Congenital changes of platelet functions in stroke-prone SHR: aggregability of gel-filtered platelets, PRP and whole blood, and effects of hypotensive treatment

Platelet aggregation in whole blood, platelet rich plasma, and gel-filtered platelets were markedly attenuated in SHRSP compared with those in age-matched normotensive WKY. The result was consistent with the previous report of washed platelets. Despite prevention of high blood pressure, a long duration of hypotensive treatment only slightly improved aggregability of washed platelets but did not restore it to the range of age-matched WKY platelets. Blood pressure, heart ratios and thrombin-induced washed platelet aggregation were examined in SHRSP, WKY, and the cross (F1: WKY x SHRSP). The higher blood pressure and heart ratios the lower platelet aggregability was observed in the three strains, and there was no overlapping distribution of these values. F1 progeny exhibited intermediate values in blood pressure, heart ratio and platelet aggregability between the parental values. These results suggested that hypofunctions of SHRSP platelet were not secondary changes due to high blood pressure, but primary changes which are genetically linked to high blood pressure.     

Regional cerebral blood flow during hypotension in normotensive and stroke-prone spontaneously hypertensive rats: effect of sympathetic denervation

This study was performed to determine whether, in hypertensive and normotensive rats, chronic sympathetic denervation impairs cerebral vasodilator responses during hypotension, and to determine whether there are regional differences in the autoregulatory response of brain vessels during hypotension. The superior cervical ganglion was removed on one side in stroke-prone spontaneously hypertensive rats (SHRSP) and normotensive (WKY) rats. Cerebral blood flow (CBF) was measured with microspheres when the rats were 5-6 months old. Chronic sympathetic denervation had little or no effect on cerebral vasodilator responses during acute hypotension in SHRSP and WKY. We suggest that the increase in incidence of ischemic infarction that we have observed previously after chronic sympathetic denervation in SHRSP probably is not the result of ischemia during episodes of hypotension. We also observed major regional differences in the response of cerebral vessels during acute hypotension in SHRSP: blood flow to brainstem was preserved better than flow to cerebrum and cerebellum. Thus the "lower limit" of the autoregulatory plateau differs in various regions of the brain in SHRSP.     

Cardiovascular effects of L-glutamate and tetrodotoxin microinjected into the rostral and caudal ventrolateral medulla in normotensive and spontaneously hypertensive rats

The purpose of this study was to compare the responsiveness of the rostral and caudal ventrolateral medulla in spontaneously hypertensive (SH) and normotensive Wistar-Kyoto (WKY) rats to microinjection of L-glutamate, and to estimate tonic output of these areas by microinjecting the neurotoxin tetrodotoxin. Rats were anesthetized with 1.25 g/kg urethane s.c., implanted with arterial (femoral) and venous (femoral) catheters, artificially ventilated and paralyzed with gallamine triethiodide (10 mg/kg). Using a ventral approach to the brainstem, the mean arterial pressure and heart rate responses to microinjection (30 nl) of L-glutamate (1, 10 and 100 mM) and tetrodotoxin (10 microM) into the rostral and caudal ventrolateral medulla were compared in SH (n = 7) and WKY (n = 7) groups. Microinjection of L-glutamate into the rostral ventrolateral medulla produced equivalent increases in mean arterial pressure (maximum +33 +/- 3 and +36 +/- 6 mm Hg, SH and WKY groups respectively) and minimal changes in heart rate. Similar administration of L-glutamate into the caudal ventrolateral medulla caused decreases in mean arterial pressure and heart rate; changes in mean arterial pressure were significantly greater in the SH group than in the WKY group (-52.3 +/- 2.9 mm Hg for SH, -22.6 +/- 2.6 mm Hg for WKY). Bilateral microinjection of tetrodotoxin into the caudal ventrolateral medulla produced significantly larger increases of mean arterial pressure in WKY rats (+8 +/- 4 vs +46 +/- 8 mm Hg for SH vs WKY). These data indicate that SH rats may have a lower tonic activity of neurons in the caudal ventrolateral medulla, resulting in a lower restraining influence on sympathetic outflow in the SH rat.     

Switch to glutamate receptor 2-lacking AMPA receptors increases neuronal excitability in hypothalamus and sympathetic drive in hypertension

Glutamatergic synaptic input in the hypothalamic paraventricular nucleus (PVN) plays a critical role in regulating sympathetic outflow in hypertension. GluR2-lacking AMPA receptors (AMPARs) are permeable to Ca(2+), and their currents show unique inward rectification. However, little is known about changes in the AMPAR composition and its functional significance in hypertension. In this study, we found that AMPAR-mediated EPSCs (AMPAR-EPSCs) of retrogradely labeled spinally projecting PVN neurons exhibited a linear current-voltage relationship in Wistar-Kyoto (WKY) rats. However, AMPAR-EPSCs of labeled PVN neurons in spontaneously hypertensive rats (SHR) displayed inward rectification at positive holding potentials, which were not altered by lowering blood pressure with celiac ganglionectomy. Blocking GluR2-lacking AMPARs with 1-naphthyl acetyl spermine (NAS) caused a greater reduction in the AMPAR-EPSC amplitude and firing activity of PVN neurons in SHR than in WKY rats. Furthermore, blocking NMDA receptors and inhibition of calpain or calcineurin abolished inward rectification of AMPAR-EPSCs of PVN neurons in SHR. The GluR2 protein level was significantly less in the plasma membrane but greater in the cytosolic vesicle fraction in SHR than in WKY rats. In addition, microinjection of NAS into the PVN decreased blood pressure and lumbar sympathetic nerve activity in SHR but not in WKY rats. Our study reveals that increased GluR2-lacking AMPAR activity of PVN neurons results from GluR2 internalization through NMDA receptor-calpain-calcineurin signaling in hypertension. This phenotype switch in synaptic AMPARs contributes to increased excitability of PVN presympathetic neurons and sympathetic vasomotor tone in hypertension.     

Responses of cardiovascular neurons in the rostral ventrolateral medulla of the normotensive Wistar Kyoto and spontaneously hypertensive rats to iontophoretic application of angiotensin II

In female pentobarbital-anesthetized Wistar Kyoto rats (WKY) and spontaneously hypertensive rats (SHR), changes in spontaneous discharges of cardiovascular neurons in the rostral ventrolateral medulla (RVL) in response to iontophoretic application of angiotensin II (Ang II) were studied and compared. It was found that iontophoretic application of Ang II to RVL increased the spontaneous neuronal activities of 30% of the cardiovascular neurons in both types of rats and that the increase was significantly greater in SHR than in WKY. In both types of rats, there was an increase in arterial blood pressure in response to iontophoretic release of Ang II to RVL. The pressor response was accompanied by tachycardia, which was significantly greater in SHR than in WKY. The present study provides evidence that Ang II acts directly on cardiovascular neurons in RVL, and in SHR, an enhanced sensitivity and responsiveness of the RVL cardiovascular neurons to Ang II may augment the sympathetic outflow from RVL and contribute to the genesis of hypertension.     

There is no valid evidence presented as to an impaired endothelial NO system in the stroke-prone spontaneously hypertensive rats

Platelet reactivity in stroke-prone spontaneously hypertensive rats (SHRSP) and normotensive Wistar–Kyoto rats (WKY) were compared. In vivo platelet reactivity was tested by the He–Ne laser-induced thrombosis model. The number of laser pulses needed to reach thrombotic occlusion of the targeted vessel was used as an index of thrombogenicity. SHRSP rats needed significantly less number of irradiation to reach occlusion than WKY rats (SHRSP vs. WKY, 5.1±0.3 vs. 8.1±0.6), indicating enhanced thrombotic response in SHRSP rats. Further, acetylcholine administration significantly increased the number of laser pulses until occlusion in WKY but not in SHRSP rats. This suggests an impaired thrombotic reaction in acetylcholine-treated WKY but not in SHRSP rats. Platelet reactivity in vitro was measured in native blood by a shear-induced haemostasis test (haemostatometry). Indexes of this test (H1/H2), which inversely correlated with platelet reactivity, were significantly greater in SHRSP than in WKY rats (SHRSP vs. WKY, H1: 1815±192 vs. 763±75; H2: 7547±723 vs. 3536±264). This suggests reduced platelet reactivity in SHRSP compared with WKY rats. Thus, the present findings show increased thrombotic tendency in SHRSP rats in vivo despite reduced platelet reactivity in vitro. To explain this contradiction, we suggest that an increased in vivo thrombotic tendency may be due to impaired nitric oxide (NO) release from endothelial cells in SHRSP rats, and that a reduced platelet reactivity in vitro may be due to an adaptation of SHRSP rats to survive at extremely high blood pressure.     

Role of reactive oxygen species in brainstem in neural mechanisms of hypertension

The involvement of reactive oxygen species such as superoxide is implicated in the pathogenesis of hypertension. The brain contains a high concentration of polyunsaturated fatty acids in its cell membranes. These fatty acids are targets of oxygen-derived free radicals. Thiobarbituric acid-reactive substances (TBARS), an indirect marker of oxidative stress, are increased in the brainstem of stroke-prone spontaneously hypertensive rats (SHRSP) compared with those of Wistar-Kyoto rats (WKY). In addition, the intensity of electron spin resonance signals taken from the rostral ventrolateral medulla (RVLM), a cardiovascular center, decreases more rapidly in SHRSP than in WKY. To confirm the role of reactive oxygen species in the RVLM or the nucleus tractus solitarius (NTS) in SHRSP, we transfected adenovirus vectors encoding the manganese superoxide dismutase (MnSOD) gene (AdMnSOD) or Cu/Zn-SOD gene (AdCu/ZnSOD) bilaterally into the RVLM or the NTS. After the gene transfer, blood pressure and heart rate of SHRSP, monitored by radio-telemetry system, were significantly decreased compared with non-treated SHRSP, but not WKY. Urinary norepinephrine excretion was significantly decreased in AdMnSOD- or AdCu/ZnSOD-transfected SHRSP, but not in WKY. Furthermore, we found that activation of NAD(P)H oxidase via Rac1 is a source of reactive oxygen species generation in the brain of hypertensive rats. Taken together, these results suggest that the increased oxidative stress in the RVLM and the NTS contribute to the central nervous system mechanisms underlying hypertension in SHRSP. We also found that atorvastatin has actions of reducing oxidative stress in the brain associated with sympatho-inhibitory effects.     

Baroreceptors mask sympathetic responses to high intraocular pressure in dogs

These experiments were designed to investigate whether increasing intraocular pressure (IOP) in anesthetized dogs produces differential control of sympathetic nerve activities to various organs (heart, kidney, liver, and spleen) and if these sympathetic responses are modified by baroreceptors. We performed simultaneous multi-recordings of cardiac, renal, hepatic and splenic sympathetic nerve activities (CNA, RNA, HNA and SpNA, respectively) during 2 min of increasing IOP to a mean pressure of 30 mmHg. After increasing IOP in dogs with the intact baroreceptors, all of measured nerve activities did not change significantly throughout the experiment. In dogs with denervation of baroreceptors (cervical vagotomy with denervation of the carotid sinus and aortic nerves), only RNA and CNA showed significant increases in response to the increased IOP. However, time course changes in HNA and SpNA did not show any significant differences as compared with the baseline or that of the control group. These results indicate that systemic sympathetic nerve responses to increasing IOP are masked by systemic baroreceptors. As animals were denervated of their systemic baroreceptors, the unidirectional sympathoexcitatory responses to increased IOP were observed on CNA and RNA, but not on HNA and SpNA. These sympathetic outflow, when systemic baroreceptors are impaired as observed in old age, may play an important role in management of glaucoma attack with the use of adrenolytic drugs.     

Hypoaggregability of washed platelets from stroke-prone spontaneously hypertensive rats (SHRSP)

The aggregation properties of washed SHRSP platelets were investigated in comparison with normotensive WKY platelets at prehypertensive (4 weeks), early hypertensive (11 weeks) and late hypertensive (17 weeks) ages in the absence of plasma factors. The number of platelets in SHRSP was markedly lower with the development of hypertension than that in WKY. The thrombin- and collagen-induced aggregation was markedly reduced in the platelets from 11 and 17 week old SHRSP compared with that of age-matched WKY, whereas the degree of platelet aggregation in 4 week old SHRSP showed a tendency to be even greater than that in WKY. The changes in blood pressure and platelet aggregability were correlated inversely. ADP did not induce aggregation in the same system used for thrombin and collagen stimulation but in another system it aggregated washed rat platelets. Aggregation responses to ADP and ionophore A23187 were also significantly lower in 14 week old SHRSP platelets than age-matched WKY platelets. Together with other evidence, these results suggest that defective Ca2+ function, rather than the presence of exhausted platelets, is responsible for hypoaggregability in SHRSP platelets.     

Sensitization to pressor effects by repeated central injections of vasopressin in conscious rats

Arginine vasopressin (AVP) injected intracerebroventricularly (i.c.v.) in the nanogram range elicits increases in mean arterial blood pressure (MAP), heart rate (HR) and efferent sympathetic nerve activity (SpNA) via central V1 AVP receptor stimulation. In this study in conscious rats we investigated, whether the cardiovascular and sympathetic responses can be augmented by repeated central applications of AVP, as has been previously shown for the convulsive responses to higher i.c.v. doses of the peptide. The AVP-induced pressor (0.1 and 1.0 ng) and the SpNA (0.1 ng) responses were significantly enhanced by a second AVP challenge 24 h after the first injection. With higher doses of the peptide (3 ng), the blood pressure responses were not different between two subsequent injections, but barrel rotation occurred in 21% of the animals upon the second challenge. The pressor responses to a threshold i.c.v. dose of 1 ng angiotensin II (ANG II) were not enhanced upon a second ANG II challenge. Our results demonstrate that AVP, unlike ANG II, can sensitize central mechanisms leading to increased MAP and SpNA responses.     

The appearance of exhausted platelets due to a duration of hypertension in stroke-prone spontaneously hypertensive rats

Using strains of spontaneously hypertensive rats with different degrees of hypertension, the influence of the duration of hypertension on platelets was examined through changes in platelet serotonin contents. The blood pressures of these strains were in the descending order of m-SHRSP greater than SHRSP greater than SHR greater than WKY. Serotonin content in normotensive WKY platelets was maintained in the range of 0.715 +/- 0.048(17) n mole/10(8) through ages 5-50 weeks in both sexes. In contrast with WKY of the same age and sex, a significant decrease in platelet serotonin content began to be observed in male m-SHRSP at 18-weeks of age, in female m-SHRSP and male SHRSP at 22-weeks of age, and in female SHRSP at 32-weeks of age, respectively. The content in SHR platelets of both sexes was unaltered up to 40-weeks of age. The time of the appearance of these exhausted platelets coincided with the reported time of scanning electron microscopic observation of vascular injuries in each strain of rats. It has been concluded that a long duration of hypertension causes platelets to become degranulated and exhausted due to in vivo activation of platelets at sites of arterial injury. Thus the changes of platelet contents could be an indicator of vascular injuries.     

Hypothalamic paraventricular nucleus inhibition decreases renal sympathetic nerve activity in hypertensive and normotensive rats

Activity of the hypothalamic paraventricular nucleus (PVN) is essential for the maintenance of vasomotor sympathetic nerve discharge (SND) and blood pressure even in the anesthetized rat. Inactivation of the paraventricular nucleus results in a large depressor and sympathoinhibitory response. The current study was designed to examine the regulation of renal sympathetic nerve activity by the paraventricular nucleus in both hypertensive and normotensive rats. Experiments were performed in anesthetized, artificially ventilated spontaneously hypertensive (SH) and Wistar-Kyoto (WKY) rats. Renal sympathetic nerve activity, blood pressure and heart rate were recorded. Bilateral microinjections of the GABA(A) receptor agonist, muscimol (1 nmol in 100 nl), were made into the paraventricular nucleus. Decreases in blood pressure (SHR: from 111+/-3 to 54+/-4 mm Hg; WKY: 84+/-2 to 48+/-3 mm Hg), heart rate (SHR: 336+/-8 to 289+/-12 bpm; WKY 309+/-7 to 258+/-13 bpm) and renal sympathetic nerve activity (to 46+/-11% and 33+/-7% of control in the WKY and SHR, respectively) were observed. The renal nerve response to inactivation of the paraventricular nucleus was not different between the strains, indicating that modulation of renal sympathetic nerve activity by the paraventricular nucleus is similar in these rat strains. This is different from the previously reported effect of paraventricular nucleus inhibition on lumbar sympathetic nerve activity [Hypertension 39 (2002) 275]. Overall, we demonstrate that the paraventricular nucleus plays a critical role in the regulation of renal SND even under basal conditions in anesthetized animals.     

Changes in ambulation and drinking behavior related to stroke in stroke-prone spontaneously hypertensive rats

In order to elucidate the behavioral changes related to stroke, ambulatory activity and water drinking were observed in stroke-prone spontaneously hypertensive rats (SHRSP). Age matched male SHRSP and Wistar Kyoto rats (WKY) were subjected to a 12 hour light and dark alternation cycle. Ambulation and drinking activity counts were determined simultaneously with an Ambulo-Drinkometer. Before stroke, ambulation and drinking activity counts in the dark phase (82%) were higher than those in the light phase (18%). Both parameters were well synchronized with the light and dark alternation cycle. With aging, daily ambulation decreased while daily drinking activity increased in SHRSP and WKY. Daily ambulation and drinking activity in 15 and 30 week old SHRSP were greater than those of WKY. It was demonstrated with an Ambulo-Drinkometer that SHRSP undergo specific behavioral changes before the onset of stroke. For instance, the 40-60 week old SHRSP showed significant individual variation in both ambulation and drinking activity. This desynchronization with the light and dark alternation cycle was followed by stroke. Twenty seven autopsies showed 11 cerebral infarctions, 10 cerebral hemorrhage and 6 cerebral hemorrhage with infarctions to be the causes of death.     

Chemical Stimulation of Renal Tissue Induces Sympathetic Activation and a Pressor Response via the Paraventricular Nucleus in Rats

Sympathetic activation and the kidney play critical roles in hypertension and chronic heart failure.The role of the kidney in sympathetic activation is still not well known.In this study,we revealed an excitatory renal reflex(ERR)in rats induced by chemical stimulation of the kidney that regulated sympathetic activity and blood pressure.The ERR was induced by renal infusion of capsaicin,and evaluated by the changes in renal sympathetic outflow,blood pressure,and heart rate.Renal infusion of capsaicin dose-dependently increased the contralateral renal sympathetic nerve activity,mean arterial pressure,and heart rate.Capsaicin in the corticomedullary border had greater effects than in the cortex or medulla.Intravenous infusion of capsaicin had no significant effects.The effects of renal infusion of capsaicin were abolished by ipsilateral renal denervation,but were not affected by bilateral sinoaortic denervation.Renal infusion of capsaicin increased the ipsilateral renal afferent activity.The ERR was also induced by renal infusion of bradykinin,adenosine,and angiotensin II,but not by ATP.Renal infusion of capsaicin increased c-Fos expression in the paraventricular nucleus(PVN)of hypothalamus.Lesion of neurons in the PVN with kainic acid abolished the capsaicin-induced ERR.These findings indicate that chemical stimulation of kidney causes an excitatory reflex,leading to sympathetic activation,pressor response,and accelerated heart rate.The PVN is an important central nucleus in the pathway of the ERR.     

Sympathetic nervous activity and arterial pressure responses during rest and acute behavioral stress in SHR versus WKY rats

The object of this experiment is to compare changes in renal sympathetic nerve activity (SNA), mean arterial blood pressure (MAP) and heart rate (HR) during rest and behavioral stress in 12–14 week old spontaneously hypertensive rats (SHR; N=12) and normotensive Wistar–Kyoto (WKY; N=12) controls. Animals were behaviorally trained by following a 15 s auditory conditional stimulus (CS+) with a 1/2 s tail shock. Resting MAP was higher (p<0.001) in SHR (154±3 mmHg, mean±SEM) compared to WKY (116±3 mmHg); conversely, there was no difference in the average resting HR. The pattern of the SNA and MAP changes during the CS+ was similar across groups, but the amplitude was larger in the SHR. The CS+ stress stimulus evoked an initial transient MAP increase averaging 14±2 mmHg in the SHR compared to 4±1 mmHg in the WKY. This pressor response was preceded by a sudden burst of SNA averaging 177±22% over baseline in SHR versus 105±13% for the WKY. HR decreased in SHR only during the second component of the CS+ trial despite the large increase in SNA. We conclude that (1) SHR have higher reactivity than WKY to stress in SNA and MAP; (2) both SHR and WKY have greater SNA and MAP responses to CS+ than CS− (i.e., the discriminative paradigm was effective); (3) control of sympathetic and parasympathetic nervous activity during sustained stress differs remarkably in hypertensive and normotensive subjects; and (4) SHR blood pressure effector mechanisms may have a higher responsiveness to sympathetic nervous activity as compared to WKY.     

Two genetic rat models of arterial hypertension show different mechanisms by which adult hippocampal neurogenesis is increased

To investigate strain differences and genetic effects on different aspects of neurogenesis, we compared young adult spontaneously hypertensive/hyperactive rats (SHR) and stroke-prone SHR (SHRSP) with the genetic control WKY strain. In both hypertensive/hyperactive strains, the number of newly generated neurons and the number of lineage-determined cells as detected by doublecortin (DCX) immunoreactivity were significantly increased. SHRSP had significantly more DCX-positive cells than the other groups. Whereas cell proliferation as measured by Ki67 expression was increased in SHR, we found no difference between SHRSP and WKY. In summary, we found increased net neurogenesis in both hypertensive/hyperactive strains. However, this phenotype was based on different mechanisms in the course of neuronal development: cell proliferation in SHR and cell survival in SHRSP. In addition, we found that within strains the number of DCX-positive cells was not predictive of the net number of new neurons and that the increase in neurogenesis was not significantly correlated with blood pressure in SHR and WKY. However, in both SHR and SHRSP, cell proliferation showed an association with blood pressure recordings.     

Cardiac sympathetic nerve activity during kainic acid–induced limbic cortical seizures in rats

We sought to define changes in cardiac sympathetic nerve activity that occur during seizures. We studied kainic acid–induced limbic cortical seizures in urethane-anesthetized rats using cardiac sympathetic nerve, blood pressure, and electrocardiography (ECG) recordings. We studied changes in ventilation rate before and during seizures. Cardiac sympathetic nerve activity was increased during limbic cortical seizures. The modest increases were similar to changes induced by nitroprusside infusion. The normal relation of cardiac sympathetic nerve activity to ventilation rate was lost during seizure activity. Changes in cardiac sympathetic nerve activity caused by changes in ventilation rate became unpredictable, and could be extreme. We conclude that the modest changes in cardiac sympathetic nerve activity contribute to the predominantly parasympathetic effects on the heart during limbic cortical seizures and periods of asphyxia. Further, ventilation rate changes might be associated with large sudden increases or decreases in cardiac sympathetic outflow during seizures.     

The role of the sympathetic nervous system in promoting liver cirrhosis induced by carbon tetrachloride, using the essential hypertensive animal (SHR).

The effects of the sympathetic nervous system on liver injury induced experimentally by carbon tetrachloride (CCl4) were examined in spontaneously hypertensive rats (SHR) and normotensive Wistar-Kyoto rats (WKY). It was found that the SHR had an elevated catecholamine (CA) content in the adrenal gland without any treatment, and fluorescence histochemistry also revealed dense adrenergic innervations in the liver. Moreover, the SHR showed greater sensitivity to CCl4 stimulation in the sympathetic nervous system than the WKY, resulting in a decreased hepatic blood flow in the acute stage and a depleted CA in the adrenal gland, a lowered blood pressure (BP) and a released non-esterified fatty acid (NEFA) from peripheral adipose tissue in the chronic stage. Upon repetition of the CCl4 treatments twice a week for 4 weeks, the liver injury was more severe in the SHR than in the WKY. Plasma glutamate-pyruvate transaminase (GPT) activity was increased in both strains but more significantly in the SHR than in the WKY. Histological examination of the liver in the SHR showed established cirrhosis, whereas only bridging fibrosis was seen in the WKY. These results suggest that the pathogenesis of the liver damage induced by CCl4 in the SHR, is attributable to the enhanced response of the sympathetic nervous system that releases massive amounts of CA which then lead to vasoconstriction and metabolic changes that promote liver damage.     

Central ANP attenuates pressor responses to central AVP in WKY and SHR

Blood pressure and heart rate responses to intracerebroventricular (ICV) injections of atrial natriuretic peptide (ANP, 125 ng) arginine vasopressin (AVP, 10 ng), combination of ANP (125 ng) and AVP (10 ng) or artificial cerebrospinal fluid (acsf, 5 microliters) were compared in conscious normotensive (WKY) and spontaneously hypertensive (SHR) rats. In both strains, ICV injection of AVP elicited significant increase of mean blood pressure (MP) and heart rate (HR). Increase of MP but not of HR was significantly greater in SHR than in WKY (p less than 0.05). Injection of acsf or ANP, as well as simultaneous administration of ANP and AVP, did not elicit significant changes of MP either in WKY or in SHR. In SHR, HR was significantly elevated by ICV injections of AVP and ANP + AVP, whereas in WKY HR was increased only after AVP. The data suggest that interaction of ANP and AVP at a central level may result in significant attenuation of central pressor effects of vasopressin.