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Cardiovascular and vasopressin (AVP) responses to hemorrhage were studied in rats with lesions of the hypothalamic supraoptic nuclei (SONL). Bleeding caused hypotension and increase in heart rate (HR) and AVP. SONL rats failed to fully recover from bleeding as compared to normal rats. Plasma AVP in SONL rats was in the normal in basal conditions, but failed to increase to levels attained in normal rats throughout the post-hemorrhage period. These data suggest that the supraoptic nuclei are the primary regulatory sites for AVP release in response to hemorrhage and that lack of adequate AVP release significantly retards blood pressure recovery after bleeding.

Catecholamine and vasopressin content were studied in discrete brain nuclei of the Sabra strain of hypertension prone (SBH) and resistant (SBN) rats. Higher concentrations of dopamine, norepinephrine and epinephrine were observed in the median eminence of SBN compared to SBH or controls (SB) rats. Dopamine and epinephrine levels were higher in the lateral septal nucleus of SBH rats as compared to SBN or SB. Vasopressin content in discrete regions along the hypothalamo-pituitary axis was elevated in both SBH and SBN as compared to SB, but were especially elevated in the SBH group. The catecholamine and vasopressin changes found in SBH are different than those described in other genetically hypertensive rats indicating a difference in either the pathogenesis or central response to hypertension of this strain.

Phencyclidine (PCP; 10 mg/kg, s.c.) produced a marked diuresis which occurred without significant changes in solute excretion. This diuresis occurred predominantly within 2 h of PCP injection, and was blocked by pretreatment with vasopressin. The maximum diuresis corresponded temporally to a significant fall in plasma vasopressin and rise in mean arterial pressure. Thus, PCP-induced diuresis is due, at least in part, to suppression of plasma vasopressin. This suppression is probably related to the rise in blood pressure, though direct effects of PCP on the neurohypophysis cannot be excluded.

The following study was designed to test the hypothesis that peripheral blood vessels of vasopressin deficient (Di/Di) rats are less responsive to pressor substances than normal rats. To address this question, pithed Di/Di and normal Long-Evans rats (LE) were exposed to intravenous injections of arginine-vasopressin, angiotensin II and noradrenaline. In addition, blood pressure increments and noradrenaline release in response to spinal cord stimulation in pithed Di/Di and LE rats were studied. The results show no abnormalities in peripheral vascular sensitivity to any of the pressor substances administered, nor was there any change in blood pressure and sympatho-adrenomedullary response to graded stimulation of the sympathetic outflow from the spinal cord. This study suggests that the failure of vasopressin deficient rats to recover from acute hemorrhage is not due to hyporesponsiveness of the peripheral vasculature to pressor agents but, rather, to the deficiency in the direct pressor effect of vasopressin.

Intracerebroventricular (ICV) injections of arginine vasopressin (AVP) in doses of 0.015 nmoles and 0.15 nmoles produced a fall in mean actual pressure heart rate and respiration in pentobarbital anesthetized rats. The changes in mean arterial pressure and respiration after the higher dose were significantly different from saline injection. In contrast, the same doses of AVP given to conscious animals increased both blood pressure and heart rate. Following the 0.15 nmole dose, there was a marked and significant rise in plasma norepinephrine and epinephrine, indicating that activation of the sympathetic nervous system was, at least in part, responsible for the rise in blood pressure. Plasma vasopressin increased by less than 10 pg/ml following injection. Similar doses of a vasopressin pressor antagonist had no significant effect on mean arterial pressure or heart rate. These results indicate that ICV injection of vasopressin has different effects on blood pressure, depending on the presence or absence of anesthesia: depressor responses in the anesthetized animal and pressor responses in the unanesthetized animal.

Two experimental approaches were used to evaluate the importance of the pressor effects of vasopressin in blood pressure recovery following hypotensive hemorrhage. Experiments using homozygous Brattleboro rats demonstrated that the hemodynamic recovery of these animals was subnormal, even though the activation and efficacy of the sympathetic nervous and renin-angiotensin systems were intact. Experiments using an antipressor vasopressin analogue in normal rats during hypotensive hemorrhage demonstrated significantly blunted blood pressure recovery in the presence of the analogue. Thus, both experiments indicate that the pressor effects of circulating vasopressin play an essential role in blood pressure recovery following hypovolemic hypotension induced by hemorrhage.

Intracerebroventricular injections of selective opioid agonists were used to investigate the role of opiate receptor subtypes in cardiovascular function in awake rats. The mu-agonist (D-Ala2,MePhe4,Gly5-ol)enkephalin (1 nmol) caused a prolonged increase in blood pressure and an initial decrease followed by a delayed increase in heart rate. These effects were antagonized by the selective mu-antagonist beta-funaltrexamine. A selective delta-agonist (dimeric tetrapeptide enkephalin) was devoid of cardiovascular effects at 10 nmol, whereas a benzomorphan kappa-agonist MRZ caused a pressor response which was not antagonized by beta-funaltrexamine. The mechanisms by which opioids elicit cardiovascular effects were analyzed in detail by using microinjections into the anterior hypothalamic area. Low doses of enkephalin produced increases in heart rate and blood pressure. Associated elevations of plasma norepinephrine and epinephrine, but not vasopressin, suggested a stimulation of sympatho-adrenomedullary pathways. Higher doses caused increases in blood pressure but decreases in heart rate. Peripheral vagal blockade with atropine methyl nitrate caused a large sudden rise in heart rate, indicating that an increased vagal outflow counteracted the sympathetic activation. Adrenal demedullated rats displayed no tachycardia after anterior hypothalamic injection of low doses of enkephalin, whereas high dose caused pronounced bradycardia. Additional treatment of demedullated rats with the sympathetic blocker bretylium led to severe hypotension in addition to bradycardia. These data provide evidence that mu-opiate receptors primarily mediate cardiovascular effects of opiates in awake rats. At low doses, a sympathetic adrenomedullary activation occurs, whereas higher doses additionally activate parasympathetic efferents, both possibly from anterior hypothalamic sites.

This study examined the cardiovascular, respiratory, and sympathetic effects of selective mu and delta opioid agonists microinjected into the hypothalamic nucleus preopticus medialis (POM) of conscious SHR and WKY rats. The mu receptor agonist D-Ala2-MePhe4-Gly5-ol-enkephalin (DAGO) at a dose of 0.6 or 6.0 nanomoles (Nmol) increased the blood pressure and heart rate in WKY rats. In SHR rats, the lower dose of DAGO similarly had a pressor effect whereas the higher dose was depressor; heart rat was increased only by the 6.0 nmol dose in these animals. In both SHR and WKY rats, this opioid caused respiratory acidosis and elevation of plasma norepinephrine (NE) and epinephrine (E); plasma vasopressin was reduced by the higher dose of DAGO. All of these effects of the mu agonist were reversed by the opiate receptor antagonist naloxone (0.5 mg/kg, i.a.). The delta opiate-receptor agonist D-Ala2-D-leu5-eukephalin at a dose of 6.0 or 20.0 nmol increased blood pressure and heart rate in both SHR and WKY rats without affecting respiratory variables. Plasma NE and EPI were elevated at the peak of the pressor period. These studies suggest that the anteroventral hypothalamic region may be an important site in central autonomic regulation by opioid peptides. The mu-receptor agonist was more potent than the delta agonist in eliciting cardiovascular and respiratory effects and associated sympatho-adrenomedullary activation.(ABSTRACT TRUNCATED AT 250 WORDS)

The anteroventral third ventricle (AV3V) region was shown to be a site of central integration of sympathetic pressor pathways and central pressor and vasopressin (VP) release by angiotensin II (ANG II). Since the AV3V area seems to have an important role in the regulation of the three major pressor systems, we investigated the role of the AV3V in cardiovascular recovery after hemorrhage, a known stimulus for sympathetic, ANG II, and VP release. Conscious AV3V-lesioned (n = 19) and sham-operated rats (n = 14) underwent bleeding (40% of blood volume) through an arterial line. Mean blood pressure, heart rate, and plasma ANG II, VP, and catecholamines were monitored over 24 h. The exact site of lesion was determined by microscopic examination. The mean blood pressure and heart rate of both groups of rats were not different before or after hemorrhage. Plasma catecholamines, ANG II, and VP responses were also the same as were hematocrit and water consumption 24 h after the bleeding. Despite the lack of difference between control and lesioned animals with regard to cardiovascular, humoral, and neuroendocrine responses to hypovolemia, the AV3V-lesioned rats had a significantly higher early mortality rate. These data indicate that the AV3V may be an important region in recuperation and survival after hemorrhagic shock, but through mechanisms unrelated to activation of VP, renin-ANG II, or the sympathetic nervous system.

In order to better understand the function of vasopressin-containing axons which project to areas outside the hypothalamus, we measured vasopressin content in hypothalamic and extrahypothalamic brain regions following various periods of oral hypertonic saline or 1 week after pituitary stalk section. The supraoptic and paraventricular nuclei and nearly all of the brain regions examined which are known to receive vasopressin-containing axons from these nuclei showed parallel changes in vasopressin levels in response to both stimuli. In response to hypertonic saline there was an initial rise followed by a fall in vasopressin content. The suprachiasmatic and lateral septal nuclei, as well as the nucleus of the solitary tract, were unaffected by either stimulus. These results indicate that there are at least two functionally different vasopressin systems within the central nervous system, one of which is responsive to osmotic stimulation.

There is evidence to suggest that histamine is a neurotransmitter in the CNS and functions in the regulation of arg-vasopressin (AVP) secretion. The posterior pituitary contains high levels of histamine and histamine N-methyltransferase (HNMT). Therefore, posterior pituitary histamine could also modulate the release of AVP. Paralleling the effect on AVP levels, the concentration of histamine in the rat posterior pituitary decreased from 18.8 +/- 2.7 ng/mg protein (x +/- SEM) to 12.9 +/- 1.9 ng/mg protein following 2 days of 2% (w/v) hypertonic saline administration and to 11.5 +/- 0.9 ng/mg protein with 7 days of treatment. Conversely, posterior pituitary HNMT activity was significantly elevated after hypertonic saline administration. Pituitary stalk transection did not reduce the concentration of histamine in the rat posterior pituitary although HNMT activity was reduced from 18.8 +/- 0.82 munits/gland to 9.22 +/- 1.56 munits/gland (x +/- SEM). These results indicate that histamine released from posterior pituitary mast cells could facilitate AVP release as part of the overall mechanism for osmotic stimulation of AVP secretion and support the concept that most posterior pituitary histamine is not neuronally derived from the brain. HNMT, on the other hand, may be contained in neurons disrupted by stalk section.

Norepinephrine and epinephrine concentrations in the caudal and rostral part of the nucleus tractus solitarii (NTS) and in locus coeruleus (LC) of Sabra hypertension prone (SBH) rats are 2-4-fold higher than in the parent Sabra (SB) strain; SB rats have higher concentrations than the Sabra hypertension resistant (SBN) rats. Dopamine concentrations were higher in SBH as compared to SB and SBN rats only in the caudal NTS. Vasopressin concentrations in the NTS of SBH were 3-fold higher than the levels found in SB or SBN rats. These data suggest that catecholamines and vasopressin in specific brainstem nuclei are involved in either the pathogenesis or central response to hypertension in SBH rats.

Chlordiazepoxide pretreatment decreased basal levels of plasma arginine-vasopressin (AVP) and attenuated picrotoxin-induced increases in plasma AVP and blood pressure compared to saline-pretreated spinal animals. Prior administration of RO 15-1788 blocked the effects of chlordiazepoxide on basal plasma AVP as well as picrotoxin-evoked changes in plasma AVP and blood pressure. Thus, interactions at the benzodiazepine receptor may influence basal and evoked changes in plasma AVP concentration.

Chronic phencyclidine treatment (10 mg/kg/day, SC for 14 days) significantly decreased the number of [3H]phencyclidine and [3H]spiperone binding sites in rat brain. [3H]Dihydromorphine binding was not affected by the same treatment. An acute treatment with phencyclidine (10 mg/kg, SC) did not modify any of the binding sites under study. These results suggest that a chronic phencyclidine treatment induces a down-regulation of phencyclidine and dopamine receptors without affecting opiate receptors. These reductions in the number of phencyclidine and dopamine binding sites might be related to the development of tolerance and/or dependence to phencyclidine.

Central catecholaminergic activity was studied by measurement of norepinephrine (NE), epinephrine (EPI), their metabolites: total 3-methoxy-4-hydroxyphenylglycol (MHPG) and 3,4-dihydroxyphenylglycol in brain nuclei in response to bilateral dorsomedullary knife-cut (DMK-cut) in rats. In saline-pretreated conscious rats DMK-cut caused a marked hypertension, tachycardia and increases in plasma NE, EPI and vasopressin. Chlorisondamine (CHL) prevented the rise in plasma catecholamines and the tachycardia but failed to prevent the hypertension and the increment in plasma vasopressin. DMK-cut decreased NE and EPI in the nucleus tractus solitari (NTS) and A2 area; there were no catecholamine changes in A1 area or the periventricular nucleus but an increase in the paraventricular nucleus (PVN), the latter effect reversed by CHL, CHL alone or combined with DMK-cut had no effect on catecholamine concentrations in NTS-A2 area but lowered MHPG content. It is suggested that DMK-cut decreases the activity of the catecholaminergic system originating in A1 and terminating in PVN, where it causes catecholamine accumulation and may be involved in vasopressin release and thereby contribute to hypertension. In NTS-A2 area, however, the DMK-cut appears to increase catecholaminergic activity since catecholamines are depleted. Central effects of DMK-cut differ from those of ganglionic blockade-induced inhibition of the baroflex presumably due to sectioning of other pathways in addition to the primary baroreceptor input.

To confirm and extend the results of previous studies which demonstrated central cardiovascular effects of vasopressin in anesthetized rats, we determined blood pressure and heart rate changes for 30 minutes after intracerebroventricular injections of arginine vasopressin, arginine vasotocin and oxytocin in conscious rats. As compared to sham injections, significantly greater increases in either systolic or diastolic blood pressure were noted over the 30 minutes which followed the injection of 0.15, 1.0 or 10.0 nM of either vasopressin or vasotocin. In animals given vasopressin, plasma levels of the peptide were determined. There was a substantial increase in plasma vasopressin only after the highest dose. Overall blood pressure responses to doses of oxytocin as high as 100 nM were not significantly different than sham injections. Heart rate following both vasopressin and vasotocin was increased at 0.15 nM, was initially decreased then increased at 1.0 nM and was substantially decreased after the 10.0 nM dose. There was a significant increase in heart rate at the 10.0 nM and 100 nM doses of oxytocin. Dose response curves for systolic blood pressure and heart rate 20 minutes after injection were similar for vasopressin and vasotocin. We conclude that arginine vasopressin has significant central pressor and tachycardic effects in conscious rats, and it is related, at least in part, to the tail structure of the peptide, which is shared with arginine vasotocin.

Spontaneous blood pressure recovery following hemorrhage in anesthetized rats in almost completely blocked by administration of captopril. This occurs despite comparable or enhanced increases in plasma levels of catecholamines and vasopressin. These findings suggest that angiotensin II, the formation of which is blocked by captopril, is essential to acute blood pressure recovery following hemorrhage and that changes in catecholamines or vasopressin are insufficient to sustain pressure recovery. The data also indicate that angiotensin II formation is not essential in the hemorrhagic stimulation of vasopressin or catecholamines.

Circadian rhythms in physiological processes and behaviors were compared with hypothalamic circadian rhythms in norepinephrine (NE) metabolites, adrenergic transmitter receptors, cAMP, cGMP and suprachiasmatic nucleus (SCN) arginine vasopressin (AVP) in a single population of rats under D:D conditions. Eating, drinking and locomotor activity were high during the subjective night (the time when lights were out in L:D) and low during the subjective day (the time when lights were on in L:D). Plasma corticosterone concentration rose at subjective dusk and remained high until subjective dawn. Binding to hypothalamic alpha 1- and beta-adrenergic receptors also peaked during the subjective night. Cyclic cGMP concentration was elevated throughout the 24-hr period except for a trough at dusk, whereas DHPG concentration peaked at dawn. Arginine vasopressin levels in the suprachiasmatic nucleus peaked in the middle of the day. No rhythm was found either in binding to the alpha 2-adrenergic receptor, or in MHPG or cAMP concentration. Behavioral and corticosterone rhythms, therefore, are parallel to rhythms in hypothalamic alpha 1- and beta-receptor binding and NE-release. Cyclic GMP falls only at dusk, suggesting the possibility that cGMP inhibits activity much of the day and that at dusk the inhibition of nocturnal activity is removed. SCN AVP, on the other hand, peaking at 1400 hr, may play a role in the pacemaking function of the SCN that drives these other rhythms.

Prostaglandin F2 alpha (PGF2 alpha) injected into the cerebroventricular system (icv) of halothane-anesthetized rats increased the arterial blood pressure, heart rate, and rectal temperature. These effects were accompanied by a preferential increase in plasma norepinephrine concentration. Plasma levels of epinephrine, renin, and vasopressin were not changed in the PGF2 alpha-icv-treated rats. Bilateral vagotomy did not affect the PGF2 alpha-induced hypertension and tachycardia nor was there any change in the selective increase in plasma norepinephrine concentration. Hexamethonium pretreatment suppressed, in a dose-response manner, the increases in blood pressure, heart rate, and rectal temperature in response to PGF2 alpha-icv. Plasma norepinephrine and epinephrine levels were not altered by PGF2 alpha-icv in hexamethonium-treated rats, but plasma vasopressin concentration was markedly elevated in all hexamethonium-infused rats. These results suggest that selective central activation of the sympathetic nervous system underlies the profound cardiovascular and temperature responses elicited by central administration of PGF2 alpha.

Three approaches to the evaluation of the central cardiovascular effects of vasopressin are briefly reviewed. These include assessment of cardiovascular regulation in Brattleboro rats, cardiovascular responses to central nervous system injections of vasopressin, and changes in central nervous system vasopressin content in spontaneous and induced hypertension. The studies indicate that vasopressin could participate in baroregulation by actions within the central nervous system, but they fail to clearly define the importance of vasopressin, if any, in this capacity.

The role of sympathetic and other pressor systems in the development of fulminant hypertension induced by baroreceptor deafferentation is still unclear. We studied the effects of acute hypertension produced by bilateral dorsomedullary knife cuts lateral to the nucleus tractus solitarii (DMK-cut) on plasma norepinephrine (NE), epinephrine (E), and vasopressin (VP) in conscious, tail-artery-cannulated rats. In saline-pretreated (SAL) rats, DMK-cut caused a significant (p less than 0.001) rise in mean blood pressure (MAP, +68 +/- 3 mm Hg), heart rate (HR, +97 +/- 19 bpm), NE (+2.5 +/- 0.3 ng/ml), E (+2.7 +/- 0.4 ng/ml), and VP (+115 +/- 34 pg/ml) compared to sham-operated rats. Neither sympathetic blockade with chlorisondamine (CHLO, 10 mg/kg, s.c.) nor elimination of the pressor effects of VP by use of Brattleboro rats or the VP pressor antagonist resulted in a maximal MAP response significantly different from that in the SAL + DMK-cut group. However, CHLO-pretreatment of Brattleboro rats completely abolished the increase in MAP and HR. It is suggested that the bilateral DMK-cut causes acute hypertension, probably due to the abolition of baroreceptor reflexes by central interruption of neural connections of the nucleus tractus solitarii. It appears that both the increased sympathoadrenomedullary activity and VP release normally contribute to this hypertension; however, either one is sufficient to sustain the elevated blood pressure.