Takeshi Tsunetoshi

Spectral change in heart rate variability in response to mental arithmetic before and after the beta-adrenoceptor blocker, carteolol

Spectral analysis of heart rate fluctuation was evaluated before and after administration of carteolol, a non-selectiveβ-adrenoceptor-blocker, to investigate the neural regulatory mechanisms underlying the haemodynamic changes induced by mental stress. Mental stress increased blood pressure and heart rate, with an increased low frequency band, and low frequency/high frequency ratio of the power spectral analysis which are indices of sympathetic activity. Carteolol did not change basal and pre-mental stress measurements of blood pressure, heart rate and spectral density. However, carteolol altered the response to mental stress with a decrease in spectral density of the low frequency band and low frequency/high frequency ratio, and an increase in the high frequency component. These results confirm that mental stress elevates blood pressure by activating the sympathetic nervous system, and suggest that blockade of theβ-adrenoceptor attenuates the pressor response by preventing the autonomic responses to mental stress.

Vasoconstriction and hypersensitivity to vasoactive substances after acute volume expansion in dogs.

In a search for factors contributing to the sustained Mood pressure (BP) elevation in acutely volume-loaded animals, dextran dissolved in lactated Ringers solution (20 ml/kg) was infused into 34 mongrel dogs over a period of 1 hour under pentobarbital anesthesia and changes in bemodynamic and humoral variables were monitored during its infusion and for 3 hours after its infusion. BP elevation during volume loading (from 114 ± 3 to 128 ± 3 [SEM] mm Hg) was attributed to an increase in cardiac output. After volume loading, some dogs maintained BP elevation whereas others did not. The former group showed an increase in total peripheral resistance, demonstrating a transformation of cardiac output to total peripheral resistance as a responsible factor in maintenance of the elevated BP. The plasma levels of norepinephrine, vasopressin, and plasma renin activity were not elevated, indicating that these vasoactive factors were not responsible for elevation of the BP or total peripheral resistance. The changes in the hematocrit, atrial natriuretk factor, urine volume, and urinary sodium excretion were identical in the two groups, and natrluresis was not prominent when total peripheral resistance was high. Pressor responses to norepinephrine and angiotensin II were potentiated 3 hours after stopping Infusion in both groups, but this potentiation was not correlated with the Increase in total peripheral resistance or mean BP. Thus, acute volume expansion produced resistance-dependent hypertension following the initial volume-dependent hypertension. It is unlikely that a vascular sensitizing natriuretk factor plays a role in the resistance-dependent BP elevation. The mechanism and physiological importance of hypersensitivity to vasoactive substances remain to be elucidated.

HAEMODYNAMIC EFFECT OF ENDOTHELIN, A NOVEL POTENT VASOCONSTRICTOR IN DOGS

1. The effects of endothelin (40 and 400 pmol/kg, intravenous (i.v.), a novel vasoconstrictor, on haemodynamics were evaluated in normal dogs and dogs treated with hexamethonium.

Effect of cromakalim (BRL 34915) on hemodynamic and electrocardiographic changes induced by endothelin in dogs

SummaryWe evaluated whether cromakalim (BRL 34915), a vasorelaxant agent which acts by opening potassium channels, could affect the systemic effects of endothelin, a newly discovered vasoconstrictive peptide. Intravenous administration of endothelin alone (400 pmol/kg) to anesthetized dogs produced blood pressure elevation, which was associated with an increase in cardiac output in the early phase, and was associated with an increase in total peripheral resistance in the late phase. Electrocardiogram showed significant ST-elevation in II, III, and aVL, and ST-depression in a VR and aVL. The same dose of endothelin given to dogs pretreated with cromakalim did not induce these hemodynamic and electrocardiographic changes. Thus, cromakalim, a potassium activator, inhibited the hemodynamic and electrocardiographic actions of endothelin, suggesting that hyperpolarization due to potassium channel activation inhibited the voltage-dependent calcium channel, which is thought to be a major mechanism for the pressor action of endothelin.

Increase in the blood pressure and decrease in the norepinephrine release in the ventrolateral medulla during intraventricular administration of hypertonic NaCl.

Norepinephrine (NE) release in the ventrolateral medulla (VLM) was serially measured in anesthetized male Wistar rats during the rise in the blood pressure (BP) produced by acute intraventricular (ICV) administration of hypertonic (1.5 M) NaCl. Catecholamine release was determined by a brain microdialysis method using high performance liquid chromatography and electrochemical detector. The release of NE in the VLM was significantly decreased after ICV 1.5 M NaCl. In another set of rats, the pressor response to acute ICV 1.5 M NaCl was attenuated by selective administration of NE to the VLM using the microdialysis method. Chronic and continuous ICV infusion of 1.5 M NaCl to conscious rats caused an increase in BP on day 10 which was associated with a decrease in NE release in the VLM; concomitant ICV infusion of NE or of a synthetic NE precursor,l-threo-3,4-dihydroxyphenylserine (l-DOPS) prevented the rise in BP as well as the reduction in NE release. These results suggest that a decrease in the NE release of the VLM may contribute to the change in BP induced by ICV infusion of hypertonic saline.

Contribution of the baroreflex afferent nerves to the production of vasoconstricted hypertension in volume-expanded dogs.

Dextran in lactated Ringers solution (20 ml/ kg) was infused for 1 hour into anesthetized dogs with slnoaortic denervation and vagotomy (deafferentatlon; n=10) and dogs treated with hexamethonium (de-efferentation; n = 13) to compare with our previous observation in dogs with an intact autonomic nervous system (control, n-34). During the infusion, increase in blood pressure associated with increase in cardiac output was observed in all three groups. The increases in blood pressure were larger in the two groups with an impaired autonomic nervous system. In the recovery period, the control dogs and the hexamethonium-treated dogs showed gradual increases in total peripheral resistance and in vasoconstricted hypertension 3 hours after stopping the infusion. In contrast, the dogs with sinoaortic denervation and vagotomy did not show any increase in total peripheral resistance. The vasoconstricted groups showed peaks of natriuresis soon after the infusion, not 3 hours after the infusion when vasoconstriction was observed, although the dogs with deafferentation did not show a significant increase in natriuresis. Norepinephrine (0.5 μg/kg) was administered intravenously before and after volume expansion, and the pressor responses in the three groups after volume expansion were enhanced similarly (143%, 128%, and 136%, respectively). These results indicate that the afferent signals from peripheral vessels to the brain contribute to the production of vasoconstricted hypertension after acute volume expansion and that the vasoconstriction is independent of pressor hypersensitivity and is dissociated in time from the natriuresis.

Effect of ouabain on hemodynamics in acute volume expanded hypertensive dogs

SummaryTo evaluate possible roles of endogenous Na+−K+-ATPase inhibitors in vasoconstricted blood pressure elevation produced by acute volume expansion, we administered ouabain (Na+−K+-ATPase inhibitor) intravenously (30 μg/kg) for 10 min to dogs, 3 h after volume expansion with dextran in lactated Ringers solution (20 ml/kg, for 1 h). Acute volume expansion resulted in the elevation of blood pressure associated with an increase in cardiac output. In some dogs the blood pressure remained elevated with gradual increase in total peripheral resistance (Group I) or with sustained high cardiac output (Group II), and in other dogs (Group III) it returned to the control level. Ouabain administration elevated the blood pressure and total peripheral resistance in these groups and sham dogs which did not have volume expansion. And these effects of ouabain were not correlated with the degree of blood pressure or vasoconstriction produced by volume expansion. Thus, it is not likely that endogenous Na+−K+-ATPase inhibitors increased to produce vasoconstricted hypertension after acute volume expansion.

Central Sodium Loading Modifies Norepinephrine Content in the Ventrolateral Medulla and Blood Pressure in Rats

We evaluated the effects of intracerebroventricular (ICV) infusion of hypertonic NaCl on blood pressure (BP) control as well as on NE content in the ventrolateral medulla (VLM). Nine groups of Wistar rats received 10 days ICV infusion of NaCl solutions containing either norepinephrine (NE, 1.3 micrograms/min) or a synthetic NE precursor, 1-threo-3,4-dihydroxyphenylserine (1-DOPS, 17 micrograms/min) for 3 concentrations (0.15M, 0.8M or 1.5M) of NaCl. On day 9, only the group on ICV infusion of 1.5M NaCl alone had a significant rise in BP (133 +/- 3 mmHg, P less than 0.05 vs control) while other groups remained normotensive. The ICV infusion of 1.5M NaCl reduced NE content, determined by a microdialysis method, in the VLM while the concomitant ICV infusion of NE or 1-DOPS restored it suggesting that the decrease in NE content in the VLM may be a contributing factor in the BP elevation by the central salt loading.

Effect of volume expansion on hemodynamic variables in nephrectomized dogs

SummaryWe have previously demonstrated that blood pressure elevation by acute blood volume expansion is volume-dependent during the infusion period and resistance-dependent in the post-infusion period in normal anesthetized dogs, and that such an increase in blood pressure is associated with a potentiation of the pressor response to norepinephrine. To evaluate the possible renal contribution to these hemodynamic changes, blood volume expansion was performed for 1 h with dextran dissolved in lactated Ringers solution (20 ml/kg) in 15 nephrectomized dogs. The mean blood pressure, cardiac output and total peripheral resistance at the end of infusion were 126%, 225% and 60%, respectively; 3 h after volume expansion they were 126%, 151%, and 92% respectively. However, in 4 dogs, there was an increase in mean blood pressure (138%) 3 h after volume expansion. This was thought to result from an increase in the total peripheral resistance (133%) associated with the recovery of cardiac output (106%). The pressor response to norepinephrine (0.5 μg/kg) was potentiated after volume expansion. These results indicate that the handling of volume by the kidney contributed to the maintenance of an elevated level of cardiac output. However, nephrectomy did not seem to interfere with the hemodynamic switching of the causative factor for blood pressure elevation from increased cardiac output to increased total peripheral resistance. Neither was the potentiation of pressor response to norepinephrine affected.