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)     

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.     

老龄化自发性高血压模型大鼠与SD大鼠左冠状动脉的应力松弛特性

背景:目前多数研究为正常人尸体和动物动脉血管的应力松弛特性,而老龄化自发性高血压模型大鼠与SD大鼠左冠状动脉应力松弛特性的研究鲜有报道。目的:对比分析老龄自发性高血压模型大鼠与SD大鼠左冠状动脉应力松弛特性,为高血压致血管损伤修复提供应力松弛指标。方法:对四五个月龄正常SD雄性大鼠左冠状动脉和老龄自发性高血压模型大鼠左冠状动脉各10个试样在日本岛津电子万能试验机上进行应力松弛实验,模拟人体温在(36.5±0.1)℃的温度场下以0.05%/s的应变增加速度对试样施加应变,设定时间为7200s。采集100个数据,采用归一化分析的方法计算两组试样的归一化应力松弛方程。结果与结论:两组试样应力松弛曲线是以对数关系变化的,SD组试样7200s应变上升量大于自发性高血压模型组,差异有显著性意义(P<0.05)。可见正常SD大鼠左冠状动脉和老龄自发性高血压模型大鼠左冠状动脉具有不同的应力松弛特性。     

Fibronectin biosynthesis in the rat aorta in vitro. Changes due to experimental hypertension.

This study was undertaken to determine if changes in fibronectin biosynthesis accompany the phenotypic changes that occur in aortic tissue following experimental hypertension. An in vitro procedure was developed to measure fibronectin synthesis in aortic rings obtained from normotensive or hypertensive rats. There was a three to sixfold increase in fibronectin biosynthesis by aortic rings taken from rats treated with deoxycorticosterone/salt for 7 and 21 d, the change being more pronounced at 21 d. In contrast, there was no major change at either time point in net incorporation into total protein. Studies comparing fibronectin biosynthesis in aortic rings from Wistar rats and spontaneously hypertensive rats at ages between 10 and 40 wk showed increased fibronectin biosynthesis in older animals of both strains, but only slight differences between strains. Studies using rats infused with angiotensin II showed a correlation between blood pressure elevation and increased aortic fibronectin biosynthesis. Western blot analysis of aortic extracts showed that the fibronectin content was increased in the hypertensive models. The in vitro procedure for measuring fibronectin biosynthesis appears to provide a reliable reflection of in vivo changes in fibronectin expression, and the methodology could prove useful for studying the factors influencing protein expression in vascular tissue.     

Intrinsic factors involved in vascular smooth muscle cell proliferation in hypertension.

The exaggerated response to growth factors of vascular smooth muscle cells from spontaneously hypertensive rats when compared to cells from normotensive control Wistar-Kyoto rats persists in culture, indicating an intrinsic/genetic defect. The time course of 3H-thymidine incorporation shows that synchronized vascular smooth muscle cells from spontaneously hypertensive rats start to synthesize new DNA earlier after mitogenic stimulation than cells from normotensive rats. Flow cytometry demonstrates that in cell populations growing in 10% calf serum for three d there is a higher proportion of cells from spontaneously hypertensive rats in the S phase of the cell cycle. The same proportions in the G2 + M phase of growing, as well as synchronized cells from normotensive and hypertensive rats indicate no difference in polyploidy. Forward light scatter analysis reveals no difference in cell size. These results suggest that the growth kinetic of vascular smooth muscle cells from normotensive and spontaneously hypertensive rats are different. Since the defect seems to be in the prereplicative phase of the cell cycle susceptible to regulation by extrinsic factors, we studied the effect of the calmodulin inhibitor, W-7, on DNA synthesis. The comparable IC50 of W-7 to inhibit cell growth of vascular smooth muscle cells of both origins indicates that the defect may not be due only to calmodulin, and furthermore suggests the involvement of a previously-reported calmodulin activator in hypertension.     

Altered pulmonary vascular smooth muscle responsiveness in monocrotaline-induced pulmonary hypertension

Studies were conducted to determine whether experimental pulmonary hypertension is associated with alterations in pulmonary vascular smooth muscle responsiveness. Adult male rats were given a single s.c. injection of monocrotaline (105 mg/kg) or saline and were sacrificed 4, 7 or 14 days later. Segments of the main trunk and right extrapulmonary artery and an intrapulmonary artery were isolated for determination of vascular reactivity to contractile and relaxant agonists. Monocrotaline treatment caused changes in mechanical properties of pulmonary arteries in that vessels isolated from rats 14 days after monocrotaline administration required greater passive loads to achieve maximal active force development. Cumulative concentration-response curves were generated to potassium chloride, angiotensin II, norepinephrine, isoproterenol and acetylcholine. Vascular contractility was enhanced in main pulmonary artery 4 days after monocrotaline injection but no differences in responsiveness between control and monocrotaline exposed vessels were observed 7 days post-treatment. In contrast, significant decreases in contractility with a specific loss in the response to angiotensin II were observed in pulmonary arteries isolated from rats 14 days after monocrotaline administration. These vessels also were less responsive to the relaxant effects of isoproterenol and acetylcholine when compared to control vessels. These results demonstrate that changes in pulmonary vascular smooth muscle responsiveness occur during evolution of pulmonary hypertension induced by monocrotaline. Enhanced contractility may contribute to inappropriate vasoconstriction early in the development of hypertensive pulmonary vascular disease but does not appear to be involved in sustained elevations in pulmonary artery pressure. Diminished relaxation observed after pulmonary hypertension was well established may contribute to the loss in efficacy of vasodilators in the long-term management of pulmonary hypertension.     

Evidence for altered Na+/H+ antiport activity in cultured skeletal muscle cells and vascular smooth muscle cells from the spontaneously hypertensive rat.

1. Intracellular pH and Na+/H+ antiport activity were determined by a fluorimetric method in cultured skeletal muscle cells (myoblasts) and aortic vascular smooth muscle cells from spontaneously hypertensive and normotensive Wistar-Kyoto rats. 2. The intracellular pH was significantly more alkaline at three different extracellular pH values in both myoblasts and vascular smooth muscle cells from the spontaneously hypertensive rats than in those from the normotensive control rats. 3. A kinetic analysis of the Na+/H+ antiport activity in these cells showed that the raised activity in the spontaneously hypertensive rats was due to an increased maximal transport capacity in vascular smooth muscle cells and to an increase in the affinity of the antiport for internal H+ in the myoblasts. 4. When the extracellular pH was reduced in the skeletal muscle cells of both types of rat, the intracellular pH fell. However, in vascular smooth muscle cells, a reduction in the extracellular pH was not associated with a fall in the intracellular pH. This resistance of the intracellular pH to changes in the extracellular pH differentiates vascular smooth muscle cells from other cells that have been studied in this way.     

Association and cosegregation of stroke with impaired endothelium-dependent vasorelaxation in stroke prone, spontaneously hypertensive rats.

While hypertension is a major risk factor for stroke, it is not its sole determinant. Despite similar blood pressures, spontaneously hypertensive rats (SHR) do not share the predisposition to cerebrovascular disease typical of stroke-prone spontaneously hypertensive rats (SHRSP). We investigated vascular function in male SHR and SHRSP as well as in SHRSP/SHR-F2 hybrid animals. Animals were maintained on the appropriate dietary regimen necessary for the manifestation of stroke. Among the hybrid animals, a group of stroke-prone and a group of stroke-resistant rats were selected. Blood pressure was similar in all groups. Endothelium-independent vascular reactivity tested on isolated rings of thoracic aorta and basilar artery after death showed similar contractile and dilatory responses to serotonin and nitroglycerin, respectively, in all groups. In contrast, endothelium-dependent relaxation, in response to acetylcholine or substance P, was markedly reduced in SHRSP compared with SHR. Similarly, reduced vasodilatory responses were present in aortae of F2 rats that had suffered a stroke when compared with SHR or F2 rats resistant to stroke. The observed association and cosegregation of stroke with significant and specific impairment of endothelium-dependent vasorelaxation among SHRSP and stroke-prone F2 hybrids, respectively, suggest a potential causal role of altered endothelium-dependent vascular relaxation in the pathogenesis of stroke.     

Studies on uptake and catabolism of vascular histamine in spontaneously hypertensive rats

Reduced vascular histamine content is postulated to contribute to increased peripheral vascular resistance in experimental hypertension in rats. Experiments were conducted to examine histamine content, in vitro uptake ability and in vitro catabolism of histamine in blood vessels from 12-week-old spontaneously hypertensive rats (SHR) and age-matched normotensive controls. Histamine content of mesenteric artery and abdominal aorta from SHR was significantly reduced (P less than .05) when compared to Wistar-Kyoto normotensive controls. This finding confirms a similar observation of reduced vascular histamine content in deoxycorticosterone acetate salt hypertensive rats reported from our laboratory. This reduction in histamine content may be more prevalent in arteries because the decrease was not observed in the portal vein from SHR. Uptake of [14C]histamine into mesenteric artery and abdominal aorta was unchanged in SHR compared to Wistar-Kyoto controls. No significant differences between slopes for uptake regression lines were observed for either mesenteric artery or abdominal aorta. Mesenteric artery exhibited a greater capacity of [14C]histamine accumulation than aorta and significant reductions in accumulation of labeled histamine after 20 and 60 min were found in this vessel from SHR. Because metabolism of histamine was inhibited by aminoguanidine, this reduction may reflect diminished retention by histamine storage sites. In vitro I-[14C]histidine uptake was significantly increased in abdominal aorta and iliac artery but not mesenteric artery from SHR. These differences were also present at the later accumulation periods of 20 and 60 min.(ABSTRACT TRUNCATED AT 250 WORDS)     

Effect of parathyroidectomy on arterial hypertrophy,vascular lesions,and aortic calcium content in deoxycorticosterone-induced hypertension

Parathyroidectomy (Px) did not prevent the development of deoxycorticosterone (DOC)-induced hypertension inasmuch as the systolic blood pressure at 4 weeks did not differ from that of parathyroid intact, DOC-treated rats. Px, however, ameliorated the percent incidence and severity index of hypertension-induced vascular lesions in the heart and kidney. There was less hyaline change in the coronary artery and renal arteriole and fewer scars in the myocardium of Px + DOC rats than in DOC-treated animals. Arterial hypertrophy in aorta, coronary artery, renal interlobular artery, and renal arteriole in hypertensive animals was not affected by Px. The aortic content of total calcium in the Px-hypertensive rats was reduced significantly as compared to parathyroid-intact hypertensive rats. The abdominal aorta in the Px + DOC group showed a greater reduction in calcium than the thoracic aorta. We conclude that calcium may not be essential in mediating hypertension-induced vascular hypertrophy. Parathyroidectomy permitted a separation of high blood pressure-hypertrophy from hyaline vascular lesions in DOC-induced hypertensive rats, likely acting upon endothelial cells to prevent movement of plasma proteins (hyaline change) from the vascular lumen into the media-subendothelial space of blood vessels.     

Vasoactivity of 20-hydroxyeicosatetraenoic acid is dependent on metabolism by cyclooxygenase

We recently demonstrated that cortical microsomes from spontaneously hypertensive rats metabolize arachidonic acid via cytochrome P450 to omega- and omega-1 hydroxylated compounds, 19- and 20-hydroxyeicosatetraenoic acids (HETE). The vascular activities of 20-HETE and the two isomers of 19-HETE were examined in rat aortic rings. The HETEs produced concentration-dependent contractions of the aortic rings. The contraction elicited by 20-HETE was abolished partially by removal of endothelium and was inhibited completely by treatment with indomethacin and reversed to a relaxation response by treatment with the endoperoxide and thromboxane receptor antagonist SQ 29548. These data suggest that the vascular effects of 20-HETE depend on subsequent metabolism by cyclooxygenase.     

Parathyroidectomy, cardiovascular reactivity and calcium distribution in aorta and heart of spontaneously hypertensive rats

In order to elucidate the mechanisms by which parathyroidectomy (PTX), performed in young spontaneously hypertensive rats (SHR), delays the development and attenuates the level of hypertension, we studied, in vivo, cardiovascular reactivity (CVR, blood pressure response to bolus noradrenaline administration), aortic calcium distribution and cardiac calcium content in SHR with or without parathyroid glands. PTX was performed in 6-week-old animals and experiments were done in pretreated anaesthetized animals 2 and 22 weeks after surgery. A significantly decreased CVR was observed 22 weeks after PTX in SHR-PTX as compared with controls. These data are not specific for hypertensive animals since similar data are also obtained on normotensive Wistar rats treated in an identical fashion. In addition, after PTX in SHR and Wistar rats myocardial (auricle and ventricle) calcium content was more rapidly reduced (after 2 weeks) than aortic membrane-bound and cellular calcium fractions. The present studies established that PTX decreased CVR and alters calcium content and distribution in the cardiovascular systems of rats from hypertensive and normotensive strains. Furthermore, the results confirm a requirement for the parathyroid glands in the pathogenesis of spontaneous hypertension in SHR and for the normal CVR.     

Sodium-potassium-adenosine triphosphatase in nephron segments of spontaneously hypertensive rats

Sodium pump activity of blood vessels has been reported to decrease in several animal models of hypertension. We studied sodium-potassium-adenosine triphosphatase (Na-K-ATPase) activity of renal tubular segments in 12-week-old spontaneously hypertensive rats and in age-matched Wistar-Kyoto normotensive rats. The enzyme activity of the individual nephron segments was determined by a microfluorometric assay in which ATP hydrolysis is coupled with NADH oxidation. In the spontaneously hypertensive rats, systolic blood pressure was significantly higher (181 +/- 3 mm Hg) than in the Wistar-Kyoto rats (134 +/- 2 mm Hg). However, there was no difference in mean Na-K-ATPase activity in any of the nephron segments from the spontaneously hypertensive compared with the Wistar-Kyoto group. It is concluded that Na-K-ATPase activity does not change in any of the nephron segments with spontaneous hypertension.     

Ca2+-activated K+ channels underlying the impaired acetylcholine-induced vasodilation in 2K-1C hypertensive rats

We tested the hypothesis that an abnormal function of K(+) channels in vascular smooth muscle cells plays a key role in the impaired acetylcholine (ACh) vasodilation in aortas from two kidney-one clip (2K-1C) hypertensive rats and further investigated the K(+) channel subtype involved in this altered response. ACh-induced endothelium-dependent relaxation was assessed in aortic rings from 2K-1C and normotensive two kidney (2K) rats. Glibenclamide, an ATP-sensitive K(+) channel blocker, did not inhibit ACh-induced relaxation in aortic rings from 2K or 2K-1C rats. The voltage-dependent K(+) channels inhibitor 4-aminopyridine attenuated ACh-induced relaxation in both groups. Charybdotoxin and iberiotoxin, blockers of Ca(2+)-sensitive (K(Ca)) and large-conductance K(Ca) (BK(Ca)) channels, respectively, reduced ACh-induced relaxation in aortic rings from 2K rats without affecting this response in those from 2K-1C rats, abolishing the differences between groups. ACh-induced relaxation in vessels from both 2K and 2K-1C rats was unaffected by apamin, a small-conductance K(Ca) blocker. NS1619 [1,3-dihydro-1-[2-hydroxy-5-(trifluoromethyl)phenyl]-5-(trifluoromethyl)-2H-benzimidazol-2-one], an activator of K(Ca), induced a smaller vasodilation in endothelium-denuded aortic rings from 2K-1C rats compared with those from 2K rats. Iberiotoxin reduced sodium nitroprusside-induced relaxation in endothelium-denuded aortic rings from 2K without affecting this response in those from 2K-1C rats. The inhibition of Na(+),K(+)-ATPase with ouabain had no effects on ACh-induced relaxation in aortic rings from 2K-1C or 2K rats. These data indicate that a deficient functional activity of BK(Ca) channels plays a key role in the impaired ACh vasodilation in aortas from 2K-1C rats.     

Effect of destruction of the vascular endothelium upon pressure/flow relations and endothelium-dependent vasodilatation in resistance beds of spontaneously hypertensive rats.

1. Pressure/flow relationships were determined in the in situ blood-perfused superior mesenteric and hindquarters vascular beds of spontaneously hypertensive rats and Wistar-Kyoto normotensive rats before and after destruction of the endothelium with detergent. The effects of indomethacin on the regression of pressure on flow were also investigated in the spontaneously hypertensive rats, as were the endothelium-dependent relaxations in response to carbachol in the mesenteric bed. 2. In the spontaneously hypertensive rats the regression line of pressure on flow in the two vascular beds was both steeper and more elevated than in the Wistar-Kyoto rats, showing that there was greater resistance to flow in the hypertensive animals. Destruction of the endothelium significantly increased the slope of the regression in both Wistar-Kyoto and spontaneously hypertensive rats: the increases in the Wistar-Kyoto rats were 2.4 +/- 0.3 fold (mesenteric) and 2.0 +/- 0.5 fold (hindquarters) which were comparable with the respective increases of 1.6 +/- 0.3 fold and 1.8 +/- 0.3 fold in the spontaneously hypertensive rats. 3. Indomethacin (5 mg/kg, intravenously) had no effect on the pressure/flow relations in either of the vascular beds of the spontaneously hypertensive rats. 4. The dose-response curves for the endothelium-dependent vasodilatation in response to carbachol were not significantly different in spontaneously hypertensive and Wistar-Kyoto rats. 5. The results suggest that tonic release of endothelium-derived relaxing factor has similar effects in modulating resistance vessel tone in vivo in both hypertensive and normotensive rats.(ABSTRACT TRUNCATED AT 250 WORDS)     

Voluntary physical exercise-induced vascular effects in spontaneously hypertensive rats

Forced training has been shown to have beneficial vascular effects in various animal exercise models. In the present study, we explored possible physiological and molecular effects of voluntary physical exercise on various vascular beds. SHR (spontaneously hypertensive rats) performed voluntary exercise for 5 weeks in a computerized wheel cage facility. Ex vivo myograph studies revealed an increased sensitivity of the ACh (acetylcholine)-mediated vasodilation in resistance arteries of the exercised animals (ED50=15.0+/-3.5 nmol/l) compared with the controls (ED50=37.0+/-8.8 nmol/l; P=0.05). The exercise/control difference was abolished after scavenging reactive oxygen radicals. In conduit arteries, ACh induced a similar vasodilatory response in both groups. The in vivo aortic wall stiffness, assessed by means of Doppler tissue echography, was significantly lower in the exercising animals than in controls. This was demonstrated by significantly increased peak systolic aortic wall velocity (P=0.03) and the velocity time integral (P=0.01) in exercising animals compared with controls. The relative gene expression of eNOS (endothelial nitric oxide synthase) was similar in both groups of animals, whereas Cu/ZnSOD (copper/zinc superoxide dismutase) gene expression was significantly increased (+111%; P=0.0007) in the exercising animal compared with controls. In conclusion, voluntary physical exercise differentially improves vascular function in various vascular beds. Increased vascular compliance and antioxidative capacity may contribute to the atheroprotective effects associated with physical exercise in conduit vessels.     

Mesenteric vascular responses of young spontaneously hypertensive rats

Frequency-responses curves for nerve stimulation and dose-response curve for norepinephrine, 5-hydroxytryptamine potassium chloride, vasopressin and acetylcholine (ACh) were determined in isolated, perfused mesenteric vascular beds from young (approximately 5 weeks) spontanelouly hypertensive (SHR) and Wistar Kyoto rats. Although mean systolic blood pressure (measured by tail cuff plethysmography) was slightly higher in the SHR, this difference was not significant. Slopes and maximum responses were increased significantly for nerve stimulation and all agonists. The basal perfusion pressure was also significantly elevated in the SHR. These differences are consistent with existing evidence that structural changes occur in blood vessels of SHR at an early stage and probably precede development of hypertension. Such structural changes could therefore contribute to development of the hypertension. Cocaine (1 microM) markedly increased responses to nerve stimulation and bolus injections of norepinephrine in preparations from SHR with little or no effect on such responses in Wistar Kyoto preparations, a result consistent with the known greater density of noradrenergic nerves in SHR vasculature. In the presence of cocaine, there was unmasked a selective super-sensitivity (significantly lower ED50) to norepinephrine in the SHR. Thus SHR mesenteric vessels may possess an alteration in adrenoreceptors or their coupling to other cellular mechanisms. Responses to ACh revealed no indication of a deficient endothelial mediated relaxation. An altered media:lumen ratio of small arteries, hypernoradrenergic innervation and supersensitivity to the transmitter may contribute to development of hypertension.     

Age-related decrease in beta adrenergic receptor-mediated vascular smooth muscle relaxation

Beta adrenergic receptor-mediated vascular smooth muscle relaxation decreases with increasing age. We have examined the mechanism responsible for this phenomenon using rat mesenteric arteries from young (5-6 weeks) and older (10-12 months) rats. The beta adrenergic agonist isoproterenol produced a dose-dependent relaxation of serotonin-constricted mesenteric artery rings from young rats, whereas the maximal ability of isoproterenol to relax arterial rings from the older rats was found to be reduced markedly (92.7 vs. 27.6%, P less than .0001). The relaxation responses caused by acetylcholine and nitroglycerin, which appear to act independently of cyclic AMP (cAMP), are similar in the two groups. The loss in responsiveness of the mesenteric artery to isoproterenol was not explained by a change in beta receptor number in the vessels (29 +/- 4 in young rats vs. 31 +/- 7 fmol/mg of protein in the older rats). The maximal stimulation of cAMP accumulation by isoproterenol was lower in the older vessels; forskolin activated cAMP accumulation equally in the two groups. However, the vessels from the older rats were less sensitive to forskolin-induced vascular relaxation. Also, the ability of dibutyryl cAMP to promote vascular relaxation was diminished in the older vessels. These data suggest that the diminished cAMP accumulation in older vessels in response to isoproterenol might not necessarily in itself explain completely the reduced physiological response and that an additional defect in the beta adrenergic-mediated relaxation in the vascular smooth muscle of older rats may lie at the level of cAMP-dependent protein kinase activation or more distally.     

A new ATP-sensitive potassium channel opener reduces blood pressure and reverses cardiovascular remodeling in experimental hypertension

Some potassium channel openers (KCOs) are potent vasodilators that mainly target the ATP-sensitive potassium channels in vascular smooth muscle cells. Their lack of tissue selectivity limits their clinical use in hypertension therapy. Iptakalim [2,3-dimethyl-n-(1-methylethyl)-2-butylamine], which belongs to a novel chemical type of KCO, possesses unique pharmacological characteristics. In vitro experiments have shown that iptakalim could limit its vasorelaxing actions to resistance vessels. In this study, we investigate the antihypertensive effects of iptakalim on two different experimental hypertensive models: stroke-prone, spontaneously hypertensive rats (SHRsps) and two-kidney with one-clip renal hypertensive dogs (2K1C RHD). In acute hypotensive tests, iptakalim showed stable, long-lasting antihypertensive effects in SHRsps and 2K1C RHDs. Mean-while, it had little effect on heart rate when compared with pinacidil, nifedipine, captopril, or bisoprolol. In experimental therapeutic tests, repeated doses in SHRsps for 30 days or in 2K1C RHDs for 14 days produced consistent antihypertensive effects without causing tolerance. In separate experiments, chronic administration of iptakalim resulted in reversing hypertensive vascular remodeling in spontaneously hypertensive rats and hypertensive cardiac remodeling in SHRsps. These results suggest that iptakalim is a promising antihypertensive drug.     

Elevated arterial cyclic AMP levels during the onset of renal hypertension in rats

1. To determine the possible role of arterial cyclic AMP in the pathogenesis of hypertensive vascular hypertrophy and hyperplasia, the changes in the level of this nucleotide were studied during the development of renal hypertension in rats with aortic ligation between the renal arteries. 2. A twofold increase in the cyclic AMP level of the thoracic aorta was observed in 9-day hypertensive rats when compared with sham-operated controls. At this time the total amounts of DNA and collagen were unchanged, although a marked increase in arterial fibrous protein was already present. 3. Arterial cyclic AMP remained significantly elevated in the thoracic aorta of 30-day hypertensive animals. At this time the hypertensive vascular alterations had reached completion as shown by the abnormal accumulation of collagen, DNA and non-fibrous protein. 4. Contrary to the events taking place in the thoracic aorta, a marked decrease in cyclic AMP was present in the abdominal portion, which was protected from high blood pressure by the aortic ligature. In this segment decreased cyclic AMP coexisted with an unchanged collagen content and a diminution in the contents of DNA and non-fibrous protein. 5. Thus a marked increase in arterial cyclic AMP precedes the initiation of DNA replication and collagen accumulation in vascular territories subjected to high blood pressure. These studies suggest the participation of this nucleotide in the vascular growth induced by hypertension.