Interactions between the rostral ventral medulla and other central sites involved in vasomotor regulation.

We showed earlier that the rostral ventral medulla can be functionally and anatomically divided into the rostral ventrolateral medulla (RVLM) and the rostral ventromedial medulla (RVMM). In this study, we examined the relationship between the lateral hypothalamus and these two medullary sites. Electrical stimulation of the lateral hypothalamus produced a pressor response mediated by increases in renal and mesenteric vascular resistance. Inactivating RVLM had no effect on this response whereas inactivating RVMM significantly blunted the pressor response and the increases in renal and mesenteric resistance. In other studies, inactivating dorsomedullary sites significantly reduced arterial pressure. Unlike RVLM, these depressor responses were not significantly altered by reducing tidal volume. Inactivating sites 0.5 mm medial and lateral to the RVMM, as well as a site 0.5 mm caudal to the RVLM, resulted in depressor responses that were unaffected by reducing tidal volume. However, inactivation of a site 1.0 mm caudal to the RVLM but still within the ventrolateral medullary pressor area, resulted in a depressor response that was enhanced by reduced tidal volume. Together, these data demonstrate a functional differentiation of medullary sites controlling vasomotor outflow.

Neonatal capsaicin treatment abolishes the nociceptive responses to intravenous 5-HT in the rat.

The intravenous (i.v.) administration of serotonin (5-HT) to lightly pentobarbital-anesthetized rats is known to produce a triad of reflex cardiovascular responses, distinct afferent-mediated pseudaffective reactions, and a vagally mediated inhibition of the nociceptive tail-flick (TF) reflex consistent with 5-HT acting as a noxious stimulus. In the present experiments we examined the involvement of capsaicin-sensitive afferents in mediating these responses. Lightly pentobarbital-anesthetized 16-week-old male Sprague-Dawley rats which had been treated as neonates (in the first 48 h of life) with capsaicin (50 micrograms/kg, s.c.) were compared to age-matched neonatal vehicle-treated controls. Whereas the i.v. administration of 5-HT produced a dose-dependent (6-96 micrograms/kg, i.v.) inhibition of the nociceptive TF reflex (ED50 = 48.1 +/- 11.3 micrograms/kg; n = 7) and distinct pseudaffective responses (usually by 24-48 micrograms/kg) in vehicle-treated rats, 5-HT (6-192 micrograms/kg, i.v.) failed to significantly alter TF latency or produce pseudaffective behaviors in the capsaicin-treated rats (n = 10). There was no difference in baseline TF latencies between the two groups. There were essentially no differences between vehicle- and capsaicin-treated rats with respect to the initial cardiopulmonary vagal afferent-mediated (Bezold-Jarisch reflex) decreases in heart rate and arterial blood pressure or the subsequent pressor phase. However, the magnitude of the late hypotensive phase was significantly greater in capsaicin-treated rats.(ABSTRACT TRUNCATED AT 250 WORDS)

Coronary vasoconstriction during stimulation in hypothalamic defense region.

Previous studies have identified a site in lateral hypothalamus (LH) in which electrical stimulation elicits coronary vasoconstriction. We injected the retrogradely transported tracer Fast Blue to determine which brain regions project to LH. Projections to or through LH were found from the paraventricular nucleus (PVN) of the hypothalamus, bed nucleus of the stria terminalis (BNST), and dorsal raphe nucleus (DRN). In chloralose-anesthetized cats, electrical stimulation in DRN and BNST failed to increase coronary vascular resistance (CVR). However, stimulation lateral to PVN in the anterior hypothalamic area (AHA), a region not labeled by the tracer, caused a transient decrease in coronary blood flow similar to that elicited from LH. The increase in CVR was accompanied by hemodynamic changes that are characteristic of the defense reaction including a cholinergically mediated decrease in hindquarter vascular resistance. This response is likely due to activation of fibers of passage and not cell bodies, since cell bodies in the region were not retrogradely labeled and coronary vasoconstriction was not seen following microinjection of several excitatory amino acids into AHA. These data suggest that coronary vasoconstriction may be a component of the defense reaction elicited by electrical activation of AHA.

Connections between hypothalamus and medullary reticular formation mediate coronary vasoconstriction.

We have recently identified discrete sites within the lateral hypothalamus and medullary reticular formation that, when stimulated electrically, produce neurally mediated coronary vasoconstriction. This study examined whether these sites are part of the same coronary vasomotor pathway. The neuronal tracing dye fast blue was injected in cats into the coronary vasoconstrictor site within medullary reticular formation. Fluorescence microscopy revealed major afferent projections originating from within the same region of midbrain ventrolateral periaqueductal gray that receives projections from lateral hypothalamus. To determine the functional importance of the proposed connections between the hypothalamic and medullary sites, anesthetized cats were prepared for continuous hemodynamic measurements. Constant current electrical stimulation within lateral hypothalamus produced significant increases in heart rate (21 +/- 6%), arterial pressure (11 +/- 3%), and femoral (36 +/- 18%) and coronary resistances (14 +/- 9%) with no change in coronary flow velocity (-1.1 +/- 2.5%). After beta-adrenoreceptor blockade, significantly greater increases in arterial pressure (35 +/- 8%) and coronary resistance (39 +/- 5%) with transient decreases in coronary flow velocity (21 +/- 6%) were seen. Microinjections of lidocaine into the medullary site blocked coronary constriction produced by lateral hypothalamic stimulation (39 +/- 5% increase in coronary resistance to electrical stimulation before and 2.4 +/- 2% increase after lidocaine in medullary reticular formation). These data provide evidence that specific regions of lateral hypothalamus and medullary reticular formation are part of a common central vasomotor projection that mediates coronary vasoconstriction in addition to other hemodynamic effects.

Electrical stimulation in perifornical lateral hypothalamus decreases coronary blood flow in cats.

Based on evidence implicating the central nervous system in the regulation of coronary vascular resistance and the knowledge that the hypothalamus is a central site for integration of cardiovascular control, studies were undertaken to determine if electrical stimulation in the hypothalamus produced coronary vasoconstriction. In anesthetized cats, following beta-adrenergic receptor blockade, stimulation in perifornical lateral hypothalamus produced a transient decrease in coronary blood flow velocity (30 +/- 5%), a small pressor effect (7 +/- 2 mmHg), and an initial decrease in hindquarter blood flow velocity (51 +/- 5%). The decrease in coronary flow velocity, which had an onset latency of 1-3 s and a duration of 5-15 s, was abolished by ipsilateral stellate ganglionectomy and by intravenous and intracoronary prazosin. The coronary vasoconstriction produced by hypothalamic stimulation was not different from that produced by cardioaccelerator nerve stimulation. These results suggest that electrical stimulation of a hypothalamic site produces an alpha-adrenergic receptor-mediated decrease in coronary blood flow that is unmasked by beta-adrenergic receptor blockade, requires the integrity of ipsilateral cardiac sympathetic innervation, and mimics the coronary response to cardioaccelerator nerve stimulation.

Selective destruction of renal afferent versus efferent nerves in rats.

Previous anatomic studies demonstrated that afferent projections from the left kidney of the rat passed predominantly through the dorsal roots of spinal segments T10-L1. Selective destruction of renal afferent nerves, without damaging renal efferent nerves, was attempted by severing the dorsal roots carrying the afferent fibers. In anesthetized rats, the dorsal left side of the spinal cord was exposed through a partial laminectomy at vertebral sections T10-L1; and the dorsal roots were carefully isolated and cut. Four to ten days after surgery, arterial pressure and hindquarter vascular resistance were maximally reduced by 14 +/- 2 mmHg and 42 +/- 1%, respectively, during electrical stimulation of renal afferent fibers in sham-operated rats. In rats with selective dorsal rhizotomy no significant changes in arterial pressure or hindquarter vascular resistance were observed after renal afferent nerve stimulation. Renal vasoconstrictor responses to electrical stimulation of the left greater splanchnic nerve or posterior hypothalamic area were not different between sham and rhizotomized rats. These data demonstrate that severing dorsal roots T10-L1 cause a functional afferent denervation of the kidney, without impairing renal efferent nerve function.

Selective antagonism of humoral versus neural vasoconstrictor responses by nisoldipine.

The effects of nisoldipine administration on vascular reactivity to humoral and neural vasoconstrictor stimuli were examined in the intact rat. For these experiments, rats were instrumented with miniaturized pulsed Doppler flow probes to allow continuous measurement of renal, mesenteric, and hindquarters blood flow. In conscious and anesthetized rats, intravenous doses of angiotensin II (75 and 150 ng/kg), norepinephrine (0.6 and 1.2 microgram/kg), and epinephrine (0.6 and 1.2 microgram/kg) caused dose-dependent increases in arterial pressure and renal and mesenteric vascular resistance. Nisoldipine (0.7 microgram/min) administration significantly attenuated (p less than 0.05) the pressor and regional vasoconstrictor actions of all three circulating pressor agents; however, nisoldipine infusion had little effect on neurally mediated regional vasoconstrictor responses elicited by electrical stimulation of the posterior hypothalamus or greater splanchnic nerve. These data indicate that nisoldipine depressed vascular responsiveness to humoral vasoconstrictor agents, while neural vasoconstrictor responses were unaffected. Thus nisoldipine appears to exert preferential antagonistic effects on humoral rather than on neural vasoconstrictor stimuli.

Central nervous system action of angiotensin during onset of renal hypertension in awake rats.

The increase in arterial pressure and vascular resistance during acute unilateral renal artery stenosis (RSt) in conscious rats is, in part, dependent on elevated neurogenic vascular tone produced by an indirect neural interaction of angiotensin II (ANG II) with the sympathetic nervous system. The present experiments examined whether this interaction occurs within the central nervous system. Conscious rats that had been chronically instrumented with miniaturized Doppler flow probes for measurement of regional vascular resistance were subjected to a 50% reduction in unilateral renal flow with an implanted pneumatic occluder. Arterial pressure increased by 35% after 60 min of RSt. In animals in which the pressor response to intracerebroventricular (icv) ANG II had been eliminated by prior surgical interruption of the "ANG II pressor pathway" in the anterior hypothalamus, the increase in blood pressure following RSt was attenuated by 44% (P less than 0.01). In a second series, a central action of ANG II during acute renal hypertension (RH) was assessed by central ANG II receptor blockade with icv saralasin. Unlike normotensive controls, acutely RH animals responded to saralasin with significant (P less than 0.01) decreases in arterial pressure (-32%) and hindquarters (-26%) and contralateral renal (-9%) resistance. These changes were accentuated (-57% decrease in pressure) in animals made areflexic by prior sinoaortic baroreceptor denervation. Thus activation of the sympathetic nervous system during the early high-renin phase of RH depends significantly on a central action of ANG II. This mechanism may account for some 40-50% of the pressure increase following acute RSt.

Preoptic-hypothalamic periventricular lesions reduce natriuresis to volume expansion.

The present experiment was designed to determine if electrolytic ablation of the periventricular tissue surrounding the anteroventral third ventricle (AV3V) altered the natriuresis typically seen during isotonic volume expansion. Control and AV3V-lesioned rats received intravenous infusions of 0.9% NaCl at 0.5 ml/min until 10% body weight was given. Arterial blood pressure was monitored, and urine was collected throughout the experiment. Following expansion, blood was processed for analysis of natriuretic hormonelike activity by chromatographic separation of plasma extracts followed by measuring antinatriferic activity across the isolated toad bladder. Urinary sodium excretion and urine volume during expansion were significantly less in rats with lesions surrounding the AV3V region than in control rats. Toad bladder bioassay showed a high level of natriuretic hormonelike activity in control animals following volume expansion, but no natriuretic hormonelike activity in plasma from volume-expanded rats with AV3V lesions. These data demonstrate that AV3V periventricular ablation attenuates the natriuresis induced by isotonic-volume expansion. In addition, preliminary results indicate the AV3V region may be a central site critical for natriuretic hormonelike activity and control of extracellular fluid volume.

Effect of lesions of the anteroventral third ventricle (AV3V) on the development of hypertension in spontaneously hypertensive rats.

Lesions of the anteroventral third ventricle (AV3V), an angiotensin and osmosensitive region of the anterior hypothalamus, prevent or abort hypertension in a number of rat models. To determine if AV3V lesions alter hypertension in spontaneously hypertensive rats (SHR), lesions and control sham lesions were made in young SHR at 28 days of age. AV3V lesions had no effect on the development of hypertension in SHR. However, lesioned rats demonstrated significantly reduced pressor responses to intracerebroventricular injections of angiotensin II (AII) and hypertonic NaCl, and drinking produced by centrally administered AII. The depressor effect of central AII receptor blockade was also significantly attenuated in lesioned SHR. These effects appeared to be of central origin since the lesion did not affect the pressor action of intravenous AII or norepinephrine (NE). It is concluded that unlike other models of experimental hypertension (steroid-salt, one-and two-kidney renal, neurogenic) the development of hypertension in SHR does not depend upon the integrity of the AV3V region.

Localization of the anterior hypothalamic angiotensin II pressor system.

Previous studies by this laboratory have shown that an electrolytic lesion of tissue surrounding the anteroventral third cerebral ventricle (AV3V) produces pressor deficits to both intravenously (i.v.) and intracerebroventricularly (i.c.v.) administered angiotensin II (AII). These studies were designed to identify the neural substrates critical to the central AII pressor response. The AII pressor system was mapped employing a spectrum of overlapping electrolytic lesions within the medial preoptic-anterior hypothalamic area. The effect of each lesion on the pressor response to AII (i.c.v.) was tested in each animal, which was then grouped as a responder (R) or nonresponder (NR). The extent of damage produced by lesions that abolished the AII response was mapped. Bilateral destruction of tissue along the lamina terminalis (LT) either below or at the level of the anterior commissure eliminated the AII pressor response as did destruction of tissue near the margin of the preoptic and anterior hypothalamic nuclei. These data suggested that an AII pressor pathway originating in the ventral AV3V region ascends along the LT to the level of the anterior commissure and then descends through the anterior hypothalamus. The path of the descending projection through the anterior hypothalamus was ascertained by making a series of horizontal knife cuts. Transections were found that effectively eliminated the central AII pressor response without impinging upon the LT. It is concluded that the anterior hypothalamus contains an efferent pathway from the AV3V region associated with the central AII pressor response.

Ultrastructural effects of anteroventral third ventricle lesions on supraoptic nuclei and neural lobes of rats.

Small lesions of the tissue surrounding the anterior ventral third ventricle (AV3V) cause adipsia, but there is no compensatory antidiuretic response. Therefore, the fine structure of the supraoptic nucleus and neural lobe, the major sites of synthesis and release of antidiuretic hormone (ADH), were compared in rats rendered adipsic by AV3V lesions 3 days earlier, rats deprived of water for 3 days and rats drinking normally. In sham-lesioned rats which were deprived of water, neuronal somas in the supraoptic nucleus show signs of stimulated secretory activity. However, the neuronal somas of supraoptic nuclei of rats which did not drink because they were made adipsic by AV3V lesions resemble those of normally hydrated controls. Neural lobes of water deprived animals contain a sharply reduced number of neurosecretory granulated vesicles and reduced apposition of glial processes with the perivascular connective tissue compared to those of normally hydrated rats. In contrast, neural lobes of rats with AV3V lesions contain large accumulations of densely packed neurosecretory vesicles, as well as abundant dense bodies and multilamellar bodies which may be evidence of increased crinophagy, and they have increased interposition of glial processes between axon endings and the perivascular connective tissue. In rats with AV3V lesions the severe dehydration due to adipsia was unable to stimulate release of ADH. The accumulation of neurosecretory vesicles in the neural lobe indicates that transport of ADH to the neural lobe was not impaired in this time period, but that exocytosis of ADH-containing neurosecretory vesicles in the neural lobe was blocked.

Capsaicin treatment in adult Wistar-Kyoto and spontaneously hypertensive rats: effects on nociceptive behavior and cardiovascular regulation.

Effects of s.c. capsaicin pretreatment on nociception, mean systemic arterial blood pressure, and dose-response curves for depressor effects of substance P (SP) and pressor effects of angiotension II (AII) and norepinephrine (NE) were examined in normotensive Wistar-Kyoto (WKY) and spontaneously hypertensive rats (SHR). Capsaicin pretreatment significantly elevated hot plate and tail flick latencies in SHR subjects but was without effect in WKY rats. Capsaicin pretreatment significantly reduced mean systemic arterial blood pressure in rats of both strains. Both vehicle- and capsaicin-treated WKY subjects exhibited greater depressor responses than did subjects of the corresponding SHR groups after i.v. SP administration. Vehicle-treated SHR subjects exhibited greater pressor responses to both AII and NE than did rats of the vehicle-treated WKY group. Capsaicin treatment decreased the sensitivity of WKY rats to the pressor effects of both AII and NE. Strain differences involving nociception, cardiovascular regulation, and responses to capsaicin may underly the results reported.

Prevention of renal hypertension and of the central pressor effect of angiotensin by ventromedial hypothalamic ablation.

Various lines of research have implicated the central nervous system in the development of renal hypertension. The ablation of a periventricular region surrounding the anteroventral third ventricle (AV3V) has been shown to block the development of renal hypertension. Because of hemodynamic effects produced by AV3V electrical stimulation can be abolished by a midline lesion of the ventromedial hypothalamic--median eminence region (VMH-ME), the effect of VMH-ME ablation on the development of renal hypertension was studied. Following recovery from surgery that destroyed the VMH-ME region the lesioned rats and controls were subjected to unilateral nephrectomy and figure-of-eight wrapping of the remaining kidney. Control animals developed renal hypertension but those with VMH-ME lesions did not. When the pressor response produced by intracerebroventricular injections of angiotensin II was studied, it was found that rats with VMH-ME lesions, as compared to neurologically intact animals, showed significantly attenuated responses. The data suggest that a neural system related to cardiovascular control descends through the VMH-ME region and that the integrity of this pathway is necessary for the development of renal hypertension.

Fine structural evidence of degeneration in supraoptic nucleus and subfornical organ of rats with lesions in the anteroventral third ventricle.

Lesions of the tissue surrounding the anteroventral third ventricle (AV3V) alter mechanisms controlling body fluid homeostasis and hemodynamics. A period of adipsia and impaired antidiuresis follows AV3V destruction, which causes lesioned animals to become severely dehydrated. In lesioned rats, mechanisms maintaining water balance appear to be refractory to angiotensin and osmotic stimuli. To further investigate the neural basis for the observed alterations in body fluid balance, the supraoptic nucleus (SON) and subfornical organ (SFO) of rats with adipsia-producing lesions in the AV3V were examined by electron microscopy. In SONs of lesioned rats, degenerating fibers and terminals were present. Degenerating axonal terminals were seen in both axodendritic and axoaxonal synapses on magnocellular neurosecretory cells. These affected terminals in the SONs of lesioned rats may arise from osmoreceptors and angiotensin receptors which have somas or fibers in the lesioned area. Some fibers containing neurosecretory granulated vesicles also underwent degeneration. Neuronal somas displaying retrograde degenerative changes were present in SFOs after AV3V lesions. Degenerating fibers, some of which may be fibers of passage through the SFO, were common. However, little evidence of degenerative changes was seen in axon terminals in the SFOs. The evidence that lesions in the AV3V damaged an efferent projection field of the SFO is discussed in light of reports that AV3V lesions destroy responses in which the SFO is believed to participate.