Effects of sinoaortic baroreceptor denervation on blood pressure and PNMT activity in medulla oblongata and spinal cord of normotensive and genetically hypertensive rats

The effects of sinoaortic denervation on arterial blood pressure and central activity of phenylethanolamine-N-methyl transferase (PNMT, the last enzyme in adrenaline biosynthesis), were compared in normotensive Wistar-Kyoto rats (WKY), spontaneously hypertensive rats (SHR) and stroke-prone spontaneously hypertensive rats (SHR-SP). Denervation of the arterial baroreceptors caused immediate increases in mean arterial blood pressure (MAP) in all three strains which were maximal at 90 min (32 mmHg in WKY, 51 mmHg in SHR and 80 mmHg in SHR-SP). Spinal cord PNMT activity increased above sham-operated levels in WKY at 90 min, but PNMT levels in SHR and SHR-SP, already significantly higher than in WKY, were not altered acutely after sinoaortic denervation. Over a seven day period after baroreceptor denervation, MAP rose by 15 mmHg in WKY and PNMT activity was about 100% greater in spinal cord and ventral medulla. In the two genetically hypertensive strains sinoaortic denervation failed to produce a further sustained rise in pressure or and PNMT activity in the ventral medulla or spinal cord. We suggest that increased activity of bulbospinal adrenaline neurons contribute to the sustained elevation in pressure seen in intact SHR and SHR-SP, as well as in WKY after denervation of arterial baroreceptors.     

Catecholamine-related gene expression correlates with blood pressures in SHR

In this study we aimed to determine whether the levels of gene expression for phenylethanolamine-N-methyltransferase (PNMT), noradrenaline transporter (NAT), alpha1A-receptor (alpha1A-R), and alpha2A-receptor (alpha2A-R) vary with resting systolic blood pressure in spontaneously hypertensive rats (SHR) compared with normotensive Wistar-Kyoto (WKY) or Sprague-Dawley (SD) rats. Sites examined included central and peripheral regions associated with the control of arterial pressure. Twenty week old SD (n=6), WKY (n=6), and SHR (n=6) were used. Systolic blood pressure was measured using tail cuff plethysmography 2 weeks before tissue extraction. RNA was isolated and reverse-transcribed into cDNA. Gene expression levels were measured, using quantitative real time PCR, relative to the expression of GAPDH. PNMT, NAT, and alpha(1A)-R mRNA expression was significantly greater in SHR tissue samples compared with normotensives. In the rostral ventrolateral medulla, PNMT mRNA in SHR was 3 times greater than that in WKY (SHR: 0.82+/-0.02%; WKY: 0.29+/-0.02%). The amount of alpha(2A)-R mRNA was significantly lower in SHR compared with normotensives. For example, the level of alpha(2A)-R mRNA in spinal cord of SHR was 3 times less than that found in WKY (SHR: 1.85+/-0.04%; WKY: 3.26+/-0.07%). PNMT, NAT, and alpha(1A)-R mRNA levels were positively correlated with systolic blood pressure in all central tissue investigated. Conversely, alpha2A-R mRNA levels in central sites were negatively correlated with systolic blood pressure. Clearly, a decrease in central alpha2A-R and an increase in alpha1A-R is consistent with the elevated blood pressure and sympathetic activity observed in SHR.     

Vascular, ganglia and cardiac catecholamine disposition in the spontaneously hypertensive rat and in the stroke-prone spontaneously hypertensive rat.

We have examined the disposition of catecholamines in cardiac tissue, mesenteric arteries and ganglia from normotensive Wistar-Kyoto rats (WKY), spontaneously hypertensive rats (SHR) and stroke-prone spontaneously hypertensive rats (SHR-SP). The norepinephrine (NE) contents of mesenteric arteries from all three strains of rats adhered to a pattern which was characterized by the largest concentrations of the catecholamine in arteries from SHR and SHR-SP rats, and the smallest values present in mesenteric arteries from WKY rats. This pattern of NE disposition was not present in either ganglia or cardiac tissue from the three strains of rats. The results highlight two features of the hypernoradrenergic hypothesis in the SHR. Firstly, the enhanced NE contents observed in the blood vessels of the two hypertensive strains are not consistently increased in sympathetic cell bodies or cardiac tissue. Secondly, the significantly enhanced concentrations of NE in the vasculature parallel the elevated direct arterial blood pressure in the two strains of hypertensive rat when compared with the normotensive strain.     

Cardiac content and plasma concentration of atrial natriuretic polypeptide (ANP) in spontaneously hypertensive rats (SHR)

The cardiac content and plasma concentration of atrial natriuretic polypeptide (ANP) in hypertensive rats were measured by using radioimmunoassay for ANP. The animals used in this study were young (5-week-old) and adult (12- to 14-week-old) spontaneously hypertensive rats (SHR), stroke-prone SHR (SHR-SP) and normotensive control Wistar-Kyoto rats (WKY). Most immunoreactive ANP in the cardiac extract of the hypertensive rats (both SHR and SHR-SP) was found to be predominantly gamma-form as well as that of WKY. Cardiac ANP content in adult SHR and SHR-SP was significantly lower than in adult WKY (p less than 0.01), although there were no differences among three groups in young rats. Similar tendencies were also observed for plasma ANP concentration. The level of plasma in adult hypertensive rats was significantly lower or tended to be lower than in adult normotensive rats. Furthermore, a high negative correlation was present between blood pressure and cardiac ANP content (r = 0.748, p less than 0.01) and between blood pressure and plasma ANP concentration (r = 0.608, p less than 0.01) in all adult rats but there were no such relationships in young rats. The present study suggests that atrial natriuretic polypeptide may contribute to the pathogenesis or maintenance of high blood pressure in the genetic hypertensive rats.     

Functional Evidence of Inhibitory Reno-renal Reflexes in Spontaneously Hypertensive Rats

The experiments were performed to study the role of the renal nerves and the reno-renal reflexes in the control of water and sodium excretion in spontaneously hypertensive rats (SHR) compared to their normotensive controls, Wistar Kyoto (WKY) rats. Unilateral renal denervation in anaesthetized animals produced a slight, progressive decrease in arterial pressure in both WKY and SHR rats. The glomerular filtration rate temporarily increased in the kidney that underwent the denervation in the SHR group only. After unilateral renal denervation a sharp increase in water and sodium excretion from the ipsilateral kidney was observed in both WKY and SHR. One hour after the denervation, the percent changes in water and sodium excretion were smaller in WKY (+32 ± 19% and +24 ± 17%) than in SHR rats (+84 ± 15% and +93 ± 20%). In the kidney contralateral to the denervation a reduction in water and sodium excretion was observed and this reduction was prompter in SHR than in WKY rats. One hour after the denervation, the percent changes in water and sodium excretion were similar in WKY (-21 ± 8% and -18 ± 7%) and SHR (-19 ± 6% and -19 ± 7%). In control groups, sham denervation did not cause significant changes in glomerular filtration rate, and urinary water and sodium excretion. Arterial pressure slightly and progressively decreased in both control groups. Electrical stimulation of the efferent renal nerves performed in WKY and SHR produced similar decreases in renal blood flow, glomerular filtration rate, and water and sodium excretion in the two groups for the same frequencies of stimulation. As this finding indicates that renal targets in hypertensive rats are normally responsive to the neural drive, our data demonstrate that renal responses to unilateral renal denervation in hypertensive rats are equal to the responses observed in normotensive rats. Our results indicate that tonically active inhibitory reno-renal reflexes normally operate in spontaneously hypertensive rats.     

Altered turnover of polyphosphoinositides in the erythrocyte membrane of the spontaneously hypertensive rat

The metabolism of inositol phospholipids of the erythrocyte membrane was compared in normotensive Wistar-Kyoto (WKY), spontaneously hypertensive (SHR), and stroke-prone SHR (SHR-SP) rats. This was performed on isolated ghost membranes by measuring the incorporation of 32P from [ gamma-32P ] adenosine triphosphate (ATP) into the diphosphoinositides (DPI) and the triphosphoinositides (TPI) which were the only 32P-labeled phospholipids. 32P-labeling of TPI was altered in adult and 3-week-old SHR as well as in SHR-SP compared to WKY controls; the radioactivity associated with TPI in hypertensive rats was about 30% lower than that associated with TPI in age-matched normotensive controls. By contrast, the radioactivity associated with DPI was similar in both hypertensive and normotensive rats. Measurement of the phosphoinositide distribution in both SHR and WKY indicates that the change observed in 32P-TPI could not be accounted for by a reduced phosphatidylinositol content in SHR membrane. Measurement of the Mg2+-activated TPI-phosphomonoesterase and of the Ca2+-activated polyphosphoinositide phosphodiesterase activities did not show any significant difference between SHR and WKY. It thus appears that the altered phosphoinositide metabolism observed in hypertensive rats was a consequence of some alteration in the activity of kinases which are responsible for the conversion of phosphatidylinositol into DPI and TPI. These results also suggest that the defect in phosphoinositide metabolism observed in genetically hypertensive rats was not a consequence of the blood pressure elevation and could be related to the pathogenesis of hypertension.     

N-domain angiotensin I-converting enzyme with 80 kDa as a possible genetic marker of hypertension

We have previously described angiotensin I-converting enzyme (ACE) forms in urine of normotensive (190 and 65 kDa) and hypertensive patients (90 and 65 kDa, N-domain ACEs). Based on the results described above, experimental and genetic models of hypertension were investigated to distinguish hemodynamic and genetic influence on the generation of ACE profile in urine: Wistar-Kyoto and Brown Norway rats (WKY and BN), spontaneously and stroke-prone spontaneously hypertensive rats (SHR and SHR-SP), one kidney/one clip rats (1K1C), deoxycorticosterone acetate (DOCA) salt-treated and untreated rats, and enalapril-treated SHR (SHRen). Two peaks with ACE activity were separated from the urine of WKY and BN rats submitted to an AcA-44 column, WK-1/BN-1 (190 kDa), and WK-2/BN-2 (65 kDa), as described for urine of normotensive subjects. The same results were obtained for urine of 1K1C and DOCA salt-treated and untreated rats, analyzed to evaluate the influence of hemodynamic factors in the ACE profile in urine. The urine from SHR, SHR-SP, and SHRen presented 80 (S-1, SP-1, Sen-1) and 65 (S-2, SP-2, Sen-2) kDa ACE forms, differing from the urine profile of normotensive rats, but similar to that described for hypertensive patients. The presence of 80 kDa ACE in urine of SHR, SHR-SP, and SHRen and its absence in urine of experimental hypertensive rats (1K1C and DOCA salt) support the hypothesis that this enzyme could be a possible genetic marker of hypertension. Taken together, our results provide evidence that ACE forms with 90/80 kDa isolated from the urine of hypertensive subjects and genetic hypertensive animals behaves as a possible genetic marker of hypertension and not as a marker of high blood pressure.     

Regional brain concentrations of calcitonin gene-related peptide in spontaneously hypertensive and normotensive Wistar-Kyoto rats

The regional brain and spinal cord concentrations of calcitonin gene-related peptide (CGRP) were measured in age-matched (22-23-week-old) spontaneously hypertensive rats (SHR) and normotensive Wistar-Kyoto (WKY) rats. The highest concentration of CGRP in the WKY rats was in the spinal cord (172 +/- 9 pmol/g), followed by the medulla oblongata/pons (88 +/- 5 pmol/g). The relative order of distribution in the remaining regions was: hypothalamus (12.6 +/- 0.8 pmol/g) = striatum greater than thalamus greater than midbrain = hippocampus greater than cortex (2.1 +/- 0.3 pmol/g). The concentration of CGRP in the cerebellum was at the level of the assay's sensitivity (0.5 pmol/g). The relative order of distribution in the SHR strain was essentially the same. However, in comparison with the WKY rats, the SHR had significantly lower levels of CGRP in the hippocampus (-47%), striatum (-49%) and medulla oblongata/pons (-24%), and in the spinal cord (-24%). In younger age-matched (16-17-week-old) rats, the spinal cord and medulla oblongata/pons concentrations of CGRP were also lower in SHR than in WKY rats. CGRP is a putative neurotransmitter which, when administered centrally or peripherally, has potent cardiovascular effects. The reduced levels of this peptide may be an important factor in the cardiovascular and/or behavioural abnormalities of the SHR strain.     

Age-related changes in neuropeptide Y immunoreactivity (NPY-ir) in the cortex and spinal cord of spontaneously hypertensive (SHR) and normotensive Wistar-Kyoto (WKY) rats

The concentrations of neuropeptide Y immunoreactivity (NPY-ir) were measured in the cortex and cervical, thoracic and lumbar spinal cord of 8-, 18- and 31-week-old normotensive Wistar-Kyoto (WKY) rats and spontaneously hypertensive rats (SHR). This peptide was measured using a highly sensitive and specific radio-immunoassay (RIA) developed in our laboratory. The concentrations of NPY-ir in the cortex, cervical and thoracic spinal cord were significantly different between the two strains, with the levels being consistently lower in the SHR strain independent of age. While there was no obvious change in the levels of NPY-ir in the cortex with increasing age, there was a general trend for the levels to fall in all three spinal cord regions. The rate of decrease of NPY-ir in the thoracic spinal cord appeared greater in the SHR compared with the WKY rats. These biochemical differences observed in the cortex and thoracic spinal cord of SHR and WKY rats may be related to the behavioural and blood pressure differences observed in these strains.     

Decreased hypothalamic and medullary GABA turnover in spontaneously hypertensive rats.

OBJECTIVE: The aim was to assess whether Gamma-aminobutyric acid (GABA) neurone activities in the central nervous system, especially in the hypothalamus and medulla oblangata, are altered in hypertension. METHODS: Central GABA content and turnover rate were measured in spontaneously hypertensive rats (SHR) and their normotensive Wistar Kyoto controls (WKY). GABA content was determined with high performance liquid chromatography, and in vivo GABA turnover rates were estimated by GABA accumulation after injection of amino-oxyacetic acid, a selective inhibitor of GABA degrading system. Two groups of nine week old male rats (32 SHR and 32 WKY) were used. RESULTS: GABA concentrations in cerebrospinal fluid were lower in SHR than in WKY. Since hypothalamus and medulla oblongata are the possible active sites of this system, basal GABA contents and in vivo GABA turnover rates were measured in hypothalamus and medulla oblongata. Basal GABA content in the medulla oblongata and hypothalamus was almost equal in SHR and WKY. On the other hand, GABA turnover rates were significantly lower in SHR than in WKY in both the hypothalamus and the medulla. CONCLUSIONS: Since it is known that GABA is an inhibitory neurotransmitter in the central nervous system and that it controls autonomic and cardiovascular activities, the findings suggest that the decreased hypothalamic and medullary GABAergic activities may permit sympathetic hyperactivity to contribute to the increase in blood pressure in SHR.     

Phospholipase C genes display restriction fragment length polymorphisms between the genomes of normotensive and hypertensive rats.

The genomic loci of four distinct phospholipase C genes (PLC-beta, PLC-gamma I, PLC-delta and PLC-gamma II) were examined for restriction fragment length polymorphisms (RFLPs) between the genomes of three normotensive [Sprague-Dawley, Donryu and Wistar-Kyoto (WKY)] and two closely related hypertensive [spontaneously hypertensive (SHR) and SHR stroke-prone (SHR-SP)] rat strains. The RFLPs observed between SHR and WKY were classified into three types. Type I RFLPs are those observed at 4.3 kilobase (kb) and 1.9 kb by AvaI digestion for PLC-gamma probe and at 1.9 kb by AccI digestion for PLC-beta probe, where RFLP banding patterns are conserved in two hypertensive (SHR and SHR-SP) and one normotensive (Sprague-Dawley) strains. Type II RFLPs are those observed by AccI, BamHI, EcoRI and PstI digestions for PLC-beta probe, where RFLP pattern observed in SHR is shared by one normotensive (Sprague-Dawley) strain but not by SHR-SP, WKY or Donryu rats. Type III RFLPs are those detected at 6.3 kb band by Bg/II digestion for PLC-beta probe and at 1.0 kb by BamHI digestion for PLC-gamma II probe, where RFLP pattern observed in SHR is shared by two normotensive rats other than WKY. No RFLP was found for PLC-gamma I probe after testing 13 restriction enzymes. Since PLC plays a pivotal role in regulating the intracellular calcium concentration and the intracellular signal transduction, these RFLPs may offer a valuable tool for the analysis of genomic predisposition for hypertension.(ABSTRACT TRUNCATED AT 250 WORDS)     

Age dependent changes in myosin ATPase activity in the myocardium of spontaneously hypertensive rats

Male spontaneously hypertensive rats (SHR) and age matched Wistar Kyoto normotensive (WKY) rats of 5 weeks, 16 weeks, and 52 weeks of age were used to determine whether duration of hypertension has any effect on contractile protein ATPase and myosin isoenzyme distribution. Myofibrils, actomyosin, and myosin were isolated from the left ventricles of WKY rats and SHR and assayed for myosin ATPase activity and myosin isoenzyme distribution. Myofibrillar ATPase activity was assayed at various free [Ca++] ranging from 10(-7) to 10(-5) mol X litre-1. Ca++ stimulated actomyosin ATPase activity was determined at several Ca++ concentrations both at low ionic strength, which favours actin-myosin interaction, and at high ionic strength, which diminishes actin interaction with myosin. Purified myosin ATPase activity was assayed in the presence of K+-EDTA and in the presence of several concentrations of Ca++. Actin activated myosin ATPase activity was assayed using 26 mumol X litre-1 skeletal muscle actin. Under all these assay conditions no differences were observed in the contractile protein ATPase activity between SHR and WKY rats in any age group. On the other hand, in both SHR and WKY rats the contractile protein ATPase activity under all assay conditions was significantly decreased in 52 week old rats compared with 5 week old rats. The predominant myosin isoenzyme was Vi in 5 week and 16 week old WKY rats and SHR. In 52 week old WKY rats and SHR, however, significant amounts of isoenzymes V2 and V3 were present along with V1. Percentage distribution of V1, V2, V3 isoenzymes calculated from densitometric scans of gels did not show any differences between WKY rats and SHR in any age group. These results suggest that neither myosin ATPase activity nor myosin isoenzyme distribution is altered in the moderately hypertrophied left ventricles of SHR. Moreover, the data indicate that the myocardium of SHR, despite the persistence of pressure overload, undergoes a similar decrease in myosin ATPase activity and an increase in myosin isoenzyme V3 to age matched normotensive WKY rats.     

Sodium responsiveness of central alpha 2-adrenergic receptors in spontaneously hypertensive rats

The responsiveness of central nervous system alpha 2-adrenergic receptors in the neural control of renal function was compared in conscious spontaneously hypertensive rats (SHR) and normotensive Wistar-Kyoto rats (WKY) on normal or high sodium intake (3-4 weeks of 1% NaCl for drinking). The responsiveness of central alpha 2-adrenergic receptors was determined by comparing among groups the dose-response curves for the effects of cumulative intracerebroventricular injections of guanabenz (5, 25, and 125 micrograms) on changes in mean arterial pressure, renal sympathetic nerve activity, and urinary sodium excretion. Guanabenz altered mean arterial pressure similarly in SHR on normal or high sodium intake and in WKY on normal or high sodium intake. High sodium intake shifted the guanabenz-renal sympathetic nerve activity and guanabenz-urinary sodium excretion dose-response curves to the left in SHR and to the right in WKY. The dose-response curves between SHR and WKY on normal sodium intake were similar. Surgical renal denervation or pretreatment with an alpha 2-adrenergic receptor antagonist (rauwolscine, 30 micrograms i.c.v.) attenuated the ability of guanabenz to inhibit renal sympathetic nerve activity or increase urinary sodium excretion in SHR and WKY on either normal or high sodium intake. We conclude that the responsiveness of central nervous system alpha 2-adrenergic receptors regarding the neural control of renal function is increased by high sodium intake in conscious SHR, but not in conscious normotensive WKY.     

Effect of Sodium Chloride on Opiate Receptor Binding in Spontaneously Hypertensive Rats: Dependence on Age

The effect of 100 mM sodium chloride on the binding of [³H]-naltrcxone to rat brain opiate receptors in spontaneously hypertensive (SHR) and normotensive (WKY) rats was studied. The percentage increase in binding in the presence of sodium chloride did not vary with age in WKY rats. Brain homogenates from 4 week old SHR rats incubated with 100 mM sodium chloride exhibited a similar increase in binding compared to age matched WKY rats. In contrast, brain preparations from 6, 14 and 20 week old SHR rats were more sensitive to sodium chloride, and the increase in binding of [³H]-naltrcxone was significantly greater in these animals than in corresponding normotensive ones. Since blood pressure is increased in SHR rats compared to WKY rats at these ages, these results suggest that elevated blood pressure may be correlated with an increase in opiate receptor sensitivity to sodium chloride. The effect of In vivo sodium chloride was examined by feeding the animals a diet containing 4% salt. This concentration of salt did not significantly alter the binding of [³H]-naltrcxone to rat brain homogenates prepared from 8 week old SHR rats. These results suggest that higher levels of sodium chloride and longer exposure to the diet may be required to observe the salt sensitivity produced by 100 mM salt in the In vitro radioreceptor assay.     

Attenuation of angiotensin type 2 receptor function in the rostral ventrolateral medullary pressor area of the spontaneously hypertensive rat

We hypothesized that blockade of angiotensin II type 2 receptors (AT₂Rs) in the rostral ventrolateral medullary pressor area (RVLM) may elicit sympathoexcitatory responses which are smaller in hypertensive rats compared to normotensive rats. This hypothesis was tested in urethane-anesthetized, artificially ventilated male 14-week-old spontaneously hypertensive rats (SHR). Age-matched male Wistar–Kyoto rats (WKY) and Wistar rats were used as controls. PD123319 (AT₂R antagonist) was microinjected into the RVLM and mean arterial pressure (MAP), heart rate (HR) and greater splanchnic nerve activity (GSNA) were recorded. Increases in MAP, HR and GSNA elicited by unilateral microinjections of PD123319 into the RVLM were significantly smaller in SHR when compared with those in WKY and Wistar rats. Unilateral microinjections of l-glutamate (l-Glu) into the RVLM elicited greater increases in MAP and GSNA in SHR compared to those in WKY. AT₂R immunoreactivity was demonstrated in the RVLM neurons which were retrogradely labeled from the intermediolateral cell column (IML) of the spinal cord. These results indicate that AT₂Rs are present on the RVLM neurons projecting to the IML and their blockade results in sympathoexcitatory responses. Activation of AT₂Rs has an inhibitory influence in the RVLM and these receptors are tonically active. Attenuation of the function of AT₂Rs in the RVLM may play a role in genesis and/or maintenance of hypertension in SHR.     

Central alpha-adrenoceptors during the development of hypertension in rats on high and low salt intake

Our purpose was to investigate the binding characteristics of central alpha-adrenoceptors during the early stages of the development of hypertension in rats on high and low salt (NaCl) intake. We measured alpha 1-[( 3H]prazosin) and alpha 2-[( 3H]rauwolscine) binding in membranes of the hypothalamus and medulla oblongata of six groups of young Wistar-Kyoto (WKY) rats, spontaneously hypertensive rats (SHR) and subtotally nephrectomized WKY (SN) rats with mean arterial blood pressure (MAP) ranging from normotensive to hypertensive levels after 1 week of salt restriction or loading. In the hypothalamus the SN-high salt rats and both SHR groups had elevated alpha 1-number but there was no change in alpha 2-number. Moreover, MAP was positively correlated with mean hypothalamic alpha 1-number in the six groups. In the medulla oblongata alpha 1-number was unaffected. However, high salt diet influenced medullary alpha 2-binding in the opposite manner in WKY rats versus SN rats and SHR. In these latter groups the affinity was increased and the number decreased in response to high salt intake. Furthermore, a positive correlation between MAP and mean alpha 1:alpha 2 ratio existed in both the hypothalamus and the medulla of the six groups. The data suggest that hypothalamic alpha 1-binding capacity was increased in SHR due principally to a genetic condition which is mimicked by salt loading in the SN rats. Medullary alpha 2-adrenoceptors of WKY, which remained normotensive despite salt loading, responded differently to high salt intake than those of the SN and SHR, whose blood pressure rose significantly.(ABSTRACT TRUNCATED AT 250 WORDS)     

Effect of Red Blood Cells and Hemoglobin on Spontaneously Hypertensive and Normotensive Rat Aortas

Experiments were designed to compare the contractile effect of red blood cells (RBC) on aortic rings with and without endothelium from normotensive Wistar-Kyoto (WKY) and spontaneously hypertensive (SHR) rats. Red blood cells of 4 week old WKY and SHR rats induced a negligible increase in tension of aortic rings, either with or without endothelium, being slightly more effective in SHR rats. However, red blood cells of 16 week old rats increased tension of WKY and SHR aortic rings, with endothelium at this age being more pronounced then red blood cells in 4 week old animals. The contractions induced by WKY and SHR red blood cells both in WKY and SHR aortic rings without endothelium at this age are significantly greater compared to the effect on aortic rings with endothelium. Red blood cell ghosts of rats of both strains increased the tension of the rings without endothelium of SHR aorta to near 50% of those induced by red blood cells, whereas they were ineffective in aortic rings without endothelium of WKY rats. Oxyhemoglobin increased the tension of 16 week SHR aortic rings both with and without endothelium, whereas the effect on the rings of WKY rats was negligible. This increase in tension was inhibited by BM 13505, nordihydroguaiaretic acid, and indomethacin in SHR rings both with and without endothelium, demonstrating an eicosanoid involvement in oxyhemoglobin-induced contractions. Hemoglobin or its metabolites may be involved in development or in maintenance of spontaneous hypertensin.     

Augmented central cholinergic mechanisms in spontaneously hypertensive rats. Involvement of deranged noradrenergic mechanisms in the brain

Intracerebroventricular (ICV) injections of carbachol produced biphasic blood pressure responses consisting of initial vasodepression of short duration followed by a sustained pressor phase, which were accompanied by corresponding changes in sympathetic nerve activity in normotensive outbred-Wistar rats (NT) under urethane-anesthesia. In both normotensive Kyoto Wistar rats (WKY) and spontaneously hypertensive rats (SHR), on the other hand, carbachol elicited purely pressor responses, and accompanying sympathetic nerve activity was little affected. The magnitude of the pressor responses was larger in SHR than in WKY or NT rats. Spinal sectioning did not affect the magnitude of the pressor responses. Vasopressor responses to intravenous injections of arginine-vasopressin were not significantly different between WKY and SHR. These results indicate that carbachol injected intracerebroventricularly produces vasopressor effects mainly by releasing pituitary hormones, probably vasopressin, and that augmented pressor responses in SHR may be due to excessive release of vasopressin. When central noradrenergic neurons had been destroyed with ICV injections of 6-hydroxydopamine in both NT and WKY rats, carbachol-induced vasopressor responses were markedly augmented and resulted in responses similar to those of SHR. These findings indicate that central noradrenergic vasodepressive neurons are deficient and that the augmented vasopressor responses to carbachol resulted from deranged central noradrenergic mechanisms in SHR.     

Stz-Induced Diabetes in Shr and Renovascular Hypertensive Rats: Dissociation Between Changes in Arterial Pressure and Vascular Collagen Synthesis

Streptozotocin (STZ)-induced diabetes depresses the rate of vascular collagen synthesis in the spontaneously hypertensive rat (SHR), but it also reduces arterial pressure (SAP) in this strain. We investigated this phenomenon further by comparing the SHR with the renovascular hypertensive (RVH) rat, because diabetes does not affect SAP in the latter model of hypertension. Renovascular hypertension was induced by clipping the left renal artery of Wistar-Kyoto (WKY) rats; sham-operated WKY were included as normotensive controls. Collagen synthesis of arterial tissue in vitro was quantified as prolyl hydroxylase activity and the rate of radioactive proline incorporation into collagen. Arterial collagen synthesis of nondiabetic SHR and RVH animals was elevated compared to that of the nonhypertensive WKY controls. STZ-induced diabetes (8 weeks) reduced SAP of SHR, but had no effect on SAP of either RVH or normotensive WKY rats. However, diabetes significantly depressed vascular collagen synthesis of both SHR and RVH rats, and, less consistently, of the WKY. The results strongly suggest that STZ-induced diabetes in SHR impairs arterial collagen synthesis independent of associated changes in arterial pressure.     

Role of Inducible Nitric Oxide Synthase in Rostral Ventrolateral Medulla in Blood Pressure Regulation in Spontaneously Hypertensive Rats

Nitric oxide (NO) in the brainstem modulates blood pressure (BP). Overexpression of inducible NO synthase (iNOS) in the rostral ventrolateral medulla (RVLM) increases BP in normotensive Wistar-Kyoto rats (WKY), but its role in BP regulation in spontaneously hypertensive rats (SHR) is unknown. We examined iNOS expression and the effect of iNOS inhibitors in the RVLM on BP and heart rate in SHR and WKY. iNOS levels in the RVLM were significantly higher in SHR than in WKY. Bilateral microinjection of aminoguanidine into the RVLM dose-dependently decreased BP and heart rate in SHR, but not in WKY. These findings suggest that iNOS expression in the RVLM of SHR contributes to increase BP.