Chronic losartan treatment decreases angiotensin II-mediated facilitation of noradrenaline release in the caudal artery of spontaneously hypertensive rats

Sympathetic activity is modulated by angiotensin II (AII), both at pre- and postsynaptic level in the rat caudal artery. In the spontaneously hypertensive rat (SHR), this artery receives more dense sympathetic innervation than blood vessels of normotensive strains. This fact seems to be linked to the enhanced pressor responses elicited by noradrenaline in SHR. In this work we describe, in the SHR, the effect of a chronic treatment with the angiotensin II AT1-receptor antagonist, losartan, in modulating noradrenergic mechanisms involved in caudal artery contraction. The effect of losartan is compared to that of captopril, given at doses leading to a similar decrease of both arterial blood pressure and left ventricular hypertrophy. The contractile response of caudal artery rings induced by endogenous noradrenaline released by low frequency transmural nerve stimulation (TNS) has been studied. Under our conditions, TNS (0.5-1 Hz) induced higher contractile responses in SHR treated with losartan than in the control and captopril-treated groups. This difference seems to be due to an increase of the postsynaptic effect of noradrenaline (NA) rather than to an increase of noradrenaline release from sympathetic endings, since i) DE50 value for NA was lower in losartan-treated SHR than in the other groups, and ii) AII induced a dose-dependent increase of TNS-evoked release of radioactivity from caudal artery segments loaded with [3H]-NA, in both control and captopril-treated groups but had no effect in the losartan-treated group. These results show that chronic treatment with losartan, although slightly enhancing the pressor effect of NA at postsynaptic level, fully supresses the facilitatory role of AII on NA release.     

Chronic and acute effects of different antihypertensive drugs on femoral artery relaxation of L-NAME hypertensive rats

We aimed to compare the effects of chronic and acute administration of structurally different antihypertensives, diuretics - indapamide and hydrochlorothiazide, ACE inhibitor - captopril and indapamide+captopril combination on endothelium-dependent relaxation of femoral artery isolated from nitric oxide (NO)-deficient rats. In the chronic experiment, femoral artery was isolated from Wistar rats receiving L-NAME (40 mg/kg/day) solely or with indapamide (1 mg/kg/day), hydrochlorothiazide (10 mg/kg/day), captopril (10 mg/kg/day), and indapamide+captopril combination for seven weeks. In the acute in vitro experiment, the incubation medium with femoral artery isolated from L-NAME-hypertensive rats was supplemented with investigated antihypertensives in the same concentration 10(-4) mol/l. Interestingly, chronic L-NAME treatment did not cause a reduction of vasorelaxation. Indapamide+captopril elevated relaxation above the control level and completely prevented blood pressure increase induced by L-NAME. Acute incubation with captopril only or indapamide+captopril improved relaxation of femoral artery isolated from L-NAME-hypertensive rats, while the incubation with all antihypertensives increased vasorelaxation of femoral artery isolated from control Wistar rats. In conclusion, NO might be involved in the indapamide- and hydrochlorothiazide-induced improvement of vasorelaxation, while different vasorelaxing factors (prostacyclin, EDHF) contribute to the captopril-induced improvement of vasorelaxation. During the chronic treatment additive and synergic effects of indapamide and captopril may contribute to the prevention of hypertension and increase of vasorelaxation.     

Histamine-induced relaxation in pulmonary artery of normotensive and hypertensive rats: relative contribution of prostanoids, nitric oxide and hyperpolarization

The aim of this study was to determine the relative contribution of nitric oxide (NO), endothelium-derived hyperpolarizing factor (EDHF) and prostanoids in histamine-induced relaxation of isolated pulmonary artery from normotensive and hypertensive rats. The hypertension was induced by oral administration of NO synthase inhibitor N(G)-nitro-L-arginine methylester (L-NAME, 50 mg/kg/day) to normotensive rats for 8 weeks. In phenylephrine-precontracted arterial rings the histamine-induced relaxation was significantly reduced in L-NAME-treated rats compared to the controls. Indomethacin (cyclooxygenase inhibitor) and glibenclamide (ATP-sensitive K+-channel blocker) did not inhibit the relaxation response in either control or hypertensive rats. On the other hand, tetraethylammonium (TEA), a K+-channel blocker with a broad specificity, significantly reduced histamine-induced relaxation in the pulmonary artery from both groups examined. The TEA-resistant relaxation was completely abolished by additional administration of L-NAME to the incubation medium. The results indicate that histamine-induced relaxation of the pulmonary artery in both normotensive and hypertensive rats is mediated mainly by nitric oxide, whereas EDHF seems to play a minor role.     

Chronic exercise alters caudal hypothalamic regulation of the cardiovascular system in hypertensive rats

Previous studies have documented a deficit in the GABA neurotransmitter system within the caudal hypothalamus (CH) of spontaneously hypertensive rats (SHR). The reduction in inhibitory influence on this cardiovascular excitatory brain region is associated with an increased neuronal activity and resting blood pressure. The purpose of this study was to determine if chronic treadmill and wheel-running activities alter the ability of the CH to regulate cardiovascular function. SHR were exercised on a treadmill (5 times/wk) at moderate intensity or allowed free access to running wheels (7 days/wk) for a period of 10 wk. Resting blood pressures were obtained before and after the exercise training periods. After the exercise period, rats were anesthetized and microinjection experiments were performed. Treadmill-trained SHR exhibited a significantly blunted developmental rise in resting blood pressure after 10 wk of exercise. A similar yet less marked effect was observed in wheel-run rats. Microinjection of the GABA synthesis inhibitor 3-mercaptopropionic acid (3-MP) into the CH of nonexercised SHR did not produce any change in arterial pressure. In contrast, microinjection of 3-MP into the CH produced significant increases in blood pressure and heart rate in exercised SHR. These results demonstrate that exercise training can alter CH cardiovascular regulation in hypertensive rats and therefore may play a role in increasing cardiovascular health.     

Impaired UTP-induced relaxation in the carotid arteries of spontaneously hypertensive rats

Uridine 5′-triphosphate (UTP) has an important role as an extracellular signaling molecule that regulates inflammation, angiogenesis, and vascular tone. While chronic hypertension has been shown to promote alterations in arterial vascular tone regulation, carotid artery responses to UTP under hypertensive conditions have remained unclear. The present study investigated carotid artery responses to UTP in spontaneously hypertensive rats (SHR) and control Wistar Kyoto rats (WKY). Accordingly, our results found that although UTP promotes concentration-dependent relaxation in isolated carotid artery segments from both SHR and WKY after pretreatment with phenylephrine, SHR exhibited significantly lower arterial relaxation responses compared with WKY. Moreover, UTP-induced relaxation was substantially reduced by endothelial denudation and by the nitric oxide (NO) synthase inhibitor N^G-nitro-L-arginine in both SHR and WKY. The difference in UTP-induced relaxation between both groups was abolished by the selective P2Y₂ receptor antagonist AR-C118925XX and the cyclooxygenase (COX) inhibitor indomethacin but not by the thromboxane-prostanoid receptor antagonist SQ29548. Furthermore, we detected the release of PGE₂, PGF_2α, and PGI₂ in the carotid arteries of SHR and WKY, both at baseline and in response to UTP. UTP administration also increased TXA₂ levels in WKY but not SHR. Overall, our results suggest that UTP-induced relaxation in carotid arteries is impaired in SHR perhaps due to impaired P2Y₂ receptor signaling, reductions in endothelial NO, and increases in the levels of COX-derived vasoconstrictor prostanoids.

     

Cerebral artery responses to pressure and flow in uremic hypertensive and spontaneously hypertensive rats

Impaired cerebral blood flow autoregulation is seen in uremic hypertension, whereas in nonuremic hypertension autoregulation is shifted toward higher perfusion pressure. The cerebral artery constricts in response to a rise in either lumen pressure or flow; we examined these responses in isolated middle cerebral artery segments from uremic Wistar-Kyoto rats (WKYU), normotensive control rats (WKYC), and spontaneously hypertensive rats (SHR). Pressure-induced (myogenic) constriction developed at 100 mmHg; lumen flow was then increased in steps from 0 to 98 microl/min. Some vessels were studied after endothelium ablation. Myogenic constriction was significantly lower in WKYU (28 +/- 2.9%) compared with both WKYC (39 +/- 2.5%, P = 0.035) and SHR (40 +/- 3.1%, P = 0.018). Flow caused constriction of arteries from all groups in an endothelium-independent manner. The response to flow was similar in WKYU and WKYC, whereas SHR displayed increased constriction compared with WKYU (P < 0.001) and WKYC (P < 0.001). We conclude that cerebral myogenic constriction is decreased in WKYU, whereas flow-induced constriction is enhanced in SHR.     

Elevated vertebrobasilar artery resistance in neonatal spontaneously hypertensive rats

Erythropoietin (Epo) is produced primarily in the kidneys upon low blood oxygen availability and stimulates erythropoiesis in the bone marrow. Recombinant human Epo (rHuEpo), a drug developed to increase arterial oxygen content in patients, is also illicitly used by athletes to improve their endurance performance. Therefore, a robust and sensitive test to detect its abuse is needed. The aim of the present study was to investigate potential human serum biomarkers of Epo abuse employing a proteomic approach. Eight healthy male subjects were injected subcutaneously with rHuEpo (5,000 IU) every second day for a 16-day period. Serum was collected before starting the treatment regime and again at days 8 and 16 during the treatment period. Samples were homogenized and proteins separated by two-dimensional gel electrophoresis (2DE). Spots that changed significantly in response to rHuEpo treatment were identified by mass spectrometry. Both the number of reticulocytes and erythrocytes increased throughout the study, leading to a significant increase in hematocrit and hemoglobin content. In addition, transferrin levels increased but the percentage of iron bound to transferrin and ferritin levels decreased. Out of 97 serum proteins, seven were found to decrease significantly at day 16 compared with pre-Epo administration, and were identified as four isoforms of haptoglobin, two isoforms of transferrin, and a mixture of hemopexin and albumin. In support, total serum haptoglobin levels were found to be significantly decreased at both days 8 and 16. Thus a 2DE proteomic approach for discovery of novel markers of Epo action appears feasible.     

Placentas from spontaneously hypertensive rats and control strain Wistar-Kyoto rats

Placentas from spontaneously hypertensive rats (SHR) were compared to those of control strain Wistar-Kyoto rats (WKY) at 15, 18 and 20 days of gestation using light microscopic techniques. Placental lesions similar to those in pregnant hypertensive women were absent in both strains; however, other abnormalities were noted. Hemorrhage at the lateral edges of the decidua basalis appeared to be more extensive in the SHR than WKY at 15 days. At the same time, bloody vaginal discharges were noted in 18% of the SHR. Leukocytic encapsulation of 20-day placentas with viable fetuses was noted in two SHR dams but not in any WKY. It is thought that these differences may be related to the high maternal blood pressure in the SHR or to hormonal imbalance associated with the stress response in the SHR due to frequent monitoring of blood pressure.     

Age-dependent ultrastructural changes of coronary artery in spontaneously hypertensive rats

The age-dependent differences in basic cardiovascular parameters, geometry and structure of coronary arteries between Wistar and spontaneously hypertensive rats (SHR) were evaluated. SHR of the age 3-, 9-, 17-, and 52-week and age-matched Wistar rats were used. Blood pressure (BP) was measured by the plethysmographic method. Animals were perfused with a glutaraldehyde fixative under pressure of 90 mmHg (3-week-old) and 120 mmHg (9-, 17-, 52-week-old). Coronary arteries were processed for electron microscopy. The proportions and cross sectional areas (CSA) of extracellular matrix in intima and media, endothelial and muscle cells were determined by point counting method. Cardiac hypertrophy and except of 3-week-old rats also BP increase and coronary wall hypertrophy was found in all ontogenic periods in SHR compared to Wistar rats. Arterial wall hypertrophy was evoked by increase of CSA of medial extracellular matrix and smooth muscle cells. In 52-week-old SHR, CSA of muscle cells did not differ from that in 17-week-old SHR but the CSA of intimal and medial extracellular matrix significantly increased. The CSA of endothelial cells and CSA of intimal extracellular matrix were increased only in 52-week-old SHR. The independency between BP and trophicity of individual components of the coronary wall during ontogeny of SHR was documented.     

Differential remodeling of carotid artery in spontaneously hypertensive and hereditary hypertriglyceridemic rats

High blood pressure, increased level of cholesterol, diabetes, hypertriglyceridemia and obesity are risk factors accompanied metabolic syndrome. The aim of the study was to compare geometry of carotid artery (AC) of 3-week-old (3w) and 52-week-old (52w) hereditary hypertriglyceridemic rats (hHTG) and spontaneously hypertensive rats (SHR) which represent a genetic model of human essential hypertension with age-matched Wistar rats. After sacrificing the rats were perfused with a glutaraldehyde fixative under the pressure 90 mm Hg (3w) and 120 mm Hg (52w) for 10 min via cannula placed into left ventricle. Middle part of AC was excised and processed according to standard electron microscopy procedure. Geometry of AC was evaluated in light microscopy. SHR vs. Wistar rats: BP of 3w did not differ, in 52w it was increased; cardiac hypertrophy was found in both ages; wall thickness (WT) and cross sectional area (CSA) in 3w did not differ, in 52w both were increased; inner diameter (ID) in 3w and 52w was decreased; WT/ID was increased in both ages. Hereditary HTG vs. Wistar rats: BP was increased in both periods; cardiac hypertrophy was observed in 3w; WT in 3w was decreased, in 52w it was increased; CSA and ID were decreased in both ages; WT/ID was increased only in 52w. Discrepancies between development of BP, cardiac hypertrophy in SHR and hHTG rats were observed. Alterations of BP were not in harmony with alterations in geometry of carotid arteries in both SHR and hHTG rats. We suggest that BP is not the main stimuli evoked hemodynamic and structural alterations of cardiovascular system in ontogenic development of SHR and hHTG rats.     

Hydrogen sulfide-induced relaxation of resistance mesenteric artery beds of rats

Hydrogen sulfide (H2S) has been shown recently to function as an important gasotransmitter. The present study investigated the vascular effects of H2S, both exogenously applied and endogenously generated, on resistance mesenteric arteries of rats and the underlying mechanisms. Both H2S and NaHS evoked concentration-dependent relaxation of in vitro perfused rat mesenteric artery beds (MAB). The sensitivity of MAB to H2S (EC50, 25.2 +/- 3.6 microM) was about fivefold higher than that of rat aortic tissues. Removal of endothelium or coapplication of charybdotoxin and apamin to endothelium-intact MAB significantly reduced the vasorelaxation effects of H2S. The H2S-induced relaxation of MAB was partially mediated by ATP-sensitive K+ (KATP) channel activity in vascular smooth muscle cells. Pinacidil (EC50, 1.7 +/- 0.1 microM, n=6) mimicked, but glibenclamide (10 microM, n=6) suppressed, the vasorelaxant effect of H2S. KATP channel currents in isolated mesenteric artery smooth muscle cells were significantly augmented by H2S. L-cysteine, a substrate of cystathionine-gamma-lyase (CSE), at 1 mM increased endogenous H2S production by sixfold in rat mesenteric artery tissues and decreased contractility of MAB. DL-propargylglycine (a blocker of CSE) at 10 microM abolished L-cysteine-dependent increase in H2S production and relaxation of MAB. Our results demonstrated a tissue-specific relaxant response of resistance arteries to H2S. The stimulation of KATP channels in vascular smooth muscle cells and charybdotoxin/apamin-sensitive K+ channels in vascular endothelium by H2S represents important cellular mechanisms for H2S effect on MAB. Our study also demonstrated that endogenous CSE can generate sufficient H2S from exogenous L-cysteine to cause vasodilation. Future studies are merited to investigate direct contribution of endogenous H2S to regulation of vascular tone.     

Delayed development of hypertension and increased aortic relaxation in spontaneously hypertensive rats after neonatal sympathectomy

The effect of neonatal sympathectomy on vasodilator responses to acetylcholine (ACh) and cAMP has been studied in aortic rings of spontaneously hypertensive rats (SHR) and normotensive animals. The relaxation of intact SHR aorta in response to ACh and cAMP was 20-35% lower than that of normotensive rats. Sympathectomy in normotensive rats did not affect the level of blood pressure and aorta reactivity to Ach. In SHR, sympathectomy caused a decrease in blood pressure, while relaxation in response to ACh and cAMP increased, as compared to intact SHR, but remained lower than in normotensive rats. The data obtained suggest that the decrease in arterial pressure of sympathectomized SHR is a result not only of the reduction in sympathetic effects but also of the increase in smooth muscle relaxation.     

Cyclic nucleotide levels in brains of control and hypertensive rats.

Adenosine 3′, 5′-monophosphate (cyclic AMP) and guanosine 3′,5- monophosphate (cyclic GMP) levels were measured in seven brain areas of spontaneously hypertensive rats (SHR) and two groups of control rats. In cerebral cortex, hypothalamus, pons-medulla oblongata and cerebellum cyclic AMP levels were higher in SHR than in Wistar-Kyoto controls. Cyclic GMP levels were higher in SHR than in Wistar-Kyoto rats in all brain areas except for the striatum and hippocampus where the levels were lower. There were also some differences in cyclic nucleotide levels between Wistar-Kyoto and Wistar-Charles River controls.     

Validation of echocardiographic and Doppler indexes of left ventricular relaxation in adult hypertensive and normotensive rats

This study was performed to validate echocardiographic and Doppler techniques for the assessment of left ventricular (LV) diastolic function in spontaneously hypertensive rats (SHR) and normotensive Wistar rats. In 11 Wistar rats and 20 SHR, we compared 51 sets of invasive and Doppler LV diastolic indexes. Noninvasive indexes of LV relaxation were related to the minimal rate of pressure decline (-dP/dt(min)), particularly isovolumic relaxation time (IVRT), the Tei index, the early velocity of the mitral annulus (E(m)) using Doppler tissue imaging, and early mitral flow propagation velocity using M-mode color (r = 0.28-0.56 and P < 0.05-0.0001). When the role of systolic load was considered, the correlation between Doppler indexes of LV diastolic function and relaxation rate [(-dP/dt(min))/LV systolic pressure] improved (r = 0.48-0.86 and P = 0.004-0.0001, respectively). Similarly, Doppler indexes of LV diastolic function and the time constant of isovolumic LV relaxation (tau) correlated well (r = 0.50-0.84 and P = 0.0002-0.0001, respectively). In addition, eight SHR and eight Wistar rats were compared; their LV end-diastolic diameters were similar, whereas the SHR LV mass was greater. Furthermore, IVRT and Tei index were significantly higher and E(m) was lower in SHR. Moreover, tau was higher in SHR, demonstrating impaired LV relaxation. In conclusion, LV relaxation can be assessed reliably using echocardiographic and Doppler techniques, and, using these indexes, impaired relaxation was demonstrated in SHR.     

Resistance exercise acutely enhances mesenteric artery insulin-induced relaxation in healthy rats

Aims

We evaluated the mechanisms involved in insulin-induced vasodilatation after acute resistance exercise in healthy rats.

Main methods

Wistar rats were divided into 3 groups: control (CT), electrically stimulated (ES) and resistance exercise (RE). Immediately after acute RE (15 sets with 10 repetitions at 70% of maximal intensity), the animals were sacrificed and rings of mesenteric artery were mounted in an isometric system. After this, concentration–response curves to insulin were performed in control condition and in the presence of LY294002 (PI3K inhibitor), L-NAME (NOS inhibitor), L-NAME + TEA (K⁺ channels inhibitor), LY294002 + BQ123 (ET-A antagonist) or ouabain (Na⁺/K⁺ ATPase inhibitor).

Key findings

Acute RE increased insulin-induced vasorelaxation as compared to control (CT: R_max = 7.3 ± 0.4% and RE: R_max = 15.8 ± 0.8%; p < 0.001). NOS inhibition reduced (p < 0.001) this vasorelaxation from both groups (CT: R_max = 2.0 ± 0.3%, and RE: R_max = − 1.2 ± 0.1%), while PI3K inhibition abolished the vasorelaxation in CT (R_max = − 0.1 ± 0.3%, p < 0.001), and caused vasoconstriction in RE (R_max = − 6.5 ± 0.6%). That insulin-induced vasoconstriction on PI3K inhibition was abolished (p < 0.001) by the ET-A antagonist (R_max = 2.9 ± 0.4%). Additionally, acute RE enhanced (p < 0.001) the functional activity of the ouabain-sensitive Na⁺/K⁺ ATPase activity (R_max = 10.7 ± 0.4%) and of the K⁺ channels (R_max = − 6.1 ± 0.5%; p < 0.001) in the insulin-induced vasorelaxation as compared to CT.

Significance

Such results suggest that acute RE promotes enhanced insulin-induced vasodilatation, which could act as a fine tuning to vascular tone.     

Sodium pump hyperpolarization-relaxation in rat caudal artery

Electrogenic ion transport contributes vitally to the Em in vascular muscle and thus is an important influence on contraction and relaxation. Agents that act on membrane ion transport will cause depolarization or hyperpolarization of sufficient magnitude to cause contraction or relaxation, respectively. In the caudal artery of the rat, the principal ion involved appears to be Na+. The transport process appears to be the Na+, K+-ATPase, which is ouabain sensitive, rather than other possible candidates such as the Na+-Ca2+ countertransport mechanism. The hyperpolarization and parallel relaxation found in caudal artery on return to K+ provide unequivocal evidence for an electrogenic Na+ pump. In contrast, the lack of a contraction on transition to O Na+ suggests that the caudal artery does not show an Na+-K+ countertransport system. Although other ion transport systems might be established later for caudal artery and other kinds of vascular muscle, it now appears that the electrogenic Na+ pump is the main ion transport system controlling contraction through a continuous contribution to Em.     

自发性高血压大鼠四氢生物碟呤治疗后动脉的结构及力学改变

目的：探讨长期四氢生物喋呤（BH4）治疗对自发性高血压大鼠（SHR）血管形态及血管力学性质的影响;方法：选用4周龄雄性SHR36只,随机分为实验组和对照组,每组18只。实验组每周2次腹腔注射BH420mg／kg,对照组注射等容量生理盐水,于实验第4、16和26周龄时各取6只测量动脉收缩压（SBP）,并使用计算机图像分析的方法分别测量主动脉血管零应力状态张开角、压力-直径关系及肠系膜动脉血管的壁／腔比值。结果：至BH4治疗后的第16和26周龄,SHR的SBP明显降低（P〈0．01）;实验组SHR胸主动脉张开角显著减小（P〈0．01）,压力-直径（P-D）关系曲线上移;实验组肠系膜动脉三级分支血管壁／腔（W／L）值减小（P〈0．05）。结论：BH4可以减弱由于长期高血压所导致的血管肥厚和管腔狭窄,恢复血管弹性。     

Hypertension exacerbates coronary artery disease in transgenic hyperlipidemic Dahl salt-sensitive hypertensive rats

BACKGROUND: The mechanisms underlying the known interaction of two complex polygenic traits, hypertension and hyperlipidemia, resulting in exacerbation of coronary artery disease have not been elucidated. Identification of critical pathways underlying said exacerbation could identify mechanism-based targets for intervention and prevention. MATERIALS AND METHODS: To investigate hypertension- atherosclerosis interaction, we studied the inbred transgenic atherosclerosis-polygenic hypertension Dahl salt-sensitive (S) rat model (Tg53), which over-expresses human cholesteryl ester transfer protein (hCETP) in the liver, and exhibits coronary artery disease and decreased survival compared with control non-transgenic Dahl S rats. Using serial-section histopathological and immunohistochemical analyses, we analyzed the coronary artery disease phenotype of Tg53 rats at end-stage marked by cardio-respiratory compromise as the experimental equivalent of acute coronary syndromes, and determined the effects of reduction of blood pressure through low salt diet (0.008% NaCl) on the coronary artery disease phenotype and survival. RESULTS: End-stage Tg53 rats exhibit coronary artery lesions in the proximal right coronary artery system which exhibit "culprit plaque" features such as plaque inflammation, matrix degradation, apoptosis, neovascularization, thrombosis and hemorrhage recapitulating said features and heterogeneity of human coronary "culprit plaques". Comparative analysis of 6 month vs end-stage lesions reveals distinct lesion development profiles of proximal coronary lesions which quickly progress from eccentric non-occlusive foam-cell rich lesions at 6 months to occlusive "culprit plaques", compared with more distal coronary lesions which exhibit occlusive thick-cap atheroma that remain relatively unchanged from 6 months to end stage. Reduction of hypertension through a low-salt (0.008% NaCl) diet increased survival (P < 0.0001) of Tg53 rats and significantly attenuated the coronary artery disease phenotype detected at 10 months of age marked by diminished apoptosis, neovascularization, matrix degradation compared with end-stage lesions detected at <8 months of age. CONCLUSIONS: End stage coronary lesions in the Tg53 rats recapitulate many, albeit not all, features of "culprit plaques" in humans supporting proposed paradigms of plaque vulnerability implicating lesion macrophage enrichment, apoptosis, matrix degradation and pathological neovascularization. Comparative time course analysis of coronary lesions reveals that plaques which develop into end-stage "culprit plaques" are distinct from "stable plaques" by location and early lesion morphology, suggesting distinct lesion development and progression pathways. The significant effects of low-salt diet-induced decrease in hypertension on right coronary disease phenotype provides compelling evidence that polygenic hypertension accelerates coronary plaque progression and complication independent of cardiac hypertrophy, and more importantly provides paradigmatic support for public health policy.     

Increased reactivity in the mesenteric artery of spontaneously hypertensive rats to phorbol ester

The contraction responses of mesenteric artery from 10 week old spontaneously hypertensive rats (SHRs) and normotensive Wistar Kyoto controls (WKYs) to phorbol 12, 13 - dibutyrate (PDBu) and agents acting on the potential-operated calcium channels were compared. The vessels from the SHR were significantly more sensitive to PDBu than those from the WKY. The PDBu-induced contractions were inhibited by nifedipine. The vessels from the SHR were also more sensitive to Bay K 8644 and KCl than the WKY. Low concentrations of PDBu (1 nM) potentiated the KCl contraction significantly more in the SHR than the WKY. It is suggested that the increased reactivity to PDBu in the SHR may in part be related to changes in the activity of the potential-operated calcium channels.     

Nifedipine-resistant Ca(++)-induced contraction in tail artery of spontaneously hypertensive rats.

Nifedipine-resistant Ca(++)-induced contractions (NR-Ca(++)-contraction) were compared in the tail arteries from SHRs and WKYs (5 and 13 week old). NR-Ca(++)-contraction of tail artery was defined as follows: Ca(++)-induced contraction in the presence of norepinephrine (NE) (10(-5) M) or 5-hydroxytryptamine (5-HT) (10(-5) M) in Ca(++)-free medium containing EGTA (0.1 mM) and nifedipine (10(-6) M). NR-Ca(++)-contractions in arteries from 5 week old SHRs and WKYs were not different. In contrast, NR-Ca(++)-contractions in arteries from 13 week old SHRs were about 2-fold greater than in arteries from 13 week old WKYs. In arteries from 13 week old WKYs and SHRs, nitroglycerin (10(-5) M) significantly reduced the NR-Ca(++)-contraction in the presence of 5-HT but not in the presence of NE. The reduction was inhibited by the presence of methylene blue (3 x 10(-6) M). 8-Bromo-cGMP (10(-4) M) reduced significantly the NR-Ca(++)-contraction in the presence of 5-HT in arteries from 13 week old SHRs and WKYs. The present experiments clearly demonstrated that the NR-Ca(++)-contractions (both in the presence of NE and 5-HT) in 13 week old SHRs were significantly greater than those in arteries from 13 week old WKYs. These results suggest that in addition to an increase in voltage-operated Ca++ mobilization reported by others, an increase in NR-Ca++ mobilization may contribute to the development of hypertension in SHR.