乌拉地尔对自发性高血压大鼠NO、ET、ANF和AngⅡ的影响

目的　研究乌拉地尔对自发性高血压大鼠NO、ET、ANF和AngⅡ的影响。方法　用分光光度法及放免法测定乌拉地尔 (urapidil)引起自发性高血压大鼠 (SHR)降压过程中血浆NO、ET、ANF和AngⅡ含量的变化。 结果　与WKY大鼠比较 ,SHR血清NO含量减少 ,血浆ET、ANF水平升高 ,而AngⅡ水平无明显差异。与SHR对照组比较 ,urapidil1、3、10mg·kg-1可明显升高血清NO水平 ,减少血浆ET、ANF水平。结论　urapidil可能通过增加内源性舒血管活性物质的释放 ,减少内源性缩血管活性物质的释放 ,调节两者之间的平衡来发挥其抗高血压作用。     

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.     

NATRIURETIC EFFECT OF CHRONICALLY ADMINISTERED α-HUMAN ATRIAL NATRIURETIC POLYPEPTIDE IN SODIUM DEPLETED OR REPLETED CONSCIOUS SPONTANEOUSLY HYPERTENSIVE RATS

Hypotensive and natriuretic effects of chronically administered alpha-human atrial natriuretic polypeptide (alpha-hANP) were investigated in conscious spontaneously hypertensive rats (SHR) and Wistar-Kyoto rats (WKY) in both sodium depletion and repletion. Systolic blood pressure was significantly reduced in SHR and WKY in both sodium deplete and replete states. Urinary sodium excretion was significantly increased in SHR and tended to be increased in WKY on sodium repletion, but remained unchanged on sodium depletion. It is suggested that extracellular fluid volume may be an important determinant factor of the natriuretic action of ANP but may not affect the hypotensive effect.     

The effect of medetomidine, an alpha 2-adrenoceptor agonist, on plasma atrial natriuretic peptide levels, haemodynamics and renal excretory function in spontaneously hypertensive and Wistar-Kyoto rats.

1. The effects of the selective alpha 2-adrenoceptor agonist, medetomidine, were assessed on plasma levels of immunoreactive atrial natriuretic peptide (IR-ANP), haemodynamics and on urine water and solute excretion in conscious, chronically cannulated, 7 month-old spontaneously hypertensive (SHR) and age-matched Wistar-Kyoto (WKY) rats, in order to examine the role of alpha 2-adrenoceptors in the control of ANP secretion. 2. A 60 min i.v. infusion of medetomidine (0.2 or 0.6 microgram kg-1 min-1) decreased heart rate dose-dependently in both strains. Medetomidine infusion (0.6 microgram kg-1 min-1) resulted in an increase in mean arterial pressure in WKY, whereas both doses decreased blood pressure in SHR. There was a slight increase in the right atrial pressure in both strains (WKY: +1.18 +/- 0.26 mmHg; SHR: +1.64 +/- 0.64 mmHg, NS) in response to infusion of 0.6 microgram kg-1 min-1 of medetomidine. 3. No differences were found in resting plasma IR-ANP levels between WKY (114 +/- 8 pg ml-1, n = 19) and SHR (117 +/- 10 pg ml-1, n = 21). Infusion of equibradycardic doses of medetomidine increased dose-dependently plasma IR-ANP levels in WKY, but did not affect the plasma IR-ANP concentration in SHR rats. 4. Despite the different effect of medetomidine on ANP release in WKY and SHR rats, i.v. administration of medetomidine affected renal excretory functions similarly in both strains; urine flow and sodium excretion increased and urine osmolality decreased significantly, while there was no consistent change in urinary potassium excretion.(ABSTRACT TRUNCATED AT 250 WORDS)     

Differential amino acid transmission in the locus coeruleus of Wistar Kyoto and spontaneously hypertensive rats

In addition to differences in their blood pressure, Wistar Kyoto (WKY) and spontaneously hypertensive rats (SHR) are known to differ in their emotional behaviour. The neurochemistry underlying these differences is not well understood. In the present study the release rates of the two main regulatory amino acids in the locus coeruleus, glutamate and gamma-aminobutyric acid (GABA), were monitored in WKY rats and SHR to investigate whether basal and/or challenged neurotransmission differs between these strains. The strains differed in their basal blood pressure (WKY 102±2 mmHg, SHR 140±4 mmHg), as well as in their emotional behaviour, since WKY rats displayed enhanced anxiety-related behaviour in the open field test (time in centre: WKY 197±40 s/30 min, SHR 741±93 s/30 min). Basal glutamate and GABA release rates did not differ between WKY rats and SHR. A rise in blood pressure induced by intravenous infusion of noradrenaline for 10 min enhanced GABA release in WKY rats by 60%, while no effect was observed in SHR. Glutamate release did not respond to experimental hypertension in both strains. Intravenous infusion of sodium nitroprusside led to a fall in blood pressure, which was less pronounced and was of shorter duration in WKY rats than in SHR. The depressor response had no effect on amino acid release in the locus coeruleus of both strains. Mild stress induced by noise or tail pinch led to slight rises in arterial blood pressure (10 mmHg and 20 mmHg respectively), which were similar in WKY rats and SHR. Tail pinch enhanced the release rates of glutamate and GABA in the locus coeruleus of WKY rats and SHR; however, no strain differences were noted. Noise stress did not significantly influence amino acid release. These findings demonstrate that SHR and WKY rats differ in GABAergic neurotransmission, which is revealed in response to specific cardiovascular challenges, but not to mild stressors. The observed lack of GABA response to blood pressure elevation in SHR may reflect a disturbed mechanism counteracting high blood pressure, possibly contributing to hypertension in this strain.     

COMPLEMENTARY CHANGES IN PLASMA ATRIAL NATRIURETIC PEPTIDE AND ANTIDIURETIC HORMONE CONCENTRATIONS IN RESPONSE TO VOLUME EXPANSION AND HAEMORRHAGE: STUDIES IN CONSCIOUS NORMOTENSIVE AND SPONTANEOUSLY HYPERTENSIVE RATS

1. Plasma concentrations of atrial natriuretic peptide (ANP) and antidiuretic hormone (ADH) were measured in conscious stroke-prone spontaneously hypertensive (SPR), spontaneously hypertensive (SHR) and normotensive Wistar-Kyoto (WKY) rats before and after acute volume expansion or haemorrhage. 2. Plasma ANP concentration was reduced to one-third of resting values 30 min after a 1.5% haemorrhage (1.5 ml of blood per 100 g bodyweight). Plasma ADH concentration rose immediately 50-fold on haemorrhage and remained elevated at 30 min. 3. Plasma ANP concentration increased 2.5-fold relative to resting values 1 min after infusion of 2.0 ml per 100 g 5% dextrose; after 10 min plasma ANP remained elevated. Plasma ADH concentration tended to fall on volume expansion although no significant decrease was observed. 4. There was no difference in the basal levels of ANP and ADH, or in the changes produced by alterations in blood volume, in hypertensive SPR and SHR compared with normotensive WKY. 5. Thus, plasma ANP concentrations moved in opposite directions in response to two physiological stimuli: volume expansion and haemorrhage. Reciprocal changes were observed in plasma ADH.     

Effects of brain natriuretic peptide-45, a circulating form of rat brain natriuretic peptide, in spontaneously hypertensive rats.

Rat brain natriuretic peptide-45 (rat BNP-45) has recently been isolated from rat heart and shown to be a circulating form of rat BNP. We investigated the effects of rat BNP-45 in anesthetized spontaneously hypertensive rats (SHR) and Wistar-Kyoto rats (WKY) and compared them with those of rat alpha-atrial natriuretic peptide (alpha-ANP). BNP-45 was a potent natriuretic and hypotensive agent in both strains. The effects were comparable with those of alpha-ANP and were far greater than those of porcine BNP-26 reported previously. In SHR blood pressure decreased more than in WKY following injection of the highest dose (2.0 nmol/kg) of BNP-45 or alpha-ANP. However, WKY were more susceptible than SHR to BNP-45 for diuresis, natriuresis and urinary cGMP excretion. Moreover, a high dose of BNP-45 led to a prolonged lowering of blood pressure and urinary cGMP excretion compared to alpha-ANP, and these features were prominent in WKY. BNP-45 disappeared more slowly than alpha-ANP when the two peptide (2.0 micrograms) were injected i.v. in WKY. Thus, rat BNP-45 and alpha-ANP had comparable hypotensive and natriuretic potency; however, the action and plasma half-life of rat BNP-45 were more prolonged.     

Effects of potassium supplementation on blood pressure, electrolytes and 3H-norepinephrine release in spontaneously hypertensive rats

Potassium supplementation has been shown to decrease blood pressure in human and animal models of hypertension. The purpose of this study was to determine if potassium supplementation altered sympathetic nerve activity by altering 3H-norepinephrine release in caudal artery preparations of spontaneously hypertensive rats (SHR) and Wistar Kyoto rats (WKY). Supplementation in the drinking water with 0.5 or 1.0% KCl for 5 weeks lowered blood pressure (19 and 25 mm Hg, respectively) in SHR but had no effect on WKY. The decrease in blood pressure with 0.5% KCl was not accompanied by significant changes in either plasma or cerebrospinal fluid (CSF) sodium or potassium levels in either SHR or WKY. 3H-Norepinephrine release induced by 56 mmol/l KCl was not altered in either SHR or WKY. However, the ability of yohimbine to enhance 3H-norepinephrine release in caudal artery preparations was significantly decreased by potassium supplementation in SHR, but was not affected in WKY. These data suggest that potassium supplementation may alter alpha 2-adrenoceptor activity. Further studies are required to determine if this altered alpha 2-adrenoceptor activity plays a direct role in the blood-pressure-lowering effects of potassium supplementation.     

Effect of clonidine on renal sodium handling in spontaneously hypertensive rats

Up-regulation of kidney α2-adrenoceptor expression has been implicated in the development of hypertension in spontaneously hypertensive rats (SHR). This study was carried out to evaluate renal sodium excretion in response to clonidine administration in SHR and control normotensive Wistar-Kyoto (WKY) rats. SHR and WKY rats (12-week-old) were placed in metabolic cages for 4 days: the first 2 days in control conditions and the following 2 days under oral clonidine treatment (100 μg/kg body weight). Clonidine produced a similar reduction in systolic blood pressure values in SHR and WKY rats, although SHR remained hypertensive. At the end of the study SHR and WKY rats presented similar noradrenaline plasma levels. However, noradrenaline kidney tissue levels were significantly higher in SHR compared to WKY rats. Under control conditions, SHR presented lower urine flow compared to WKY rats. Clonidine produced a significant decrease in urine flow in WKY rats but not in SHR. Furthermore, clonidine also produced a significant reduction in urinary sodium, potassium, and creatinine excretion in WKY rats, but had no effect in SHR. In conclusion, in SHR the reduction in systolic blood pressure and sympathetic activity produced by clonidine was not accompanied by a decrease in urine volume and sodium excretion.     

LONG-TERM EFFECTS OF HIGH CALORIE SUCROSE-ENRICHED DIET AND STREPTOZOTOCIN-INDUCED DIABETES ON INSULIN RESISTANCE IN SPONTANEOULY HYPERTENSIVE RATS§

1. The effects of two experimental manipulations on insulin resistance were compared in spontaneously hypertensive rats (SHR) and normotensive Wistar-Kyoto (WKY) rats. Rats were fed a high calorie sucrose-enriched diet (high calorie diet) or were made diabetic by the injection of streptozotocin (STZ). 2. After treatment with the high calorie diet for 8 weeks, blood pressure increased in SHR, but not in WKY rats. In contrast, STZ treatment decreased blood pressure in SHR, but increased it in WKY rats. 3. Plasma glucose levels during oral glucose loading were higher in SHR than in WKY rats. Glucose tolerance was impaired to a greater extent by both the high calorie diet and STZ in SHR than in WKY rats. Hyperinsulinaemia induced by the high calorie diet was severe in SHR compared with WKY rats. 4. Abnormalities in lipid metabolism induced by a high calorie diet or STZ-induced diabetes were more marked in SHR than in WKY rats. 5. Steady-state plasma glucose levels in the insulin suppression test were higher in SHR than in WKY rats, both of which were treated by either the high calorie diet or STZ. These findings indicate that insulin-stimulated glucose uptake by high calorie diet or STZ-induced diabetes was impaired to a greater extent in SHR than in WKY rats. 6. It is concluded, therefore, that SHR fed on high calorie diet or SHR with STZ-induced diabetes are suitable models to study the effects of antihypertensive treatment on glucose tolerance, insulin resistance or lipid metabolism as well as blood pressure.     

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     

Release of atrial natriuretic peptide from rat myocardium in vitro: effect of minoxidil-induced hypertrophy.

1. Ventricular hypertrophy is characterized by stimulation of ventricular synthesis of atrial natriuretic peptide (ANP). To examine the role of ventricular ANP levels in the secretion of ANP into the circulation, atrial and ventricular levels of immunoreactive-ANP (IR-ANP) as well as ANP messenger RNA (mRNA), and the release of IR-ANP from isolated perfused hearts, both before and after atrialectomy, were measured simultaneously in control and minoxidil-treated Wistar-Kyoto (WKY) and spontaneously hypertensive (SHR) rats. 2. IR-ANP levels in the ventricles of untreated, 12 month-old SHR with severe ventricular hypertrophy were increased when compared to age-matched WKY rats. Minoxidil treatment for 8 weeks in both strains resulted in a decrease in mean arterial pressure and increases in ventricular weight to body weight ratios, plasma IR-ANP concentrations (in WKY from 133 +/- 20 to 281 +/- 34 pg ml-1, P less than 0.01; in SHR from 184 +/- 38 to 339 +/- 61 pg ml-1, P less than 0.05), and in ventricular IR-ANP contents (in WKY: 53%; in SHR: 41%). A highly significant correlation was found between ventricular IR-ANP content and ventricular weight to body weight ratio (r = 0.59, P less than 0.001, n = 26). 3. When studied in vitro, in isolated perfused heart preparations, the hypertrophied ventricular tissue after atrialectomy secreted more ANP into the perfusate than ventricles of the control hearts; ventricles contributed 28%, 22%, 18% and 15% of the total ANP release to perfusate in the minoxidil-treated SHR, control SHR, minoxidil-treated WKY and control WKY, respectively.(ABSTRACT TRUNCATED AT 250 WORDS)     

Quinapril effects on resistance artery structure and function in hypertension

The effects of chronic treatment with quinapril on blood pressure, vascular reactivity and structure of resistance arteries were examined in adult, male spontaneously hypertensive (SHR) and Wistar-Kyoto (WKY) rats. SHR and WKY at 15 weeks of age were treated with quinapril (10 mg/kg per day) for 10 weeks. Structural changes in the mesenteric arteries were measured by optical sectioning with confocal microscopy and in renal arteries by light microscopic measurements. Apoptotic cells in the mesenteric vessel wall were identified using the terminal deoxynucleotide transferase-mediated dUTP-nick end-labelling (TUNEL) method. The response of mesenteric arteries to noradrenaline, electrical stimulation, acetylcholine and sodium nitroprusside was studied using a pressure myograph system. Treatment with quinapril significantly lowered systolic blood pressure and ventricular weight in both SHR and WKY. It reduced wall thickness and medial volume in mesenteric arteries from SHR and WKY and media-to-lumen ratio in interlobular arteries of SHR. It also decreased the number of smooth muscle layers in SHR and increased the number of apoptotic smooth muscle cells in both SHR and WKY. In addition, treatment normalized the augmented contractile responses and improved the impaired relaxation response of SHR mesenteric arteries to the level of WKY. We conclude that treatment with quinapril lowered blood pressure and improved cardiac and vessel structure and vessel function. An increase in apoptotic process of medial smooth muscle cells is one of the mechanisms underlying the vascular structural improvement.     

Comparative effects of verapamil and volume overload on atrial natriuretic factors and the renin-angiotensin aldosterone-vasopressin system.

The authors compared the effects of verapamil (120 mg three times daily for 3 days) with those of acute volume expansion with normal saline on the plasma levels of atrial natriuretic factors (ANF), renin (PRA), angiotensin II (AII), aldosterone (ALD), and arginine-vasopressin (AVP) in healthy subjects. A randomized, double-blind, placebo-controlled study of crossover design was employed, where each individual received two acute volume overloads 1 week apart, one during placebo and the other during treatment with verapamil. Verapamil reduced blood pressure (BP) and increased the plasma levels of ANF, PRA, AII, ALD, and AVP. Strong positive correlations were observed between PRA, AII, ALD, and AVP, but not with ANF. Acute volume expansion (1500 mL saline in 15 minutes, in supine legs-up position) similarly to verapamil increased ANF levels; however, opposite to verapamil, it reduced PRA-AII-ALD, did not modify AVP levels, and increased BP. The mechanisms of these changes are discussed. In verapamil-treated subjects, volume expansion produced an additional increase in ANF and inhibited the PRA-AII-ALD axis, suggesting that in young healthy individuals, verapamil does not interfere with the reflex compensatory hormonal mechanisms activated under circumstances of acute volume-salt overload, with rapid expansion of the central vascular compartment. Our study indicates that verapamil and volume expansion represent two different stimuli for ANF secretion associated with opposite changes in the PRA-AII-ALD axis. In addition, verapamil can be used as a tool to study and understand the simultaneous increases in ANF and in PRA, AII, and AVP, characteristics of congestive heart failure.     

Role of cardiac hypertrophy in reducing the sensitivity of cardiopulmonary reflex control of renal sympathetic nerve activity in spontaneously hypertensive rats

The gain of the volume-sensitive cardiopulmonary reflex (VSCR) is impaired in spontaneously hypertensive rats (SHR). Sensitivity of VSCR control of efferent renal sympathetic nerve activity (RSNA) in SHR is restored when cardiac hypertrophy and hypertension are reduced by enalapril treatment. The present study investigated which of these two parameters, cardiac hypertrophy or hypertension, has more influence on the impairment of VSCR control of RSNA in SHR. Rats (SHR or Wistar-Kyoto (WKY) rats) were treated with enalapril (10 mg/kg per day; SHRE and WKYE groups, respectively) or hydralazine (5 mg/kg per day; SHRH and WKYH groups, respectively) mixed in their food for 1 month. Control SHR and WKY rats were fed a normal diet. After the treatment regimen, the VSCR was evaluated by determining the decrease in RSNA elicited by acute isotonic saline volume expansion. Mean arterial pressure (MAP) was assessed via an intrafemural catheter and cardiac hypertrophy was determined by the left ventricular (LV) weight/bodyweight (BW) ratio. Afferent baroceptor nerve activity (BNA) was also evaluated during volume expansion to verify participation of the baroreflex. Volume expansion produced an attenuated renal sympathoinhibitory response in SHR compared with WKY rats. Enalapril treatment restored the volume expansion-induced decrease in RSNA in SHRE (-41 +/- 8%) compared with WKY rats (-44 +/- 3%). Although both enalapril and hydralazine treatment reduced MAP in SHR (P < 0.01; 126 +/- 5, 133 +/- 6 and 160 +/- 6 mmHg in SHRE, SHRH and SHR, respectively), hydralazine did not restore the sensitivity of VSCR control of RSNA in SHRH. Spontaneously hypertensive rats with established hypertension had a higher LV/BW ratio compared with WKY rats (3.22 +/- 0.14 vs 1.98 +/- 0.06 mg/g, respectively; P < 0.01). Enalapril reduced the LV/BW ratio in SHRE (2.30 +/- 0.07 mg/g; P < 0.01). Although hydralazine reduced LV hypertrophy, there was a weaker reduction in SHRH (2.68 +/- 0.04 mg/g; P < 0.05) compared with SHRE. There was no statistically significant difference among the WKY rat, WKYE and WKYH groups (P > 0.05). There was no change in afferent BNA during volume expansion in normal or hypertensive animals. Taken together, these results indicate that the impairment of VSCR control of RSNA in the SHR model of hypertension correlates better with the magnitude of cardiac hypertrophy than the level of arterial pressure.     

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.     

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.     

Antihypertensive and hormonal activity of MK 954 in spontaneously hypertensive rats.

MK 954 (DuP 753), a recently developed angiotensin II (Ang II) receptor antagonist, was administered orally for 2 weeks to spontaneously hypertensive (SHR) and Wistar-Kyoto rats (WKY). Whereas the basal levels of plasma Ang II were lower in SHR than in WKY, treatment with MK 954 markedly reduced blood pressure in SHR but not in WKY. Plasma renin activity, Ang I and Ang II were increased, while plasma aldosterone was decreased in both strains. These results no only indicate therapeutic efficacy of this agent in the chronic treatment of human hypertension, but also support the idea that the renin-angiotensin system plays an important role in the control of blood pressure in SHR.     

Effects of antihypertensive drugs on capillary rarefaction in spontaneously hypertensive rats: intravital microscopy and histologic analysis

We investigated the effects of chronic oral antihypertensive treatment on functional and structural capillary rarefaction in spontaneously hypertensive rats (SHR). Wistar Kyoto rats (WKY) were used as a normotensive control group. In untreated rats, intravital videomicroscopy showed that functional capillary density was lower in SHR skeletal muscle (WKY 395 +/- 17 and SHR 258 +/- 13 capillaries/mm, P < 0.01) and ear skin (WKY 391 +/- 18 and SHR 210 +/- 15 capillaries/mm, P < 0.01). A linear relationship was seen between skeletal muscle and skin capillary densities (r = 0.654, P < 0.0001). Histologic analysis showed that SHR had a lower capillary-to-fiber ratio in the skeletal muscle (WKY 1.74 +/- 0.08 and SHR 1.40 +/- 0.06, P < 0.01). Capillary volume density-to-fiber volume density ratio in the left ventricle of SHR was also reduced (WKY 0.55 +/- 0.09 and SHR 0.42 +/- 0.09, P < 0.01). The animals were treated with the angiotensin-converting enzyme (ACE) inhibitor enalapril, the angiotensin II type I receptor (AT1) receptor antagonist losartan, the beta-blocker atenolol, or the calcium channel blocker nifedipine, resulting in similar reductions in systolic blood pressure (19.8%, 19.1%, 17.4%, and 18.2%, respectively, P > 0.05). Atenolol did not induce any change in functional capillary density of SHR. Losartan and nifedipine completely reversed functional capillary rarefaction in both muscle and cutaneous tissues, whereas enalapril significantly increased functional capillary density only in the skin. The skeletal muscle capillary-to-fiber ratio was normalized by enalapril, losartan, and nifedipine. Treatments with enalapril or losartan normalized the cardiac structural capillary rarefaction of SHRs, whereas atenolol and nifedipine had no effect. Our results suggest that different pharmacologic classes of antihypertensive drugs with similar effect on blood pressure differ in terms of their effect on the microcirculation.     

Urinary responses to acute moxonidine are inhibited by natriuretic peptide receptor antagonist

We have previously shown that acute intravenous injections of moxonidine and clonidine increase plasma atrial natriuretic peptide (ANP), a vasodilator, diuretic and natriuretic hormone. We hypothesized that moxonidine stimulates the release of ANP, which would act on its renal receptors to cause diuresis and natriuresis, and these effects may be altered in hypertension. Moxonidine (0, 10, 50, 100 or 150 microg in 300 microl saline) and clonidine (0, 1, 5 or 10 microg in 300 microl saline) injected intravenously in conscious normally hydrated normotensive Sprague-Dawley rats (SD, approximately 200 g) and 12-14-week-old Wistar-Kyoto (WKY) and spontaneously hypertensive rats (SHR) dose-dependently stimulated diuresis, natriuresis, kaliuresis and cGMP excretion, with these effects being more pronounced during the first hour post-injection. The actions of 5 microg clonidine and 50 microg moxonidine were inhibited by yohimbine, an alpha2-adrenoceptor antagonist, and efaroxan, an imidazoline I1-receptor antagonist. Moxonidine (100 microg) stimulated (P<0.01) diuresis in SHR (0.21+/-0.04 vs 1.16+/-0.06 ml h(-1) 100 g(-1)), SD (0.42+/-0.06 vs 1.56+/-0.19 ml h(-1) 100 g(-1)) and WKY (0.12+/-0.04 vs 1.44+/-0.21 ml h(-1) 100 g(-1)). Moxonidine-stimulated urine output was lower in SHR than in SD and WKY. Moxonidine-stimulated sodium and potassium excretions were lower in SHR than in SD, but not WKY, demonstrating an influence of strain but not of pressure. Pretreatment with the natriuretic peptide antagonist anantin (5 or 10 microg) resulted in dose-dependent inhibition of moxonidine-stimulated urinary actions. Anantin (10 microg) inhibited (P<0.01) urine output to 0.38+/-0.06, 0.12+/-0.01, and 0.16+/-0.04 ml h(-1) 100 g(-1) in SD, WKY, and SHR, respectively. Moxonidine increased (P<0.01) plasma ANP in SD (417+/-58 vs 1021+/-112 pg ml(-1)) and WKY (309+/-59 vs 1433+/-187 pg ml(-1)), and in SHR (853+/-96 vs 1879+/-229 pg ml(-1)). These results demonstrate that natriuretic peptides mediate the urinary actions of moxonidine through natriuretic peptide receptors.