Capsaicin treatment in adult Wistar-Kyoto and spontaneously hypertensive rats: effects on substance P contents of peripheral and central nervous system tissues

The effects of s.c. capsaicin treatment on the contents of immunoreactive substance P (ISP) in several peripheral and central nervous system tissues were examined in normotensive Wistar-Kyoto (WKY) and spontaneously hypertensive (SHR) rats. Significant differences between vehicle-treated subjects of the WKY and SHR strains were observed in the ISP contents of both superior cervical and celiac sympathetic ganglia. Capsaicin pretreatment significantly reduced the ISP contents of both sympathetic ganglia in both strains. Capsaicin pretreatment significantly elevated the ISP contents of adrenal medullae only in rats of the SHR strain. The effects of s.c. capsaicin administration on the ISP contents of several selected isolated brain nuclei were also examined. No statistically significant strain or treatment differences in the SIP contents of the nucleus tractus solitarii nucleus locus ceruleus and periaqueductal central gray were observed. The ISP contents of the nucleus raphe magnus, periventricular preoptic area, and nucleus amygdaloideus medialis were significantly greater in vehicle-treated SHR rats than in vehicle-treated WKY animals. Capsaicin pretreatment significantly increased the ISP contents of both the periventricular preoptic area and nucleus amygdaloideus medialis in SHR rats. These results indicate that the effects of capsaicin treatment of the ISP contents of nervous systems tissues vary with both the tissues examined and the strain of rat. In addition, the previously reported long-lasting hypotensive effect produced by capsaicin in both the WKY and SHR strains may be related to the significant depletion of the ISP contents in peripheral sympathetic ganglia in both strains.     

Central alpha 2-adrenoceptor-mediated pressor response to clonidine in conscious, spontaneously hypertensive rats.

Pressor responses to intracerebroventricular (i.c.v.) injection of clonidine were investigated in conscious spontaneously hypertensive rats (SHR) and normotensive Wistar Kyoto rats (WKY). Clonidine (1-10 micrograms, i.c.v.) caused a dose-dependent pressor response and decrease in heart rate in both SHR and WKY. In SHR, low doses (1, 2.5 micrograms) but not high doses (5, 10 micrograms) of i.c.v.-clonidine induced a depressor response following the pressor response. Both pressor and depressor responses to i.c.v.-clonidine were significantly greater in SHR than in WKY. In both SHR and WKY, pressor responses to i.c.v.-clonidine were abolished by pentobarbital anesthesia, pretreatment with i.v.-furosemide (5 mg/kg), 24-hr water deprivation and pretreatment with i.c.v.-yohimbine (100 micrograms), but not by pretreatment with i.v.-yohimbine (100 micrograms) and i.c.v.-prazosin (10 micrograms). On the 1st day after surgery for arterial catheter implantation, SHR reduced their water intake, and i.c.v.-clonidine (5 micrograms) caused a slight pressor response, whereas the same dose of clonidine on the 7th day after surgery resulted in a marked pressor response. These results suggest that clonidine caused a central alpha 2-adrenoceptor-mediated pressor response, which is greater in SHR than in WKY and is sensitive to body fluid volume changes and anesthesia.     

Effects of endothelin-1 on isolated vascular beds from normotensive and spontaneously hypertensive rats

Endothelin-1 and noradrenaline induced dose-dependent pressor responses in isolated in situ blood perfused mesenteric arterial beds and isolated tail arterial beds of anaesthetised spontaneously hypertensive rats (SHR) and normotensive Wistar-Kyoto rats (WKY). In the tail the sensitivity and maximum to either agonist were the same in SHR and WKY whereas in the mesenteric bed the maximum pressor responses to both agonists were increased in SHR. This effect of endothelin-1 may contribute to the greater increase in blood pressure it induces in anaesthetised SHR compared with WKY.     

Prominent depressor response to endothelin in spontaneously hypertensive rats

Administration of endothelin (0.03-3.0 micrograms/kg i.v.) caused transient depressor responses followed by sustained pressor responses in anesthetized spontaneously hypertensive rats (SHR) and normotensive Wistar-Kyoto rats (WKY). The initial depressor response occurred at lower doses (0.1 versus 0.3 micrograms/kg i.v.) in SHR versus WKY. The secondary pressor response was attenuated in SHR compared to WKY in both the threshold dose (3.0 versus 0.1 microgram/kg i.v.) and maximum effect at high doses (52 versus 91% at 3.0 micrograms/kg i.v.). In conscious SHR and WKY, endothelin elicited comparable initial depressor responses with increases in heart rate; the secondary pressor responses were attenuated compared to those in anesthetized rats. Therefore endothelin elicits a prominent depressor response, which may be associated with afterload reduction, in SHR.     

Enhanced presynaptic beta 2-adrenoceptor-mediated facilitation of the pressor responses in the prehypertensive SHR

The effects of beta-adrenoceptor agonists and antagonists on pressor responses of the isolated perfused mesenteric arteries to periarterial nerve stimulation (PNS) in the prehypertensive 4-week-old spontaneously hypertensive rat (SHR) and the age-matched Wistar Kyoto rats (WKY) were examined. The systolic arterial blood pressure (SBP) of SHR and WKY were not significantly different at this young age. The pressor responses of the mesenteric arteries to PNS at various stimulating frequencies, however, were significantly greater in SHR than WKY. Cocaine, isoproterenol (a nonselective beta-adrenoceptor agonist) and salbutamol (a selective beta 2-adrenoceptor agonist) significantly enhanced the pressor responses to PNS in SHR and WKY, with significantly greater increase in SHR than WKY. The nonselective beta-adrenoceptor antagonist (propranolol) and the selective beta 2-adrenoceptor antagonist (ICI 118,551) significantly inhibited the pressor response to PNS in SHR without affecting that in WKY. The selective beta 1-adrenoceptor antagonist (practolol) was without effect on the PNS-induced pressor responses in both SHR and WKY. These results demonstrate that the presynaptic beta 2-adrenoceptor-mediated facilitation of neurogenic pressor response in mesenteric arteries already are enhanced in 4-week-old SHR. In view of the higher concentration of circulating epinephrine (Epi) in prehypertensive SHR, the enhanced facilitatory modulation via presynaptic beta 2-adrenoceptors in prehypertensive SHR may be involved in development of hypertension.     

Potentiation of pressor responses to serotonin by ketamine in isolated perfused rat mesentery

The effects of ketamine on vasoconstrictor responses to periarterial sympathetic nerve stimulation (PNS), norepinephrine (NE), and 5-hydroxytryptamine (5-HT) were studied in normotensive Wistar Kyoto rats (WKY) and spontaneously hypertensive rats (SHR). The isolated mesenteric arteries were perfused at a constant rate (5 ml/min), and the perfusion pressure was recorded. The pressor responses to PNS (8 Hz, 2 ms, 30 s) were augmented by ketamine (2 X 10(-5) and 10(-4) M) in WKY and SHR. Those to intraarterially infused NE (3 X 10(-10) M) were statistically unaltered. However, in three of seven arterial preparations from WKY and in six of nine preparations from SHR, ketamine (2 X 10(-5) and 10(-4) M) decreased the pressor responses to NE. In contrast, the responses to intraarterial 5-HT (1.3 X 10(-9) mol) were potentiated by ketamine (2 X 10(-5) and 10(-4) M) in SHR and WKY--to a much greater extent in SHR. Fractional release of tritium by PNS from isolated mesenteric arteries previously labeled with 1-[7,8-(3)H]NE (10(-7) M) was unaltered by ketamine (10(-4) M) in SHR and WKY. Cocaine (10(-5) M) prevented the ketamine-induced potentiation of PNS and 5-HT responses. Ketamine as well as cocaine inhibited the accumulations of [3H]5-HT and [3H]NE in intact mesenteric arteries from SHR and WKY to a comparable extent. In tissues denervated by 6-hydroxydopamine, the accumulation of 5-HT was about 70% (WKY) and 60% (SHR) of those in intact tissues, whereas that of NE was about 11% (WKY) and 9% (SHR).(ABSTRACT TRUNCATED AT 250 WORDS)     

Exaggerated pressor response to centrally administered renin in freely moving, spontaneously hypertensive rats

The cardiovascular responses to intracerebroventricular (i.c.v.) injection of renin were compared between freely moving normotensive Wistar Kyoto rats (WKY) and spontaneously hypertensive rats (SHR). The i.c.v. injection of renin (0.05-1.0 mU) produced a dose-dependent and a long-lasting rise in mean blood pressure associated with variable changes in heart rate (HR) in both WKY and SHR. However, the blood pressure and HR were not affected by intravenously injected renin (0.1 mU). The pressor response to i.c.v. injected renin was greater in SHR than in WKY, the dose-response curve for renin in SHR being to the left of that in WKY. Central (i.c.v.) pretreatment with [Sar1, Ile8]angiotensin II (50 micrograms) largely abolished the pressor response to i.c.v. injected renin in both WKY and SHR. The i.c.v. injection of angiotensin II (ANG II) (10-100 ng) induced a dose-dependent pressor response which was antagonized by central pretreatment with [Sar1, Ile8]ANG II (50 micrograms). The pressor response to ANG II was also greater in SHR than in WKY. These results suggest that the pressor response to centrally administered renin as well as to ANG II, which is mediated via ANG II receptors located in the brain, is enhanced in SHR.     

ENHANCED SENSITIVITY OF MEDULLARY DEPRESSOR NEURONS TO N-METHYL-D-ASPARTATE–GLYCINE SITE ANTAGONISTS IN THE SPONTANEOUSLY HYPERTENSIVE RAT

1. The effects of the specific N -methyl- D -aspartate (NMDA)–glycine site antagonist 5-fluoro indole-2-carboxylic acid (FICA) and NMDA, microinjected into the vasodepressor caudal ventrolateral medulla, were compared in spontaneously hypertensive rats (SHR) and in Wistar-Kyoto (WKY) rats.
2. 5-Fluoro indole-2-carboxylic acid elicited a significant pressor response (+20.0±4.9 mmHg) in SHR, but no change was found in the basal blood pressure of WKY rats.
3. The depressor response due to NMDA microinjection was significantly larger in SHR (–48.0±4 mmHg) than in WKY rats (–23.0±1.9 mmHg).
4. Pre-injection of FICA attenuated the depressor effects of NMDA significantly, this blockade being significantly more pronounced in SHR (37.0±2.7 mmHg) than in WKY rats (12.0± 1.2 mmHg).
5. The enhanced responses to FICA may reflect the lower levels of the endogenous NMDA–glycine antagonist kynurenic acid in SHR compared with WKY rats.     

Potentiation by quipazine of adrenergic transmission in mesenteric arteries of spontaneously hypertensive rats

The effect of quipazine on vasoconstrictor responses to periarterial sympathetic nerve stimulation (NS: 8 Hz, 2 ms, 30 s) and to exogenous norepinephrine (NE) were investigated in the isolated perfused mesenteric arteries of the spontaneously hypertensive rats (SHR) and the normotensive Wistar Kyoto rats (WKY). Quipazine (100 nM) potentiated the pressor response to NS significantly more than that to NE in both SHR and WKY. This agent (30 and 100 nM) also significantly increased the NS-evoked 3H overflow in the [3H]NE pretreated mesenteric vasculature of SHR, but not of WKY, suggesting facilitation of transmitter release. The summation of the pre- and postsynaptic effects of quipazine may account for its greater amplifying effects on NS in SHR, while this agent may act mainly postsynaptically in WKY. The presynaptic action is not attributable to alpha-adrenoceptor blockade but probably to a serotonin-like agonistic action, and the postsynaptic action appears to be mediated by ketanserin-sensitive (5HT2) receptors.     

POTENTIATION OF DIPSOGENIC ACTIONS BY CENTRALLY ADMINISTERED TYPE-C NATRIURETIC PEPTIDE IN SPONTANEOUSLY HYPERTENSIVE BUT NOT WISTAR-KYOTO RATS

1. The effects of type-C natriuretic polypeptides (CNP) on the central dipsogenic and pressor responses to angiotensin II (AngII) were studied by the administration of agents into the lateral cerebral ventricle under conscious and unrestrained conditions in normotensive Wistar-Kyoto (WKY) and spontaneously hypertensive rats (SHR). 2. The fluid intake induced by AngII (25 ng) and water deprivation were potentiated after pretreatment with CNP in SHR but not in WKY rats. However, carbachol-induced water intake was not altered by pretreatment with CNP (2.5 μg) in either WKY rats or SHR. 3. In contrast, CNP did not influence the pressor responses to AngII in either WKY rats o. SHR.     

Comparison of the purinergic contribution to sympathetic vascular responses in SHR and WKY rats in vitro and in vivo

Isolated tail arteries from spontaneously hypertensive rats (SHR) were more responsive than those from Wistar-Kyoto (WKY) control rats to exogenously applied noradrenaline (NA), ATP, alpha,beta-methylene ATP (mATP), KCl and sympathetic nerve stimulation. The sympathetic contractile responses of the SHR and WKY were both reduced to 10-20% of control by alpha 1-adrenoceptor antagonism. The pressor responses to sympathetic nerve stimulation were significantly greater in the SHR than the WKY rats at all stimulation frequencies examined (1-10 Hz). There was no significant difference between SHR and WKY rats in the magnitude of pressor responses produced by i.v. administration of NA or mATP. The pressor responses to sympathetic nerve stimulation in the pithed SHR were no more resistant to alpha-adrenoceptor antagonism than those of the WKY. The results suggest that the contribution by ATP to sympathetic vasoconstriction is no greater in SHR than WKY.     

Adrenomedullin inhibits the pressor effects and decrease in renal blood flow induced by norepinephrine or angiotensin II in anesthetized rats.

Adrenomedullin (AM), a hypotensive peptide originally isolated from human pheochromocytoma, has been reported to regulate renal functions. In patients with glomerulonephritis, the serum levels of AM are elevated as well as hypertensive agents norepinephrine (NE) and angiotensin II (AII). The effects of AM on the NE- or AII-induced pressor effects and renal blood flow responses, however, are not well clarified. We examined the effects of AM on blood pressure and renal blood flow induced by NE or AII in anesthetized rats. Arterial blood pressure and renal blood flow were measured using a calibrated pressure transducer and a laser Doppler flowmeter, respectively. Drugs were injected into the tail vein with a syringe. Intravenous administration of AM (1-3 nmol/kg) decreased the arterial blood pressure in anesthetized rats in a dose-dependent manner, whereas it did not affect the renal blood flow. NE or AII administration in anesthetized rats caused both increases in blood pressure and decreases in renal blood flow. Simultaneous administration of AM with NE or All prevented the increasing effects of blood pressure and inhibited the decreases in renal blood flow caused by NE or AII. These findings suggest that AM may have a protective role against the pressor effects and decrease in renal blood flow caused by NE or AII.     

Possible involvement of an impaired baroreflex mechanism but not the renin-angiotensin system and vasopressin in the enhanced pressor responsiveness to physostigmine in spontaneously hypertensive rats

Effects of physostigmine on heart rate, mean arterial pressure (MAP), plasma renin concentration (PRC) and vasopressin (AVP) release were investigated in spontaneously hypertensive (SHR) and Wistar-Kyoto (WKY) rats. Physostigmine (100 micrograms/kg, i.a.) produced a greater and prolonged hypertensive response in the SHR than in the WKY. Heart rate was increased by physostigmine in SHR rats while it was unchanged in the WKY. PRC was unchanged or even slightly decreased in these animals when MAP was increased by physostigmine. An AVP pressor antagonist did not attenuate the pressor and cardiac effects of physostigmine in these animals. These data indicate that an impaired baroreflex mechanism or a different mode of sympathetic neuronal activation by physostigmine through the central mechanism appears to be contributory, at least in part, to the enhanced pressor responsiveness in the SHR. The renin-angiotensin system and AVP do not appear to be involved in the enhanced pressor responsiveness to physostigmine in SHR rats.     

Antagonism of alpha 1-adrenoceptor-mediated vascular contraction by urapidil in isolated arterial strips of spontaneously hypertensive rats

Antagonism of alpha 1-adrenoceptor-mediated vascular contraction by urapidil was examined in helical strips of femoral and mesenteric arteries isolated from 13-week-old Aoki spontaneously hypertensive rats (SHR) and age-matched normotensive Wistar-Kyoto (WKY) rats, since this agent has antihypertensive effect through antagonizing peripheral alpha-adrenoceptors. Schild plot analyses clearly demonstrated the existence of only alpha 1-adrenoceptors in these arteries from both strains. Therefore, it is possible to demonstrate alpha 1-adrenoceptor blocking effects of nonselective alpha-adrenoceptor antagonists as well as selective alpha 1-adrenoceptor antagonists. Urapidil antagonized the alpha 1-adrenoceptor-mediated vascular contraction in a competitive fashion. The pA2 value for urapidil against alpha 1-adrenoceptors was not significantly different between SHR and WKY rats. The addition of 10(-5) M norepinephrine (NE) produced a sustained contraction in a SHR femoral artery, whereas in a WKY rat femoral artery this agonist produced a transient contraction followed by a sustained relaxation. Urapidil elicited a dose-dependent relaxation with a IC50 value of 6.50 in the SHR femoral artery precontracted with NE. In the presence of 3 x 10(-7) M timolol, a beta-adrenoceptor antagonist, femoral arteries from both strains exhibited similar magnitude of contraction in response to the stimulation with 10(-5) M NE. Under these conditions, urapidil elicited a similar extent of relaxation between SHR and WKY rats. On the other hand, the addition of 10(-5) M NE produced a sustained contraction in mesenteric arteries from both SHR and WKY rats. The contraction expressed as a ratio to the maximum developed by KCl depolarization was significantly greater in SHR than in WKY rats. In these arteries, the relaxing effect of urapidil was more evident in SHR than in WKY rats. Contractile responses to NE and relaxing effects of urapidil were not affected by timolol. These results suggest that urapidil effectively antagonized enhanced alpha 1-adrenoceptor responses seen in SHR arteries.     

Nitric oxide-mediated changes in vascular reactivity in pregnancy in spontaneously hypertensive rats.

1. To examine the mechanisms which may account for pregnancy-induced vasodilatation in spontaneously hypertensive rats (SHR), we have investigated the changes in vascular reactivity and the effects of endothelial nitric oxide (NO) inhibition in the in situ blood-perfused, mesenteric resistance vessels of 18-20 day pregnant SHR. The effects of NG-nitro-L-arginine (L-NOARG) were compared in pregnant and nonpregnant SHR and gestation matched normotensive Wistar-Kyoto (WKY) rats. 2. Intra-arterial mean blood pressures (MBP) were similar in pregnant and nonpregnant SHR. Basal perfusion pressures (BPP) were decreased in pregnant compared with nonpregnant SHR. Pregnant WKY had lower MBP and BPP than either pregnant or nonpregnant SHR. 3. Vasoconstrictor responses to electrical stimulation (ES) and intra-arterial noradrenaline (NA) were decreased in pregnant compared with nonpregnant SHR. These responses were still greater in pregnant SHR when compared with pregnant WKY. Vascular reactivity to angiotensin II (AII) in pregnant SHR was reduced to a similar level to that in pregnant WKY. 4. L-NOARG (5 mg kg-1, i.v.), an inhibitor of nitric oxide synthase, increased MBP and BPP in all groups. After L-NOARG, BPP were equalized between pregnant and nonpregnant SHR. Pregnant WKY still showed lower MBP and BPP than SHR groups. 5. L-NOARG potentiated vascular responses to ES, NA and AII in all groups. The blunted vascular responses to NA and ES were normalized and the reactivity to AII was only partially reversed in pregnant SHR compared with nonpregnant SHR. Pregnant WKY still had much lower vascular responses to ES and NA than either pregnant or nonpregnant SHR.(ABSTRACT TRUNCATED AT 250 WORDS)     

Upregulation of tachykinin NK-1 and NK-3 receptor binding sites in the spinal cord of spontaneously hypertensive rat: impact on the autonomic control of blood pressure

1 Effects of intrathecally (i.t.) injected tachykinin NK-1 and -3 receptor agonists and antagonists were measured on mean arterial blood pressure (MAP) and heart rate (HR) in awake unrestrained spontaneously hypertensive rats (SHR,15-week-old) and age-matched Wistar Kyoto rats (WKY). Quantitative in vitro autoradiography was also performed on the lower thoracic spinal cord of both strains and Wistar rats using specific radioligands for NK-1 receptor ([(125)I]HPP[Arg(3),Sar(9),Met(O(2))(11)]SP (3-11)) and NK-3 receptor ([(125)I]HPP-Asp-Asp-Phe-N-MePhe-Gly-Leu-Met-NH(2)). 2 The NK-1 agonist [Sar(9),Met(O(2))(11)]SP (650 and 6500 pmol) decreased MAP and increased HR in WKY. The fall in MAP was blunted in SHR and substituted by increases in MAP (65-6500 pmol) and more sustained tachycardia. The NK-3 agonist senktide (6.5-65 pmol) evoked marked increases in MAP and HR (SHR>WKY), yet this response was rapidly desensitized. Cardiovascular effects of [Sar(9),Met(O(2))(11)]SP (650 pmol) and senktide (6.5 pmol) were selectively blocked by the prior i.t. injection of LY303870 (NK-1 antagonist, 65 nmol) and SB235375 (NK-3 antagonist, 6.5 nmol), respectively. Antagonists had no direct effect on MAP and HR in both strains. 3 Densities of NK-1 and -3 receptor binding sites were significantly increased in all laminae of the spinal cord in SHR when compared to control WKY and Wistar rats. The dissociation constant was however not affected in SHR for both NK-1 (K(d)=2.5 nM) and NK-3 (K(d)=5 nM) receptors. 4 Data highlight an upregulation of NK-1 and -3 receptor binding sites in the thoracic spinal cord of SHR that may contribute to the hypersensitivity of the pressor response to agonists and to the greater sympathetic activity seen in this model of arterial hypertension.     

Adrenomedullary and beta-adrenergic participation in enhanced sympathetic pressor responses of spontaneously hypertensive rats

The beta-adrenergic and adrenomedullary components of pressor responses to sympathetic nerve stimulation were studied in spontaneously hypertensive rats (SHR) and normotensive Wistar Kyoto rats (WKY). The effects of electrical stimulation of the entire spinal cord of pithed rats pretreated with tubocurarine and atropine were studied on systolic blood pressure, heart rate and plasma cyclic AMP levels. The heart rate increase upon low frequency stimulation (1 Hz) and the blood pressure elevation upon stimulation at higher frequencies (3 and 5 Hz) were higher in SHR than in WKY whereas the increase in circulating cyclic AMP level was not different in the two strains. Pretreatment with propranolol (2.5 mg X kg-1) further enhanced the pressor responses in SHR but not in WKY, although it inhibited the heart rate acceleration and decreased the circulating level of cyclic AMP similarly in the two strains. After acute adrenalectomy, the elevations of blood pressure and circulating cyclic AMP levels were reduced to an identical level in SHR and WKY. These results show that the marked enhancement of the pressor response observed in SHR upon stimulation of the entire sympathetic outflow is mostly of adrenomedullary origin and includes a hypotensive component due to beta-adrenoceptor stimulation which is not present in WKY.     

Interactions between angiotensin II and alpha-adrenoceptor agonists mediating pressor responses in the pithed rat.

1. The aim of the study was to investigate the interactions between angiotensin II (AII) and adrenoceptor-mediated pressor responses in the pithed rat. Emphasis was placed on the effects of AII on blood pressure per se and the possibility of differential effects on alpha 1- and alpha 2-adrenoceptor-mediated pressor responses. 2. A low concentration of the angiotensin converting enzyme (ACE) inhibitor, teprotide (1 mg kg-1) lowered the resting diastolic blood pressure (BP) and attenuated only the second phase components of pressor responses to both alpha 1- and alpha 2-adrenoceptor agonists. Infusion of AII (50 ng kg-1 min-1) did not reverse the attenuating effect of teprotide and did not reliably restore the basal diastolic BP. 3. Although teprotide (10 mg kg-1) did not produce a greater fall in diastolic BP than did the low dose (1 mg kg-1), it attenuated the peak and second phase pressor responses to alpha 1- and alpha 2-adrenoceptor agonists but had no effect on pressor responses to AII or 5-hydroxytryptamine (5-HT). Infusion of AII reversed the effects of teprotide (10 mg kg-1) provided that rats were pretreated with flurbiprofen (5 mg kg-1), confirming that the depressor effects of the higher dose of teprotide are AII-dependent but that demonstration of this was complicated by products of cyclo-oxygenase. 4. The AII-receptor antagonist, saralasin (4 micrograms kg-1 min-1) attenuated alpha 1- and alpha 2-adrenoceptor-mediated pressor responses in a manner similar to that of teprotide (10 mg kg-1), suggesting that in this pithed rat model the alpha-adrenoceptor-mediated responses were selectively facilitated by endogenous AII. 5. Infusion of AII (50 ng kg-1 min-1) over a 60 min period did not produce a pressor response in the absence of other drugs but did facilitate pressor responses to alpha-adrenoceptor agonists. This confirms that AII can modulate alpha-adrenoceptor-mediated responses independently of basal blood pressure. 6. Overall the results indicate a facilitatory role for endogenous AII on alpha-adrenoceptor-mediated pressor responses. This is discussed in relation to the failure to demonstrate this convincingly under similar conditions on sympathetic nerve-mediated pressor responses.     

Catecholaminergic and opioidergic mechanisms involved in the hypotensive response of pindolol

The present study evaluated the involvement of opioidergic and catecholaminergic mechanisms in the hypotensive action of pindolol. Pindolol (1 mg/kg i.a.) was administered to unanesthetized spontaneously hypertensive rats (SHR) and Wistar Kyoto (WKY) rats instrumented for direct arterial pressure monitoring. Peripheral administration of pindolol produced a significant decrease in blood pressure in both SHR and WKY rats with SHR animals having a greater response. Heart rate was reduced in SHR; however, a tachycardia was observed in WKY rats. Pretreatment with naloxone (100 micrograms/kg i.a.) 10 min prior to pindolol administration prevented the hypotensive response. Similar pretreatment with yohimbine, an alpha 2-receptor antagonist, also prevented the pindolol-induced hypotensive response in both SHR and WKY rats. Neither naloxone nor yohimbine alone significantly affected blood pressure or heart rate. These results suggest that opioidergic and catecholaminergic mechanisms are involved in the hypotensive action of pindolol.     

Release of serotonin in the locus coeruleus of normotensive and spontaneously hypertensive rats (SHR)

The aim of the present work was to clarify whether differences exist between the release of endogenous serotonin in the locus coeruleus of normotensive and hypertensive rats. The locus coeruleus was superfused with artificial cerebrospinal fluid (aCSF) through a push-pull cannula and serotonin and its metabolite 5-hydroxyindoleacetic acid (5-HIAA) were determined in the superfusate by HPLC combined with electrochemical detection. Compared with normotensive Wistar-Kyoto (WKY) rats, the basal release rate of serotonin in the locus coeruleus of spontaneously hypertensive rats (SHR) was increased more than twofold. Intravenous infusion of noradrenaline (4 μg/kg min) increased mean arterial blood pressure to the same extent in hypertensive and normotensive rats. The pressor response was associated with an increased serotonin release. In WKY rats, the release of serotonin in the locus coeruleus evoked by noradrenaline infusion was more pronounced than in SHR. In WKY rats, intravenous infusion of sodium nitroprusside (150 μg/kg min) led to a fall in blood pressure which was less pronounced and lasted shorter than in SHR. The depressor response was associated with decreased serotonin release. In WKY rats, the decrease in serotonin release evoked by sodium nitroprusside was more pronounced and lasted longer than in SHR. Neither noradrenaline nor sodium nitroprusside influenced the outflow of 5-HIAA. The sensory stimuli noise and tail pinch led to a slight rise in arterial blood pressure which was similar in WKY rats and SHR. These stimuli enhanced the release rate of serotonin and the outflow of 5-HIAA to the same extent in the locus coeruleus of normotensive and hypertensive rats. The findings suggest that the enhanced release of serotonin in the locus coeruleus of genetically hypertensive rats reflects a mechanism counteracting the disturbed blood pressure homeostasis. Stressors influence blood pressure and release of serotonin in the locus coeruleus of SHR and WKY rats to the same extent. Received: 16 November 1998 / Accepted: 22 February 1999