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.     

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.     

Role of cyclic AMP protein kinase in decreased arterial cyclic AMP responsiveness in hypertension

A decreased relaxation responsiveness to isoproterenol and forskolin is manifest in aortic smooth muscle isolated from spontaneously hypertensive rats (SHR) when compared with normotensive Wistar Kyoto (WKY) rats. Inasmuch as the effector of cyclic AMP (cAMP) is cAMP-dependent protein kinase, we sought to determine if alterations in this enzyme might be responsible for this decreased responsiveness to cAMP-increasing vasodilators. The concentration of cAMP protein kinase activity in aortic, carotid and caudal arteries (approximately 300 pmol/mg of protein per min) was similar in both WKY and SHR. Activity in femoral arteries from SHR and WKY rats was greater (approximately 600 pmol/mg/min); branches of the femoral artery from SHR had less protein kinase activity (660 pmol/mg/min) than their WKY counterparts (1000 pmol/mg/min). There were no differences between WKY and SHR in isozymic distribution of soluble cAMP protein kinase in any of these sources of arterial smooth muscle. Concentration and temporal-related relaxation of KCl-contracted aortic muscle strips by forskolin was associated with concomitant activation of cAMP protein kinase in both groups. The rate and extent of kinase activation was similar for both groups even though the rate and extent of relaxation was markedly less in SHR. These findings show that neither the concentration, isozymic distribution nor activation of cAMP-dependent protein kinase are different in aortic smooth muscle isolated from SHR when compared with WKY animals. Thus, decreased relaxation responsiveness to cAMP-increasing vasodilators is probably not related to events proximal to and including activation of arterial cAMP-dependent protein kinase.     

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.     

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。     

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.     

Decreased membrane fluidity of erythrocytes and cultured vascular smooth muscle cells in spontaneously hypertensive rats: an electron spin resonance study

1. Membrane fluidity of erythrocytes and cultured vascular smooth muscle cells was studied in spontaneously hypertensive rats (SHR; Okamoto and Aoki strains) by means of an electron spin resonance (e.s.r.) and a spin-label technique. 2. The values of outer hyperfine splitting (2T') and of the order parameter (S) determined from e.s.r. spectra for a fatty acid spin-label agent (5-nitroxy stearate) were significantly higher in erythrocytes of SHR (4 and 10-13 weeks of age) than in those of age-matched Wistar-Kyoto rats (WKY). This finding suggests that the membrane fluidity of erythrocytes might be decreased in SHR. 3. The fluidity of cultured vascular smooth muscle cells obtained from 10-13-week-old SHR was also reduced compared with that from WKY. 4. These results suggest that the decreased membrane fluidity might be a genetically determined abnormality of the cell membranes in SHR.     

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)     

Acute and chronic captopril, but not prazosin or nifedipine, normalize alterations in adrenergic intracellular Ca2+ handling observed in the mesenteric arterial tree of spontaneously hypertensive rats

The effect of hypertension and acute (36-h) or chronic (from age 6 to 16 weeks) antihypertensive treatment with prazosin (2 mg kg(-1) per day), nifedipine (50 mg kg(-1) per day), or captopril (50 mg kg(-1) per day) on Ca2+ mobilization due to alpha1-adrenoceptor activation was analyzed in functional studies using arterial rings [four conductance/distributing vessels: aorta, main mesenteric, iliac, and tail arteries and two resistance vessels; first and second small mesenteric artery branches obtained from spontaneously hypertensive rats (SHR, 6 and 16 weeks old) and age-matched Wistar Kyoto rats (WKY)]. Maximal response to noradrenaline in the presence of extracellular Ca2+ is not affected by hypertension or by the antihypertensive treatment. The extracellular Ca2+-independent contractile responses increased with age in iliac, tail, and small mesenteric arteries (SMA) and were further increased in SHR in SMA from both young and adult animals and in the main mesenteric artery of adult SHR. In main mesenteric artery, this increased contraction in SHR was associated with a higher increase in cytosolic [Ca2+] mobilized by noradrenaline without changes in the total stored Ca2+. Acute or chronic treatment with captopril abolished the differences observed between WKY and SHR in the noradrenaline-induced contraction in mesenteric arteries loaded in Ca2+-free medium. In contrast, animals acutely treated with prazosin or chronically treated with either prazosin or nifedipine exhibit the same differences in Ca2+ handling than untreated rats. In conclusion, these differences are not a consequence of increased blood pressure but precede it and can only be normalized by inhibition of the rennin-angiotensin system.     

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)     

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)     

Age-dependent increase in arterial smooth muscle calcium in spontaneously hypertensive rats

Alterations in cellular calcium metabolism in essential hypertensive and in the SHR have been described. In the present study, particle-induced X-ray emission (PIXE) was used to get some information on the spatial distribution of Ca2+ in aortas of spontaneously hypertensive rats (SHR) and normotensive controls aged 1 week, 4 weeks, and 12 weeks. It was found that the Ca2+ content was not elevated in the aortic smooth muscle of SHR aged 1 week (n = 9) as compared to normotensive controls (n = 8) (186.8 +/- 89.9 micrograms Ca2+/g tissue vs 254.0 +/- 73.7 micrograms Ca2+/g tissue. The Ca2+ content was significantly raised in the aortic smooth muscle of SHR aged 4 weeks (n = 9) as compared to 4-weeks-old WKY rats (n = 12) (726.0 +/- 130.4 Ca2+/g tissue vs 440.3 +/- 214.4 Ca2+ micrograms/g tissue and in SHR aged 3 months (n = 15) as compared to WKY rats (n = 12), respectively (3317.0 +/- 734.0 micrograms Ca2+/g tissue vs. 1632.0 +/- 569.6 micrograms Ca2+/g tissue). The results confirm the age-related increase in the arterial Ca2+ content in normotensive rats and demonstrate additionally that this age-related rise in arterial Ca2+ content is accelerated in SHR.     

Endothelial modulation of vascular relaxation to nitrovasodilators in aging and hypertension

Blood vessel responses to relaxant drugs have been reported to change with aging and with the development of hypertension. In view of the requirement of endothelial cells for the activity of many relaxant drugs, we examined the role of the endothelium in the relaxation response of vascular tissue. Aortic and mesenteric ring segments from normotensive and hypertensive rats, ages 5 to 6, 15 to 18 and 30 to 31 weeks, were examined for relaxation to sodium nitroprusside, sodium nitrite, atrial natriuretic factor and 8-bromo-cyclic GMP. Relaxation responses to the nitrovasodilators were reduced progressively with aging in ring segments of Wistar-Kyoto rats (WKYs) and spontaneously hypertensive rats (SHRs) with intact endothelium; however, intact SHR ring preparations displayed less relaxation to nitrovasodilators at 15 to 18 and 30 to 31 weeks than those of WKYs. Rubbed (endothelium denuded) ring preparations displayed greatest relaxation to nitrovasodilators with no difference being observed between SHR and WKY preparations at any age tested. Relaxation to atrial natriuretic factor and 8-bromo-cyclic GMP was not different between rubbed and unrubbed ring segments or between SHRs and WKYs, indicating no detectable impairment of the overall relaxation response in the vascular smooth muscle of SHRs. These results suggest that the total functional capacity of vascular smooth muscle to relax to nitrovasodilators is not changed with aging or hypertension. However, the endothelial cells exert modulatory influences upon the vascular smooth muscle to reduce overall responsiveness to nitrovasodilators, an effect that is enhanced with aging and the development of genetic hypertension.     

Influence of experimental reduction of media/lumen ratio on arterial myogenic properties of spontaneously hypertensive and Wistar-Kyoto rats

In the present study, myogenic properties of femoral arteries from control hindlimbs and those distal to external iliac artery partial ligation of spontaneously hypertensive rats (SHRs) and normotensive Wistar-Kyoto (WKY) rats were assessed. Arterial pressure was reduced distal to the ligature in both strains. Media thickness/lumen diameter (M/L) ratios of control (unligatured) SHRs were greater than in unligatured WKY rats and were reduced in arteries distal to the ligature (ligatured) within each strain. In none of the comparisons was a greater M/L ratio associated with greater maximal myogenic contractions, but increased M/L ratios were associated with a shift of myogenic activity to a higher pressure range in all comparisons. SHR ligatured arteries produced greater pressure-dependent contractile responses than WKY rat unligatured arteries, although arterial structures were not significantly different. Wall stress was similar in all arteries within the 60-120 mmHg pressure range with myogenic tone in spite of large differences in arterial structure. The utilization of arteries with experimentally altered structure provides further evidence that increased M/L ratios are not associated with greater peak pressure-dependent contractile responses and that arterial wall stress is maintained within a narrow range through an interaction between arterial wall geometry and smooth muscle contractile function.     

Enhanced slow-pressor response to angiotensin II in spontaneously hypertensive rats

Rapid-pressor and slow-pressor responses to angiotensin (ANG) II and norepinephrine (NE) in spontaneously hypertensive rats (SHR) and Wistar Kyoto control rats (WKY) were examined. All animals were treated from 4 wk of age with captopril (100 mg/kg/day in drinking water) to prevent development of hypertension so that changes in responsiveness could not be attributed to disparate base-line blood pressures or to hypertension-induced injury of the cardiovascular system. In 11-wk, conscious, unrestrained, captopril-treated rats, ANG II and NE induced rapid-pressor responses (i.e., a rapid increase in arterial blood pressure that reached a maximum within 10 min) that were of similar magnitude in SHR and WKY. In an additional group of 9-wk captopril-treated rats, both ANG II and NE caused slow-pressor responses (i.e., a slow increase in arterial blood pressure over 2 wk). Although the slow-pressor response to NE was similar in SHR versus WKY, the slow-pressor response to ANG II was much greater in SHR compared with WKY. Further studies were conducted in captopril-treated (from 4 wk of age) SHR and WKY to investigate whether the increased slow-pressor response to ANG II in SHR was mediated by an enhanced ability of ANG II to potentiate peripheral sympathetic neurotransmission, contract vascular smooth muscle, increase sympathetic tone to nonadrenal sites, release aldosterone, and/or reduce renal function. No evidence was found that supported a role for the aforementioned nonrenal actions of ANG II. However, 11-wk captopril-treated SHR were 10-fold more sensitive to the antidiuretic, antinatriuretic, and renal vascular effects of intrarenal infusions of ANG II compared with captopril-treated WKY. Also, chronic (1 wk) intrarenal infusions of a very low dose of ANG II (1 ng/min) caused a marked slow-pressor response in 11-wk captopril-treated SHR but did not alter arterial blood pressure in WKY. We conclude that 1) the slow-pressor response to ANG II is greatly enhanced in SHR, 2) this enhancement is specific with respect to type of response (slow not rapid) and pressor agent (ANG II not NE), 3) a genetic defect underlies the increased slow-pressor response to ANG II in SHR, and 4) the enhanced slow-pressor response to ANG II contributes significantly to the pathophysiology of hypertension in SHR. Finally, the current studies are consistent with our working hypothesis that the kidneys mediate the enhanced slow-pressor response to ANG II in SHR.     

Effects of propranolol and yohimbine on periarterial nerve stimulation-induced release of endogenous norepinephrine from the mesenteric vasculature of Wistar Kyoto and spontaneously hypertensive rats

The overflow of endogenous norepinephrine (NE) from the mesenteric vasculature of the isolated mesentery of Wistar Kyoto rats (WKY) and spontaneously hypertensive rats (SHR) was determined in response to periarterial nerve stimulation (PNS) before and after pretreatment with propranolol or yohimbine. Propranolol pretreatment did not significantly alter spontaneous NE overflow, total NE overflow, NE overflow/stimulus or fractional NE overflow in either WKY or SHR mesenteric vascular preparations at any of the PNS frequencies used. Yohimbine pretreatment did not significantly alter spontaneous NE overflow but did significantly increase total NE overflow, NE overflow/stimulus and fractional NE overflow at all PNS frequencies used in both WKY and SHR preparations. The magnitude of the effect of yohimbine on NE overflow/stimulus did not differ between WKY and SHR over the range of PNS frequencies used. The lack of effect of propranolol on NE overflow suggests that corelease of epinephrine is not sufficient to activate beta adrenergic receptor-mediated modulation of noradrenergic neurotransmission in either WKY or SHR mesenteric vascular preparations under the in vitro study conditions used. However, the effects of yohimbine indicate that prejunctional alpha-2 adrenergic receptor-mediated inhibition of noradrenergic neurotransmission is operative in both WKY and SHR mesenteric vascular preparations. These effects of yohimbine also suggest that no significant differences exist between the functional level of prejunctional alpha-2 adrenergic receptor-mediated autoinhibitory modulation of noradrenergic neurotransmission in mesenteric vascular preparations from adult WKY and SHR under the in vitro study conditions used.     

Left ventricular diastolic function of spontaneously hypertensive rats and its relationship to structural components of the left ventricle

Left ventricular (LV) diastolic function was investigated in three different age groups (15, 28 and 50 weeks) of paired spontaneously hypertensive (SHR) and normotensive (WKY) rats under pentobarbital anaesthesia. A time constant of LV pressure decay, represented by T, was used as an index of LV relaxation. We assessed the relationship between haemodynamic parameters and LV structural components as quantified by microspectrophotometry (MSP), using multivariate analysis. T was significantly prolonged in the 28 and 50 week old SHR compared with their normotensive counterparts (P less than 0.05 and P less than 0.01, respectively). T was prolonged by volume loading but was not affected with afterload elevation by angiotensin infusion in all age groups of the SHR and WKY. LV wall thickness was greater in the SHR at all ages and was positively correlated with T (r = 0.42, P less than 0.05). A significant correlation was found between the increase in cardiac muscle fibre and collagen, the decrease in elastin and glycoprotein, and T on multivariate analysis (r = 0.53, P less than 0.05). We conclude that LV relaxation of SHR is disturbed from a relatively young age (28 weeks), for which we consider myocardial hypertrophy and LV structural changes found by MSP as being responsible.