Shogo Sesoko

BRAIN ANGIOTENSIN AND CIRCULATORY CONTROL

1. Components of the renin‐angiotensin system (RAS) are found in the brain; both outside and inside the blood‐brain barrier.

Brain angiotensin II contributes to the development of hypertension in Dahl-Iwai salt-sensitive rats.

Objective: To examine the role of brain angiotensin II in the development of salt-induced hypertension in Dahl-Iwai salt-sensitive (DIS) rats. Methods: Male DIS and Dahl-Iwai salt-resistant (DIR) rats aged 5 or 6 weeks were implanted with an intracerebroventricular cannula, and either chronic intracerebroventricular infusion of 5 µg/day CV-11974, a non-peptide type-1 angiotensin II receptor antagonist or artificial cerebrospinal fluid (aCSF) was started. The rats were fed a diet containing 8% sodium chloride. Results: On day 11 or 12 of chronic infusion, DIS rats given CV-11974 intracerebroventricularly exhibited a significantly lower mean arterial pressure than DIS rats given aCSF intracerebroventricularly or intravenous infusion of CV-11974. In DIR rats, intracerebroventricular infusion of CV-11974 did not alter the mean arterial pressure. Sodium and water balances were similar in all of the groups. Plasma vasopressin and noradrenaline levels did not differ among the groups, although the plasma renin concentration was significantly lower in DIS rats given aCSF intracerebroventricularly. Arterial baroreflex control of heart rate and pressor response to intravenous injection of phenylephrine were not altered in rats given CV-11974 intracerebroventricularly. Conclusion: The integrity of the brain renin-angiotensin system is necessary for the development of salt-induced hypertension in DIS rats.

Multiple risk factor clustering of hypertension in a screened cohort.

Objective A family history of hypertension, obesity, diabetes mellitus, hypercholesterolaemia and hypertriglyceridaemia have all been associated with the risk for hypertension. We evaluated whether the clustering of these risk factors increases the risk for hypertension or whether the accumulation of risk factors is associated with the blood pressure level in non-hypertensive subjects. Methods and subjects We assessed the clinical data and family history of hypertension (in parents and siblings) for 9914 individuals (6163 men and 3751 women, 18–89 years old) who were screened in Okinawa, Japan, in 1997. Results In 9914 subjects (2465 hypertensive and 7449 non-hypertensive subjects), all the five factors were positively associated with hypertension. The odds ratios (95% confidence interval) for the number of risk factors were 1.88 (1.62–2.18) for one risk factor, 3.06 (2.62–3.57) for two, 5.25 (4.37–6.30) for three, 8.71 (6.48–11.72) for four and 24.48 (8.49–70.56) for five, after adjusting for age, sex, alcohol consumption, cigarette smoking and physical exercise habits. In non-hypertensive subjects, multivariate regression analyses showed that the number of risks was positively correlated with blood pressure; the regression coefficient was 1.96 (P < 0.0001) for systolic blood pressure, and 1.47 (P < 0.0001) for diastolic blood pressure after adjusting for age and sex. Conclusions Clustering of risk factors was significantly associated with hypertension. The number of risk factors positively correlated with the blood pressure levels in nonhypertensive subjects. The accumulation of risk factors may play an important role in the pathogenesis of hypertension, and thus the aggregation of risk factors may need to be addressed in primary prevention efforts related to hypertension.

Short-term effects of angiotensin II blockade on renal blood flow and sympathetic activity in awake rats.

To investigate the effects of an angiotensin II type 1 receptor antagonist (CV-11974) on renal blood flow and renal sympathetic nerve activity compared with a calcium antagonist (nicardipine), we measured both parameters in conscious spontaneously hypertensive rats aged 13 to 15 weeks. One to 2 days after surgery, CV-11974 (n = 9) and nicardipine (n = 8) were intravenously administered to decrease arterial pressure in a similar time course and degree of hypotension. CV-11974 increased renal blood flow by 23 +/- 4% at the maximal fall in mean arterial pressure (-32 +/- 1 mm Hg), and renal nerve activity increased by 70 +/- 7%. The maximal increase in renal blood flow (+27 +/- 4%) was observed when mean pressure was reduced by approximately 20 mm Hg. The maximal reduction of renal vascular resistance (-33 +/- 3%) correlated significantly with pretreatment levels of plasma renin concentration (r = -.792). In contrast, nicardipine produced a progressive reduction of renal blood flow and marked increases in heart rate and renal nerve activity. Increases in heart rate and nerve activity were greater than those with CV-11974 treatment (P < .001). At the maximal fall in mean pressure (-32 +/- 1 mm Hg), renal blood flow decreased by 23 +/- 4%, which was significantly correlated with percent changes in renal nerve activity (+150 +/- 11%, r = -.744). Renal denervation in another set of rats (n = 6) improved renal blood flow and renal vascular resistance responses to nicardipine.(ABSTRACT TRUNCATED AT 250 WORDS)

Modulation of baroreflex function by angiotensin II endogenous to the caudal ventrolateral medulla

Neurons in the ventrolateral medulla (VLM) mainly determine the tonic sympathetic activity. The caudal VLM (CVLM) relays baroreflex signals to the rostral VLM. We have reported that endogenous angiotensin II (ANG II) contributes to the ongoing activity of the VLM neurons. In the present study, we examined if ANG II endogenous to the CVLM modulates the baroreflex function in anesthetized normotensive Sprague-Dawley rats. Changes in renal sympathetic nerve activity (RSNA) in response to changes in mean arterial pressure (MAP) induced by i.v. infusion of phenylephrine and nitroglycerin were recorded before and after bilateral microinjection of [Sar1, Thr8]-ANG II, an ANG II antagonist, into the CVLM. The ANG II antagonist injection into the CVLM significantly increased MAP and RSNA by 17.6 +/- 8.0 mmHg (mean +/- S.D.) and 36.3 +/- 18.1%, respectively. It also significantly increased the baroreflex sensitivity (BS) from -0.49 +/- 0.38 to -0.74 +/- 0.37%/mmHg during nitroglycerin infusion. In contrast, the BS examined by phenylephrine infusion was not altered by the pretreatment with ANG II antagonist. Injection of artificial CSF affected neither the baseline values of MAP and RSNA nor the BS. These results suggest that ANG II endogenous to the CVLM exert a modulating role in baroreflex control of RSNA.

Contribution of α2-adrenoceptors in caudal ventrolateral medulla to cardiovascular regulation in rat

The inhibitory action of α2-agonists on the cardiovascular neurons has been elucidated in the rostral ventrolateral medulla (RVLM) but not in the caudal ventrolateral medulla (CVLM). Our study aimed to clarify whether microinjection of clonidine into the CVLM elicits any cardiovascular effect and whether endogenous α2-adrenoceptor-mediated mechanisms contribute to the tonic activity of the CVLM neurons. In male Sprague-Dawley rats (7-9 wk old, 270-320 g) anesthetized with urethan, unilateral microinjection of 8 nmol of clonidine into the CVLM ( n = 10) increased mean arterial pressure (MAP) and renal sympathetic nerve activity (RSNA) by 12.1 ± 1.8 mmHg (mean ± SE, P < 0.01) and 25.8 ± 4.8% ( P < 0.01), while heart rate (HR) remained unaltered. Unilateral microinjection of 2 nmol of SKF-86466, a selective blocker of the α2-adrenoceptors, into the CVLM ( n = 10) decreased MAP, HR, and RSNA (-11.6 ± 2.6 mmHg, -26 ± 7 beats/min, and -15.3 ± 1.7%, respectively, P < 0.01 for each). Artificial cerebrospinal fluid caused neither a cardiovascular effect nor a sympathetic response. Prior injection of SKF-86466 into the ipsilateral CVLM attenuated the effects of clonidine. Bilateral microinjection of muscimol into the RVLM abolished the effects of both clonidine and SKF-86466 injected into the CVLM. The pressor and sympathoexcitatory effects of clonidine injected into the CVLM suggest a neuroinhibitory action of the drug on the CVLM neurons. In addition,the depressor and sympathoinhibitory effects of SKF-86466 injected into the CVLM indicated that activation of α2-adrenoceptors by endogenous ligand inhibits CVLM neurons. The effects of clonidine and the α2-adrenoceptor antagonist in the CVLM require the integrity of the RVLM.The inhibitory action of alpha 2-agonists on the cardiovascular neurons has been elucidated in the rostral ventrolateral medulla (RVLM) but not in the caudal ventrolateral medulla (CVLM). Our study aimed to clarify whether microinjection of clonidine into the CVLM elicits any cardiovascular effect and whether endogenous alpha 2-adrenoceptor-mediated mechanisms contribute to the tonic activity of the CVLM neurons. In male Sprague-Dawley rats (7-9 wk old, 270-320 g) anesthetized with urethan, unilateral microinjection of 8 nmol of clonidine into the CVLM (n = 10) increased mean arterial pressure (MAP) and renal sympathetic nerve activity (RSNA) by 12.1 +/- 1.8 mmHg (mean +/- SE, P < 0.01) and 25.8 +/- 4.8% (P < 0.01), while heart rate (HR) remained unaltered. Unilateral microinjection of 2 nmol of SKF-86466, a selective blocker of the alpha 2-adrenoceptors, into the CVLM (n = 10) decreased MAP, HR, and RSNA (-11.6 +/- 2.6 mmHg, -26 +/- 7 beats/min, and -15.3 +/- 1.7%, respectively, P < 0.01 for each). Artificial cerebrospinal fluid caused neither a cardiovascular effect nor a sympathetic response. Prior injection of SKF-86466 into the ipsilateral CVLM attenuated the effects of clonidine. Bilateral microinjection of muscimol into the RVLM abolished the effects of both clonidine and SKF-86466 injected into the CVLM. The pressor and sympathoexcitatory effects of clonidine injected into the CVLM suggest a neuroinhibitory action of the drug on the CVLM neurons. In addition, the depressor and sympathoinhibitory effects of SKF-86466 injected into the CVLM indicated that activation of alpha 2-adrenoceptors by endogenous ligand inhibits CVLM neurons. The effects of clonidine and the alpha 2-adrenoceptor antagonist in the CVLM require the integrity of the RVLM.

Effects of air-jet stress on renal blood flow in spontaneously hypertensive rats

BackgroundStressful psychological stimuli produce an increase in renal sympathetic nerve activity (RSNA) and a decrease in renal blood flow. Very few direct analyses of the relationship between RSNA and renal blood flow during the application of psychological stimuli have been conducted by recording these 2 measurements simultaneously in the same individual animals.MethodsWe simultaneously measured RSNA and renal blood flow as a Doppler shift in conscious, unrestrained, spontaneously hypertensive rats. The rats were stressed by directing a continuous air jet at their faces for 20 seconds.ResultsAir-jet stimulus increased RSNA 81%±15% (mean±standard error of the mean, n=10), mean arterial pressure (21±3 mm Hg), and renal vascular resistance (37%±6%), and decreased renal blood flow (−15%±2%). The percentage change in RSNA correlated positively with the change in mean arterial pressure (r=0.934,P<0.001) and percentage change in renal vascular resistance (r=0.912), and negatively with the percentage change in renal blood flow (r=−0.804). The denervation of renal nerves prevented renal blood flow from decreasing in response to air-jet stress.ConclusionsA reduction in renal blood flow in response to short-term air-jet stress is elicited mainly by neural mechanisms in spontaneously hypertensive rats. Enhancement of RSNA by air-jet stimulus exerts a potent constricting effect on the renal vascular bed, resulting in a reduction in renal blood flow.

Neural effects of natural behavior on renal blood flow in spontaneously hypertensive rats

BackgroundIn states of stress and exercise, renal blood flow is shown to be depressed, mainly through neural mechanisms. Little is known, however, about the effects of natural or spontaneous behaviors on renal blood flow and renal sympathetic nerve activity.MethodsWe simultaneously measured renal sympathetic nerve activity and renal blood flow as a Doppler shift during grooming and exploring behaviors in spontaneously hypertensive rats. We also tested the effects of vasodilating drugs on changes in renal blood flow.ResultsGrooming behavior (n=21) increased renal sympathetic nerve activity, mean arterial pressure, and decreased renal blood flow. Percentage changes in renal sympathetic nerve activity correlated negatively with percentage changes in renal blood flow. Exploring with rearing (n=14) induced similar but larger changes in these variables. Denervation of renal nerves suppressed a reduction in renal blood flow during these behaviors. After intravenous injection of manidipine (a calcium channel blocker) or CV-11974 (an angiotensin II receptor antagonist), the behavior-induced reduction in renal blood flow was significantly smaller than that found before treatment, despite similar increases in renal sympathetic nerve activity.ConclusionNatural behaviors decrease renal blood flow in relation to the enhancement of renal sympathetic nerve activity, which is similar to the responses of the animals to stressful psychologic stimuli. Vasodilating drugs can attenuate the reduction in renal blood flow.