Mechanisms of altered sensitivity to endothelin-1 between aortic smooth muscles of spontaneously hypertensive and Wistar-Kyoto rats

Endothelin-1 (ET-1) caused a dose-dependent vasoconstriction in rat aortic strips in vitro. The sensitivity to ET-1 was significantly higher in 12-week-old spontaneously hypertensive rats (SHR) than in age-matched Wistar-Kyoto (WKY) rats. In contrast, the sensitivity was not different between SHR and WKY rats at 6 weeks of age, which was close to that of 12-week-old SHR. Receptor binding study in microsomal preparations of the aortas with [125I]ET-1 showed that maximum binding value for ET-1 receptor in 12-week-old SHR was only 1.5-fold greater than that in WKY rats and that there was no significant difference in the Kd values. K(+)-depolarization induced vasoconstrictive responses that were also augmented in 12-week-old SHR. Resting membrane potential of the aorta was significantly depolarized in tissues from 12-week-old SHR compared with age-matched WKY rats. The resting membrane potentials were similar in the aorta from 6-week-old SHR and WKY rats, and were between those of 12-week-old SHR and WKY rats. When the aortic strips from 12-week-old WKY rats were partially depolarized in high K(+)-solution or in the presence of ouabain (0.1 mM), the vasoconstrictor effect of ET-1 became similar to that on the strips from SHR in a normal solution. These results suggest that, although age-dependent changes appear to be complicated, the lower resting membrane potential may account considerably for the larger sensitivity to ET-1 in the aorta from 12-week-old SHR than that from age-matched WKY rats.     

Endothelial regulation of cyclic GMP and vascular responses in hypertension

The mechanism whereby endothelial modulation of drug-induced vascular responses might change during hypertension was examined. Acetylcholine (ACh) (1 microM) induced maximal relaxation of aortic ring segments with intact endothelium from both Wistar-Kyoto, normotensive rats (WKY) and spontaneously hypertensive rats (SHR) at 5 to 6 weeks of age. At 15 to 18 weeks of age the relaxation response to ACh was reduced in rings from both SHR and WKY (to a greater extent in SHR) and was attenuated even more in the deoxycorticosterone acetate (DOCA)-salt hypertensive rat. The contractile responses of aortic preparations to norepinephrine (NE) (0.1 microM) were similar between 5-6-week-old and 15-18-week-old WKY, but were increased in 15-18-week-old SHR compared to 5-6-week-old SHR. Endothelial cell removal increased contractile responses to NE to a greater extent in WKY than SHR but this did not affect that seen in DOCA-salt hypertensive rats. Methylene blue treatment increased contractions of aortic rings with intact endothelium from 15-18-week-old WKY and SHR to the level detected in rubbed arteries, but it did not affect the NE-induced constriction of intact aortic rings from DOCA-salt hypertensive rats. Basal cyclic GMP concentrations in intact aortic rings were not different between SHR and WKY at 5 to 6 weeks of age. The basal aortic cyclic GMP was unchanged in WKY at 15 to 18 weeks of age, but decreased in SHR and in DOCA-salt hypertensive rats of the same age.(ABSTRACT TRUNCATED AT 250 WORDS)     

替米沙坦对自发性高血压大鼠颈动脉Ⅰ型、Ⅲ型胶原及转化生长因子β_1表达的影响

目的:研究自发性高血压大鼠(SHR)颈动脉Ⅰ型、Ⅲ型胶原及转化生长因子1β(TGF-1β)的表达,并探讨替米沙坦的干预作用。方法:30只雄性12周龄的SHR大鼠随机分为3组:高血压组(SHR)、替米沙坦低剂量组(T e lL)、替米沙坦高剂量组(T e lH),并设同周龄雄性的W KY大鼠为对照组(W KY,n=10),干预18周。观察各组大鼠收缩压(SBP)、免疫组化评估颈动脉Ⅰ型、Ⅲ型胶原及TGF-1β的表达。结果:(1)2周后T e lH组SBP明显低于SHR组(P<0.01),其降压作用持续至实验结束,而T e lL组SBP与SHR组差异无统计学意义(P>0.05);(2)SHR组颈动脉外膜Ⅰ型胶原的表达明显高于W KY组(P<0.01),T e lH、T e lL组颈动脉外膜Ⅰ型胶原的表达低于SHR组(P<0.05);(3)SHR组颈动脉外膜Ⅲ型胶原的表达明显低于W KY组(P<0.01),T e lH组颈动脉外膜Ⅲ型胶原的表达高于SHR组(P<0.01);(4)SHR组颈动脉中膜TGF-1β的IOD值明显低于W KY组(P<0.01),T e lH、T e lL组颈动脉中膜TGF-1β的IOD值高...     

Contractile effects of Bay k 8644, a dihydropyridine calcium agonist, on isolated femoral arteries from spontaneously hypertensive rats

Agonist actions of methyl-1,4-dihydro-2,6-dimethyl-3-nitro-4-(2-trifluoromethylphenyl)- pyridine-5-carboxylate (Bay k 8644) were investigated in femoral and mesenteric arteries from 6-week-old spontaneously hypertensive rats (SHRs), and data compared with findings in normotensive Wistar-Kyoto rats (WKYs). The addition of Bay k 8644 produced a dose-dependent contraction in SHR femoral artery with a pD2 value of 8.55. Maximum contraction induced by this agonist (1 X 10(-7) M) was comparable to the maximum developed by K+-depolarization. Bay k 8644 was much less effective in eliciting the contractile responses on WKY femoral artery. Contractile responses of mesenteric and tail arteries to Bay k 8644 were weak and were not significantly different between SHR and WKY. Thoracic aorta was sensitive to the contractile response to Bay k 8644, but the sensitivity was not significantly different between SHR and WKY. Increased responsiveness to exogenously applied K+ was also observed in SHR femoral artery as compared to WKY. Contractile responses of SHR femoral artery to Bay k 8644 were antagonized competitively by nifedipine (pA2 = 8.36), a dihydropyridine Ca++ antagonist, but noncompetitively by diltiazem, a non-dihydropyridine Ca++ antagonist. When the effect of nifedipine on the dose-response curve for Bay k 8644 was determined in WKY femoral artery, there was a similar extent of rightward displacement of the dose-response curve to that seen in SHR. Nifedipine was less efficacious in relaxing the contractile response to Bay k 8644 compared to the contractile response to K+ in SHRs femoral arteries.(ABSTRACT TRUNCATED AT 250 WORDS)     

Spontaneously hypertensive rat resistance artery structure related to myogenic and mechanical properties

This investigation related arterial structure to myogenic (pressure-dependent) contractile responses in resistance arteries from spontaneously hypertensive rats (SHRs) and Wistar-Kyoto (WKY) normotensive control rats under pressurized conditions in vitro. Femoral and mesenteric resistance arteries from either strain were cannulated and pressurized in an arteriograph for the determination of pressure-diameter relationships under passive and active conditions in the range 5-200 mmHg transmural pressure. Arterial geometrical measurements were made under relaxed conditions at 100 mmHg. Media thickness/lumen diameter (M/L) ratios were significantly increased in SHR femoral (5.00+/-0.44% compared with 3.63+/-0.34%; P<0.05) and mesenteric (4.40+/-0.29% compared with 2.62+/-0.23%; P<0.001) arteries compared with those from WKY rats. Maximum myogenic contractions, assessed as minimum normalized diameters, were not significantly different in SHR and WKY rat femoral (0.41+/-0.03 and 0.40+/-0.02 respectively) or mesenteric (0.56+/-0.02 and 0.63+/-0.03 respectively) arteries. Arterial mechanical analyses demonstrated that incremental elastic modulus is reduced in SHR mesenteric arteries, but is not significantly different in SHR femoral arteries, compared with those from WKY rats. Additionally, wall stress at estimated in vivo pressures under passive and active conditions are similar in SHR and WKY rat arteries. These data demonstrate that increased M/L ratios in resistance arteries from SHRs are not associated with increased maximum pressure-dependent contractile responses. Increased M/L ratios in resistance arteries from SHRs are not accounted for by increased vessel wall stiffness, but the hypertension-associated arterial geometrical abnormalities act to normalize wall stress in the face of increased arterial pressure.     

Radiotelemetric evaluation of hemodynamic effects of long-term ethanol in spontaneously hypertensive and Wistar-Kyoto rats

This study determined the hemodynamic effects of chronic ethanol in telemetered freely moving age-matched spontaneously hypertensive (SHR) and Wistar-Kyoto (WKY) rats. Changes in blood pressure (BP), heart rate (HR), and plasma norepinephrine (as index of sympathetic activity) were evaluated in pair-fed rats receiving liquid diet with or without ethanol (5%, w/v) for 12 weeks. The SHRs exhibited higher baseline BP and lower HR compared with WKY rats. When normalized for body weight, daily ethanol intake was higher in SHRs compared with WKY rats. However, blood ethanol concentration was similar except for a higher level in SHRs at weeks 7 through 9. Ethanol had no effect on BP in WKY rats but caused decreases in BP in SHRs that reached a maximum (approximately 30 mm Hg) at week 5 and remained thereafter. Ethanol also caused reductions in the BP variability and the circadian fluctuations in BP in SHRs but not in WKY rats. Plasma norepinephrine levels were elevated by ethanol in WKY rats, but not in SHRs. The HR was not affected by ethanol in SHRs and showed increases in WKY rats. These findings suggest that chronic ethanol feeding differentially affects BP in SHRs (hypotension) and WKY rats (no effect). The lack of a hypotensive response to ethanol in WKY rats may relate, at least partly, to the associated sympathoexcitation. The present study used the telemetry technique for BP measurement, which eliminates the confounding and stressful effects of other conventional techniques.     

Cytoplasmic free [Ca2+] is increased in the platelets of spontaneously hypertensive rats and essential hypertensive patients

The cytoplasmic free calcium concentration [( Ca2+]i) was assessed with the fluorescent dye Quin 2 in platelets and lymphocytes of spontaneously hypertensive rats (SHR), normotensive Wistar-Kyoto rats (WKY), essential hypertensive patients (EHP) and normotensive human control subjects (NCS). [Ca2+]i was significantly higher in the platelets of 8- and 20-week-old SHR in comparison with WKY. However, no difference was evident after weaning. Changes of cellular calcium in hypertensive rats apparently evolved simultaneously with the development of high arterial pressure. [Ca2+]i was significantly higher in platelets of EHP than in NCS. In lymphocytes of SHR, [Ca2+]i was not different from WKY at 4 and 8 weeks, but was increased at 14 weeks and at older ages. In EHP, intralymphocytic [Ca2+] was only modestly higher than in controls. On the whole, the results suggest that control of cytoplasmic calcium in these blood cells is similarly affected in human and animal models of primary hypertension.     

Low-dose angiotensin II reduces urinary cyclic AMP excretion in spontaneously hypertensive, but not normotensive, rats: independence from hypertension and renal hemodynamic effects of angiotensin.

The purpose of this study was to determine whether the greater inhibitory effect of angiotensin II (Ang II) on urinary cAMP excretion in spontaneously hypertensive rats (SHRs) compared with normotensive Wistar-Kyoto (WKY) rats is secondary to hypertension and/or renal hemodynamic changes induced by Ang II. SHRs and WKY rats were treated chronically from conception, 6 weeks of age, or 10 weeks of age (n = 8-10) with the angiotensin-converting enzyme inhibitor captopril (100 mg/kg/day). A fourth group was not treated chronically with captopril (n = 7). At approximately 13 weeks of age, all rats were anesthetized, given a bolus of captopril (30 mg/kg), and received an intrarenal infusion of a low dose of Ang II (1 ng/min). SHRs compared with WKY rats were normotensive, mildly hypertensive, and moderately hypertensive when treated with captopril from conception, 6 weeks of age, and 10 weeks of age, respectively, whereas untreated SHRs were severely hypertensive. In SHRs, Ang II decreased urinary cAMP excretion (p <.001), and this effect was independent of duration of captopril pretreatment (p = .696). In WKY rats, Ang II did not affect urinary cAMP excretion. Low-dose Ang II caused small and similar changes in renal blood flow and glomerular filtration rate in SHRs versus WKY rats and did not affect urine volume in either strain. We conclude that the greater effect of Ang II on urinary cAMP excretion in SHRs is not due to hypertension or to the renal hemodynamic effects of Ang II, but most likely to a greater effect of Ang II on some compartment of renal adenylyl cyclase activity in SHRs.     

Evidence for enhanced inhibitory modulation by cyclooxygenase products of noradrenergic neurotransmission in the mesenteric vasculature of young spontaneously hypertensive rats.

The effects of cyclooxygenase inhibition by indomethacin and meclofenamate on pre- and postjunctional aspects of noradrenergic neurotransmission were determined in mesenteric vascular preparations from 4- to 6-week-old spontaneously hypertensive rats (SHRs) and normotensive Wistar-Kyoto rats (WKYs). Perfusion pressure responses to periarterial nerve stimulation and to exogenous norepinephrine (NE) were significantly greater in SHR than in WKY preparations, whereas fractional NE overflow was equivalent between the two strains. Indomethacin and meclofenamate enhanced perfusion pressure responses to periarterial nerve stimulation in both strains. Fractional NE overflow was significantly enhanced by indomethacin but only at 14 Hz in SHR preparations, whereas it was unaffected in WKY preparations. The combination of indomethacin and cocaine resulted in a significant enhancement of perfusion pressure responses to periarterial nerve stimulation in both strains that was significantly greater than that produced by either drug alone. This effect was significantly greater in SHR than in WKY preparations. This combination also resulted in a significant enhancement of responses to exogenous NE in both strains. Fractional NE overflow was significantly increased in SHR preparations in the presence of the combination of cocaine and indomethacin, whereas it remained unaltered in WKY preparations. These findings suggest that a cyclooxygenase product exerts both pre- and postjunctional inhibitory effects on vascular noradrenergic neurotransmission that differ in these two strains of rats. The prejunctional inhibitory effect of this cyclooxygenase product was observed only in SHR preparations and was especially evident in the presence of cocaine.     

自发性高血压大鼠心脏和肾脏血管紧张素转换酶2和血管紧张素转换酶的表达

目的 观察不同月龄的自发性高血压大鼠(SHR)的心脏和肾脏血管紧张素转换酶2(ACE2)和血管紧张素转换酶(ACE)的Mrna和蛋白质表达水平,探讨ACE2/ACE与血压状态的内在联系.方法 12周龄雄性自发性高血压大鼠(spontaneously hypertensive rat,SHR)18只和12周龄WKY大鼠(Wistar-Kyoto rats,WKY)18只.随机分为SHR组和WKY组,每组抽取各9只,处死进行与喂养12周后处死的24周龄大鼠相同的研究内容.采用实时定量RT-PCR法(Real-time Quantitative RT-PCR)检测ACE2、ACE Mrna(messenger ribonucleic acid,Mrna)的表达,免疫组织化学榆测ACE2、ACE等蛋白的表达.结果 (1)与同周龄WKY组比较,SHR组的血压显著增加(P均＜0.01),心脏和肾脏的ACE2 Mrna表达显著降低(P均＜0.01),ACEmRNA表达显著升高(P＜0.05,P＜0.01);与12周龄SHR组比较,24周龄SHR的血压亦显著增加(P＜0.01),ACE2 Mrna表达显著降低(P均＜0.01),ACE Mrna表达显著升高(P均＜0.01).(2)与同周龄的WKY组比较,SHR组心脏和肾脏的ACE2免疫染色表达显著减少,ACE免疫染色表达显著增多.结论 心脏和肾脏的ACE2/ACE Mrna表达与血压升高相关.     

Phosphodiesterase isozyme inhibition and the potentiation by zaprinast of endothelium-derived relaxing factor and guanylate cyclase stimulating agents in vascular smooth muscle

We have examined the interaction of zaprinast with mediators of guanylate cyclase on the relaxation of aortic smooth muscle. Zaprinast, a selective inhibitor of the low Km-cyclic GMP (cGMP) phosphodiesterase [low Km cGMP phosphodiesterase (PDE)], was equally effective in relaxing phenylephrine-contracted aortas from spontaneously hypertensive rats (SHR) and Wistar-Kyoto rats (WKY) with an intact endothelium [EC50 = 7.6 (3.5-16.6) microM vs. 9.3 (4.1-21.3) microM, respectively]. In contrast, the vasorelaxant activity of zaprinast in intact and denuded phenylephrine-contracted guinea pig aortas, as well as denuded (SHR and WKY) aortas was minimal. Sodium nitroprusside and atriopeptin II were significantly (P less than .05) more potent as vasorelaxants in denuded SHR aortas when compared with denuded aortas from WKY. Pretreatment with zaprinast potentiated the vasorelaxant potency of sodium nitroprusside in both SHR and WKY aortas whereas atriopeptin II responses were potentiated only in WKY aortas. In studies with the low Km cGMP PDE, isolated via DEAE column chromatography, the apparent Km for cGMP and potency of zaprinast were approximately 2-fold greater (P less than .05) in WKY when compared with the same PDE isozyme isolated from SHR aortic preparations. However, the Vmax (picomoles per milligram per minute) for cGMP hydrolysis was greater in SHR than in WKY. In conclusion, these data show that, although there are no apparent differences in the influence of spontaneously released endothelium-derived relaxing factor from SHR and WKY aortas, reactivity differences to other agents known to stimulate guanylate cyclase activity exist between SHR and WKY denuded aortas.(ABSTRACT TRUNCATED AT 250 WORDS)     

Sustained antihypertensive effects of chronic administration of two kappa-opioid agonists in spontaneously hypertensive rats.

The ability of two nonpeptide kappa-opioid receptor agonists, U-50, 488H and U-62,O66E (spiradoline), to lower arterial pressure on chronic administration to 12-week-old male spontaneously hypertensive rats (SHRs) and age-matched normotensive Wistar Kyoto (WKY) rats was assessed. Each drug was infused subcutaneously at approximately 9.6 mg/kg/d, over a 14-day period with Alzet osmotic pumps in each strain of rat. Arterial pressures were determined daily in each rat by photoelectric tail-cuff plethysmography. Control rats received similar infusions of 0.9% NaCl. Body weights and water consumption were also recorded daily. Both drugs effected a 10% to 20% sustained lowering of arterial pressure beginning on the second day of infusion, until explantation of the pumps on day 14. Heart rates similarly were decreased by 10% to 15% in SHRs. By contrast, neither drug caused significant decrements in arterial pressure or heart rate in the normotensive WKY group. Control infusions of 0.9% NaCl had no significant effects on arterial pressure or heart rate in either SHRs or WKY rats. U-62,066E, but not U-50,488H, caused sustained increased water consumption in both SHRs and WKY rats, with a greater effect in the SHR strain. This likely was accompanied by a water diuresis. Body weight gains over the 14-day period were similar for both strains of rats treated with U-50,488H, compared with saline-treated controls, but rats of both strains infused with U-62,066E gained significantly less weight than saline controls over the 14-day period. The results are supportive of further experimental evaluations of the potential antihypertensive use of nonpeptide kappa-opioid agonist drugs.     

Endothelial and smooth muscle properties of coronary and mesenteric resistance arteries in spontaneously hypertensive rats compared to WKY rats

Summary— To investigate if the functional alterations observed in resistance arteries of spontaneously hypertensive rats (SHRs) were also present at the coronary level, in vitro experiments were performed in mesenteric resistance arteries (MRA) and in right (RIC) and left interventricular coronary (LIC) arteries taken from 15–25-week-old SHR and age-matched Wistar Kyoto rats WKYs. Using a passive extension protocol, internal diameters corresponding to 100 mmHg intraluminal pressure (D₁₀₀) were determined and vessels were set up to a normalized internal diameter (0.9 D₁₀₀). SHR mesenteric resistance arteries had a significantly smaller diameter compared to WKY arteries, whereas both types of SHR coronary arteries had a greater diameter compared to those of WKY rats. In arteries in the absence of contracting agonist, nitro-L-arginine (NOLA, 100 μM) induced a progressive rise in basal tone, which could be reversed by subsequent addition of L-arginine (100 μM) but not D-arginine (100 μM). When expressed as percent of maximal contractions induced by agonists (noradrenaline, NA [10 μM] in MRA; serotonin, 5-HT [10 μM], in RIC and LIC), these contractions were significantly stronger in WKY compared to SHR coronary and mesenteric resistance arteries. In NA-precontracted MRA and 5HT-precontracted coronary arteries in the presence of indomethacin (10 μM), the magnitude of acetylcholine-induced maximal relaxations (expressed as percent of maximal contractions induced by agonists) was greater in WKY compared to SHR arteries. After a 30-min incubation period, NOLA (100 μM) completely inhibited relaxations induced by acetylcholine (0.01–10 μM) in all types of precontracted arteries. Subsequent additions of sodium nitroprusside, (SNP, 10 μM) induced complete relaxations in all preparations. These results show that a basal release of NO or NO-like compound by endothelial cells is present in isolated mesenteric resistance and coronary arteries of WKY rats and SHRs. The contribution of endothelium-derived relaxing factor-nitric oxide (EDRF-NO) to arterial tone was lower in MRA compared to coronary arteries in both strains and in SHR compared to WKY arteries. In the SHR preparations, the impaired relaxation induced by acetylcholine appeared to be due to a functional alteration of the endothelium in the presence of normal reactivity of the smooth muscle cells.     

Time course of changes in the norepinephrine content of tissues from spontaneously hypertensive and Wistar Kyoto rats

The change in norepinephrine (NE) content with age (from 2 days to 17 weeks old) was examined in a variety of tissues from spontaneously hypertensive rats (SHR) and normotensive Wistar Kyoto (WKY) rats. NE content was determined by either a catechol-O-methyltransferase-based radioenzymatic assay or high performance liquid chromatography with electrochemical detection. Regardless of the age of the animal, NE content per gram of tissue was significantly greater in mesenteric arteries and kidneys from SHR compared to WKY tissues, whereas NE content per whole kidney was similar between the two rat strains. The time course of enhanced NE content in caudal arteries and aortas from SHR followed the development of hypertension. In the spleen, NE content per gram of tissue was elevated in young SHR; however, in adult rats NE content was not significantly different between the two rat strains. Because spleens from WKY rats were substantially larger, total NE content per spleen was significantly greater in tissues from WKY rats. Cardiac contents of NE were similar in SHR and WKY rats at all ages examined. Adrenal epinephrine concentrations were similar in SHR and WKY rats, whereas NE content was elevated in the SHR at 46 and 81 days of age. The results of the present study demonstrate that the appearance of increased NE levels in some SHR tissues occurs before the development of hypertension in this model. If NE content is a valid index of sympathetic innervation, enhanced innervation may contribute to the vascular medial hypertrophy observed in young SHR and the elevation of blood pressure in these rats.     

alpha 2-Adrenoceptors potentiate angiotensin II- and vasopressin-induced renal vasoconstriction in spontaneously hypertensive rats

Hypertension in spontaneously hypertensive rats (SHRs) is due in part to enhanced effects of vasoactive peptides on the renal vasculature. We hypothesize that the G(i) signal transduction pathway enhances renovascular responses to vasoactive peptides in SHRs more so than in normotensive Wistar-Kyoto (WKY) rats. To test this hypothesis, we examined in isolated perfused kidneys from SHRs and WKY rats the renovascular responses (assessed as changes in renal perfusion pressure in mm Hg) to angiotensin II (10 nM) and vasopressin (3 nM) in the presence and absence of UK-14,304 [5-bromo-N-(4,5-dihydro-1H-imidazol-2-yl)-6-quinoxalinamine; an agonist that selectively activates the G(i) pathway by stimulating alpha(2)-adrenoceptors]. In SHR, but not WKY, kidneys, UK-14,304 (10 nM) enhanced (P < 0.05) renovascular responses to angiotensin II (control WKY, 43 +/- 6; UK-14,304-treated WKY, 52 +/- 19; control SHR, 66 +/- 17; UK-14,304-treated SHR, 125 +/- 16) and vasopressin (control WKY, 42 +/- 17; UK-14,304-treated WKY, 36 +/- 11; control SHR, 16 +/- 8; UK-14,304-treated SHR, 83 +/- 17). Pretreatment of SHRs with pertussis toxin (30 microg/kg, intravenously, 3-4 days before study) to inactivate G(i) blocked the effects of UK-14,304. Western blot analysis of receptor expression in whole kidney and preglomerular microvessels revealed similar levels of expression of AT(1), V(1a), and alpha(2A) receptors in SHRs compared with WKY rats. We conclude that activation of alpha(2)-adrenoceptors selectively enhances renovascular responses to angiotensin II and vasopressin in SHRs via an enhanced cross talk between the G(i) signal transduction pathway and signal transduction pathways activated by angiotensin II and vasopressin.     

Differential effects of dopaminergic drugs on open-field behavior of spontaneously hypertensive rats and normotensive Wistar-Kyoto rats

Brain catecholamines may play a role in the development of hypertension in the spontaneously hypertensive rat (SHR). To investigate central dopaminergic function in this strain, the effect of various dopaminergic drugs on open-field activity was assessed. In general, basal levels of ambulation were similar in SHRs and their controls, the Wistar-Kyoto rats (WKY). Exploratory rearing activity was increased in SHRs, however. Haloperidol inhibited open-field ambulation in SHRs and WKY, but higher doses were needed in the SHR. Apomorphine inhibited ambulatory activity in WKY but had virtually no effect in SHRs. Amphetamine and the dopamine uptake inhibitor GBR-12909 increased ambulation in SHRs and WKY to a similar extent. Central administration of haloperidol or sulpiride decreased ambulatory activity in WKY, but had no effect in SHRs at the doses used. SCH-23390 decreased ambulation scores both in SHRs and WKY, with the effect being slightly greater in the latter strain. In all cases exploratory rearing was affected as well by the drugs used. The large difference in base-line scores has to be taken into account when interpreting these data, however. Also, for comparison the noradrenergic drugs clonidine and desipramine were tested. Both elicited decreases in activity which were identical in SHRs and WKY. These results show that a number of dopaminergic drugs have differential effects on open-field activity of SHRs as compared to WKY. Ambulatory activity appeared more resistant to inhibition in SHRs than in WKY. The possibility that these results could reflect altered dopaminergic function in SHR involved in the development of hypertension in this strain is discussed.     

Defective modulation of noradrenergic neurotransmission by exogenous prostaglandins in aging spontaneously hypertensive rats

Inhibition of cyclooxygenase enhances mesenteric vascular responses to periarterial (sympathetic) nerve stimulation (PNS) in 16-week-old spontaneously hypertensive rats (SHR), but not in 25-week-old SHR. In contrast, cyclooxygenase inhibition enhances mesenteric vascular responses to PNS similarly in 16- and 25-week-old Wistar-Kyoto normotensive rats (WKY). Thus, the modulation of noradrenergic neurotransmission by endogenous PGs becomes defective as SHR age, whereas in WKY this does not occur. The purpose of this study was to determine to what extent alterations in the concentrations of PGs and/or biological response to PGs contribute to this age/hypertension-related abnormality in SHR. All studies were conducted in the in situ autoperfused rat mesentery, and plasma levels of PGE2 and 6-keto-PGF1 alpha were determined by negative-ion, chemical-ionization, gas chromatography-mass spectrometry after derivatization and clean-up of samples by two thin-layer chromatographic steps. Base-line mesenteric venous plasma levels of PGs were similar in 16-week-old SHR vs. 16-week-old WKY; however, base-line levels of PGE2 were approximately 6-fold greater than base-line levels of 6-keto-PGF1 alpha in both strains. PNS at 7 Hz approximately doubled mesenteric venous plasma levels of PGE2 in both 16-week-old SHR and WKY, but PNS did not increase levels of 6-keto-PGF1 alpha in either strain. Inasmuch as mesenteric venous plasma levels of PGE2 were responsive to PNS, the effect of aging on PGE2 levels was studied. In both strains, the base-line mesenteric venous plasma levels of PGE2 and the PNS-induced increase in PGE2 levels were similar in 16-week vs. 25-week-old animals. In 16-week-old SHR, infusions of PGE2, arachidonic acid and PGI2 directly into the mesenteric artery inhibited vascular responses to PNS. However, in 25-week-old SHR, even high doses of PGE2 or arachidonic acid failed to inhibit vascular responses to PNS, and the inhibitory potency of PGI2 was shifted 10-fold to the right compared to 16-week-old SHR. In contrast, PGE2 and arachidonic acid had similar effects on neurotransmission in 25-week-old WKY compared to 16-week-old WKY, and aging had a lesser effect on the inhibitory potency of PGI2 (i.e., 3-fold rightward shift of the dose-response curve). Adenosine also inhibited vascular responses to PNS; however, the inhibitory potency of adenosine was only slightly and similarly affected by aging in SHR and WKY.(ABSTRACT TRUNCATED AT 400 WORDS)     

Effect of acute and chronic treatment of tin on blood pressure in spontaneously hypertensive rats.

Cytochrome P450-dependent metabolites of arachidonic acid (AA) are increased in the kidneys of spontaneously hypertensive rats (SHR) as compared to control rats (WKY) in the period of rapid elevation of blood pressure (BP) from 5 to 13 weeks. We treated rats with stannous chloride (SnCl2) (10 mg/100 g body weight/day for 4 days) to decrease selectively renal cytochrome P450 content through increasing renal heme oxygenase activity. A decrease in renal cytochrome P450-dependent AA metabolites was associated with decreased BP and increased urinary Na+ excretion in 7- but not in 20-week-old SHR rats. Chronic treatment with SnCl2 (10 mg/100 g body weight twice a week) from 5 to 20 weeks prevented the elevation of BP in SHR rats. Further, the antihypertensive effects of tin persisted for 7 weeks beyond its discontinuation. BP in WKY rats was unaffected by tin. Both the acute and chronic treatment with tin are the first studies to demonstrate amelioration of hypertension in SHR by an intervention which is targeted at a single enzyme system.     

细胞间黏附分子-1在高血压左室肥厚发病中的作用

目的　研究细胞间黏附分子 - 1(ICAM - 1)在高血压左室肥厚发生中的作用。方法　 12周龄雄性WKY大鼠和自发性高血压大鼠 (SHR)共 34只 ,分为对照组、高血压组、抗ICAM - 1抗体治疗组。抗ICAM - 1抗体治疗组经尾静脉注射抗ICAM - 1单克隆抗体 12周。断头处死大鼠后留取心肌标本 ,进行HE、VG染色 ,观察心肌细胞形态和胶原分布情况 ;免疫组化染色及ED1标记显示心肌巨噬细胞浸润 ;逆转录 -聚合酶链反应 (RT -PCR)检测心肌ICAM - 1mRNA表达 ;酶链免疫吸附实验 (ELISA)检测ICAM - 1的蛋白表达。结果　与对照组WKY大鼠比较 ,SHR肥厚心肌中ICAM - 1的mRNA及蛋白表达显著增加 (P <0 0 1,P <0 0 5 ) ,巨噬细胞浸润明显 (P <0 0 1)。应用抗ICAM - 1抗体治疗后 ,SHR心肌ICAM - 1的表达水平显著下调 (P <0 0 1,P <0 0 5 ) ,巨噬细胞浸润数减少 (P <0 0 5 ) ,心肌细胞肥大和间质纤维化程度明显减轻。结论　在高血压左室肥厚的发病过程中 ,心肌ICAM - 1过度表达及其介导的炎性细胞浸润可能具有重要作用     

Modulation of contractile function through neuropeptide Y receptors during development of cardiomyocyte hypertrophy

Severity of left ventricular hypertrophy (LVH) correlates with elevated plasma levels of neuropeptide Y (NPY) in hypertension. NPY elicits positive and negative contractile effects in cardiomyocytes through Y(1) and Y(2) receptors, respectively. This study tested the hypothesis that NPY receptor-mediated contraction is altered during progression of LVH. Ventricular cardiomyocytes were isolated from spontaneously hypertensive rats (SHRs) pre-LVH (12 weeks), during development (16 weeks), and at established LVH (20 weeks) and age-matched normotensive Wistar Kyoto (WKY) rats. Electrically stimulated (60 V, 0.5 Hz) cell shortening was measured using edge detection and receptor expression determined at mRNA and protein level. The NPY and Y(1) receptor-selective agonist, Leu(31)Pro(34)NPY, stimulated increases in contractile amplitude, which were abolished by the Y(1) receptor-selective antagonist, BIBP3226 [R-N(2)-(diphenyl-acetyl)-N-(4-hydroxyphenyl)methyl-argininamide)], confirming Y(1) receptor involvement. Potencies of both agonists were enhanced in SHR cardiomyocytes at 20 weeks (2300- and 380-fold versus controls). Maximal responses were not attenuated. BIBP3226 unmasked a negative contraction effect of NPY, elicited over the concentration range (10(-12) to 3 x 10(-9) M) in which NPY and PYY(3-36) attenuated the positive contraction effects of isoproterenol, the potencies of which were increased in cardiomyocytes from SHRs at 20 weeks (175- and 145-fold versus controls); maximal responses were not altered. Expression of NPY-Y(1) and NPY-Y(2) receptor mRNAs was decreased (55 and 69%) in left ventricular cardiomyocytes from 20-week-old SHRs versus age-matched WKY rats; parallel decreases (32 and 80%) were observed at protein level. Enhancement of NPY potency, producing (opposing) contractile effects on cardiomyocytes together with unchanged maximal response despite reduced receptor number, enables NPY to contribute to regulating cardiac performance during compensatory LVH.