Shingo Kawasaki

SYMPATHETIC INHIBITION AND ATTENUATION OF SPONTANEOUS HYPERTENSION BY PVN LESIONS IN RATS

To determine whether the paraventricular nucleus (PVN) contributes to the development of hypertension in spontaneously hypertensive rats (SHR), we compared cardiovascular responses to ganglionic blockade with hexamethonium or vasopressin antagonism with dPVAVP in sham-operated or PVN lesioned SHR and Wistar-Kyoto rats (WKY). Lesions were produced electrolytically when the rats were 5 weeks old. During the next 3 weeks, tail-cuff measurements showed that the development of hypertension in SHR was inhibited, while systolic pressure in WKY was unaffected. Mean pressures recorded directly from the femoral artery at 8 weeks of age were lower in lesioned than in sham-operated SHR (141 +/- 5 vs 110 +/- 3 mm Hg, P less than 0.05), but did not differ in corresponding WKY groups (110 +/- 4 vs 112 +/- 5 mm Hg). Depressor responses to ganglionic blockade induced by i.v. injection of hexamethonium (25 mg/kg) were significantly larger in sham-operated than in lesioned SHR (-41 +/- 4% vs -28 +/- 3%, P less than 0.05). By contrast, vasopressin antagonism with dPVAVP did not alter blood pressure in all rat groups. In 24-h urine samples, excretion of vasopressin was unaffected, but that of norepinephrine was significantly reduced in lesioned SHR. These findings suggest that the PVN contributes to the development of spontaneous hypertension by sympathetic activation without increasing vasopressin secretion.

Central attenuation of aortic baroreceptor reflex in prehypertensive DOCA-salt-loaded rats.

To determine whether the arterial baroreceptor reflex can act to oppose the development of hypertension, deoxycorticosterone acetate (DOCA)-salt hypertension was produced in sinoaortlcdenervated and sham-operated rats. Systolic blood pressure measured by tail cuff started to increase in both sinoaortic-denervated and sham-operated rats 7 days after DOCA treatment, and the hypertension developed identically in both denervated and sham-operated rats. These findings suggest that the baroreceptor reflex cannot act against the development of hypertension. To determine whether the baroreceptor reflex is attenuated before the development of hypertension, bradycardic and sympathoinhibitory responses to i.v. injections of norepinephrine were examined. Bradycardic and sympathoinhibitory responses were significantly smaller in DOCA-salt-treated rats in both prehypertensive (5th day after DOCA-salt treatment) and hypertensive stages (21st day after treatment). In urethane-anesthetized DOCA-loaded and control rats on the 5th day after treatment, aortic depressor nerve stimulation elicited frequency-dependent depressor and bradycardic responses accompanied by inhibition of sympathetic nerve activity in both DOCA-loaded and control rats. However, those responses were significantly smaller in DOCA-loaded rats than in control rats. These results suggest that the central component of the baroreceptor reflex mediated by the aortic depressor nerve is impaired before hypertension develops and that this impairment may contribute to the development of hypertension in DOCA-salt-treated rats.

Attenuated cardiovascular and sympathetic nerve responses to aortic nerve stimulation in DOCA-salt hypertensive rats

In order to verify, whether baroreflex sensitivity is changed centrally in DOCA-salt hypertension, the left aortic depressor nerve (ADN) was electrically stimulated in DOCA-salt hypertensive rats. After 3 weeks, tail-cuff systolic pressure was significantly higher in DOCA-salt treated rats than in untreated rats (169 +/- 4 versus 130 +/- 4 mmHg, respectively; P less than 0.001). After cutting both ADN and the carotid sinus nerves, the central cut end of the left ADN was electrically stimulated and frequency dependent depressor, bradycardic and sympatho-inhibitory responses were elicited in both control and DOCA-salt hypertensive rats. However, these responses were significantly smaller in DOCA-salt hypertensive rats than in normotensive controls. Bradycardic and sympatho-inhibitory responses to i.v. injection of norepinephrine were also blunted in DOCA-salt hypertensive rats. These findings suggest that baroreflexes were centrally attenuated in DOCA-salt hypertensive rats and possibly contribute to overall baroreflex attenuation.

EFFECTS OF SALT AND DOCA ON HYPOTHALAMIC AND BAROREFLEX CONTROL OF BLOOD PRESSURE

Cardiovascular and sympathetic nerve responses to electrical stimulation of either the aortic depressor nerve (ADN) or the posterior hypothalamus were recorded from rats treated with salt, DOCA, or DOCA/salt and compared with those from untreated controls. By the 7th day, tail-cuff systolic pressures were significantly elevated in rats treated with salt or DOCA/salt. And by the 21st day, all treated rats (i.e. with salt, DOCA, or DOCA/salt) had elevated pressures together with attenuated ADN responses and augmented hypothalamic responses. After 5 days, DOCA/salt treated rats already had attenuated responses to ADN stimulation and augmented responses to hypothalamic stimulation even though their systolic pressures were still unaltered. These findings suggest that combined treatment with salt and DOCA altered central blood pressure regulation even before hypertension developed.

Attenuation of Hypothalamo-Sympathetic Hyperactivity by Renal Denervation in Experimental Hypertensive Rats

To clarify the effect of renal nerves on hypothalamic cardiovascular regulation in hypertension, posterior hypothalamus was electrically stimulated in renal denervated SHR (RD-SHR) and DOCA hypertensive (RD-DOCA) rats during recording blood pressure and sympathetic nerve activity. In urethane anesthetized SHR, mean blood pressure was not different between RD- and sham-operated SHR 48 hours after denervation, but two weeks later, blood pressure was lower in RD-SHR. Pressor and sympathetic nerve responses to hypothalamic stimulation were partly attenuated 48 hours after denervation, but two weeks later, attenuation was strong. The development of hypertension was abolished during two weeks observation in RD-SHR. In DOCA hypertensive rats, the development of hypertension was significantly inhibited by renal denervation. Pressor and sympathetic nerve responses to hypothalamic stimulation were significantly diminished in RD-DOCA rats. Water intake and urine volume was identical in both groups. These results suggest that renal denervation inhibited the development of hypertension accompanied with the inhibition of hypothalamo-sympathetic nerve system, furthermore, it is indicated that hypothalamic cardiovascular regulation controlled by afferent renal nerve could contribute to the development of hypertension in SHR and DOCA hypertensive rats.

Central Effect of Captopril on Baroreflex

To clarify effect of converting enzyme inhibitors (CEI) on heart rate regulation, captopril (2 mg/kg) was injected intravenously (i.v.) with or without pretreatment of atropine and also responses to intracisternal (i.c.) injections were examined. Captopril induced bradycardia with lowering blood pressure, and this bradycardia was abolished by pretreatment of atropine. Reduction of heart rate by i.c. injection of captopril was significantly larger than those of i.v. injection. Furthermore, to determine whether CEI can modify baroreflexes centrally, the aortic depressor nerve (ADN) was stimulated electrically in captopril treated rats. Vasodepressor and sympatho-inhibitory responses induced by ADN stimulation were significantly attenuated by captopril, while the bradycardiac response was not changed. These findings suggest that captopril attenuated centrally vasodepressor and sympatho-inhibitory responses of the baroreflex and activated centrally cardiac vagal efferent activity.

Calcium Suppresses Central Angiotensin II Pressor Response Less in Shr

To determine whether calcium alters central cardiovascular regulation, cardiovascular responses to intracerebroventricular (ICV) injection of calcium were recorded in conscious Wistar rats. Calcium injection consistently produced dose-dependent decreases in mean parterial pressure and heart rate. Pretreatment with a calcium channel blocker, diltiazem, attenuated cardiovascular responses to calcium. Decreases in plasma norepinephrine indicated the contribution of sympatho-inhibition to vasodepression by calcium. Preceding calcium injection reduced pressor responses to ICV-injected angiotensin II. These findings suggest that there is a pharmacological interaction between calcium and angiotensin II in the central nervous system. In spontaneously hypertensive rats (SHR), cardiovascular responses to calcium was larger than Wistar Kyoto rats (WKY). By contrast, calcium reduced pressor responses to angiotensin II only in WKY but not in SHR. Because the central interaction between calcium and angiotensin II has been different in SHR, our results imply that this difference may be related to the maintenance of high blood pressure in SHR.

Salt increases blood pressure with biphasic changes in hypothalamic responsiveness in rats

Tail-cuff systolic pressures became elevated in male Wistar rats fed chow containing 8% NaCl for 4 weeks. After 4 weeks of salt loading, pressor and sympathetic responses to ventromedial hypothalamic stimulation were larger in salt-loaded rats. When similar experiments were done following sinoaortic denervation, all of the effects previously induced by dietary salt loading persisted. By contrast, after only 1 week of salt loading, pressor and sympathetic responses to hypothalamic stimulation were reduced, instead of being increased. Since circulating plasma volume was increased in week 1, it was considered possible that reduced hypothalamic responsiveness was due to enhanced cardiopulmonary baroreflexes. Supporting this interpretation, bilateral vagotomy reversed the hypothalamic inhibition occurring in week 1. Although neither the site nor mechanism causing sympathetic hyperactivity has been determined, our results indicate that chronic dietary salt loading has biphasic effects on the ventromedial hypothalamus: an initial inhibition in the first week followed by stimulation thereafter. These results could mean that dietary salt loading eventually increases sympathetic activity and thereby induces hypertension by stimulating the ventromedial hypothalamus.