV3V region selectively enhances baroreflex-induced bradycardia by stimulation of α2-adrenergic receptors during acute pressor responses.

Anteroventral Third Ventricle Periventricular Tissue Contributes To Cardiac Baroreflex Responses

1. The studies reviewed in the present paper demonstrate that the anteroventral third ventricle (AV3V) region contains tissue that can modify cardiac baroreflex sensitivity in response to circulating angiotensin (Ang)II and hyperosmolality.

Neurotransmitter Interaction in Release of Intranuclear Oxytocin in Magnocellular Nuclei of the Hypothalamus

Abstract: Oxytocin (OT) is released within the paraventricular (PVN) and supraoptic (SON) nuclei of the hypothalamus in response to several stimuli. However, the neurotransmitters that control this intranuclear OT release are unknown. In vivo microdialysis was used to examine the roles of norepinephrine and histamine in intranuclear OT release in conscious, lactating female rats. Administration of α‐ or β‐noradrenergic agonists, or histamine, increased OT release in the PVN. In addition, the increase in PVN OT evoked by exogenous histamine was prevented by simultaneous blockade of either H1 or H2 receptors. Furthermore, histamine‐induced release of intranuclear OT was also prevented by blockade of α‐adrenergic receptors. Finally, the increase in magnocellular OT release induced by suckling was abolished by administration of α‐adrenergic antagonists. These data demonstrate that norepinephrine and histamine are important neurotransmitters for release of intranuclear OT, and histamine releases intranuclear OT by stimulating norepinephrine release.

Systemic angiotensin II alters intrinsic heart rate through central mechanisms.

Angiotensin II (ang II)-induced increases in intrinsic heart rate (IHR), and the resulting tachycardia, may contribute to development of renal hypertension. Whether circulating ang II affects the cardiac pacemaker through peripheral mechanisms or through actions in the central nervous system (CNS) has not been directly tested. These studies determined the role of a central site of ang II action, the tissue surrounding the anteroventral third ventricle (AV3V), in increased IHR induced by systemic ang II. Blood pressure and heart rate were measured in male rats with lesions of the AV3V region and in control-operated animals during i.v. infusion (3 h) of ang II, norepinephrine, or vehicle. IHR was evaluated at the end of the infusion period. Systemic ang II increased blood pressure equally in both experimental groups. However, heart rate was reduced only in animals with AV3V lesions. Furthermore, ang II increased IHR only in control-operated rats. Changes in blood pressure, heart rate, and IHR in response to norepinephrine infusion were similar between animals with AV3V lesions and control-operated rats. These data demonstrate that systemic ang II mediates IHR through actions in the CNS, specifically the AV3V region.