Neuropeptide changes in the suprachiasmatic nucleus are associated with the development of hypertension

ABSTRACT

Human postmortem studies as well as experimental animal studies indicate profound changes in neuropeptide expression in the suprachiasmatic nucleus (SCN) in several pathological conditions including hypertension. In addition, animal experimental observations show that the SCN peptides, vasopressin (AVP) and vasoactive intestinal peptide (VIP) are essential for adequate rhythmicity. These data prompted us to investigate whether changes in these neuronal populations could be the cause or consequence of hypertension. Changes in blood pressure and levels of neuropeptide expression in the SCN were determined during development of hypertension in spontaneously hypertensive rats (SHR), in 2K1C reno-vascular induced hypertensive animals and their respective controls. During the pre-hypertensive stage (5 weeks of age), the VIP and AVP content was higher and the somatostatin (SOM) content was lower in the SHR SCN. At the onset of hypertension (12 weeks of age), when blood pressure levels had just reached about 140 mmHg, AVP and SOM content in the SCN was not different anymore in SHRs compared to control, but VIP was still higher. After 16 weeks, the AVP content was decreased, but SOM was increased and the overall level of VIP in the SCN was still higher in SHRs compared to controls. None of the aforementioned changes in the SCN was observed after induction of hypertension in the 2K1C model. However, while VIP was increased in the NTS projecting medial region of the SCN in SHR animals only after the establishment of hypertension, VIP was decreased in the same region in the 2K1C induced hypertensive rats. Consequently, the present findings confirm previous studies in human and rat indicating that changes in the SCN are strongly associated with the development of hypertension. In addition, the changes in peptide content in the 2K1C animals indicate that the SCN is also able to respond to increases in blood pressure.     

Prolactin and LH release in response to vasoactive intestinal peptide (VIP) administration in spontaneously hypertensive and normotensive rats.

Vasoactive intestinal peptide (VIP) was injected intravenously at a dose of 10 micrograms in spontaneously hypertensive and normotensive Wistar-Kyoto rats. In order to evaluate the hemodynamic and hormonal effects of this peptide, the mean arterial pressure, heart rate as well as a serum rLH and rPRL levels, the contents of LH-RH in hypothalamus and the content of LH in pituitary tissue were determined. The same procedure was applied in rats receiving placebo. Serum rPRL concentration was measured additionally after combined administration of VIP+dopamine. VIP injection produced a decrease in mean arterial pressure and an increase in heart rate in both spontaneously hypertensive and normotensive rats. Serum rPRL concentration was significantly increased at 10 minutes after injection. The combined therapy (VIP+dopamine) partially inhibited this response. Serum rLH concentration, the content of LH-RH in hypothalamic tissue as well as the content of pituitary LH after VIP injection in spontaneously hypertensive and normotensive rats did not differ from the values obtained for the control group. Conclusions: 1. VIP injection produced the dramatic hypotensive effects in hypertensive rats; 2. A marked increase in PRL concentration in response to VIP was partially inhibited by dopamine in hypertensive and normotensive rats; 3. VIP injection did not change LH-RH and LH release in both hypertensive and normotensive rats.     

内皮素-1前体基因反义寡核苷酸对正常和高血压大鼠血流动力学的影响

我们筛选出针对内皮素－１（ＥＴ－１）前体基因反义硫代寡核苷酸片断（ＥＴＡＳＯＤＮ）,已证明ＥＴＡＳＯＤＮ能显著抑制培养内皮细胞ＥＴ－１的生成,本应用该片断,对下沉和腹主动脉狭窄－高盐摄入型高血压大鼠侧脑室进行注射,记录注射前后血流动力学指标、注射后侧脑室周围组织中ＥＴ－１的含量及分布,ＥＴＡＳＯＤＮ对正常和高血压大鼠的影响,发现高血压大鼠脑干ＥＴ－１含量明显高于正常大鼠;ＥＴＡＳＯＤＮ能降低高血压     

Angiotensins in plasma of hypertensive rats and human

The plasma levels of des-aspartate-angiotensin I (DAA-I) in three models of hypertensive rats and hypertensive subjects were determined and compared with their normotensive controls. The rationale for the study was based on our earlier findings showing that DAA-I is a physiological angiotensin peptide that is involved in the pathophysiology of the cardiovascular system. The determination was carried out by the technique of capillary electrophoresis. Plasma level of angiotensin I, angiotensin II, and angiotensin III was also determined as a measurement of the status of the renin-angiotensin system in the different models of hypertension. DAA-I was found to be significantly lower in the spontaneously hypertensive rats (SHR) (46.6 +/- 2.5 pmol/l compared to 66.1 +/- 3.4 pmol/l for the normotensive control Wistar Kyoto rats), renal hypertensive rats (54.2 +/- 5.1 pmol/l compared to 72 +/- 2.5 pmol/l for the normotensive control Sprague-Dawley rats), and essential human hypertensive subjects (15.2 +/- 0.9 pmol/l compared to 19.5 +/- 2.5 pmol/l for the normotensive adult), whilst plasma concentration of angiotensin I and angiotensin II is reflective of the state of the renin-angiotensin system in the particular model of hypertension. When the SHR and human hypertensive subjects were treated with an angiotensin converting enzyme (ACE) inhibitor, the plasma level of DAA-I increased significantly. These findings suggest that the low plasma level of DAA-I could be a characteristic defect of the renin-angiotensin system in the two genetic models of hypertension (SHR and human essential hypertensive subjects). The increase of the nonapeptide following ACE inhibitor treatment could be an important hitherto unrecorded contributory factor to the effectiveness of ACE inhibitors in combating heart pathology.     

Role of autonomic nervous system on heart rate in experimental hypertension

Heart rate and the role of the autonomic nervous system in hypertensive conscious rats by subtotal nephrectomy were studied. Heart rate is significantly higher in the hypertensive rats. Sympathetic blockade with an intravenous injection of propranolol produces a higher decrease in heart rate of hypertensive rats than in control rats. Intravenous injection of atropine produces an increase in heart rate in both groups of animals. It is significantly higher in the control rats than in hypertensive animals. When the autonomic nervous system is blocked with atropine and propranolol, intrinsic heart rate is similar in both groups of animals. Similar results are obtained after blocking ganglionic transmission with hexamethonium. No significative differences are observed in heart rate after intracerebroventricular injection of hemicholinium-3 between both groups of rats. Results show an increased cardiac sympathetic tone, reduced parasympathetic activities, no alterations in the pacemaker activity and implications of central acetylcholine. These alterations in the autonomic nervous system have an important role in the maintenance of elevated heart rate in this experimental model of arterial hypertension.     

Calcitonin gene-related peptide and hypertension

Capsaicin-sensitive sensory nerves participate in the regulation of cardiovascular functions both in the normal state and the pathophysiology of hypertension through the actions of potent vasodilator neuropeptides, including calcitonin gene-related peptide (CGRP). CGRP, a very potent vasodilator, is the predominant neurotransmitter in capsaicin-sensitive sensory nerves, and plays an important role in the initiation, progression and maintenance of hypertension via: (1) the alterations in its synthesis and release and/or in vascular sensitivity response to it; (2) interactions with pro-hypertensive systems, including renin-angiotensin-aldosterone system, sympathetic nervous system and endothelin system; and (3) anti-hypertrophy and anti-proliferation of vascular smooth muscle cells. The decrease in CGRP synthesis and release contributes to the elevated blood pressure, as shown in the spontaneously hypertensive rats, alpha-CGRP knockout mice, Dahl-salt or phenol-induced hypertensive rats. In contrast, the increase in CGRP levels or the enhancement of vascular sensitivity response to CGRP plays a beneficial compensatory depressor role in the development of hypertension, as shown in deoxycorticosterone-salt, sub-total nephrectomy-salt, N(omega)-nitro-L-arginine methyl ester or two-kidney, one-clip models of hypertension in rats. We found that rutaecarpine causes a sustained depressor action by stimulation of CGRP synthesis and release via activation of vanilloid receptor subtype 1 (VR1) in hypertensive rats, which reveals the therapeutic implications of VR1 agonists for treatment of hypertension.     

Heart receptors for VIP, PHI and secretin are able to activate adenylate cyclase and to mediate inotropic and chronotropic effects. Species variations and physiopathology

We have assessed the presence of VIP/PHI/secretin receptors in heart by: (1) testing the ability of the corresponding peptides to activate adenylate cyclase in cardiac membranes from rat, dog, Cynomolgus monkey and man, and (2) examining the ability of the same peptides to exert inotropic and chronotropic effects on heart preparations from rat and Cynomolgus monkey in vitro. Based on their affinity for natural peptides and synthetic analogs, two types of VIP/PHI/secretin receptors were characterized: the relatively nonspecific "secretin/VIP receptor" of rat heart (that is "secretin-preferring" only in that secretin was more efficient than VIP in stimulating adenylate cyclase), and the "VIP/PHI-preferring" receptor of man, monkey and dog heart. Four physiopathological situations affecting secretin/VIP receptors in rat heart were explored: In male rats from the Okamoto strain and the Lyon strain, two strains presenting spontaneous hypertension, heart membranes exhibited a markedly decreased response of adenylate cyclase to secretin/VIP, with lesser alterations in the responses to isoproterenol and glucagon. This impairment developed in parallel with the occurrence of hypertension and was reproduced in normotensive rats submitted to chronic isoproterenol treatment (but not in Goldblatt hypertensive rats). These findings are consistent with a hyperactivity of norepinephrine pathways in spontaneously hypertensive rats, leading to a reduced number of cardiac post-junctional secretin/VIP receptors bound to adenylate cyclase. Heart membranes from genetically obese (fa/fa) Zucker rats also exhibited severely decreased responses to secretin/VIP with lesser alterations in the responses to glucagon and isoproterenol. These anomalies were specific for the heart, and developed in concomitance with obesity. The first anomaly could not be corrected by severe food restriction. Secretin stimulation of heart adenylate cyclase was also selectively altered in streptozotocin-diabetic rats. Thus, two types of diabetic cardiomyopathy were characterized by a severe local alteration of secretin/VIP receptors coupled to adenylate cyclase. Hypothyroidism, provoked in rat by thyroidectomy or propylthiouracil treatment, again induced a marked decrease in secretin-stimulated cardiac adenylate cyclase activity. In rat papillary muscle electrically stimulated in vitro, secretin exerted a positive inotropic effect. This effect was reduced in obese (fa/fa) Zucker rats. In rat right atrium, secretin also exerted a positive chronotropic effects.(ABSTRACT TRUNCATED AT 400 WORDS)     

异丙肾上腺素对心内神经节中肽能递质VIP影响

异丙肾上腺素是临床常用的心脏骤停的抢救药物。为了研究该药对心内神经节中肽能递质的影响,本文在大鼠皮下注射异丙肾上腺素５ｍｇ／ｋｇ,连续三天,后固定取心房后壁,用免疫组化结合图像分析,观察心内神经节中肽能递质ＶＩＰ的变化。对照组大鼠心内神经节中含有ＶＩＰ免疫反应（ＶＩＰ－ＩＲ）阳性神经纤维和胞体;实验组大鼠心内神经节中含有ＶＩＰ－ＩＲ阳性神经纤维和胞体呈不同程度增多。其中ＶＩＰ－ＩＲ阳性神经纤维积分光密度较对照组增加２５．３％,而神经胞体积分光密度只增加８．１％。结果提示：１．大鼠心内神经节中ＶＩＰ－ＩＲ阳性神经纤维可能有两个来源：即心内ＶＩＰ－ＩＲ阳性神经节细胞和心外副交感神经元;２．异丙肾上腺素对心脏的作用并非单一的直接作用,其中部分是通过影响心内神经节中肽能递质的变化而发挥间接作用。     

An immunohistochemical study of endocrine cells in the stomach of hypertensive rats.

Essential hypertension is a complex disease with both genetic and environmental determinants. The effect of spontaneous hypertension on the distribution and occurrence of somatostatin-, gastrin- and serotonin-immunoreactive cells in the fundus and pylorus of the rat stomach was examined by immunohistochemistry. The animals were killed by decapitation at 4 and 16 weeks of age (5 control rats and 5 hypertensive rats). Endocrine cells generally increase in number in hypertensive rats as compared to control rats. However, the detailed responses of endocrine cells to hypertension depend on the cell type, region of gastric mucosa and age of animals. The present results suggest that hypertension has an influence on the intrinsic regulatory system by endocrine cells control in the rat stomach.     

Pharmacology of the Adenosine A3 Receptor in the Vasculature and Essential Hypertension

Background

Essential hypertension is considered to be a multifactorial disorder and its aetiology has yet to be clearly identified. As the adenosine receptors have a significant role in mediating vasodilation, alterations in their structures or signalling pathways may be involved in the development of hypertension. This study aimed to measure the expression of adenosine A₃ receptors in a range of cardiovascular tissues and determine whether they could be altered with essential hypertension, and to functionally test responses to adenosine A₃ receptor agonists in coronary blood vessels using the isolated perfused heart preparation.

Methods

mRNA samples from cardiovascular tissues and a range of blood vessels were collected from 10 week old male spontaneously hypertensive rats and age-gender matched Wistar rats (n = 8). The Langendorff heart perfusion preparation was used to characterise adenosine A₃ receptor mediated coronary vasodilation in the rat heart.

Results

Adenosine A₃ receptor agonists induced coronary vasodilation. The expression of adenosine A₃ receptors in cardiovascular tissues was altered in a tissue-specific pattern. Specifically, down-regulation of adenosine A₃ receptor expression occurred in hypertensive hearts, which might be associated with attenuated vasodilator responses observed in coronary vessels to adenosine A₃ receptor agonists.

Conclusions

This study demonstrated alterations in the expression of adenosine A₃ receptors occurred in a tissue specific mode, and reduced adenosine A₃ receptor mediated coronary vasodilation in hearts from spontaneously hypertensive rats. Our findings with regard to changes in the adenosine A₃ receptor in hypertensive hearts suggest that adenosine A₃ receptor might play a role in the physiopathology of essential hypertension and potentially open the way to pharmacologic manipulation of vasomotor activity by the use of adenosine A₃ receptor agonists.     

Expression of certain proteins in the subfornical organ and cerebrospinal fluid of spontaneously hypertensive rats

The objective of this study was to analyze the proteins in the cerebrospinal fluid of spontaneously hypertensive rats and to study their possible role in the relationship between hydrocephalus, arterial hypertension and variations in the subfornical organ. Brains and cerebrospinal fluid from control Wistar-Kyoto rats and spontaneously hypertensive rats sacrificed with chloral hydrate were used. Cerebrospinal fluid and extract of subfornical organ were processed by protein electrophoresis. Antisera against protein bands of 141, 117 and 48 kDa and Concanavalin A were used for immunohistochemical and western blot study of the subfornical organ, adjacent circumventricular structures and cerebrospinal fluid. Ventricular dilation in the spontaneously hypertensive rats and the presence of quite a lot of protein bands in the cerebrospinal fluid of the hypertensive rats, which were either not observed or scarcely present in the cerebrospinal fluid of the Wistar-Kyoto rats, were confirmed. The subfornical organ, third ventricle ependyma and choroideus plexus showed immunoreactive material for antibodies against 141kDa, 117 and 48 kDa proteins band (anti-B1, anti-B2 and anti-B3). The larger amount of the immunoreactive material was found in the subfornical organ of the spontaneously hypertensive rat. Our results and the alterations observed by other authors in the subfornical organ in hydrocephalic and hypertensive rats support the possibility that this circumventricular organ, some proteins of the cerebrospinal fluid and ventricular dilation could be connected with the physiopathology of this type of hypertension.     

The borderline hypertensive rat (BHR): a new model for the study of environmental factors in the development of hypertension

While many studies have attempted to produce hypertension through the use of various environmental stressors, few have succeeded in producing chronic elevations in blood pressure beyond levels considered to be borderline hypertensive (140-160 mm Hg systolic). The problem with most studies stems from the use of genetically normotensive animals and the selection of stressors to which animals readily adapt. A new approach is suggested, which recognizes the role of genetics in human essential hypertension. Animals with one hypertensive parent do not develop spontaneous hypertension but show a more sensitive cardiovascular response to environmental stressors than animals with normotensive parents. Preliminary studies revealed that animals with a mixed genetic history of hypertension develop spontaneous borderline hypertension. When subjected to shock-shock conflict, these borderline hypertensive rats (BHR) developed permanent hypertension that failed to abate even after a ten-week, shock-free recovery period. The hypertension was accompanied by elevated heart weight to body weight ratios and by significant cardiac pathology. Subsequent work has demonstrated that these animals also become hypertensive when fed a high-sodium diet. Finally, in a series of exercise studies, we found that BHRs subjected to a shock stressor were protected against stress-induced hypertension if they exercised daily. The potential of this model for studies of the mechanisms by which environmental variables produce permanent hypertension is discussed.     

Peripheral neurogenic mechanisms in deoxycorticosterone acetate--salt hypertension in the rat

The finding of elevated circulating catecholamine levels in experimental and human hypertension suggests an active sympathoadrenal participation in the pathogenesis of hypertension. In deoxycorticosterone acetate (DOCA)-salt hypertensive rats and in spontaneously hypertensive rats (SHR) the sympathoadrenal reactivity was found to be potentiated in response to various stimuli suggesting alterations in baroreflex functions or in local modulatory mechanisms. Several studies have suggested an attenuation of the alpha 2-presynaptic or local inhibitory mechanism and a potentiation of the beta 2-facilitatory presynaptic mechanism in the peripheral sympathetic system, thus possibly explaining the potentiated sympathoadrenal reactivity in those hypertensive animals. At postsynaptic adrenergic sites, beta-adrenoceptor numbers were reported to be decreased, whereas alpha 1-adrenoceptor numbers were unchanged in the cardiovascular system of DOCA hypertensive rats, thus favoring a dominance of alpha 1-postsynaptic responses in those animals. In support of this concept, the production of inositol monophosphate, used as an index of inositol triphosphate production, was found to be markedly enhanced following norepinephrine-induced alpha 1-stimulation in atria and ventricles as well as in mesenteric and femoral arteries of DOCA-salt hypertensive rats thus suggesting an increased reactivity of the second messenger system linked to alpha 1-adrenoceptors. Since similar abnormalities were also observed in SHR and in human hypertension, it thus appears that an imbalance between alpha- and beta-postsynaptic receptors may exist in various forms of hypertension. These studies therefore suggest the existence of multiple abnormalities in pre- and post-synaptic adrenergic mechanisms in experimental and human hypertension.(ABSTRACT TRUNCATED AT 250 WORDS)     

The Orexin System and Hypertension

In this review, we focus on the role of orexin signaling in blood pressure control and its potential link to hypertension by summarizing evidence from several experimental animal models of hypertension. Studies using the spontaneously hypertensive rat (SHR) animal model of human essential hypertension show that pharmacological blockade of orexin receptors reduces blood pressure in SHRs but not in Wistar–Kyoto rats. In addition, increased activity of the orexin system contributes to elevated blood pressure and sympathetic nerve activity (SNA) in dark-active period Schlager hypertensive (BPH/2J) mice, another genetic model of neurogenic hypertension. Similar to these two models, Sprague-Dawley rats with stress-induced hypertension display an overactive central orexin system. Furthermore, upregulation of the orexin receptor 1 increases firing of hypothalamic paraventricular nucleus neurons, augments SNA, and contributes to hypertension in the obese Zucker rat, an animal model of obesity-related hypertension. Finally, we propose a hypothesis for the implication of the orexin system in salt-sensitive hypertension. All of this evidence, coupled with the important role of elevated SNA in increasing blood pressure, strongly suggests that hyperactivity of the orexin system contributes to hypertension.     

Intrathecal PACAP-38 causes increases in sympathetic nerve activity and heart rate but not blood pressure in the spontaneously hypertensive rat

The rostral ventrolateral medulla contains presympathetic neurons that project monosynaptically to sympathetic preganglionic neurons (SPN) in the spinal cord and are essential for the tonic and reflex control of the cardiovascular system. SPN directly innervate the adrenal medulla and, via postganglionic axons, affect the heart, kidneys, and blood vessels to alter sympathetic outflow and hence blood pressure. Over 80% of bulbospinal, catecholaminergic (C1) neurons contain pituitary adenylate cyclase-activating polypeptide (PACAP) mRNA. Activation of PACAP receptors with intrathecal infusion of PACAP-38 causes a robust, prolonged elevation in sympathetic tone. Given that a common feature of most forms of hypertension is elevated sympathetic tone, this study aimed to determine in the spontaneously hypertensive rat (SHR) and the Wistar Kyoto rat (normotensive control) 1) the proportion of C1 neurons containing PACAP mRNA and 2) responsiveness to intrathecal PACAP-38. We further investigated whether intrathecal infusion of the PACAP antagonist, PACAP(6-38), reduces the hypertension in the SHR. The principal findings are that 1) the proportion of PACAP mRNA-containing C1 neurons is not different between normotensive and hypertensive rats, 2) intrathecal PACAP-38 causes a strain-dependent, sustained sympathoexcitation and tachycardia with variable effects on mean arterial pressure in normotensive and hypertensive rats, and 3) PACAP(6-38) effectively attenuated the effects of intrathecal PACAP-38, but had no effect alone, on any baseline variables. This finding indicates that PACAP-38 is not tonically released in the spinal cord of rats. A role for PACAP in hypertension in conscious rats remains to be determined.     

Functional and structural pattern of arterial responses in hereditary hypertriglyceridemic and spontaneously hypertensive rats in early stage of experimental hypertension

It has been shown that endothelium-derived nitric oxide (NO) plays an important role in regulation of vascular tone in the prenatal and early postnatal period. The aim of this paper was to determine the reactivity and accompanying structural changes in thoracic aorta from 4-week-old spontaneously hypertensive rats (SHR) and rats with hereditary hypertriglyceridemia (hHTG) in comparison with age-matched normotensive controls. For functional studies thoracic aorta was excised, cut into rings and mounted in organ baths for measurement of isometric contractile force. For morphological studies cardiovascular system of rats was perfused with glutaraldehyde fixative (at 100 mm Hg) via cannula placed in the left ventricle. Morphological changes of thoracic aorta were measured using light microscopy. Systolic blood pressure (SBP) in SHR (98+/-1 mm Hg) did not significantly differ from that of age-matched control rats (95+/-4 mm Hg), but was slightly increased in hHTG rats (110+/-2 mm Hg, P<0.05). Heart weight/body weight ratio was higher in SHR and hHTG rats than in control group indicating the hypertrophy of the heart in both models of hypertension. Endothelium-dependent relaxation of aorta induced by acetylcholine was preserved in all groups and did not differ from that in control normotensive rats. The maximal isometric contraction of thoracic aorta to noradrenaline (NA) was reduced in hypertensive groups and the concentration-response curves to NA were shifted to the right indicating increased sensitivity of smooth muscle to NA. The values of wall thickness and cross sectional area as well as inner diameter of thoracic aorta in SHR and hHTG rats were significantly decreased in comparison to control groups. Endothelial dysfunction seems to be absent in all young rats before development of hypertension. In conclusion, our observations indicate that in early stage of experimental hypertension NO-dependent relaxation is preserved so that putative impairment of this function provides no significant pathogenic contribution to the onset of hypertension in these two experimental models.     

Hereditary hypertriglyceridemic rat: a suitable model of cardiovascular disease and metabolic syndrome?

Hypertriglyceridemia and hypertension seem to be very important cardiovascular risk factors. The Prague hereditary hypertriglyceridemic (hHTG) rat was developed as a model of human hypertriglyceridemia. It was demonstrated that these rats are not obese, they are hypertensive and insulin resistant and they have some disturbances in glucose metabolism. Several QTLs were identified for blood pressure, its particular components (dependent on major vasoactive systems) and plasma triglycerides throughout the genome of hHTG rats by using of F(2) hybrids strategy. It is evident that hHTG rats are a suitable model for the study of metabolic disturbances in relation to blood pressure as well as for the search of genetic determinants of these abnormalities. Numerous abnormalities of blood pressure regulation as well as alterations in the structure and function of cardiovascular apparatus (heart, conduit and resistance arteries) were found in hHTG rats. A special attention was paid to possible changes in the efficiency of various vasoactive systems such as nitric oxide, renin-angiotensin-aldosterone system and sympathetic nervous system, which seem to contribute substantially to cardiovascular and/or metabolic abnormalities observed in Prague hereditary hypertriglyceridemic rats.     

Altered regulation of renal nitric oxide and atrial natriuretic peptide systems in angiotensin II-induced hypertension

The present study was aimed to determine whether there is an altered role of local nitric oxide (NO) and atrial natriuretic peptide (ANP) systems in the kidney in association with the angiotensin (Ang) II-induced hypertension. Male Sprague-Dawley rats were used. Ang II (100 ng·min?1·kg?1) was infused through entire time course. Thirteenth day after beginning the regimen, kidneys were taken. The protein expression of NO synthase (NOS) and nitrotyrosine was determined by semiquantitative immunoblotting. The mRNA expression of components of ANP system was determined by real-time polymerase chain reaction. The activities of soluble and particulate guanylyl cyclases were determined by the amount of cGMP generated in responses to sodium nitroprusside and ANP, respectively. There developed hypertension and decreased creatinine clearance in the experimental group. The protein expression of eNOS, nNOS and nitrotyrosine was increased in the cortex, while that of iNOS remained unaltered. The urinary excretion of NO increased in Ang II-induced hypertensive rats. The catalytic activity of soluble guanylyl cyclase was blunted in the glomerulus in Ang II-induced hypertensive rats. The mRNA expression of ANP was increased in Ang II-induced hypertensive rats. Neither the expression of NPR-A nor that of NPR-C was changed. The protein expression of neutral endopeptidase was decreased and the activity of particulate guanylyl cyclase was blunted in the glomerulus and papilla in Ang II-induced hypertensive rats. In conclusion, the synthesis of NO and ANP was increased in the kidney of Ang II-induced hypertension, while stimulated cGMP response was blunted. These results suggest desensitization of guanylyl cyclase in the kidney of Ang II-induced hypertensive rats, which may contribute to the associated renal vasoconstriction and hypertension.     

Plasma concentrations of endothelin-1 in spontaneously hypertensive rats and DOCA-salt hypertensive rats

To investigate the possible involvement of endothelin-1 (ET-1), an endothelium-derived potent vasoconstrictor peptide, in the pathophysiology of hypertension, plasma ET-1 levels in 15-week-old spontaneously hypertensive rats (SHR) and DOCA-salt hypertensive rats were measured with a sandwich-type enzyme immunoassay. The vasocontractile effect of ET-1 in aortic helical preparations was significantly more sensitive in DOCA-salt hypertensive rats than in control sham-operated rats, but plasma levels of ET-1 did not differ between them. Plasma ET-1 levels in genetically hypertensive rats (SHR and stroke-prone SHR) were significantly lower than those in age-matched normotensive Wistar-Kyoto (WKY) rats. The plasma concentrations of big ET-1, a precursor of ET-1, in both SHR and SHR-SP were significantly lower than those of WKY, suggesting that the production of ET-1 is decreased in rats of genetic hypertension. Although the vascular reactivity to ET-1 increased in both DOCA-salt hypertensive and genetically hypertensive rats, present findings of the plasma ET-1 levels suggest that the role of ET-1 in the vascular control system may be different in DOCA-salt hypertensive rats and genetically hypertensive rats.