Effects of dicentrine on haemodynamic, plasma lipid, lipoprotein level and vascular reactivity in hyperlipidaemic rats.

1. The effects of dicentrine on haemodynamic, plasma lipid, lipoprotein level and vascular reactivity were investigated in Wistar-Kyoto (WKY) and spontaneously hypertensive (SH) rats, fed a high fat-high cholesterol diet. 2. In high fat-high cholesterol (HF-HC) diet fed WKY and SH rats, oral administration of dicentrine (5 and 10 mg kg-1, twice a day) for 4 weeks caused significant reductions in total plasma cholesterol (CE) by reducing the low density lipoprotein (LDL) fraction, and reductions in total plasma triglyceride (TG) by reducing the very low density lipoprotein (VLDL) fraction. 3. Dicentrine therapy was associated with increased high density lipoprotein (HDL)-cholesterol levels; thus the ratio of total plasma cholesterol to HDL-cholesterol was improved. 4. In HF-HC diet fed conscious WKY and SH rats, oral administration of dicentrine (5 and 10 mg kg-1, twice a day) also evoked dose-related decreases in mean arterial pressure (MAP) which were of greater magnitude in SH rats. Neither dose of dicentrine caused a significant change in heart rate (HR). 5. The aortic arches from SH rats fed the HF-HC diet for 8 weeks were significantly more affected by the atherosclerotic lesions than the abdominal aortae and renal arteries of WKY and SH rats. Oral administration of dicentrine (5 and 10 mg kg-1) for 4 weeks did not diminish the atherosclerotic lesion areas in WKY and SH rats. 6. In aortae of the hyperlipidaemic rats, significantly attenuated EC50 values and augmented maximal responses for phenylephrine-induced contraction were obtained. Endothelium-dependent relaxation to acetylcholine was abolished, while endothelium-independent relaxation to nitroprusside was well preserved.(ABSTRACT TRUNCATED AT 250 WORDS)     

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.     

Comparative effects of alpha-methyldopa, propranolol and hydralazine therapy on cardiac adenylate cyclase activity in normal and spontaneously hypertensive rats

Normotensive (WKY) and spontaneously hypertensive (SHR) male rats were treated orally, one week after weaning and for 9 weeks, with alpha-methyldopa (100 mg/kg per day), propranolol (30 mg/kg per day) or hydralazine (10 mg/kg per day). Untreated WKY and SHR rats served as controls. The development of hypertension in SHR rats were attenuated by treatment but none of the drugs was able to restore the impairment in isoproterenol, secretin and glucagon responsiveness of cardiac adenylate cyclase activity which is characteristic of these animals. In heart membranes from both WKY and SHR rats, alpha-methyldopa treatment increased the number of beta-adrenoceptors by 20-32% and the maximal response of adenylate cyclase activity to isoproterenol and glucagon by 20-34%. By contrast, the beta-blocker propranolol was ineffective on these parameters. The results obtained are consistent with the hypothesis that the change in adenylate cyclase seen in SHR rats is genetic in origin and is not a consequence of hypertension.     

Antihypertensive effect of naftopidil (KT-611), a novel alpha 1-adrenoceptor antagonist, in freely moving experimental hypertensive rats and dogs

The antihypertensive effect of naftopidil (KT-611) following single oral administration was investigated in normotensive Wistar Kyoto rats (WKY), spontaneously hypertensive rats (SHR), DOCA-Salt hypertensive rats (DHR), 2-kidney 1-clip renal hypertensive rats (RHR) and Grollman type renal hypertensive dogs with 1-kidney (RHD); and it was compared with that of the selective alpha 1-adrenoceptor antagonist prazosin. The blood pressure and heart rate were measured under the unanesthetized, unrestrained state through an arterial catheter that was chronically implanted into the abdominal aorta. In SHR and WKY, both KT-611 (10 and 30 mg/kg, p.o.) and prazosin (1 and 3 mg/kg, p.o.) markedly inhibited the pressor response to the alpha 1-adrenoceptor agonist phenylephrine (3 micrograms/kg, i.v.). KT-611 (10 to 100 mg/kg, p.o.) showed a dose-dependent hypotensive effect in SHR, DHR and RHR but not in WKY. The hypotensive effect of KT-611 reached maximum at 0.5-1 hr, lasted for 4-6 hr and was more potent in DHR and RHR than in SHR. The potency of KT-611 was 1/10-1/30 weaker than that of prazosin. In RHD, single oral administration of KT-611 (1 to 10 mg/kg) caused a dose-dependent and long-lasting hypotensive effect. These results suggest that KT-611 has a long-lasting hypotensive effect in experimental hypertensive animal models.     

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.     

HAEMODYNAMIC RESPONSES TO RAT ADRENOMEDULLIN IN ANAESTHETIZED SPONTANEOUSLY HYPERTENSIVE RATS

1. The haemodynamic effects of rat adrenomedullin (AM), a novel hypotensive peptide, were examined in anaesthetized 16–18 week old spontaneously hypertensive rats (SHR) and Wistar-Kyoto rats (WKY). 2. An intravenous injection of rat AM dose-dependently reduced the mean blood pressure (MBP) with a concomitant fall in total peripheral resistance index (TPRI) and an increase in cardiac index (CI) in both strains of rats. Per cent changes in MBP, TPRI and CI were not different between SHR and WKY. 3. The plasma half-life of rat AM in SHR was similar to that in WKY when it was administered at the dose of 1.0 nmol/kg. 4. These findings indicate that AM has a potent vasorelaxant activity in both SHR and WKY. The haemodynamic responsiveness to exogenous AM and its pharmaeokinetics in SHR were comparable with those in WKY.     

奈比洛尔对自发性高血压大鼠循环和主动脉肾素-血管紧张素系统的影响

目的：探讨奈比洛尔（Nebivolol）对自发性高血压大鼠循环和主动脉肾素-血管紧张素系统（RAS）的影响。方法：18只自发性高血压大鼠（SHR）和6只同源正常血压大鼠Wistar-Kyoto（WKY）随机分为：（1）奈比洛尔组（n=6）：SHR给予奈比洛尔5mg·kg-1·d-1;（2）卡托普利组（n=6）：SHR给予卡托普利15mg·kg-1·d-1;（3）SHR对照组（n=6）;（4）WKY对照组（n=6）。奈比洛尔、卡托普利溶于蒸馏水中灌胃,对照组给予等体积蒸馏水灌胃。给药8周后测定血浆肾素活性（PRA）,血浆和主动脉血管紧张素Ⅱ（AngⅡ）、一氧化氮（NO）浓度,NO/AngⅡ和血管紧张素转化酶（ACE）活性。结果：与WKY比较,SHR血浆和主动脉NO含量降低,AngⅡ水平显著增加,NO/AngⅡ降低;主动脉ACE活性明显增加,而血浆ACE活性则降低;但PRA在两组间无显著性差异。奈比洛尔治疗对SHR血浆AngⅡ含量和ACE活性无影响,但可降低主动脉AngⅡ水平,抑制主动脉ACE活性,从而增加血浆及主动脉NO含量和NO/AngⅡ。结论：奈比洛尔抑制肾素-血管紧张素系统,可能是其降低血压的机制之一。     

INVOLVEMENT OF HYPOTHALAMIC ADRENALINE IN THE CLONIDINE WITHDRAWAL SYNDROME IN NORMOTENSIVE AND SPONTANEOUSLY HYPERTENSIVE RATS

1. The concentrations of adrenaline and other catecholamines (noradrenaline and its major metabolite DHPG, dopamine and its major metabolite DOPAC) were measured in the hypothalamus and medulla oblongata of normotensive Wistar-Kyoto (WKY) and spontaneously hypertensive rats (SHR) which had received a continuous subcutaneous infusion of clonidine (10 micrograms/kg per h) for 10 days, and also in WKY and SHR rats which were killed 15-18 h after the cessation of the 10-day infusion. 2. The concentrations of adrenaline in the hypothalamus and medulla oblongata/pons of the clonidine treated WKY and SHR rats were not different from their respective controls. However, the adrenaline concentrations in the hypothalamus (but not the medulla oblongata) were significantly decreased in the post-infusion WKY and SHR. 3. These results suggest that hypothalamic adrenergic mechanisms may have a common involvement in the post-clonidine infusion syndromes displayed by the WKY and SHR strains.     

INCREASED Na+/H+ EXCHANGE ACTIVITY IN VASCULAR SMOOTH MUSCLE CELLS OF SPONTANEOUSLY HYPERTENSIVE RATS AND POSSIBLE INVOLVEMENT OF PROTEIN KINASE C

1. Na+ influx into cultured vascular smooth muscle cells (VSMC) obtained from spontaneously hypertensive rats (SHR) and from Wistar-Kyoto rats (WKY) was measured. Na+ influx via the Na+/H+ exchange system was measured as the rate of 22Na+ influx into cultured VSMC sensitive to ethylisopropylamiloride (EIPA), a specific inhibitor of the exchange system. 2. The total 22Na+ influx rate in SHR was significantly higher than in WKY (6.08 +/- 0.16 vs 4.13 +/- 0.09 nmol/min per mg protein; P less than 0.001; n = 14). The EIPA (1 X 10(-4) mol/L)-sensitive 22Na+ influx rate in SHR was significantly higher than that in WKY (4.32 +/- 0.27 vs 2.17 +/- 0.14 nmol/min per mg protein; P less than 0.001; n = 14). There was no difference in EIPA-insensitive 22Na+ influx between SHR and WKY. The EIPA-sensitive 22Na+ influx rate into VSMC was significantly decreased in SHR but not in WKY by the addition of 1 X 10(-4) mol/L 1-(5-isoquinoline-sulfonyl)-methylpiperazine (H-7), an inhibitor of protein kinase C (PK-C). 3. These results suggest that the increase in Na+ influx in SHR may be due to elevation of the Na+/H+ exchange activity, and possible involvement of PK-C in the increased Na+/H+ exchange activity in VSMC from SHR.     

Pharmacokinetic-pharmacodynamic modeling of diltiazem in spontaneously hypertensive rats: a microdialysis study

INTRODUCTION: The aim of the present work was to study the applicability of a modified E(max) pharmacodynamic model for the pharmacokinetic-pharmacodynamic (PK-PD) modeling of diltiazem in spontaneously hypertensive rats (SHR) and normotensive Wistar Kyoto (WKY) rats. METHODS: A "shunt" microdialysis probe was inserted in a carotid artery of anaesthetized SHR and WKY rats for simultaneous determination of unbound plasma concentrations of diltiazem and their effects on mean arterial pressure (MAP) and heart rate (HR) after the intravenous application of 1 and 3 mg kg(-1) of the drug. Correlation between diltiazem plasma levels and their cardiovascular effects was established by fitting the data to a conventional and modified E(max) model. RESULTS: Volume of distribution and clearance of diltiazem was greater in SHR than in WKY animals. A proportional increase of area under curve with dose increment was observed in WKY animals but not in SHR. A good correlation between plasma unbound concentrations of diltiazem and their hypotensive and chronotropic effects was found in both experimental groups using both PK-PD models. The application of the modified E(max) model for PK-PD modeling of diltiazem allowed a more accurate and precise estimation of PK-PD parameters than the E(max) equation do. Chronotropic effect of 3 mg kg(-1) diltiazem was lower in SHR compared to WKY animals. Initial sensitivity (S(0)) to diltiazem chronotropic effect was greater in SHR with regards to WKY animals after administration of 1 mg kg(-1). S(0) to diltiazem hypotensive effect was greater in SHR with regards to WKY animals after administration of both doses of diltiazem. DISCUSSION: Microdialysis sampling is a useful technique for the pharmacokinetic study and pharmacokinetic-pharmacodynamic (PK-PD) modeling of diltiazem. The modified E(max) model allows an accurate estimation of drug sensitivity in conditions when maximal pharmacological response can not be attained. Genetic hypertension induced changes in the pharmacokinetic and PK-PD behavior of diltiazem suggesting that SHR is an interesting animal model for pre-clinical evaluation of calcium channel blockers.     

CORONARY VASCULAR RESPONSE TO ENDOTHELIN IN ISOLATED PERFUSED HEARTS OF SPONTANEOUSLY HYPERTENSIVE RATS

1. The coronary vasoconstrictive response to endothelin (ET-1) was evaluated using the isolated perfused hearts of 15 week old spontaneously hypertensive rats (SHR) and age-matched Wistar-Kyoto rats (WKY). Endothelin produced marked increases in perfusion pressure (PP) in both SHR and WKY. The effects of ET-1 were more potent than those of acetylcholine, vasopressin and angiotensin II. The vascular response to ET-1, expressed as the increase in PP, was greater in SHR than in WKY. 2. Nicardipine (10(-8) mol/L) shifted the concentration-PP response curve for ET-1 to the right. The extent of the rightward shift was greater in SHR than in WKY. Additionally in SHR, Bay K-8644 elicited a dose-dependent increase in PP, the effect being more potent than that in WKY. 3. The increased response of the coronary vasculature to ET-1 was observed after 15 weeks of age but not at 6 weeks, indicating that enhancement of the response develops with ageing in SHR. 4. Enhancement of the vascular response to ET-1 in SHR was prevented by chronic (10 weeks) treatment with enalapril (10 mg/kg per day), but not by hydralazine (30 mg/kg per day). 5. These results indicate that the coronary vascular response to ET-1 increases with age in SHR. The mechanism of the enhanced response may involve the activation of dihydropyridine-sensitive Ca2+ channels, however, this type of mechanism may also be modulated at least in part by the renin-angiotensin system.     

Pharmacological Activity of DC−015, a Novel Potent and Selective α1-Adrenoceptor Antagonist

The pharmacological activity of 3?((4?(2?methoxyphenyl)piperazin?1?yl)methyl)?2,3?dihydroimidazo(1,2?c)quinazolin?5(6H)-one (DC?015), a newly synthesized quinazoline derivative, was determined in rat isolated thoracic aorta and pressor responses were determined in spontaneously hypertensive rats (SHR). Experimental results indicated that DC?015 is an α₁-adrenoceptor-blocking agent in rat thoracic aorta as revealed by its competitive antagonism of phenylephrine-induced vasocontraction (pA₂ = 10m?54 ± 0m?55). These effects still persisted in denuded aorta. It was as potent as prazosin (pA₂ = 10m?04 ± 0m?63). At higher concentrations (1m?0 μM), DC?015 also expressed 5?hydroxytryptamine (5?HT) receptor competitive antagonism, but this 5?HT blocking effect was not found in the prazosin-administration group. [³H]Inositol monophosphate formation stimulated by phenylephrine (30 μM) in rat thoracic aorta was diminished by DC?015 (3 and 10 nM) and prazosin (10 nM); whereas the cAMP content of rat thoracic aorta was not altered by DC?015 and prazosin. Furthermore, intravenous administration of DC?015 and prazosin (both at 0m?01, 0m?05 and 0m?1 mg kg¹¹) induced a dose-dependent reduction of mean arterial pressure which reached a maximal effect at 5 min after injection and persisted over 2 h in SHR. A higher dose of DC?015 (0m?1 mg kg^?1, i.v.) did not cause any significant changes in heart rate, whereas, the same dose of prazosin (0m?1 mg kg^?1, i.v.) produced a decrease which seems to parallel the time course of the hypotensive response. We can conclude that the DC?015 is a potent, highly selective α₁-adrenoceptor antagonist in vascular smooth muscle.     

Comparative effects of tramadol on vascular reactivity in normotensive and spontaneously hypertensive rats

The aim of the present study was to determine the effects of tramadol on vascular reactivity in aortic rings from Wistar-Kyoto (WKY) rats and spontaneously hypertensive rats (SHR). Aortic rings, with or without endothelium, were obtained from male WKY rats and SHR (15-20 weeks old) and prepared for isometric tension recording. Aortic rings were precontracted with phenylephrine (10 micromol/L) or 40 mmol/L KCl and then exposed to cumulative concentrations of tramadol (0.1-1 mmol/L). Tramadol produced a concentration-dependent relaxation of precontracted aortic rings from WKY rats and SHR, which was not dependent on functional endothelium. Vascular relaxation was significantly greater in rings from SHR than WKY rats. The concentration of tramadol necessary to produce a 50% reduction of the maximal contraction to phenylephrine (IC(50)) in rings with and without endothelium from SHR was 0.47 +/- 0.08 and 0.44 +/- 0.03 mmol/L, respectively (P = 0.76). Tramadol attenuated the contracture elicited by Ca2+ in depolarized tissue, suggesting that it may inhibit L-type Ca2+ channels. However, pretreatment with nicardipine (1 micromol/L) prevented the relaxation induced by tramadol in aortic rings from WKY rats and partially reduced its inhibitory effect in aortic rings from SHR. 6. Pretreatment of endothelium-denuded aorta with glybenclamide (3 micromol/L), 4-aminopyridine (3 mmol/L), tetraethylammonium (3 mmol/L) and naloxone (100 micromol/L) did not affect tramadol-induced vasodilation of aortic rings from either WKY rats or SHR. Intravenous administration of tramadol (10 mg/kg) to conscious SHR significantly reduced both systolic and diastolic blood pressure from 171.4 +/- 5.3 to 129.3 +/- 5.3 (P = 0.002) and from 125.0 +/- 6.5 to 57.8 +/- 8.9 mmHg (P = 0.003), respectively.     

EFFECTS OF HIGH SALT INTAKE ON CONTROL OF HINDLIMB VASCULAR RESISTANCE BY ARTERIAL BROREFLEX AND VAGAL AFFERENTS IN SPONTANEOUSLY HYPERTENSIVE RATS

1. This study aimed to examine whether a high salt diet alters control of vascular resistance by arterial baroreflex and vagal afferents in spontaneously hypertensive rats (SHR) and Wistar Kyoto rats (WKY). 2. SHR and WKY aged 8 weeks were fed either high (8%) or normal salt (0.4%) diet for 4 weeks. Arterial baroreflex control of hindlimb vascular resistance was assessed by examining reflex-induced vasodilation and vasoconstriction in response to phenylephrine and nitroprusside, respectively, in the constant-flow perfused hindlimb of urethane-anesthetized rats. 3. Tonic influence of the cardiopulmonary vagal afferents was evaluated by examining the effects of vagotomy on hindlimb vascular resistance and on the gain of arterial baroreflex control of hindlimb vascular resistance. 4. The gain of the arterial baroreflex control of hindlimb vascular resistance in response to both phenylephrine and nitroprusside were not significantly different between SHR receiving high and normal salt diets, and between WKY receiving high and normal salt diets. 5. Vagotomy increased hindlimb vascular resistance in all four groups of rats. However the magnitude of the increase in hindlimb vascular resistance was less in SHR on a high salt diet than those in SHR on a normal salt diet but similar between the two groups of WKY. Vagotomy increased the slope of arterial baroreflex control of hindlimb vascular resistance in SHR receiving a normal salt diet and the two groups of WKY but not in SHR receiving a high salt diet. 6. These results suggest that a high salt diet attenuates the inhibitory influence of vagal afferents on the control of vascular resistance in SHR but not in WKY, while the arterial baroreflex control of vascular resistance is preserved during high salt diet in both SHR and WKY.     

ANGIOTENSIN CONVERTING ENZYME INHIBITOR, CAPTOPRIL, INHIBITS CARDIAC HYPERTROPHY WITHOUT CHANGING COLLAGEN TYPES AND CONCENTRATION IN SPONTANEOUSLY HYPERTENSIVE RATS

1. The effects of the ACE inhibitor, captopril, on collagen metabolism in spontaneously hypertensive rats (SHR) with cardiac hypertrophy was examined. Captopril (100 mg/kg per day) was administered in drinking water to 20 week old male SHR for 12 weeks. Collagen concentration was calculated from hydroxyproline content, and relative proportions of types I, III and V collagen were determined by non-interrupted SDS-polyacrylamide gel electrophoresis (SDS-PAGE). These parameters were examined in age and sex matched Wistar-Kyoto (WKY) rats, as well as in non-treated SHR, and compared with those of captopril-treated SHR. 2. Captopril significantly reduced both blood pressure (191 ± 12.1 vs 146 ± 11.2 mmHg, P < 0.01), and the ratio of left ventricular (LV) weight to bodyweight (BW; 2.38 ± 0.17 vs 2.05 ± 0.12 mg/g, P < 0.01). There were no significant differences in collagen concentration among WKY rats, captopril-treated SHR and non-treated 32 week old SHR. However, total collagen content in captopril-treated SHR reduced significantly compared with non-treated 32 week old SHR (16.8 ± 2.0 vs 21.3 ± 0.8 mg, P < 0.01). The relative proportion of type V collagen was significantly higher in both captopril-treated (58.6 ± 3.4 vs 46.8 ± 1.3%, P < 0.01) and non-treated 32 week old SHR (59.9 ± 3.1 vs 46.8 ± 1.3%, P < 0.01) compared with WKY rats. However, there were no significant differences between captopril-treated SHR and non-treated 32 week old SHR. 3. The data from this study showed that captopril reduced cardiac hypertrophy, as reported previously, but did not change collagen types and concentration of the hypertrophied myocardium in SHR.     

Increased 45Ca influx in response to alpha 1-adrenoceptor stimulation in spontaneously hypertensive rat caudal artery

The isometric tension development and 45Ca influx in response to norepinephrine (NE) and methoxamine stimulation were investigated in caudal arteries of spontaneously hypertensive rats (SHR) and Wistar Kyoto normotensive rats (WKY). The maximum isometric tension developed as well as 45Ca influx in response to NE and methoxamine stimulation were significantly increased (p less than 0.05) in SHR caudal arteries as compared with WKY. On the other hand, neither the isometric tension developed nor the 45Ca influx in response to K+ depolarization were different between WKY and SHR caudal arteries. Estimation of [3H]prazosin binding to the membranes isolated from caudal artery of WKY and SHR showed a single class of high-affinity binding sites with Kd values for SHR 128 +/- 14 pM and for WKY 141 +/- 19 pM, and Bmax values for SHR 108 +/- 14 fmol/mg protein and for WKY 113 +/- 21 fmol/mg protein. From these results, we conclude: (a) Increased contractile response of SHR caudal artery rings to alpha 1-adrenoceptor stimulation appears at least in part to be due to an increased Ca2+ influx through receptor-operated Ca2+ channels; (b) the affinity or density of alpha 1-adrenoceptors estimated by [3H]prazosin binding is not altered in the SHR caudal artery.     

BLOOD PRESSURE, SALT APPETITE AND MORTALITY OF GENETICALLY HYPERTENSIVE AND NORMOTENSIVE RATS MAINTAINED ON HIGH AND LOW SALT DIETS FROM WEANING

1. Blood pressure, bodyweight, saline preference and mortality rate were examined in spontaneously hypertensive rats (SHR) of the Okamoto strain and normotensive control Wistar-Kyoto (WKY) rats maintained on low (0.1% NaCl w/w), control (0.8% w/w) and high (3% w/w) salt diets from weaning until 6 months of age. 2. The growth rate of SHR on high salt diet was not significantly different from that on control diet but SHR maintained on a low salt diet exhibited a markedly reduced growth rate. While the growth rate of WKY on low salt diet was not significantly different from that on control diet, the bodyweights of WKY on high salt diet were significantly greater than those of animals on control diet. 3. While low salt diet markedly attenuated the development of hypertension in the SHR, high salt diet significantly exacerbated the blood pressure of this strain. Neither high nor low salt diet altered the blood pressure of WKY. 4. SHR on high and low salt diets had an increased mortality rate compared with SHR on control salt diet but these differences were of slight statistical significance. Conversely, WKY on all three diets exhibited similar mortalities over the 6-month observation period. There were no significant differences in mortalities between SHR and WKY on any diet. 5. The preference for 0.9% saline, when offered as a choice with water, was not significantly different between SHR on the different diets. WKY on high salt diet, however, exhibited a significantly reduced preference for saline over the 10-day test period compared with animals on control or low salt diet. 6. Thus dietary salt modulates the hypertension of SHR but not the blood pressure of WKY. SHR would appear to require more dietary sodium for normal growth and perhaps full expression of its hypertension. The higher and lower blood pressures of the SHR on high and low salt diet, respectively, were associated with increased mortality, which was a trend not seen in the WKY.     

The differential effects of prazosin and hydralazine on sympathoadrenal activity in conscious rats

The ability of the vasodilator hydralazine and the alpha 1-adrenoceptor antagonist prazosin to increase sympathoadrenal outflow was compared by measuring plasma norepinephrine and epinephrine concentrations, norepinephrine clearance and norepinephrine spillover rate into plasma in conscious Sprague-Dawley rats and spontaneously hypertensive rats (SHR). Even though the vasodepressor effect of 1 mg/kg (i.p.) of prazosin (-23 mm Hg) was significantly less than that caused by 1 mg/kg (i.p.) of hydralazine (-31 mm Hg) in normotensive rats, the increases in plasma norepinephrine concentration and norepinephrine spillover rate were significantly larger in prazosin-treated rats. In conscious SHR, 0.5 mg/kg (i.p.) of prazosin and 0.3 mg/kg (i.p.) of hydralazine lowered blood pressure to the same extent (-22 mm Hg), but prazosin again produced significantly larger increases in plasma norepinephrine concentration and norepinephrine spillover rate. Neither prazosin nor hydralazine affected norepinephrine clearance, and only prazosin elicited a significant rise in plasma epinephrine concentration. This differential effect of prazosin and hydralazine on sympathoadrenal activity is best explained by the differing effects of these drugs on venous return and thus the afferent activity of the cardiopulmonary baroreceptors.     

The interaction between noradrenaline and ATP upon polyphosphoinositide metabolism and contraction in tail arteries from normo- and hypertensive rats.

The effects of, and interaction between, noradrenaline and alpha,beta-methylene ATP upon polyphosphoinositide (PPI) breakdown, investigated by measuring the accumulation of inositol phosphates, and contraction, were studied in tail arteries from normo- (WKY) and spontaneously-hypertensive (SHR) rats. Noradrenaline (10(-7)-10(-3) M) evoked a prazosin (10(-6) M)-sensitive, concentration-dependent increase in total inositol phosphate accumulation in both WKY and SHR rats. No significant differences were observed in either the maximal response or in the concentration range over which noradrenaline evoked this response, between these two populations. Noradrenaline (5 x 10(-7)-5 x 10(-5) M) evoked a concentration-dependent contraction of arteries from both SHR and WKY rats. The responses to noradrenaline were about 2-fold greater at all effective concentrations of noradrenaline in SHR compared with WKY rats. alpha,beta-Methylene ATP (10(-6) M) did not alter noradrenaline-stimulated total inositol phosphate accumulation, in arteries from either SHR or WKY rats, measured either as the maximal response or as the EC50. alpha,beta-Methylene ATP (5 x 10(-6) M), by itself, evoked a contractile response, which was quantitatively similar in SHR and WKY rats, and was additive with the contractile responses to noradrenaline (5 x 10(-7)-5 x 10(-5) M). The maximum response produced by a combination of noradrenaline and alpha,beta-Methylene ATP was quantitatively similar to that produced by noradrenaline alone. No evidence of synergism between alpha,beta-Methylene ATP and noradrenaline upon contraction was observed.(ABSTRACT TRUNCATED AT 250 WORDS)     

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.