Koichi Higashimori

Evidence for endothelin-1 release from resistance vessels of rats in response to hypoxia

To elucidate further the contribution of endothelin into endothelium-dependent vasoconstriction evoked by hypoxia, we observed endothelin release during hypoxia. Endothelin was detectable in perfusate from mesenteric artery. Immunoreactive endothelin was confirmed as endothelin-1 by a reverse phase-HPLC. Endothelin release increased 4.1 +/- 1.3 to 12.4 +/- 2.0 pg/30 min without changing perfusion pressure. Thirty minutes of hypoxia stimulated endothelin release by 71 +/- 11% (P less than 0.05) and was associated with an elevation of perfusion pressure. These results suggest that endothelin contributes to endothelium-dependent vasoconstriction by hypoxia in mesenteric artery and may play an important role in the local peripheral vascular tone.

Converting enzyme inhibitors regressed cardiac hypertrophy and reduced tissue angiotensin II in spontaneously hypertensive rats

To examine the role of the tissue renin-angiotensin system in left ventricular hypertrophy, converting enzyme inhibitors were administered orally to 12-week-old male spontaneously hypertensive rats (SHR) for 4 weeks, and cardiac tissue angiotensin II was measured. Treatment with enalapril (10 mg/kg per day) and trandolapril (1 mg/kg per day) lowered systolic blood pressure, left ventricular weight and left ventricular angiotensin II content. Plasma angiotensin II concentration was increased by the treatment with enalapril whereas trandolapril did not cause any change. There was significantly positive correlation between left ventricular weight and angiotensin II content. Because angiotensin II promotes cell proliferation, these results suggest that cardiac tissue angiotensin II, rather than circulating angiotensin II, may account for the pathophysiology of left ventricular hypertrophy in SHR.

Role of cardiac angiotensin II in isoproterenol-induced left ventricular hypertrophy.

Angiotensin II (Ang II) has been shown to induce proliferation of cardiac myocytes. To examine the role of Ang II in left ventricular (LV) hypertrophy, isoproterenol was infused subcutaneously into 9-week-old male Wistar rats at 4.2 mg/kg/day for 7 days. Infusion of isoproterenol increased LV weight and Ang II concentrations in plasma and in LV tissue. In anephric rats, LV weight and tissue Ang II were increased similarly, but plasma Ang II was not changed by isoproterenol. Concomitant oral administration of trandolapril and isoproterenol prevented increases in both LV Ang II and LV weight. Treatment with hydralazine decreased blood pressure in a similar way as trandolapril but did not affect either LV weight or LV Ang II. Plasma Ang II was not decreased by either trandolapril or hydralazine when administered in combination with isoproterenol. These results suggest that cardiac tissue Ang II regulates myocyte growth in isoproterenol-induced LV hypertrophy, and the reduction of Ang II partly explains the prevention of cardiac hypertrophy by the converting enzyme inhibitor.

Circulating factor with ouabain-like immunoreactivity in patients with primary aldosteronism

Circulating factor with ouabain-like immunoreactivity was studied in patients with primary aldosteronism. Anti-ouabain antibody was prepared from specific pathogen-free rabbits. In the plasma of patients with primary aldosteronism, the level of a factor with ouabain-like immunoreactivity was 2.59 +/- 1.39 pmol ouabain equivalent/ml plasma. This value was significantly (p less than 0.05) higher than that of age-matched normotensive subjects, 1.06 +/- 0.86 pmol ouabain equivalent/ml plasma. The plasma level of ouabain-like immunoreactivity correlated significantly (p less than 0.05) with blood pressure. These results indicate that the factor with ouabain-like immunoreactivity may play a pathophysiological role in the maintenance of the high blood pressure observed in patients with primary aldosteronism.

Effects of endothelin on neuroeffector junction in mesenteric arteries of hypertensive rats.

The effect of endothelin, a novel vasoconstrictor peptide, on the adrenergic neuroeffector junction was investigated in isolated perfused mesenteric arteries of spontaneously hypertensive rats (SHR) and Wistar-Kyoto (WKY) rats. The vasoconstrictor responses to periarterial sympathetic nerve stimulation and exogenous norepinephrine were determined. Infusion of endothelin-1 increased the baseline perfusion pressure dose dependentiy to similar extents in the two strains. A subpressor dose of endothelin-1 (1010 M) enhanced the pressor response to norepinephrine; its effect was greater in WKY rats than in SHR. Endothelin-1 (10−12 to 1010 M) attenuated the pressor response to sympathetic nerve stimulation, and the degree of inhibition tended to be less in SHR than in WKY rats. Higher doses (3xlO10 and 109 M) of endothelin-1 enhanced the pressor response to nerve stimulation in both WKY rats and SHR. Endothelin-1 inhibited norepinephrine release from rat mesenteric arteries; the inhibition was significantly less in SHR than in WKY rats. These results suggest that endothelin enhances the responsiveness of tt-adrenergic receptors to catecholamines, whereas it inhibits presynaptic adrenergic neurotransmission. Thus, endothelin can interact with the neuroeffector junction in addition to having a vasoconstricting effect in peripheral vessels. The difference in the mode of modulation by endothelin at the vascular neuroeffector junction in SHR from that in WKY rats might explain the maintenance of hypertension.

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.

THE ANGIOTENSIN‐CONVERTING ENZYME INHIBITOR, PERINDOPRIL, PREVENTS CARDIAC HYPERTROPHY IN LOW‐RENIN HYPERTENSIVE RATS

1. To examine whether an angiotensin‐converting enzyme (ACE) inhibitor prevents left ventricular (LV) hypertrophy even in low‐renin hypertension, we studied the effect of the administration of perindopril on cardiac hypertrophy induced by partial renal ablation in hypertensive rats.

DIFFERENTIAL CONTROL OF VASCULAR TONE AND HEART RATE BY DIFFERENT AMINO ACID NEUROTRANSMITTERS IN THE ROSTRAL VENTROLATERAL MEDULLA OF THE RAT

1. To test the hypothesis that a central mechanism may play a role in the minimal reflex tachycardia noted in response to peripheral converting enzyme inhibition, we compared the effects of intravenous (i.v.) ceronapril (CER) with nitroglycerin (NTG) on neurotransmitter release in the rostral ventrolateral medulla (RVLM), using an in vivo microdialysis method in pentobarbital anaesthetized rats.

THE EFFECTS OF CENTRAL ADMINISTRATION OF ANGIOTENSIN II TYPE-1 RECEPTOR ANTAGONIST, CV-11974, IN NEPHRECTOMIZED SPONTANEOUSLY HYPERTENSIVE RATS

1. The role of the brain renin‐angiotensin system in the pathogenesis of genetic hypertension was evaluated using a specific non‐peptide angiotensin II type‐1 receptor antagonist, TCV‐116.

Direct evidence for the local generation of vascular angiotensin II and its prostaglandin-mediated release from isolated hind legs in the rat.

We examined the effect of prostaglandin synthesis inhibitors (indomethacin and meclofenamate) on the release of immunoreactive angiotensins I (irAng I) and II (irAng II) from isolated perfused rat hind-leg vasculature in order to delineate the possible relevance of prostaglandins to the vascular renin-angiotensin system in vitro. Isolated rat hind-legs were perfused with Krebs-Ringer solution and release of irAng I and irAng II into the perfusate was directly measured by using a Sep-Pak C18 cartridge connected to the perfusion system. The spontaneous release of irAng I and irAng II was as high as 600–700 pg per 30 min and was stable for at least 3 h. Addition of indomethacin and meclofenamate (10-8 to 2 x 10-6 mol/l) to the perfusion medium suppressed the release of both irAng I and irAng II to a similar extent in a dose-dependent fashion (P < 0.001); the maximal percentage inhibition of irAng II release that was evoked by these inhibitors (2 x 10-6 mol) was 60 ± 6% (P < 0.001) for indomethacin and 50 ± 4% (P < 0.001) for meclofenamate. There was a highly significant positive correlation between the amount of irAng I released and the amount of irAng II that was altered by indomethacin (r = 0.91) or meclofenamate (r = 0.94). These results provide direct proof of the local generation and subsequent release of Ang II by peripheral vascular tissue and suggest that prostaglandin plays an important role in the regulation of vascular Ang II release.