Mitsuaki Nakamaru

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.

Endothelin inhibits renin release from isolated rat glomeruli

The effect of endothelin on renin release from isolated rat glomeruli was examined. Endothelin inhibited basal renin release in a dose-dependent manner with an IC50 of 1.0 x 10(-9) M. Endothelin also inhibited renin release stimulated by isoproterenol (10(-5) M). Nifedipine (10(-5) M), a calcium channel blocker, induced an increase in renin release. Endothelin did not affect this nifedipine-induced renin release. These results suggest that endothelin inhibits renin release via a calcium entry mechanism and increases intracellular calcium.

The Seasonal Variation of Blood Pressure in Patients with Essential Hypertension

We examined the role of dietary electrolytes and humoral factors in causing seasonal changes in blood pressure. Normal subjects had no seasonal difference in blood pressure, although urinary sodium and norepinephrine were significantly higher in winter than in summer. In patients with essential hypertension blood pressure, urinary sodium and norepinephrine excretion and plasma norepinephrine concentration were significantly higher in winter. Plasma renin activity, plasma and urinary aldosterone and urinary kallikrein excretion were not significantly different between the two seasons in both normal subjects and hypertensive patients. In conclusions, the blood pressure of patients with essential hypertension has a seasonal variation with higher pressures in the winter than in the summer. Increased sympathetic nervous activity and an increased load of sodium presented to the kidney for excretion may be contributing factors in the rise in blood pressure in winter in patients with essential hypertension.

Endothelin enhances adrenergic vasoconstriction in perfused rat mesenteric arteries

The interaction of endothelin with alpha-adrenergic receptors was examined in isolated perfused rat mesenteric arteries. Infusion of porcine or rat endothelin increased the baseline perfusion pressure dose-dependently. Subpressor doses of both porcine (10(-11) and 10(-10)M) and rat (10(-10) and 10(-9)M) endothelin enhanced the pressor responses to norepinephrine. Nicardipine (10(-7)M), a calcium channel blocker, attenuated this potentiation. These results suggest that endothelin enhances the responsiveness of alpha-adrenergic receptors to catecholamines probably through the increase in calcium influx. Thus endothelin may interact with sympathetic nerve activity in addition to having a direct vasoconstrictor action in peripheral vascular tissue.

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.

Endothelin inhibits presynaptic adrenergic neurotransmission in rat mesenteric artery

The effect of endothelin(ET) on adrenergic neurotransmission was examined in isolated perfused rat mesenteric arteries. Porcine ET(10(-12) to 10(-10)M) attenuated the pressor response to sympathetic nerve stimulation (NS). It also stimulated the release of prostaglandin E2 (PGE2), but its inhibition of the pressor response to NS was not affected by indomethacin treatment. ET also caused dose-dependent inhibition of [3H]norepinephrine release during NS. Higher doses of ET rather enhanced the pressor response to NS. These results suggest that ET inhibits presynaptic adrenergic neurotransmission without mediation of PGE2, while it potentiates the responsiveness of the postsynaptic alpha-adrenergic receptor. Thus ET appears to act directly on the neuroeffector junction as well as on the peripheral vasculature.

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.

Hormonal responses to long‐term converting enzyme inhibition in hypertensive patients

Captopril was given alone and in combination with diuretics to 49 patients with hypertension for 1 to 12 mo. Within 2 mo blood pressure reduction correlated with pretreatment plasma renin activity and response to the infusion of angiotensin II antagonist, but these effects were not present at 4 mo. Plasma and urinary aldosterone were suppressed but serum converting enzyme activity, plasma bradykinin, kallikrein, and prostaglandins (E and F) were in the normal range throughout the study period. Indomethacin (150 mg/day) for 1 wk abolished the hypotensive effect of captopril. Despite sustained reduction of blood pressure, plasma catecholamines were not elevated and urinary catecholamines were suppressed in patients on captopril alone. It is concluded that another mechanism, such as enhancement of renal or local kinin‐prostaglandin system, as well as suppression of the renin‐angiotensin‐aldosterone system may be involved in the long‐term efficacy of captopril. Sympathetic activity may also be depressed and contribute to the hypotensive effect.

Role of vascular angiotensin II released by beta-adrenergic stimulation in rats.

The effect of a beta-adrenoceptor agonist on the release of the components of the vascular renin-angiotensin system was examined in vitro. Isolated rat mesenteric arteries were perfused in an open system with Krebs-Ringer solution and released immunoreactive angiotensin II (ANG IIir) into the perfusate was directly determined using a Sep-Pak C-18 cartridge connected to the perfusion system. Renin activity in the concentrated perfusate was also determined. Isoproterenol (1 nM-1 microM) increased the release of ANG IIir in a dose-dependent manner. The increase in ANG IIir release during isoproterenol (1 microM) infusion was inhibited by propranolol (1 microM) or captopril (2 microM). Isoproterenol-induced increment of ANG IIir release was blocked by the selective beta 2-adrenoceptor antagonist, ICI 118,551 (1 microM), but not by the selective beta 1-adrenoceptor antagonist, atenolol (1 microM). Renin activity in the perfusate was measurable, but did not increase in response to isoproterenol (1 microM) infusion. There was no significant difference in the response of ANG IIir release to isoproterenol between spontaneously hypertensive rats and Wistar-Kyoto rats. The present results indicate that locally generated ANG II is released by beta 2-adrenoceptor activation. The beta-adrenoceptor agonist and the vascular renin-angiotensin system may play an important role for the regulation of peripheral vascular tone.

Effect of Age on Active and Inactive Plasma Renin in Normal Subjects and in Patients with Essential Hypertension

The effect of age on the levels of active and trypsin‐activatable inactive plasma renin was examined in 41 normal subjects and 54 patients with essential hypertension, during recumbency and after stimulation with furosemide and ambulation. Active renin levels in supine subjects and patients decreased with age. Inactive renin levels did not change with age in normal subjects, whereas in hypertensive patients they decreased with age. Following stimulation with furosemide and ambulation, the levels of active renin increased but the responsiveness to stimulus decreased with age in both groups. In contrast, inactive renin levels slightly increased after furosemide administration and ambulation, resulting in an increased proportion of active to total renin. These data show that an acute stimulation with furosemide and ambulation affects mainly the active form of plasma renin, and the effect of age on inactive plasma renin in normal subjects may be different from that in patients with essential hypertension.