ABNORMALITY OF THE GLOMERULAR ANGIOTENSIN II RECEPTOR IN EXPERIMENTAL DIABETIC NEPHROPATHY

1. The combined effect of diabetes and hypertension on the plasma angiotensin II (AII)/glomerular AII receptor (AII-R) relationship in streptozotocin-induced diabetes was investigated as well as the effect of glycaemic control on this relationship. 2. Diabetes was induced in spontaneously hypertensive rats (SHR) and Wistar-Kyoto (WKY) rats with streptozotocin 60 mg/kg and blood sugars maintained between 18–21 mmol/L (uncontrolled diabetes) and 4–8 mmol/L (controlled diabetes). Rats were killed on days 1 and 7. Angiotensin II receptor was estimated by saturation analysis and plasma AII by radio-immunoassay. 3. Angiotensin II receptors were significantly higher in non-diabetic SHR than WKY rats (708 ± 62 and 388 ± 36 fmol/mg protein, respectively, P = 0.0008). Plasma AII were comparable in both groups (47 ± 2.7, 38 ± 3.5 pg/mL, respectively) and a significant inverse relationship between AII/AII-R was observed (WKY P = 0.02 and SHR P = 0.004). 4. On day 7, plasma AII and AII-R levels in diabetic groups were comparable with those of their non-diabetic controls. Diabetic WKY rats maintained an inverse correlation between AII and AII-R (controlled P= 0.04 and uncontrolled P= 0.015), but this did not occur in the SHR. 5. Absence of receptor response to varying ligand concentrations in the diabetic SHR may contribute to the development of nephropathy. Glycaemic control does not appear to reverse this abnormality in the SHR, so that co-existent hypertension may have a more direct influence on renal function.     

ANGIOTENSIN II RECEPTORS AND RENIN IN THE PORCINE UTERUS: MYOMETRIAL AT2 AND ENDOMETRIAL AT1 RECEPTORS ARE DOWN-REGULATED DURING GESTATION

1. The aim of the present study was to characterize the angiotensin II (AngII) receptor subtypes in the porcine uterus and the variation of receptor densities and renin concentrations during gestation. 2. In myometrium from non-pregnant sows, the AngII receptors were almost exclusively AT₂ receptors. During gestation, the AngII receptor density was decreased and the AT₁ receptor became predominant in the last part of gestation as a result of a down-regulation of the AT₂ receptor. 3. In the endometrium, the AT₁ receptor was predominant both in non-pregnant sows and throughout gestation. The AngII receptor density was decreased during gestation as a consequence of down-regulation of the AT₁ receptor. 4. The renin concentrations in the myometrium and endometrium of pregnant sows did not differ from those in non-pregnant animals. 5. The finding of enzymatically active renin and high densities of AngII receptors in the porcine uterus is in accordance with a functional renin-angiotensin system (RAS), which may be important for an increased vascular permeability and stimulated angiogenesis in early pregnancy and for contraction of the myo-metrial smooth muscle cells during parturition. The predominance of ATi receptors in the endometrium of non-pregnant sows differs from an earlier finding in non-pregnant women, where AT2 receptors were predominant in the endometrium. This is in accordance with earlier studies, indicating species differences in the expression and possibly also the physiological roles of the RAS in reproductive tissues.     

A STUDY OF ANGIOTENSIN II RECEPTORS AFTER CHRONIC INHIBITION OF NITRIC OXIDE SYNTHASE IN THE SPONTANEOUSLY HYPERTENSIVE RAT

1. Nitric oxide (NO) synthase inhibition, induces a sustained increase in blood pressure and amplifies the pressor response to infused angiotensin II (AngII). This study was designed to investigate the contribution of AngII receptors to the elevated blood pressure and enhanced pressor response to AngII in the spontaneously hypertensive rat (SHR) chronically treated with N^G-nitro-l -arginine-methyl ester (l -NAME). 2. Two groups of 13 week old female SHR were housed four to a box. Group I rats received l -NAME for 7 days (2.5 mg/kg per day) in their drinking water. Group II rats received water only. Blood pressure was monitored daily by tail-cuff plethysmography. Plasma AngII was measured by radioimmunoassay. Aortic and uterine receptor binding was determined by saturation analysis using [¹²⁵I]-Sar⁸, Ile¹)AngII. Data was analysed using the computer program ligand. 3. Mean systolic blood pressure was significantly elevated in rats treated with l -NAME compared with the control group. Plasma AngII concentration was slightly decreased in rats treated with l -NAME compared with control. Densities of both aortic and uterine AngII receptors increased significantly following NO synthase inhibition. Receptor affinity in the aorta decreased in the l -NAME group compared with control. However, uterine AngII receptor affinity was unchanged. 4. We conclude that the increased blood pressure and enhanced pressor responsiveness that occurs with chronic inhibition of NO synthesis may result partly from increased vascular AngII receptor expression.     

EFFECT OF AN ANTIHYPERTENSIVE DRUG ON BRAIN ANGIOTENSIN II LEVELS IN RENAL AND SPONTANEOUSLY HYPERTENSIVE RATS

1. Although numerous studies suggest that brain angiotensin (AII) may play an important role in the regulation of blood pressure, it is still unclear what factors may influence brain All. In this study, we hypothesized that brain AII is influenced by circulating factors. To investigate the role of blood pressure and plasma All in brain AII level, we studied the effect of an antihypertensive drug on brain AII in two-kidney, one-clip (2K1C) and spontaneously hypertensive (SHR) rats. 2. Hydralazine (20mg/kg per day) and vehicle (water) were given to 2K1C rats between 2 and 6 weeks after operation and SHR for 4 weeks. In addition, vehicle was applied to sham operated rats and Wistar-Kyoto (WKY) rats. Brain and plasma AII was measured by a highly sensitive radioimmunoassay coupled with high performance liquid chromatography. 3. Hydralazine treatment effectively lowered blood pressure to the same levei of sham-operated and WKY rats. 2K1C rats showed significantly higher plasma All than sham rats, but hydralazine treatment did not show any change in plasma AII. Brain AII in the hypothalamus region of 2K1C rats showed a significantly higher level than sham rats. Interestingly, hydralazine treatment diminished this increase in brain AII. In contrast, SHR showed higher brain A11 levels in the hypothalamus, brainstem and cerebellum than in WKY rats, whereas there was no significant change in plasma AII concentration between SHR and WKY rats. In contrast to the results found in 2K1C rat experiments, hydralazine treatment failed to decrease brain AII levels despite lowered blood pressure. 4. In conclusion, brain AII is affected by systemic blood pressure in 2K1C hypertensive rats, but not in SHR, and the mechanisms which cause the difference between 2K1C rats and SHR are unknown in this study.     

ROLE OF UTERINE FACTORS IN THE DEVELOPMENT OF HYPERTENSION IN SHR

1. To examine whether the uterine environment plays a role in the development of hypertension in the spontaneously hypertensive rats (SHR), we have compared fetal weight, placental weight, and amniotic fluid composition of SHR and Wistar-Kyoto (WKY) rats after 20 days of gestation. 2. Pregnant SHR and WKY were anaesthetized at 20 days of gestation and the uterus and embryonic sacs removed. Fetal and placental weights were recorded and amniotic fluid collected for measurement of volume, osmolality and electrolyte composition. 3. No significant difference was found in litter size and placental weight between SHR and WKY. Total embryonic sac weight and fetal weight of SHR were significantly lower than WKY. Amniotic fluid volume, sodium concentration and osmolality of SHR were significantly higher than WKY, while amniotic fluid potassium concentration of SHR was significantly lower than WKY. 4. Thus, the SHR foetus was significantly underweight compared to the WKY and was bathed in amniotic fluid with a significantly higher osmolality and sodium concentration. As the mature foetus is known to drink amniotic fluid, it is hypothesized that the elevated Na/K ratio in SHR amniotic fluid may instigate or accelerate the hypertensive process.     

EFFECT OF TRANSFORMING GROWTH FACTOR-β1 ON PLATELET-DERIVED GROWTH FACTOR RECEPTOR BINDING AND GENE EXPRESSION IN VASCULAR SMOOTH MUSCLE CELLS FROM SHR AND WKY RATS

1. This study examined the effects of transforming growth factor-βl (TGF-β1) on platelet-derived growth factor-BB (PDGF-BB)-stimulated DNA synthesis, [¹²⁵I]-PDGF-BB receptor binding and PDGF-β receptor mRNA expression in vascular smooth muscle cells (VSMC) isolated from Wistar-Kyoto (WKY) rats and spontaneously hypertensive rats (SHR). 2. TGF-β1 inhibited by 40% DNA synthesis stimulated by PDGF-BB in VSMC from WKY rats but potentiated by 20% growth factor-stimulated DNA synthesis in VSMC from the SHR. 3. Since the difference in effect of TGF-β1 could not be attributed to differential regulation of [¹²⁵I]-PDGF-BB binding activity and PDGF-β receptor mRNA expression, it is suggested that alterations in intracellular signalling pathways may account for the differential effects of TGF-β1 on PDGF-BB-stimulated DNA synthesis in VSMC from SHR and WKY rats.     

Modulation of uterine GABAA receptors during gestation and by tetrahydroprogesterone

Binding of a GABAA receptor agonist, [3H]muscimol, was studied in rat uterine membranes of non-pregnant rats and those at days 15 and 19 of pregnancy. Also, an interaction of the uterine GABAA receptors with tetrahydroprogesterone was examined. At day 15 of gestation [3H]muscimol binding was twice as high as in non-pregnant rats, but at day 19 it was reduced. These changes resulted from an increase of the receptor affinity and decrease of the receptor density, at days 15 and 19, respectively. Since tetrahydroprogesterone, in vitro, also increased [3H]muscimol binding, we propose that this steroid may participate in regulation of uterine function during pregnancy.     

Angiotensin II responses of vascular smooth muscle cells from hypertensive rats: enhancement at the level of p42 and p44 mitogen activated protein kinase

1. Stimulation of the AT₁ receptor by angiotensin II (AII) gives a larger mitogenic response in vascular smooth muscle cells from spontaneously hypertensive rats (SHR) compared to those from normotensive (WKY) controls. Here we investigated whether the p42 and p44 mitogen activated protein kinase (MAPK) pathway is differentially regulated in these cells by AT₁ receptors.
2. We showed that there is a similar level of p42 and p44 MAPK immunoreactivity in the SHR and WKY derived cells.
3. However, by use of an antiserum specific for the tyrosine phosphorylated form of MAPK, and an assay with a nonapeptide MAPK substrate, we showed that AII (100 nM)-stimulated phosphorylation and activation of p42^mapk and p44^mapk are enhanced in the SHR derived cells.
4. This increased MAPK activity in SHR derived cells was also seen on protein kinase C activation with 100 nM phorbol myristate acetate (PMA). The size and time course of the response to PMA was the same as that to AII in each cell type.
5. The protein kinase C inhibitor Ro 31-8220 attenuated the early (2 min) phase of AII stimulation of MAPK activity and the entire stimulation caused by PMA. At longer times of AII stimulation both p42^mapk and p44^mapk were activated by an Ro 31-8220-insensitive mechanism.
6. Agonist or PMA stimulation of MAPK activity was inhibited by the tyrosine kinase inhibitor genistein. AII stimulated tyrosine protein phosphorylation to a greater degree in SHR than WKY cells.
7. These results show that the MAPK response of SHR derived cells is increased over that of WKY cells by mechanisms independent of the enhanced stimulation of phospholipase C; amplification at the level of sequential protein kinase C and tyrosine kinase steps leads to the enhanced responsiveness of MAPK in the SHR derived cells.

     

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)     

EFFECTS OF NITRIC OXIDE SYNTHASE INHIBITION AND ENDOTHELIN ETA RECEPTOR BLOCKADE ON HAEMODYNAMICS IN HYPERTENSIVE RATS

1. The objectives of the present study were to study regional differences in haemodynamics between spontaneously hypertensive (SHR) and normotensive Wistar-Kyoto (WKY) rats induced by the nitric oxide synthase (NOS) inhibitor N^G-monomethyl -l -arginine (l -NMMA) and the endothelin ET_A receptor antagonist BQ123 in vivo in tissues known to be important for blood pressure (BP) regulation (heart, kidney and skeletal muscle). Furthermore, the effect of acetylcholine (ACh) infusion (2 μg/kg per min) was examined after l -NMMA or BQ 123. The microsphere method was used for determinations of cardiac index (CI) and regional haemodynamics. 2. N^G-Monomethyl-l -arginine (20mg/kg) increased BP (26–48%; P < 0.01) and reduced CI in both rat strains. BQ 123 (1 mg/kg) reduced BP slightly (-4 to 11 %; P < 0.05). 3. N^G -Monomethyl-l -arginine significantly increased myocardial and skeletal muscle vascular resistance in SHR only; however, in the kidney, l -NMMA reduced blood flow and increased vascular resistance in both rat strains. 4. BQ 123 induced minor changes in regional haemodynamics that were not significantly different between the two strains. 5. Acetylcholine following BQ123 induced an increase in myocardial blood flow in WKY rats, but decreased blood flow in SHR. Acetylcholine following l -NMMA reduced myocardial blood flow in both strains. 6. Acetylcholine following BQ 123 induced renal vasodilation in WKY rats but, following l -NMMA, ACh did not induce renal vasodilation in either rat strain. In contrast, l -NMMA did not abolish the vasodilation of acetylcholine in skeletal muscle in WKY rats. 7. In conclusion, the contribution of nitric oxide to basal vessel tone was not impaired in the heart, skeletal muscle and kidney in SHR. Antagonism of ET_A receptors caused similar haemodynamic responses in both rat strains in these organs. Furthermore, NOS inhibition, but not ET_A blockade, blunted the expected ACh-induced vasodilation in the heart and kidney in WKY rats, but not in skeletal muscle in both strains.     

Mechanism of Relaxation Via TASK-2 Channels in Uterine Circular Muscle of Mouse

Plasma pH can be altered during pregnancy and at labor. Membrane excitability of smooth muscle including uterine muscle is suppressed by the activation of K⁺ channels. Because contractility of uterine muscle is regulated by extracellular pH and humoral factors, K⁺ conductance could be connected to factors regulating uterine contractility during pregnancy. Here, we showed that TASK-2 inhibitors such as quinidine, lidocaine, and extracellular acidosis produced contraction in uterine circular muscle of mouse. Furthermore, contractility was significantly increased in pregnant uterine circular muscle than that of non-pregnant muscle. These patterns were not changed even in the presence of tetraetylammonium (TEA) and 4-aminopyridine (4-AP). Finally, TASK-2 inhibitors induced strong myometrial contraction even in the presence of L-methionine, a known inhibitor of stretchactivated channels in myometrium. When compared to non-pregnant myometrium, pregnant myometrium showed increased immunohistochemical expression of TASK-2. Therefore, TASK-2, seems to play a key role during regulation of myometrial contractility in the pregnancy and provides new insight into preventing preterm delivery.     

NEUROVASCULAR FUNCTION DURING PREGNANCY IN THE SPONTANEOUSLY HYPERTENSIVE RAT

1. Blood pressure (BP) declines dramatically in the final week of gestation in the pregnant spontaneously hypertensive rat (SHR). This study investigated the hypothesis that alterations of vascular neuroeffector function in the pregnant SHR and normotensive Wistar-Kyoto (WKY) rat are responsible for this decline. 2. Pregnancy in SHR and WKY rats was associated with a significant drop in BP in the last week of gestation. 3. Responses of the perfused mesenteric vasculature to bolus doses of noradrenaline (NA) and potassium chloride (KCl) were decreased in preparations from SHR rats 4 days before delivery. This decreased responsiveness was absent in preparations from SHR rats 1 day before delivery. Responses of the perfused mesenteric vasculature to sympathetic nerve stimulation were not influenced by pregnancy in the SHR. 4. It is concluded that while there are dynamic changes occurring in neurovascular function just prior to delivery, it is unlikely that they are wholly responsible for the dramatic decline in blood pressure in the SHR rat.     

EFFECTS OF VERAPAMIL AND DILTIAZEM ON DOPAMINE RELEASE IN THE CENTRAL NERVOUS SYSTEM OF SPONTANEOUSLY HYPERTENSIVE RATS

1. The purpose of the present study was to investigate the effects of Ca²⁺-antagonists (verapamil and diltiazem) on dopamine release in the central nervous system in hypertension. 2. Striatal slices obtained from spontaneously hypertensive rats (SHR) and Wistar-Kyoto (WKY) rats were prelabelled with [³H]-dopamine, and superfused with Krebs-Ringer solution in vitro. The slices were stimulated electrically at a frequency of 1 Hz. 3. Stimulation-evoked release of [³H]-dopamine from striatal slices was significantly decreased in SHR compared with WKY rats. 4. Exposure of slices to verapamil and diltiazem significantly increased the stimulation-evoked [³H]-dopamine release. The facilitatory effects of the Ca²⁺-antagonists on dopamine release were significantly greater in SHR than in WKY rats. 5. Because central nervous system dopaminergic mechanisms appear to be depressor, the results suggest that the pronounced effects of verapamil and diltiazem on dopamine release in SHR might be involved in the central hypotensive mechanisms of the Ca²⁺-antagonists.     

AUGMENTATION OF ANGIOTENSIN II RELEASE FROM ISOLATED MESENTERIC ARTERIES OF WISTAR-KYOTO AND SPONTANEOUSLY HYPERTENSIVE RATS FOLLOWING NEPHRECTOMY

1. We previously reported that angiotensin II release from the mesenteric arteries of Wistar-Kyoto (WKY) and spontaneously hypertensive rats (SHR) increased in a time-dependent manner as a result of the isolation of the arteries and perfusion. This phenomenon appeared to be due to the withdrawal of circulating angiotensin II (AII). 2. The purpose of the present study was to test the hypothesis that vascular AII generation may be negatively regulated by circulating AII in WKY and SHR, and to clarify the role of this vascular angiotensin II in the sustained hypertension of SHR following nephrectomy. 3. The mesenteric arteries from kidney-intact and nephrectomized WKY and SHR were perfused and the amount of AII released into the perfusate was measured. The effects of the angiotensin converting enzyme inhibitor, captopril, and the effects of supplementation of renal renin and circulating angiotensins to nephrectomized rats, by blood exchange between kidney-intact and nephrectomized rats, on AII release were examined to clarify the pathway of vascular AII generation after nephrectomy. 4. Nephrectomy caused augmentation of vascular AII release both in WKY and SHR in spite of the abolishment of circulating renin. Captopril reduced this enhanced release of AII, but blood exchange did not affect it. There was no significant difference in these responses between WKY and SHR. 5. These results suggest that WKY and SHR have in common a potent pathway for production of vascular AII in response to the withdrawal of circulating AII, although this pathway is not responsible for the sustained hypertension of SHR after nephrectomy. The precise pathophysiological role of this pathway remains to be elucidated.     

Alterations of cyclo-oxygenase products and NO in responses to angiotensin II of resistance arteries from the spontaneously hypertensive rat.

1. The involvement of cyclo-oxygenase (COX) products and nitric oxide (NO) in contractile responses of resistance arteries to angiotensin II (AII) were investigated in small mesenteric arteries from spontaneously hypertensive rats (SHR) and Wistar Kyoto (WKY) rats. 2. In endothelium intact vessels, AII induced concentration-dependent responses without any significant difference between the two strains. However, removal of functional endothelium resulted in enhanced sensitivity to AII, the pD2 value increasing from 8.4 +/- 0.2 to 8.9 +/- 0.2 (P < 0.05) in WKY and from 8.2 +/- 0.1 to 8.6 +/- 0.1 (P < 0.05) in SHR (not significantly different between strains, n = 9 - 12). In addition, endothelium removal enhanced maximal contractions elicited by AII in SHR (1.4 +/- 0.1 to 2.1 +/- 0.2 mN mm-1, n = 5; P < 0.05) but not in WKY (1.0 +/- 0.1 to 1.2 +/- 0.1 mN mm-1, n = 5) vessels. 3. In the absence of functional endothelium, the COX inhibitor indomethacin (10(-5) M) reduced contractile responses elicited by AII in SHR arteries, resulting in 33 +/- 5% (n = 5) decrease in maximal contraction. However, it produced minimal if any, effect on responses of WKY vessels. In both strains, the TP receptor antagonist GR32191 B (3 x 10(-6) M) did not modify contractions elicited by AII in these conditions. 4. In the presence of functional endothelium, indomethacin (10(-5) M) almost abolished the responses to AII in both strains. GR32191 B (3 x 10(-6) M) reduced the sensitivity of WKY arteries to AII (pD2 = 8.1 +/- 0.1, P < 0.01) without any effect on maximal contraction. In SHR arteries, it markedly reduced maximal contraction (47 +/- 3.5%). 5. In both strains, the NO synthase inhibitor NG-nitro-L-arginine methy lester (L-NAME; 10(-4) M) had no effect in the absence of functional endothelium but it markedly reduced the inhibitory influence of endothelium on contractile responses to AII. Furthermore, in arteries with endothelium, it reduced the effect of both indomethacin and GR32191 B to the same level as observed in vessels without functional endothelium. 6. The results suggest that enhanced contraction caused by COX products was counteracted by enhanced relaxation caused by endothelium-derived NO in resistance mesenteric arteries of the SHR exposed to AII, compared to WKY arteries. The COX products involved in alterations of SHR responses comprised an endothelium-derived prostaglandin activating TP receptors and another nonendothelial unidentified vasoconstrictor compound which did not activate these receptors.     

HYPOTENSIVE EFFECT OF CHRONICALLY INFUSED ADRENOMEDULLIN IN CONSCIOUS WISTAR-KYOTO AND SPONTANEOUSLY HYPERTENSIVE RATS

1. The hypotensive effect of chronically infused human adrenomedullin (hAM), a potent vasodilator peptide that has been reported to have a natriuretic action, was examined in normotensive Wistar-Kyoto (WKY) rats and spontaneously hypertensive rats (SHR). 2. Conscious WKY rats and SHR were infused with 200 ng/h synthetic hAM for 14 days by means of osmotic minipumps. Control groups were infused at the same schedule with 0.9% saline. Systolic blood pressure (SBP) and daily urinary excretion of Na⁺ and K⁺ were measured before and during the infusion period. In addition, plasma renin activity (PRA), aldosterone and hAM concentrations were measured on day 14 of infusion. 3. A significant reduction in SBP was observed in hAM-treated SHR at day 2 and SBP remained significantly lower throughout the experiment compared with control SHR. Similarly, SBP in the hAM-treated WKY rats was found to be significantly lower than in control WKY rats during infusion. However, the hypotensive effect was not accompanied by any significant increase in urinary volume or Na⁺ excretion in hAM-treated rats of either strain. Chronic infusion with hAM significantly suppressed PRA and lowered the concentration of plasma aldosterone in WKY rats but not in SHR. The plasma hAM levels in treated WKY rats and SHR were 0.0 ± 9.4 and 0.6 ± 0.2 fmol/mL, respectively. 4. These findings demonstrate that chronically infused hAM has a hypotensive effect in both WKY rats and SHR without an increase in urinary volume or Na⁺ excretion at a plasma AM concentration within the physiological limit.     

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.     

The abnormal renal vasodilator response to D1-like receptor stimulation in conscious SHR can be normalized by AT1 blockade

BACKGROUND: We previously showed that the renal vasodilator response to a D1-like receptor agonist is blunted in conscious SHR compared with WKY rats. The mechanism of this impaired dopaminergic responsiveness in SHR is unclear. An altered balance between the renin-angiotensin-aldosterone system (RAAS) and the dopaminergic system may be involved. To determine the interaction between the RAAS and the dopaminergic system in the blunted D1-like responsiveness in SHR, we studied the renal vasodilator response to the D1-like receptor agonist fenoldopam before and after 7 days of pretreatment with the AT1-receptor antagonist (AT1-A) L158,809 in conscious SHR and WKY rats. METHODS: Effective renal plasma flow (ERPF) was measured by the clearance of I-hippuran. Mean arterial pressure (MAP) was measured via an intraarterial catheter. RESULTS: Without pretreatment, MAP was reduced to comparable degrees by fenoldopam in WKY (-7 +/- 4%, ns) and SHR (-6 +/- 1%, P < 0.05). However, ERPF was significantly more increased (P < 0.006) by fenoldopam in WKY (+26 +/- 2%, P < 0.0001) than in SHR (+2 +/- 2%, ns). AT1-A treatment reduced MAP and increased ERPF and glomerular filtration rate significantly in both strains. Pretreatment with AT1-A significantly potentiated the fenoldopam-induced rise in ERPF in SHR, but not in WKY, without affecting the blood pressure responses in either strain. As a result, during pretreatment with an AT1-A, the rise in ERPF by fenoldopam was similar in both strains (SHR +25 +/- 2%, P < 0.0001; WKY +33 +/- 2%, P < 0.0001). CONCLUSIONS: These results suggest that the RAAS accounts for the blunted renal vasodilator response to a D1-like receptor agonist in SHR. A dysbalance between the dopaminergic system and the RAAS may be involved in the abnormal renal hemodynamic regulation in SHR.     

ENDOTHELIUM-DERIVED RELAXING FACTOR, HYPERTENSION AND CHRONIC PARATHYROIDECTOMY IN SPONTANEOUSLY HYPERTENSIVE AND WISTAR-KYOTO RATS

• 1 Parathyroidectomy (PTX) lessens the development of hypertension in young spontaneously hypertensive rats (SHR) and the involved mechanisms remain to be elucidated. We have studied here the aortic vascular reactivity to both norepinephrine (NE) and acetylcholine in 10 week old male PTX SHR and Wistar-Kyoto (WKY) rats.
• 2 Depolarized (KCl 100 mmol/L) and NE (1 μmol/L or cumulative 10^-9-10^--⁵ mol/L) precontracted intact aortic rings from PTX rats show a significant and unexpected increase of maximal contractile responses in normotensive and hypertensive animals. These results are also obtained with low extracellular ionized calcium levels (0.625 and 0.9 mmol/L) similar to PTX ionized plasma calcium. N^ω-Nitro-L-arginine methyl ester (l-NAME, 20 μmol/L) potentiates the NE response in SHR and WKY rats, more significantly in control than in PTX animals.
• 3 In the presence of indomethacin (10 μmol/L) in SHR the potentiating effect of PTX on NE contraction is still observed, ruling out a specific production of vasoconstrictors from the arachidonic cascade by the PTX rat aortic endothelium.
• 4 After PTX a moderate impairment of acetylcholine relaxant responses is observed in SHR and WKY rat aortas and basal aortic cyclic guanosine 3′-4′ monophosphate (cGMP) content is also decreased; nevertheless sodium nitroprusside causes a similar relaxation. Furthermore in l-NAME-treated aortas and in the presence of l-arginine (100 μmol/L), acetylcholine (1 μmol/L) produces a significantly less pronounced relaxation in PTX rats.
• 5 In conclusion, the enhancement of NE contractile response in PTX rat aortas is not linked to the strain but probably related to a decrease in endothelial nitric oxide (NO) release or activity. Enhancement of force generation that we describe does not directly participate in the attenuated hypertension observed in SHR after parathyroidectomy.

     

A comparative autoradiographic study of the density of [<Superscript>3</Superscript>H]SR95531, [<Superscript>3</Superscript>H]MK-801 and [<Superscript>3</Superscript>H]cGMP binding in the locus coeruleus and central pontine grey of spontaneously hypertensive and Wistar–Kyoto rats

The Spontaneously Hypertensive rat (SHR) has been previously shown to have a host of neurochemical differences compared with their normotensive counterpart, the Wistar–Kyoto (WKY) rat. Using quantitative receptor autoradiography, the density of GABA_A and NMDA receptors and [³H]cGMP binding within the locus coeruleus (LC) and central pontine grey (CGPn) were compared in the SHR and WKY rat using the radioligands [³H]SR95531, [³H]MK-801 and [³H]cGMP respectively. It was found that [³H]SR95531 binding was significantly greater in both the LC and CGPn of the SHR compared with the WKY rat (unpaired t test; P<0.05). Greater binding densities of [³H]MK-801 and [³H]cGMP were also observed in the LC of the SHR compared with the WKY rat; however, no differences in the binding density of these two ligands were observed in the CGPn. It is suggested that these neurochemical differences within the LC of the SHR may relate to phenotypic differences between SHR and WKY rats that have previously been reported.