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)     

Smooth muscle alpha-2 adrenoceptors mediate vasoconstrictor responses to exogenous norepinephrine and to sympathetic stimulation to a greater extent in spontaneously hypertensive than in Wistar Kyoto rat tail arteries

The alpha adrenoceptor-mediated vasoconstriction in isolated perfused tail arteries from spontaneously hypertensive (SHR) and age matched Wistar Kyoto (WKY) normotensive rats has been examined. Responses induced by periarterial field stimulation, exogenous norepinephrine or the selective alpha-1 adrenoceptor agonist methoxamine were preferentially antagonized by prazosin in both SHR or WKY tail arteries. However, in SHR only, the alpha-2 adrenoceptor antagonist idazoxan (RX 781094) at low concentrations, significantly antagonized responses to periarterial field stimulation and to exogenous norepinephrine. Except at rather high concentrations, idazoxan was inactive as an antagonist of responses induced by methoxamine. The alpha-1 adrenoceptor blocking agent prazosin was a very potent antagonist of the responses induced by periarterial field stimulation and by methoxamine. These results indicate that alpha-2 adrenoceptors predominate in both SHR and WKY tail arteries, but a significant subpopulation of smooth muscle alpha-2 adrenoceptors is present in tail arteries of SHR but not of WKY rats. In contrast to WKY normotensive rats, postjunctional alpha-2 adrenoceptors may also be involved in the vasoconstrictor responses to sympathetic nerve stimulation in tail arteries of SHR.     

Effects of Bay k 8644 and nifedipine on isolated dog cerebral, coronary and mesenteric arteries

Vasoconstrictor effects of Bay k 8644, a dihydropyridine Ca++ agonist, and vasorelaxant effects of nifedipine were investigated in helical strips of dog cerebral (basilar, posterior cerebral and middle cerebral) and peripheral (coronary and mesenteric) arteries. The addition of Bay k 8644 produced a dose-dependent contraction in the absence of any contractile agent in the basilar artery with a pD2 value of 8.53. Similar sensitivity to Bay k 8644 was observed in the posterior cerebral, middle cerebral or coronary artery. Bay k 8644 was much less effective in producing a contraction in the mesenteric artery. An elevation of the concentration of extracellular K+ eliminated the difference between the responses to Bay k 8644 in the basilar and mesenteric artery. Contractile responses of the basilar artery to Bay k 8644 were antagonized competitively by nifedipine (pA2 = 8.17), but non-competitively by diltiazem. The pA2 values for nifedipine antagonism of Bay k 8644 responses with the elevated K+ were the same between the basilar and mesenteric arteries. Increased sensitivity to exogenously added K+ also was observed in cerebral and coronary arteries when compared with the mesenteric artery. The addition of nifedipine to an unstimulated strip produced a dose-dependent relaxation in cerebral and coronary arteries, but not in the mesenteric artery. When the cerebral and peripheral arteries were contracted with K+ to the same magnitude, nifedipine produced similar relaxations among these arteries. Nifedipine was less efficacious in antagonizing the contractile response to Bay k 8644 compared with the contractile response to K+ in cerebral arteries. These results suggest that 1) the voltage-dependent Ca++ channels in the cerebral and coronary arteries are in different states of activation from those in the mesenteric artery, 2) Bay k 8644 contracts the cerebral and coronary arteries by acting primarily on the same site, presumably dihydropyridine receptors of the voltage-dependent Ca++ channels at which nifedipine acts, 3) the dihydropyridine receptors were the same between the basilar and mesenteric arteries and 4) there may be a difference in the state of the Ca++ channel in the arteries between the stimulation with Bay k 8644 and K+-depolarization.     

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.     

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.     

Antihypertensive effect of NKY-722, a new water-soluble 1,4-dihydropyridine derivative, on conscious spontaneously hypertensive rats

3-(4-Allyl-1-piperazinyl)-2,2-dimethylpropyl methyl 1,4-dihydro-2,6-dimethyl-4-(3-nitrophenyl)-3,5-pyridine dicarboxylate dihydrochloride (NKY-722) produced a dose-dependent antihypertensive effect in conscious spontaneously hypertensive rats (SHR). In this respect NKY-722 was more potent and longer-acting than nicardipine. In canine isolated mesenteric arteries, exposed to a Ca2+-free medium containing high K+, NKY-722 inhibited Ca2+-induced contraction in concentration-dependent manner, suggesting the calcium antagonism as the mechanism of action.     

ROLE OF ENDOTHELIUM ON PHENYLEPHRINE-TRIGGERED CONTRACTILE EVENTS IN AORTA OF SPONTANEOUSLY HYPERTENSIVE RATS

The ability of basal release of endothelium derived relaxing factor (EDRF) to alter contractile events in phenylephrine (PE)-triggered contraction was tested on ring segments of the thoracic aorta removed from spontaneously hypertensive rats (SHR) and normotensive Wistar-Kyoto rats (WKY). In normal medium, PE (1 microM) elicited similar whole contractions in endothelium denuded arteries of SHR and WKY. The presence of endothelium only reduced the WKY response. On aorta incubated in a Ca2+ free-medium, PE (1 microM) induced an initial phasic contraction due to intracellular Ca2+ release. This was followed by a tonic contraction after Ca2+ (2.5 mM) was restored to the bath. This sustained contraction was dependent on extracellular calcium influx. Identical phasic and tonic contractions were observed in endothelium denuded rings of SHR and WKY. However, the presence of endothelium only reduced the sustained contraction of WKY arteries. When experiments were carried out in medium containing D600 (1 microM), the presence of endothelium diminished the whole contraction of both SHR and WKY rings whereas the sustained but not the phasic contractions of WKY was also inhibited. This inhibitory effect of endothelium on WKY sustained contraction was significantly higher in the presence of D600. The calcium antagonist reduced both the whole and the tonic contractions of all preparations but was ineffective on the phasic one. The D600 inhibitory action on the sustained contraction was more pronounced in denuded SHR rings than in the corresponding WKY arteries. Thus it is concluded that there is a basal influence of endothelium in both SHR and WKY. Under our conditions, the endothelial function inhibited the extracellular Ca2+ influx and especially the part of Ca2+ influx insensitive to D600. This part of Ca2+ influx is diminished in SHR and thus the efficacy of endothelium products (e.g. EDRF) is reduced in this strain.     

Haemodynamic response following a 10% topload infusion of HemolinkTM in conscious, anaesthetized and treated spontaneously hypertensive rats

HemolinkTM (HLK), a haemoglobin-based oxygen carrier (HBOC), is currently undergoing Phase II/III clinical trials in surgical patients. It causes some blood pressure rise in animal and human tests. This study was designed to investigate the systemic haemodynamic response to HemolinkTM in spontaneously hypertensive rats (SHR rats). Conscious or anaesthetized SHR rats and control Wistar Kyoto rats (WKY rats) received either HemolinkTM or homologous plasma as a 10% topload infusion. Some awake animals were pretreated with nifedipine and followed by HLK infusion. In the conscious animal study, HLK induced a greater pressure rise and less bradycardia in SHR rats than in WKY rats. In the anaesthetized animal experiment, HLK-induced pressure rise and bradycardia were similar in both strains and less pronounced than in the conscious animals. In the nifedipine pretreated SHR rats, HLK-induced pressure rise was significantly smaller than that observed in nontreated SHR rats and was not different from that of nontreated WKY rats. The HLK-induced bradycardia was significantly smaller in nifedipine-treated animals than in the nontreated SHR or WKY rats. This study suggests that the pressor effect of HemolinkTM can be attenuated in hypertensive animals with general anaesthesia or treatment with antihypertensive agents.     

Hypotensive and diuretic actions of diltiazem in spontaneously hypertensive and Wistar Kyoto rats

We investigated the hypotensive and diuretic effects of diltiazem and hydralazine in conscious, spontaneously hypertensive rats (SHR) and their counterpart, Wistar Kyoto rats (WKY). Orally administered diltiazem induced dose-dependent hypotension both in SHR (10-60 mg/kg) and in WKY (30-100 mg/kg) and the effects were more pronounced in SHR than in WKY. Diltiazem did not cause tachycardia in either strain. Moreover, hypotensive doses of diltiazem acutely increased urinary excretion of sodium as well as urine volume in saline-loaded SHR and WKY. Chronic administration of diltiazem (30 mg/kg/day for 8 weeks) to young SHR caused no changes in body fluid distribution or in plasma sodium concentration. On the other hand, hydralazine not only showed almost the same hypotensive potency in SHR and WKY but also resulted reflex tachycardia in both strains. In addition, hydralazine (5 mg/kg) decreased urinary sodium excretion in saline-loaded SHR. In conclusion, it was suggested that diltiazem is an antihypertensive agent with an enhanced hypotensive action in the hypertensive state and without tachycardia and sodium retention effects.     

Autoradiographic study of smooth muscle cell proliferation in spontaneously hypertensive rats

1. The rate of smooth muscle cell proliferation in age-matched 1-4-week-old spontaneously hypertensive (SHR) and normotensive Wistar-Kyoto (WKY) rats was compared using autoradiography. 2. Labelling index, defined as labelled cells/sum of labelled and unlabelled cells x 1000, was obtained from perfusion-fixed superior mesenteric and large mesenteric arteries. 3. In the large mesenteric arteries, the smooth muscle cell labelling indices were similar between the SHR and WKY at all age groups, except at 1 week of age when the smooth muscle labelling index was higher in the SHR. 4. In the superior mesenteric arteries, labelling indices were similar between the rat strains at all age groups. 5. We conclude that, in the SHR, a rapid proliferation of smooth muscle cells in the large mesenteric arteries occurred during the first week of life. This resulted in a higher number of smooth muscle cell layers in the media of muscular arteries. 6. The increased proliferation may play a role in the subsequent development of hypertension in the SHR.     

Erythrocyte membrane calcium adenosine 5'-triphosphatase activity in the spontaneously hypertensive rat

1. Ca2+-adenosine 5'-triphosphatase (Ca2+-Mg2+-ATPase) activity was studied simultaneously in calmodulin-deficient erythrocyte ghost membranes and inside-out vesicles (IOVs) from 12-week-old female spontaneously hypertensive rats (SHR) and their matched controls: [Wistar-Kyoto normotensive rats (WKY)], and in detergent extracts of ghost membranes. 2. Both adenosine 5'-triphosphate (ATP)-dependent Ca2+ uptake by IOVs and Ca2+-dependent ATP hydrolysis activity of ghost membranes were reduced significantly in the SHR compared with WKY, when either the calmodulin-independent or calmodulin-stimulated activities were compared. 3. The ratios between Ca2+ uptake and ATP hydrolysis activities in the SHR remained approximately 1.0, showing a proportional reduction in both activities. 4. No difference in affinity for calmodulin was observed between SHR and WKY. 5. No significant difference in Ca2+-dependent ATP hydrolysis activity was observed between SHR and WKY after detergent solubilization of erythrocyte ghost membranes. 6. These results suggest that the number of Ca2+-Mg2+-ATPase units are similar in SHR and WKY and that the reduced activity in the intact SHR membrane is due to altered membrane environment.     

Enhanced in vivo responsiveness of presynaptic angiotensin II receptor-mediated facilitation of vascular adrenergic neurotransmission in spontaneously hypertensive rats

Presynaptic angiotensin II (AII) receptor-mediated facilitation of vascular adrenergic neurotransmission was studied in the in situ, blood-perfused mesentery of 13- to 16-week-old spontaneously hypertensive rats (SHR) and age-matched normotensive Wistar Kyoto rats (WKY). Mesenteric arterial perfusion pressure frequency-response curves to periarterial adrenergic nerve stimulation (PNS) and dose-response curves to exogenous norepinephrine (NE) were obtained in SHR and WKY. The effects of the following treatments on the mesenteric vascular perfusion pressure responses (PPR) to PNS and NE were studied: All alone infused i.a. at 1 and 5 ng/min; All infused at 5 ng/min after [Sar1-lle8]All infused at 20 ng/min; [Sar1-lle8]All infused at 20 ng/min alone; captopril alone at 0.1 mg/kg i.v.; All infused i.a. at 0.3 and 1 ng/min after captopril at 0.1 mg/kg and angiotensin I injected at 3 dose levels after captopril at 0.1 mg/kg. Control PPR to PNS and NE were greater in SHR than in WKY. Comparisons of PPR in SHR to those in WKY were made, therefore, at the predetermined PPR levels of 15, 20, 30, 40, 50, 60 and 70 mm Hg. All alone shifted the PNS frequency-response curve to the left to a greater extent in the SHR than in the WKY when infused at 5 ng/min but not when infused at 1 ng/min. Both infusion rates of All had significantly different effects on the dose-response curves to NE in WKY and SHR. The effects of All infusion (5 ng/min) on both the response to PNS and to NE were antagonized completely by the concurrent infusion of [Sar1-lle8] All at 20 ng/min.(ABSTRACT TRUNCATED AT 250 WORDS)     

Toll-like receptor 4 contributes to blood pressure regulation and vascular contraction in spontaneously hypertensive rats

Activation of TLRs (Toll-like receptors) induces gene expression of proteins involved in the immune system response. TLR4 has been implicated in the development and progression of CVDs (cardio-vascular diseases). Innate and adaptive immunity contribute to hypertension-associated end-organ damage, although the mechanism by which this occurs remains unclear. In the present study, we hypothesize that inhibition of TLR4 decreases BP (blood pressure) and improves vascular contractility in resistance arteries from SHR (spontaneously hypertensive rats). TLR4 protein expression in mesenteric resistance arteries was higher in 15-week-old SHR than in age-matched Wistar controls or in 5-week-old SHR. To decrease the activation of TLR4, 15-week-old SHR and Wistar rats were treated with anti-TLR4 (anti-TLR4 antibody) or non-specific IgG control antibody for 15 days (1 μg per day, intraperitoneal). Treatment with anti-TLR4 decreased MAP (mean arterial pressure) as well as TLR4 protein expression in mesenteric resistance arteries and IL-6 (interleukin 6) serum levels from SHR when compared with SHR treated with IgG. No changes in these parameters were found in treated Wistar control rats. Mesenteric resistance arteries from anti-TLR4-treated SHR exhibited decreased maximal contractile response to NA (noradrenaline) compared with IgG-treated SHR. Inhibition of COX (cyclo-oxygenase)-1 and COX-2, enzymes related to inflammatory pathways, decreased NA responses only in mesenteric resistance arteries of SHR treated with IgG. COX-2 expression and TXA2 (thromboxane A2) release were decreased in SHR treated with anti-TLR4 compared with IgG-treated SHR. Our results suggest that TLR4 activation contributes to increased BP, low-grade inflammation and plays a role in the augmented vascular contractility displayed by SHR.     

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.     

Y-27152, a long-acting K+ channel opener with less tachycardia: antihypertensive effects in hypertensive rats and dogs in conscious state.

(+)-(3S,4R)-4-(N-Acetyl-N-benzyloxyamino)-6-cyano-3,4-dihydro-2,2- dimethyl- 2H-1-benzopyran-3-ol (Y-27152) is a new K+ channel opener with a long duration of action and less tachycardia. In this study, Y-27152 was compared with a K+ channel opener lemakalim and a Ca++ channel blocker nifedipine for antihypertensive activity in conscious spontaneously hypertensive rats (SHR) and two-kidney, one-clip renal hypertensive dogs (RHD). In conscious SHR, Y-27152 (0.1-1 mg/kg, p.o.) produced long-lasting dose-related decreases in systolic blood pressure. At 1 mg/kg, the maximum response occurred 5 to 7 hr after dosing, and 24 hr later, the pressure was still significantly reduced. Heart rate was not changed by these doses of Y-27152, whereas equihypotensive doses of lemakalim or nifedipine were strongly tachycardic. The cardiovascular effects of Y-27152 were antagonized by glibenclamide (20 mg/kg, i.v.). In conscious unrestrained RHD, Y-27152 at doses of 0.01, 0.03 and 0.1 mg/kg lowered blood pressure with a slow onset and long duration of action and had only a minimal effect on heart rate, whereas both lemakalim and nifedipine reduced blood pressure and markedly increased heart rate. No tolerance to the antihypertensive effect of Y-27152 (0.1 mg/kg) occurred during an 8-week repeated daily dosing to RHD and plasma renin activity, and aldosterone levels were not elevated during this period. In rat aortic rings contracted with 20 mM KCl, Y-27152 did not modify the tension; however, its desbenzyl form (Y-26763) produced vasorelaxation, and this effect was antagonized competitively by glibenclamide.(ABSTRACT TRUNCATED AT 250 WORDS)     

RNA干扰GPR14对自发性高血压大鼠血压和心血管重构的影响

目的观察RNA干扰技术下调尾加压素Ⅱ(UⅡ)特异性受体G蛋白偶联受体14(GPR14)对自发性高血压大鼠(SHR)血压和心血管重构的影响。方法 SHR或Wistar-Kyoto(WKY)大鼠均随机分为两组:裸病毒(Ad)对照组和Ad-GPR14-shRNA治疗组,分别尾静脉注射对照Ad和表达GPR14基因特异短发夹RNA(shRNA)的重组腺病毒载体Ad-GPR14-shRNA。注射前1周和注射后0、1、2、3、4周检测心脏、胸主动脉GPR14表达情况和尾动脉压变化情况。检测注射后2周心脏、胸主动脉和肠系膜上动脉组织病理学。结果 Ad-GPR14-shRNA注射后1周即显著降低WKY大鼠和SHR心脏、胸主动脉GPR14表达和尾动脉压,该效果可持续至第4周,2周时最明显,并且SHR大鼠降低更显著;Ad-GPR14-shRNA治疗2周时SHR组左心重/体质量显著下降、心肌细胞横断面积显著减少、心肌纤维化显著减弱、主动脉和肠系膜上动脉中膜厚度/官腔内径比值显著下降。结论 RNA干扰能有效降低心肌和血管GPR14表达,降低SHR血压并改善心血管重构,靶向GPR14的RNA干扰有望成为高血压病基因治疗的有效方法。     

Relationship between noradrenaline and nonlinear indexes of blood pressure dynamics in normotensive and spontaneously hypertensive rats

Recent studies in normotensive Wistar-Kyoto (WKY) and spontaneously hypertensive (SHR) rats show that some nonlinear indexes derived from the recurrence plot method may be better markers of sympathetic activity than the spectral powers of blood pressure (BP). We herein investigated the relationships between nonlinear indexes and plasma noradrenaline concentration in conscious WKY rats and SHRs. Blood pressure was recorded for 30 min after intravenous injection of saline (0.9% NaCl, 100 microL/kg), hexamethonium (20 mg/kg), atropine (0.5 mg/kg), atenolol (1 mg/kg) or prazosin (1 mg/kg). Spectral power in the low-frequency (LF) band and the nonlinear index (L(max)), calculated on diastolic (DBP) and systolic blood pressures (SBP), were used to analyse the BP signal. Noradrenaline concentration was determined by radioenzymatic technique. A robust stepwise regression analysis - using noradrenaline concentration as dependent variable, and LF, L(max) and treatment, as independent variables -shows that treatment is the main variable explaining the variance of noradrenaline level in WKY rats, excluding the use of the pooled data to explore the relationship between noradrenaline concentration and LF or L(max). In contrast, in SHRs, treatment has no effect on the variance of noradrenaline concentration and the pooled data were then used. In this group, no correlation was observed between noradrenaline concentration and LF. In contrast, very high positive correlation was observed between noradrenaline level and L(max)-DBP (r = 0.59; P = 0.0005) or L(max)-SBP (r = 0.53; P < 0.002). The results strengthen our previous suggestion that nonlinear indexes may be better tools than spectral powers to investigate the sympathetic nervous system.     

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.     

Vasopressin-mediated contractions in mesenteric arteries from spontaneously hypertensive rats: differences in response compared with Wistar-Kyoto animals

1. The sensitivity of mesenteric resistance arterioles to [arginine]vasopressin (AVP) was investigated in spontaneously hypertensive rats (SHR) and control Wistar-Kyoto rats (WKY). No difference in pAVP (-log dose of AVP producing 50% of the maximum response) was observed [SHR 0.21 +/- 0.03 m-units/ml (n = 10) vs WKY 0.15 +/- 0.06 m-units/ml (n = 9)], although SHR vessels exhibited greater absolute tension development. 2. Both strains of rat displayed tachyphylaxis to repeated stimulation with AVP, and oscillatory tension changes were observed in all vessels from SHR and rarely in WKY vessels at activating concentrations of AVP. 3. AVP did not elicit a contractile response after noradrenaline-induced calcium depletion. 4. After vessels were depleted of calcium by using a combination of calcium-free media and noradrenaline stimulation, restoration of calcium in the presence of AVP elicited a greater contractile response in SHR vessels. 5. The results therefore provide evidence for an increased calcium response to AVP in SHR resistance vessels, although this was only demonstrable by calcium recovery experiments.     

Role of endothelium on the effects of neuropeptide Y in mesenteric resistance arteries of spontaneously hypertensive and Wistar-Kyoto normotensive rats

The role of the endothelium in the effects of neuropeptide Y (NPY) and norepinephrine was investigated in mesenteric resistance arteries of the spontaneously hypertensive rat (SHR) and of the normotensive Wistar-Kyoto rat (WKY). Endothelium-dependent relaxation to acetylcholine (1 microM) was reduced in arteries of SHR compared with WKY. In the presence of the endothelium, the vessels of the two strains responded similarly to norepinephrine and NPY (100 nM) produced only a slight contraction. After removal of the endothelium, the response to norepinephrine was greater in WKY than in SHR. Furthermore, endothelium denudation enhanced markedly contraction elicited by NPY in WKY (up to 40% of the maximal effect of norepinephrine), but not in SHR. NPY potentiated the contractile response to low concentrations of norepinephrine (less than 300 nM) in both strains regardless whether the endothelium was intact or not. These results indicate that the contractile responses to NPY and to norepinephrine are inhibited by the endothelium in vessels of WKY, but not in those of the SHR. Furthermore, the potentiating effect of NPY occurs via an endothelium-independent mechanism in mesenteric arteries of both SHR and WKY. It is proposed that the differential responses between the two strains are related to abnormal function of the endothelium and to decreased responsiveness of smooth muscle cells in mesenteric resistance arteries of SHR compared to WKY.