EFFECT OF RENAL NERVE DENERVATION ON TISSUE CATECHOLAMINE CONTENT IN SPONTANEOUSLY HYPERTENSIVE RATS

1. To clarify the possible role of tissue catecholamines in the development of hypertension, we investigated the effect of bilateral renal denervation on the catecholamine contents of central and peripheral tissues in spontaneously hypertensive rats (SHR). 2. Norepinephrine (NE) content in renal cortex, renal medulla, and adrenal gland was higher in 7 week old SHR than age-matched Wistar-Kyoto rats (WKY). Dopamine (DA) content in the brainstem and hypothalamus was also higher in SHR, but NE and epinephrine (EPI) content in these areas were not different between strains. Similar differences in catecholamines were observed in 9 week old rats in which a sham operation of bilateral renal denervation was performed 2 weeks previously. 3. Bilateral renal denervation produced an almost complete reduction of NE content in the kidney in both strains and prevented the development of hypertension. DA content in the brainstem was also decreased by renal denervation in SHR but not in WKY. NE and EPI content in central tissues were not affected by renal denervation. 4. These results suggest that DA content in brainstem area, as well as NE content in the kidney, have a relationship in the development of hypertension in SHR.     

EFFECTS OF RENAL DENERVATION AND ATRIAL NATRIURETIC FACTOR ON TUBULAR REABSORPTION IN ANAESTHETIZED RATS

1. The effects of acute unilateral renal denervation were examined in 17 anaesthetized rats. Renal haemodynamic changes were monitored using standard clearance techniques. Lithium clearance was used to assess fractional proximal sodium and water reabsorption. 2. Denervation resulted in ipsilateral renal vasodilatation with marked natriuresis and diuresis, a small increase (15%, P less than 0.05) in glomerular filtration rate (GFR) and a consequent reduction in filtration fraction. Fractional lithium reabsorption decreased (67.3 +/- 2.9% to 54.5 +/- 4.0%, P less than 0.01) and absolute proximal reabsorption did not change, indicating impairment of proximal glomerulotubular balance (GTB). No similar changes in haemodynamic or transport parameters were observed in the contralateral, innervated kidney, although vascular resistance increased. 3. In 9 experiments following denervation of the left kidney, systemic low dose infusion (10 ng/min) of atrial natriuretic factor (ANF) resulted in a fall in mean arterial blood pressure from 116 +/- 3 mmHg to 107 +/- 3 mmHg (P less than 0.05). In the denervated kidney ANF increased urine flow rate and sodium excretion to rates above those established following denervation alone. However, in the right kidney, despite the increased filtered load (35%, P less than 0.01), the natriuretic and diuretic responses to ANF were abolished. 4. In the denervated kidney, ANF further reduced the fractional reabsorption of lithium from 53.6 +/- 2.3% to 45.6 +/- 3.8% (P less than 0.05). GFR increased by 32% (a total of 49% higher than during pretreatment) but absolute proximal reabsorption (APR) did not change. However, in the right, innervated kidney ANF infusion produced a 35% increase in GFR accompanied by a 53% rise in APR. 5. It is concluded that the natriuresis induced by unilateral denervation is due predominantly to impaired proximal GTB. The natriuretic action of ANF was associated with further impairment of proximal GTB, not dependent upon decreasing activity of renal sympathetic nerves, but was abolished when filtration fraction and renal sympathetic tone were elevated.     

Early renal denervation prevents development of hypertension in growth-restricted offspring

1. Low birth weight is associated with an increased risk for the development of hypertension. Our laboratory uses a model of reduced uterine perfusion in the pregnant rat that results in intrauterine growth-restricted (IUGR) offspring that develop hypertension at a prepubertal age. Although hypertension develops in both prepubertal male and female IUGR offspring, only male IUGR offspring remain hypertensive after puberty. We reported previously that bilateral renal denervation abolishes hypertension in adult male IUGR offspring, indicating an important role for the renal nerves in the maintenance of established IUGR-induced hypertension. We also reported that angiotensin-converting enzyme inhibition abolishes hypertension in adult male IUGR offspring. However, activation of the renin-angiotensin system does not occur in male IUGR offspring until after puberty, or after the development of established IUGR-induced hypertension. Therefore, the mechanisms involved in the development of IUGR-induced hypertension may differ from those involved in the maintenance of established IUGR-induced hypertension. Thus, the purpose of the present study was to determine whether the renal nerves play a causative role in the early development of IUGR-induced hypertension in prepubertal IUGR offspring. 2. Intrauterine growth-restricted and control offspring were subjected to either bilateral renal denervation or sham denervation, respectively, at 4 weeks of age. Mean arterial pressure (MAP) was determined at 6 weeks of age in conscious, chronically instrumented animals. Adequacy of renal denervation was verified by renal noradrenaline content. 3. Whereas renal denervation had no effect on MAP in control offspring (103 +/- 2 vs 102 +/- 3 mmHg for sham vs denervated, respectively), it reduced blood pressure in growth-restricted offspring (114 +/- 3 vs 104 +/- 1 mmHg for sham vs denervated, respectively; P < 0.01). Renal noradrenaline content was significantly reduced in denervated animals relative to sham operated rats. 4. Thus, the data indicate a role for the renal nerves in the aetiology of IUGR-induced hypertension and suggest that the renal nerves may participate in the early development of hypertension in IUGR offspring in addition to established hypertension observed in adult male IUGR offspring.     

Inhibition of Ang II and renal sympathetic nerve influence dopamine-and isoprenaline-induced renal haemodynamic changes in normal Wistar-Kyoto and spontaneously hypertensive rats

1. This study was undertaken to elucidate the effects of inhibiting the renin-angiotensin system (RAS) with losartan, and acute unilateral renal denervation on renal haemodynamic responses to intrarenal administration of vasoconstrictor doses of dopamine and vasodilator doses of isoprenaline in Wistar-Kyoto (WKY) and spontaneously hypertensive rats (SHR). 2. Acute unilateral renal denervation of the left kidney in rats was confirmed by a drop in the renal vasoconstrictor response to renal nerve stimulation (P < 0.05) along with diuresis and natriuresis. Rats were pretreated with losartan for 7 days and thereafter animals fasted overnight were anaesthetized (sodium pentobarbitone, 60 mg/kg i.p.) and acute renal haemodynamic responses studied. 3. Dose-response curves were constructed for dopamine and isoprenaline that induced falls or increases in renal blood flow, respectively. It was observed that renal vascular responses were greater in the denervated as compared with rats with intact renal nerves (all P < 0.05). Dopamine-induced renal vasoconstrictor responses were markedly lower in losartan-treated denervated WKY and SHR compared with their untreated counterparts (all P < 0.05). It was also observed that in losartan-treated and denervated WKY rats the vasodilatory responses to isoprenaline were markedly lower compared with untreated rats (all P < 0.05). However, in SHR, under the same conditions, there was no difference in the renal response to isoprenaline whether or not rats were treated with losartan (P > 0.05). 4. The data obtained showed that the renal vasoconstrictor effect of dopamine depends on intact renal nerves and RAS in WKY and SHR. Isoprenaline responses were likewise sensitive to renal denervation and RAS inhibition in WKY rats but not SHRs. Our observations reveal a possible relationship between renal AT(1) receptors and alpha(1)-adrenoceptors in WKY and SHR. There is also evidence to suggest an interaction between renal beta-adrenoceptors and AT(1) receptors in WKY rats.     

PERTUSSIS TOXIN-SENSITIVE G-PROTEINS AND REGULATION OF BLOOD PRESSURE IN THE SPONTANEOUSLY HYPERTENSIVE RAT

1. Increased Gi-protein-mediated receptor-effector coupling in the vasculature of the spontaneously hypertensive rat (SHR) has been proposed as a contributing factor in the maintenance of elevated blood pressure. If increased Gi-protein-mediated activity plays an important role in hypertension in SHR, then inhibition of Gi-proteins by pertussis toxin would be expected to decrease blood pressure in this genetic hypertensive model. To address this hypothesis, studies were undertaken comparing the cardiovascular effects of pertussis toxin in SHR and normotensive Wistar-Kyoto (WKY) rats. 2. Spontaneously hypertensive and WKY rats were instrumented with radiotelemetry devices and blood pressure measurements were recorded in conscious rats. Following a single injection of pertussis toxin (10 micrograms/kg, i.v.), mean arterial blood pressure fell from 161 +/- 3 to 146 +/- 1 mmHg in the SHR and the effect was sustained for more than 2 weeks. In contrast, 10 micrograms/kg, i.v., pertussis toxin produced no significant effect on blood pressure in WKY rats (103 +/- 4 vs 101 +/- 5 mmHg). 3. In a separate study, SHR and WKY rats were administered 30 micrograms/kg, i.v., pertussis toxin or 150 microL/kg, i.v., saline and, 3-5 days later, rats were anaesthetized and instrumented to permit measurement of blood pressure and renal function. At this higher dose, pertussis toxin reduced blood pressure in both strains of rat, although the effect was markedly greater in SHR (approximately 40 mmHg decrease) compared with WKY rats (approximately 15 mmHg decrease). In SHR, pertussis toxin increased renal blood flow (from 5.7 +/- 0.3 to 7.5 +/- 0.8 mL/min per g kidney) and decreased renal vascular resistance (from 31 +/- 2 to 19 +/- 2 mmHg/mL per min per g kidney). In WKY rats, pertussis toxin had no significant effect on renal parameters. 4. Results from these studies indicate that a pertussis toxin-sensitive Gi-protein-mediated pathway contributes to the maintenance of hypertension and elevated renal vascular tone in the SHR.     

THE EFFECT OF ADRENAL DENERVATION ON ACTH-INDUCED HYPERTENSION IN SHEEP

SUMMARY 1. The effect of surgical denervation of the adrenal gland on ACTH-induced hypertension in the sheep has been examined. ACTH (80 iu/day) was administered for 5 days to eight sheep before and after bilateral surgical denervation of the adrenal.
2. In intact sheep, ACTH-induced hypertension is associated with a significant increase in cardiac output and heart rate. Adrenal denervation obtained by sectioning of the lumbar sympathetic and splanchnic nerves supplying the adrenal gland did not alter the magnitude or time course of the hypertension, or the increase in heart rate.
3. Adrenal denervation did not affect the increase in plasma sodium, the fall in plasma potassium, the initial urinary sodium retention, the increase in water turnover or the changes in blood corticosteroids which are seen during ACTH administration to intact sheep. However, in these adrenally denervated sheep ACTH treatment did not significantly change cardiac output.
4. This study suggests an important role for a factor or factors from the adrenal cortex in causing ACTH-induced hypertension.     

Effect of acute unilateral renal denervation on renal hemodynamics in spontaneously hypertensive rats

1 This study was undertaken to characterize the renal responses to acute unilateral renal denervation in anaesthetized spontaneously hypertensive rats (SHR) by examining the effect of acute unilateral renal denervation on the renal hemodynamic responses to a set of vasoactive agents and renal nerve stimulation. 2 Twenty-four male SHR rats underwent acute unilateral renal denervation and the denervation was confirmed by significant drop (P < 0.05) in renal vasoconstrictor response to renal nerve stimulation along with marked diuresis and natriuresis following denervation. After 7 days treatment with losartan, the overnight fasted rats were anaesthetized (sodium pentobarbitone, 60 mg kg(-1) i.p.) and renal vasoconstrictor experiments were performed. The changes in the renal vasoconstrictor responses were determined in terms of reductions in renal blood flow caused by renal nerve stimulation or intrarenal administration of noradrenaline, phenylephrine, methoxamine and angiotensin II. 3 The data showed that there was significantly (all P < 0.05) increased renal vascular responsiveness to the vasoactive agents in denervated rats compared to those with intact renal nerves. In losartan-treated denervated SHR rats, there were significant (all P < 0.05) reductions in the renal vasoconstrictor responses to neural stimuli and vasoactive agents as compared with that of untreated denervated SHR rats. 4 The data obtained in denervated rats suggested an enhanced sensitivity of the alpha(1)-adrenoceptors to adrenergic agonists and possible increase of AT(1) receptors functionality in the renal vasculature of these rats. These data also suggested a possible interaction between sympathetic nervous system and renin-angiotensin system in terms of a crosstalk relationship between renal AT(1) and alpha(1)-adrenoceptor subtypes.     

The contribution of adrenoceptor subtype(s) in the renal vasculature of diabetic spontaneously hypertensive rats

1. Diabetes and hypertension are both associated with an increased risk of renal disease and are associated with neuropathies, which can cause defective autonomic control of major organs including the kidney. This study aimed to examine the alpha(1)-adrenoceptor subtype(s) involved in mediating adrenergically induced renal vasoconstriction in a rat model of diabetes and hypertension. 2. Male spontaneously hypertensive rats (SHR), 220-280 g, were anaesthetized with sodium pentobarbitone 7-day poststreptozotocin (55 mg x kg(-1) i.p.) treatment. The reductions in renal blood flow (RBF) induced by increasing frequencies of electrical renal nerve stimulation (RNS), close intrarenal bolus doses of noradrenaline (NA), phenylephrine (PE) or methoxamine were determined before and after administration of nitrendipine (Nit), 5-methylurapidil (5-MeU), chloroethylclonidine (CEC) and BMY 7378. 3. In the nondiabetic SHR group, mean arterial pressure (MAP) was 146+/-6 mmHg, RBF was 28.0+/-1.4 ml x min(-1) x kg(-1) and blood glucose was 112.3+/-4.7 mg x dl(-1), and in the diabetic SHR Group, MAP was 144+/-3 mmHg, RBF 26.9+/-1.3 ml(-1) min x kg(-1) and blood glucose 316.2+/-10.5 mg x dl(-1). Nit, 5-MeU and BMY 7378 blunted all the adrenergically induced renal vasoconstrictor responses in SHR and diabetic SHR by 25-35% (all P<0.05), but in diabetic rats the responses induced by RNS and NA treated with 5-MeU were not changed. By contrast, during the administration of CEC, vasoconstrictor responses to all agonists were enhanced by 20-25% (all P<0.05) in both the SHR and diabetic SHR. 4. These findings suggest that alpha(1A) and alpha(1D)-adrenoceptor subtypes contribute in mediating the adrenergically induced constriction of the renal vasculature in both the SHR and diabetic SHR. There was also an indication of a greater contribution of presynaptic adrenoceptors, that is, alpha(1B)-, and/or alpha(2)-subtypes.     

Angiotensin-converting enzyme inhibition in adult hypertensive rats: a stereological study of renal filtration surface area

1. Angiotensin-converting enzyme (ACE) inhibitor treatment leads to beneficial effects on kidney function. The aim of the present study was to determine whether ACE inhibition at high or low doses affects glomerular capillary surface area and length, glomerular number or total renal filtration surface area in rats with established hypertension and, if so, to determine whether these effects are mediated through bradykinin potentiation. 2. Spontaneously hypertensive rats (SHR) were treated with the ACE inhibitor perindopril at either 3 or 0.1 mg/kg per day (high and low doses, respectively) from 16 to 24 weeks of age. Some rats were concomitantly treated with the bradykinin B2 receptor antagonist S16118 (10 nmol/kg per day). Blood pressure was measured twice weekly during the treatment period. At 24 weeks of age, rats were perfusion fixed at 140 mmHg, the kidneys removed, embedded in resin and examined stereologically to estimate glomerular number and volume, length and surface area of glomerular capillaries and total renal filtration surface area. 3. High- and low-perindopril treatment significantly reduced systolic blood pressure compared with control SHR. However, the rats treated with low-dose perindopril were still considered hypertensive. Neither low-dose nor high-dose perindopril treatment had any observable effect on glomerular number (23 876 +/- 1201 vs 26 240 +/- 1465 glomeruli/kidney, respectively) or volume (2.25 +/- 0.21 and 1.96 +/- 0.06 x 10-3 mm3, respectively) compared with controls (glomerular number 25866 +/- 1210 glomeruli/kidney; glomerular volume 2.24 +/- 0.21 x 10-3 mm3). As a result, there was no significant difference in total renal filtration surface area between any of the experimental groups (8161.6 +/- 550.9, 8699.7 +/- 427.6, 9081.9 +/- 453.6, 8830.2 +/- 521.2 and 8559.4 +/- 341.4 mm2 for SHR, SHR low-dose perindopril, SHR low-dose perindopril + B2 antagonist, SHR high-dose perindopril and SHR high-dose perindopril + B2 antagonist, respectively). Coadministration of the bradykinin antagonist had no observable effect on any of the parameters studied. 4. In conclusion, because neither high-dose nor low-dose perindopril had any effect on total renal filtration surface area, the observed beneficial effects of ACE inhibition on kidney function are not the result of enhancement in glomerular capillary surface area.     

Binding of 3H-(3-MeHis2) thyrotropin-releasing hormone to spinal cord membranes of spontaneously hypertensive and Wistar-Kyoto normotensive rats

Previous studies from this laboratory had indicated that in spontaneously hypertensive (SHR) rats the development of hypertension paralleled increases in brain receptors for thyrotropin-releasing hormone (TRH). The increase appeared to be confined to hypothalamus and striatum. The present studies were undertaken to determine the binding characteristics of TRH receptors in the peripheral tissues of SHR and normotensive Wistar-Kyoto (WKY) rats. TRH receptors were labeled with 3H-MeTRH. The binding of 3H-MeTRH to membranes prepared from spinal cord, heart, lung, kidney and adrenal gland of SHR and WKY rats was determined. In WKY rats, the binding of 3H-MeTRH to various tissue membranes was in the following order: spinal cord greater than kidney greater than lung greater than heart = adrenals. The binding of 3H-MeTRH to spinal cord membranes of SHR rats was significantly higher in comparison to WKY rat tissues, whereas the binding of 3H-MeTRH in kidney, heart, lung and adrenals of the two strains of rats did not differ. The increase in the binding of 3H-MeTRH to spinal cord of SHR rats was due to increases in the Bmax values and not in the Kd values. The results suggest that in addition to the brain, TRH receptors in the spinal cord of SHR rats are also up-regulated and may also play an important role in the regulation of blood pressure.     

Prevention by blockade of angiotensin subtype1-receptors of the development of genetic hypertension but not its heritability.

1. We determined whether early inhibition of angiotensin II subtype1 (AT1) receptors by the newly synthesized nonpeptidic antagonist, A-81988, can attenuate the development of hypertension in spontaneously hypertensive rats (SHR) and if the altered blood pressure phenotype can be passed on to the subsequent generation, not exposed to the antagonist. 2. Pairs of SHR were mated while drinking tap water or A-81988 in tap water, and the progeny was maintained on the parental regimen until 14 weeks of age. At this stage, A-81988-treated rats showed lower systolic blood pressure and body weight values (136 +/- 5 versus 185 +/- 4 mmHg and 247 +/- 4 versus 283 +/- 4 g in controls, P < 0.01); while heart rate was similar. In addition, mean blood pressure was reduced (101 +/- 7 versus 170 +/- 7 mmHg in controls, P < 0.01), and the pressor responses to intravenous or intracerebroventricular angiotensin II were inhibited by 27 and 59%, respectively. Heart/body weight ratio was smaller in A-81988-treated rats (3.2 +/- 0.1 versus 3.8 +/- 0.1 in controls, P < 0.01). 3. The antihypertensive and antihypertrophic effect of A-81988 persisted in rats removed from therapy for 7 weeks (systolic blood pressure: 173 +/- 4 versus 220 +/- 4 mmHg, heart/body weight ratio: 3.4 +/- 0.1 versus 4.1 +/- 0.1 in controls at 21 weeks of age, P < 0.01 for both comparisons), whereas the cardiovascular hypertensive phenotype was fully expressed in the subsequent generation that was maintained without treatment.(ABSTRACT TRUNCATED AT 250 WORDS)     

Neutralization of proANP (1-30) exacerbates hypertension in the spontaneously hypertensive rat

1. The aim of the present studies was to determine the role of proANP (1-30) in the regulation of arterial pressure. It was hypothesized that blocking endogenous proANP (1-30) would exacerbate the hypertension in susceptible animal models. 2. Pentobarbital-anaesthetized spontaneously hypertensive rats (SHR) were pretreated i.v. with 1.2 mL rabbit serum containing an antibody directed specifically against rat proANP (1-30) (SHR-AB group; n = 7) or an equal volume of normal rabbit serum as a control (SHR-NRS group; n = 5). 3. Following a 1 h equilibration period and two 30 min baseline periods, rats were volume expanded with 3 mL of 6% albumin in Krebs' solution and observed for an additional 3 h to determine the effects of the anti-proANP on arterial pressure. 4. Arterial pressure increased in both groups compared with their own baselines with volume expansion, but was significantly greater in the anti-proANP SHR group compared with the SHR-NRS group throughout the volume expansion period. A maximum difference of 21 mmHg between the anti-proANP SHR group and the NRS-SHR group was observed at 150 min of the study (183 +/- 5 vs 162 +/- 3 mmHg, respectively; P < 0.005. 5. These results suggest a protective role for proANP (1-30) in the SHR model of hypertension.     

Role of cardiac hypertrophy in reducing the sensitivity of cardiopulmonary reflex control of renal sympathetic nerve activity in spontaneously hypertensive rats

The gain of the volume-sensitive cardiopulmonary reflex (VSCR) is impaired in spontaneously hypertensive rats (SHR). Sensitivity of VSCR control of efferent renal sympathetic nerve activity (RSNA) in SHR is restored when cardiac hypertrophy and hypertension are reduced by enalapril treatment. The present study investigated which of these two parameters, cardiac hypertrophy or hypertension, has more influence on the impairment of VSCR control of RSNA in SHR. Rats (SHR or Wistar-Kyoto (WKY) rats) were treated with enalapril (10 mg/kg per day; SHRE and WKYE groups, respectively) or hydralazine (5 mg/kg per day; SHRH and WKYH groups, respectively) mixed in their food for 1 month. Control SHR and WKY rats were fed a normal diet. After the treatment regimen, the VSCR was evaluated by determining the decrease in RSNA elicited by acute isotonic saline volume expansion. Mean arterial pressure (MAP) was assessed via an intrafemural catheter and cardiac hypertrophy was determined by the left ventricular (LV) weight/bodyweight (BW) ratio. Afferent baroceptor nerve activity (BNA) was also evaluated during volume expansion to verify participation of the baroreflex. Volume expansion produced an attenuated renal sympathoinhibitory response in SHR compared with WKY rats. Enalapril treatment restored the volume expansion-induced decrease in RSNA in SHRE (-41 +/- 8%) compared with WKY rats (-44 +/- 3%). Although both enalapril and hydralazine treatment reduced MAP in SHR (P < 0.01; 126 +/- 5, 133 +/- 6 and 160 +/- 6 mmHg in SHRE, SHRH and SHR, respectively), hydralazine did not restore the sensitivity of VSCR control of RSNA in SHRH. Spontaneously hypertensive rats with established hypertension had a higher LV/BW ratio compared with WKY rats (3.22 +/- 0.14 vs 1.98 +/- 0.06 mg/g, respectively; P < 0.01). Enalapril reduced the LV/BW ratio in SHRE (2.30 +/- 0.07 mg/g; P < 0.01). Although hydralazine reduced LV hypertrophy, there was a weaker reduction in SHRH (2.68 +/- 0.04 mg/g; P < 0.05) compared with SHRE. There was no statistically significant difference among the WKY rat, WKYE and WKYH groups (P > 0.05). There was no change in afferent BNA during volume expansion in normal or hypertensive animals. Taken together, these results indicate that the impairment of VSCR control of RSNA in the SHR model of hypertension correlates better with the magnitude of cardiac hypertrophy than the level of arterial pressure.     

Effect of inhibition of nitric oxide synthesis on the uptake of LDL and fibrinogen by arterial walls and other organs of the rat.

1. The effects of administering 3 mg ml-1 NG-nitro-L-arginine methyl ester (L-NAME), an inhibitor of nitric oxide (NO), on the uptake of low density lipoprotein (LDL), fibrinogen and blood pressure were determined in conscious, unrestrained, cannulated normotensive and spontaneously hypertensive (SHR) Wistar rats. 2. The uptake of LDL and fibrinogen, labelled respectively with 125I or 131I via the adduct tyramine cellobiose ([125I]TC-LDL and [131I]TC-fibrinogen), were compared in aortic walls, heart, skeletal muscle, lung, liver, kidney and adrenal during the final 24 h of 6 days' administration of L-NAME in the drinking water. 3. In control normotensive rats, the systolic blood pressure did not change significantly over 6 days, while administration of L-NAME in normotensive rats increased the blood pressure progressively and significantly to about 170 mmHg over the same period. 4. In normotensive rats L-NAME increased significantly the uptake of both LDL and fibrinogen by aortic walls and heart, but not by muscle, lung, liver, kidney and adrenal. 5. The blood pressure in SHR was about 170 mmHg before administration of L-NAME and did not increase significantly after 6 days of treatment. In these rats the uptake of LDL or of fibrinogen was increased only in the heart but not in aortic walls nor in any of the other organs.(ABSTRACT TRUNCATED AT 250 WORDS)     

Nitric oxide inhibition accelerates hypertension and induces perivascular inflammation in rats

1. Inflammatory changes in peripheral arteries have been reported in animal models of hypertension. Whether they occur in cerebral arteries (CA) with hypertension induced by deprivation of endogenous nitric oxide (NO) remains unknown. 2. In the present study, we compared the arteriolar injury score (AIS) and perivascular inflammation in CA between hypertensive and normotensive rats following NO deprivation with the NO synthase inhibitor N(omega)-nitro-L-arginine methyl ester (L-NAME). Five-week-old male spontaneously hypertensive rats (SHR) and Wistar -Kyoto (WKY) rats were fed with L-NAME (1 mg/mL) for 4 weeks. 3. Nitric oxide deprivation resulted in time-dependent elevations in tail-cuff pressure (representing systolic blood pressure (SBP)) in both SHR and WKY rats. The magnitude of increase in SBP was larger in SHR (+81.0 +/- 3.2 vs+25.0 +/- 2.2 mmHg; P < 0.01). Arteriolar hyalinosis and AIS in various segments of the CA were assessed with periodic acid-Schiff staining and inflammatory cells were immunostained with the antibody against macrophage/monocyte marker (ED1). The ED1+ cells appeared in the middle CA of L-NAME-treated SHR as early as 2 weeks after treatment. These cells were not observed in L-NAME-treated WKY rats and untreated SHR. More ED1+ cells were found in L-NAME-treated SHR than L-NAME-treated WKY rats after 4 weeks treatment. 4. The AIS and number of ED1+ cells around the perivascular area of the internal carotid artery were significantly higher in L-NAME-treated compared with untreated rats (AIS: 137 +/- 28 vs 46 +/- 10 for WKY rats, respectively; 169 +/- 18 vs 53 +/- 6 for SHR, respectively (P < 0.01); ED1+ cells: 7.9 +/- 0.6 vs 1.3 +/- 0.9 for WKY rats, respectively; 13.6 +/- 2.7 vs 2.1 +/- 0.9 for SHR, respectively (P < 0.01)), although SBP was higher in untreated SHR than in L-NAME-treated WKY rats (170 +/- 4 vs 137 +/- 4 mmHg, respectively; P < 0.05). 5. These findings suggest that ED1+ cells appeared in the middle CA of L-NAME-SHR as early as 2 weeks after treatment. Chronic inhibition of NO accelerates hypertension and induces perivascular inflammation.     

Post-resistance exercise hypotension in spontaneously hypertensive rats is mediated by nitric oxide

1. Postexercise hypotension (PEH) plays an important role in the non-pharmacological treatment of hypertension. It is characterized by a decrease in blood pressure (BP) after a single bout of exercise in relation to pre-exercise levels. 2. The present study investigated the effect of a single session of resistance exercise, as well as the effect of nitric oxide (NO) and the autonomic nervous system (ANS), in PEH in spontaneously hypertensive rats (SHR). 3. Catheters were inserted into the left carotid artery and left jugular vein of male SHR (n = 37) for the purpose of measuring BP or heart rate (HR) and drug or vehicle administration, respectively. Haemodynamic measurements were made before and after acute resistance exercise. The roles of NO and the ANS were investigated by using N(G)-nitro-L-arginine methyl ester (L-NAME; 15 mg/kg, i.v.) and hexamethonium (20 mg/kg, i.v.) after a session of acute resistance exercise. 4. Acute resistance exercise promoted a pronounced reduction in systolic and diastolic BP (-37 +/- 1 and -8 +/- 1 mmHg, respectively; P < 0.05), which was suppressed after treatment with L-NAME. The reduction in systolic BP caused by exercise (-37 +/- 1 mmHg) was not altered by the administration of hexamethonium (-38 +/- 2 mmHg; P > 0.05). After exercise, the decrease in diastolic BP was greater with hexamethonium (-26 +/- 1 mmHg; P < 0.05) compared with the decrease caused by exercise alone. 5. The results suggest that acute resistance exercise has an important hypotensive effect on SHR and that NO plays a crucial role in this response.     

Functional beta1- and beta2-adrenoceptors in the left and right atrium of pre-hypertensive rats

There is a small increase in the functional beta2-adrenoceptor response on the spontaneously hypertensive rat (SHR) left atrium in the early stages of hypertension. In the present study, the functional beta1- and beta2-adrenoceptors of the left and right atrium in SHR pre-hypertension and age-matched (5-week-old) Wistar Kyoto (WKY) rats were characterized. Contractility methods with isoprenaline, T-0509 (a selective beta1-adrenoceptor agonist) and procaterol (a selective beta2-adrenoceptor agonist) were used. At 5 weeks, the SHRs were pre-hypertensive. Isoprenaline was more potent on the left atrium of 5-week-old SHRs than WKY rats. Bisoprolol, a selective beta1-adrenoceptor antagonist, was more potent against isoprenaline and T-0509 on the SHR than WKY rat left atrium. ICI 118,551, a selective beta(2)-adrenoceptor antagonist, was more potent against procaterol and T-0509 on the SHR than WKY rat left atrium. The results with bisoprolol and ICI 118,551 suggest that there are more functional beta(1)- and beta(2)-adrenoceptors on the left atrium of 5-week-old SHRs than WKY rats. Isoprenaline, T-0509 and procaterol were equipotent on the right atrium of 5-week-old WKY rats and SHRs. Bisoprolol was more potent against isoprenaline, T-0509 and procaterol on the SHR than WKY rat right atrium. ICI 118,551 was more potent against T-0509, but not isoprenaline and procaterol, on the SHR than WKY rat left atrium. This suggests there are more functional beta1-adrenoceptors, and probably more functional beta2-adrenoceptors, on the right atrium of 5-week-old SHRs than WKY rats. These functional differences in beta1- and beta2-adrenoceptor-mediated responses of the left and right atria of pre-hypertensive SHRs cannot be caused by hypertension, and may be associated with the onset of hypertension.     

OCCLUSION OF THE ADRENAL VEIN LEADS TO AN INCREASE IN RENAL VASCULAR RESISTANCE IN THE IPSILATERAL KIDNEY

1. The aim of the present study was to investigate the effect of an acute increase in blood flow through the adrenal-renal vascular connection (ARVC), due to occlusion of the adrenal vein, on renal blood flow (RBF) and renal vascular resistance (RVR). 2. Experiments were performed in Wistar-Kyoto rats. Animals were divided into four groups. In the first group, the adrenal vein was clamped using a metal clip. In the second group, the tissue between the adrenal gland and the kidney was cut before clamping. In the third and fourth groups, α-adrenoceptor blockade was induced by intravenous infusion of phentolamine before clamping the adrenal vein. In addition, in the fourth group, tissue between the adrenal gland and the kidney was cut before clamping. 3. In the first group, occlusion of the adrenal vein caused an increase in RVR, followed by a decrease in RBF. In the second, third and fourth groups, the same procedure did not change either RBF or RVR. 4. We conclude that the augmented inflow of catecholamines to the kidney through the ARVC changes the haemodynamics of the kidney and may contribute to development of arterial hypertension due to occlusion of the adrenal vein.     

The bradykinin B1 receptor and the central regulation of blood pressure in spontaneously hypertensive rats.

1. We evaluated if the brain bradykinin (BK) B1 receptor is involved in the regulation of blood pressure (BP) in conscious rats. 2. Basal mean BP and HR were 115 +/- 2 and 165 +/- 3 mmHg and 345 +/- 10 and 410 +/- 14 beats min in Wistar Kyoto (WKY) and spontaneously hypertensive rats (SHR), respectively. Intracerebroventricular (i.c.v.) injection of 1 nmol B1 receptor agonist Lys-desArg9-BK significantly increased the BP of WKY and SHR by 7+/-1 and 19+/-2 mmHg, respectively. One nmol Sar[D-Phe8]-desArg9-BK, a kininase-resistant B1 agonist, increased the BP of WKY and SHR by 19+/-2 and 17+/-2 mmHg, respectively and reduced HR in both strains. 3. I.c.v. injection of 0.01 nmol B1 antagonists, LysLeu8-desArg9-BK or AcLys[D-betaNal7,Ile8]-desArg9-BK (R715), significantly decreased mean BP in SHR (by 9+/-2 mmHg the former and 14+/-3 mmHg the latter compound), but not in WKY. In SHR, the BP response to R715 was associated to tachycardia. 4. I.c.v. Captopril, a kininase inhibitor, increased the BP of SHR, this response being partially prevented by i.c.v. R715 and reversed into a vasodepressor effect by R715 in combination with the B2 antagonist Icatibant. 5. I.c.v. antisense oligodeoxynucleotides (ODNs) targeted to the B1 receptor mRNA decreased BP in SHR, but not in WKY. HR was not altered in either strain. Distribution of fluorescein-conjugated ODNs was detected in brain areas surrounding cerebral ventricles. 6. Our results indicate that the brain B1 receptor participates in the regulation of BP. Activation of the B1 receptor by kinin metabolites could participate in the pathogenesis of hypertension in SHR.     

Delayed hypotensive effect of the thromboxane A2/prostaglandin H2 receptor antagonist S-1452 in spontaneously hypertensive rats

1. Several lines of evidence indicate that thromboxane (Tx) A2 may contribute to the development and maintenance of hypertension. The present study was undertaken to evaluate the role of TxA2 in the development of hypertension in spontaneously hypertensive rats (SHR) by using an orally active, highly specific TxA2/prostaglandin H2 receptor antagonist S-1452. 2. Vehicle (1% arabic gum solution) alone was given orally to Wistar-Kyoto (WKY) rats (n = 15) and SHR (n = 14), while S-1452 (10 mg/kg per day, twice daily) was administered orally to SHR (n = 16) for 18 weeks (from 5 to 23 weeks of age). 3. No significant difference was observed in tail-cuff blood pressure (BP) between vehicle- and S-1452-treated SHR before and at 5 and 11 weeks after treatment. Thereafter, BP was further elevated in vehicle-treated SHR, but was significantly blunted in SHR treated with S-1452 at 15 (224+/-8 vs 211+/-13 mmHg; P < 0.01) and 18 weeks (227+/-9 vs 206+/-10 mmHg; P < 0.001); this was associated with reduced proteinuria. 4. Urinary TxB2 in vehicle-treated SHR, especially during the early period, was significantly greater than that in WKY rats, while no significant difference was observed in urinary 6-ketoprostaglandin F1alpha (6-keto-PGF1alpha) between the two groups. Treatment with S-1452 reduced urinary excretion of TxB2 at 18 weeks. 5. The present study shows that S-1452, at the dose used, does not reduce BP during the early period of the development of hypertension. These results suggest that the role of enhanced TxA2 production in the development of hypertension is small, if any, in SHR. Delayed response of BP may be independent of the direct pharmacological effects of S-1452.