Minako Oguro

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.

Chronic central GABAergic stimulation attenuates hypothalamic hyperactivity and development of spontaneous hypertension in rats.

To determine whether chronic central γ-aminobutyric acid (GABA) stimulation would attenuate development of hypertension, tail-cuff systolic pressures were measured in male spontaneously hypertensive rats (SHR) treated with either an inhibitor of GABA breakdown (valproate, VPA), or a GABA-receptor agonist (muscimol). When VPA was injected intraperitoneally (i.p.) daily for 4 weeks, tail-cuff systolic pressures were decreased during the last 2 weeks. On the other hand, continuous infusion of muscimol into the lateral cerebral ventricle for 14 days using an osmotic minipump decreased systolic pressures throughout the 10-day observation period. During terminal experiments under urethane anesthesia, pressor and sympathetic nerve responses to electrical stimulation of the ventromedial hypothalamus were reduced in VPA- or muscimol-treated SHR. Pressor responses to intravenously (i.v.) injected norepinephrine (NE) were unaltered by either treatment, indicating that diminished pressor responsiveness to hypothalamic stimulation was not due to diminished cardiovascular reactivity. Regardless of either VPA acid or muscimol treatment, basal blood pressure (BP), heart rate (HR), and responses to hypothalamic stimulation were lower in normotensive Wistar-Kyoto controls (WKY) than in SHR. In addition, chronic treatment with either drug had weaker hypotensive and hypothalamic depressant effects in WKY than in SHR. Our results suggest that in SHR the central GABAergic system is impaired and that chronic treatment with GABAergic stimulants can attenuate development of spontaneous hypertension by reducing hypothalamic overactivity.

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.

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.