No abstract

Endothelin, a recently discovered endothelium-derived peptide, has been reported to produce potent vasoconstriction in various vessels of experimental animals. To study the involvement of endothelin in the regulation of vascular tonus in humans, isolated human mesenteric arteries were investigated by both pharmacological and immunohistochemical methods. The vasoconstrictor action of endothelin-1 was examined on ring segments of human mesenteric arteries.Endothelin-1 induced a slowly developing and sustained contraction, with an EC50 value (half-maximal effective concentration) of 2.9x 10-9 M, two orders of magnitude smaller than that of norepinephrine (EC50 of 3.9xlO0`M), indicating that the vasoconstrictor action of endothelin-1 is about 100 times more potent than that of norepinephrine. The contractile effect of endothelin-1 was affected neither by adrenergic, cholinergic, histaminergic, nor serotonergic antagonists, nor by inhibitors of arachidonic acid metabolism. The vasoconstrictor response to endothelin-1 was effectively antagonized by nicardipine, a dihydropyridine Ca21 channel blocker. Endothelin-1 profoundly augmented contractile response to Ca21 in partially depolarized tissues. Immunohistochemical studies revealed for the first time that endothelin-like immunoreactivity was localized in endothelial cells of human mesenteric artery. The results of the present study indicate that endothelin-1 is one of the most potent vasoconstrictors in the human mesenteric artery and that it induces vasoconstriction via an ultimately accelerating Ca21 influx through voltage-dependent Ca21 channels. Since endothelin-1 can be located in human endothelial cells, it may play an important physiological or pathophysiological role. (Circulation 1990;81:1874-1880 Since the discovery of endothelium-dependent vasodilation by Furchgott and Zawadzki in 1980,1 it has become evident that the endothelial cells covering the luminal surface of blood vessels play a key role in the motor effects of certain vasoactive substances.2 In addition to mediating relaxations, endothelial cells can also facilitate conFrom the

To evaluate the effect of exercise on left ventricular diastolic filling, the following were measured at rest and during exercise in 14 control subjects and 15 athletes, using digitized M-mode echocardiography: the peak early diastolic lengthening rate of the left ventricular dimension and the filling volume and the filling fraction during the first 0.10 s of diastole. During ergometer exercise performed at a level that increased the heart rate to 100 beats/min, there were significant increases in the peak normalized lengthening rate of the left ventricular dimension (control subjects, 4.2 +/- 1.3 vs. 6.1 +/- 1.1 s-1, mean +/- SD, P less than 0.001; athletes, 5.3 +/- 0.9 vs. 7.4 +/- 1.1 s-1, P less than 0.001), filling volume (control subjects, 15 +/- 12 vs. 33 +/- 10 ml, P less than 0.001; athletes, 21 +/- 12 vs. 63 +/- 18 ml, P less than 0.001), and filling fraction (control subjects, 21 +/- 14 vs. 42 +/- 17%, P less than 0.005; athletes, 21 +/- 13 vs. 54 +/- 12%, P less than 0.01). The peak lengthening rate of the left ventricular dimension, the filling volume, and the filling fraction were significantly greater in athletes than in control subjects during exercise (P less than 0.005, P less than 0.001, and P less than 0.05, respectively). Augmented early diastolic filling may be a mechanism to provide adequate filling for the ventricle at high heart rates produced by exercise, especially in athletes.

SUMMARY The duration of the acceleration phase of pulmonary systolic flow was measured by pulsed Doppler echocardiography in 39 normal subjects and 67 patients with heart disease to evaluate the reliability of this Doppler index as an estimate of pulmonary arterial pressure. The mean (SD) Doppler index in patients with abnormal mean pulmonary arterial pressure ( > 15 mm Hg) was significantly shorter than that in normal subjects (1 10 (30) ms vs 150 (10) ms). The Doppler index was significantly related to the mean pulmonary arterial pressure (r = -0 75) the pulmonary blood flow (r = 0 46), and the total pulmonary vascular resistance (r =-0-68). Forty four of 45 patients with an abnormal index (< 120 ms) showed abnormal mean pressure (> 15 mm Hg). Without exception patients with a low index ( < 90 ms) had distinct pulmonary hypertension ( > 25mm Hg). Twelve of 22 patients with a normal index (> 130 ms), however, also showed abnormal pressures. Nine of the 12 had an atrial septal defect and they had high pulmonary arterial pressure associated with high blood flow. Eighteen patients with valvar heart disease, whose mean pulmonary arterial pressure ranged from 16mm Hg to 24mm Hg, had a significantly shorter acceleration phase and a higher total vascular resistance than 11 patients with atrial septal defect in whom the pressure range was similar (120(20) ms vs 140(20) ms, 3 8 (1 1) hybrid resistance unit vs 1 6 (0-5)).Thus although the acceleration time of the pulmonary systolic flow is useful for the evaluation of pulmonary hypertension, it is a complex index that is affected not only by pulmonary arterial pressure but also by pulmonary blood flow and pathological changes in the pulmonary vascular bed. Accepted for publication 12 March 1986 patients with pulmonary hypertension is characteristically shorter than that in normal subjects,4 and the duration of the acceleration phase decreases as the pulmonary hypertension progresses.4 5 This Doppler index may provide a non-invasive method for the evaluation of pulmonary arterial pressure. Pulmonary arterial pressure, however, depends on pulmonary flow volume and pulmonary vascular impedance. The -duration of the acceleration phase in a patient with high flow volume may be different from that in another patient with high peripheral resistance, even if pulmonary arterial pressure is the same in both patients. Furthermore, right ventricular contractility may affect the pulmonary systolic flow pattern.We have studied the relation between the duration of the acceleration phase of pulmonary systolic flow and haemodynamic variables in various diseases to 158

Endothelin, an endothelium-derived vasoconstrictor peptide, and angiotensin II were intravenously injected into the femoral vein of normotensive Wistar-Kyoto (WKY) rats that had been anesthetized with urethane. Blood pressure and heart rate were recorded from a cannula inserted into the carotid artery. All experiments were carried out after treatment with adrenergic and cholinergic antagonists. Endothelin showed a potent, dose-dependent pressor action. The dose-response relations for the increase in blood pressure of rats receiving endothelin were comparable with those of rats receiving angiotensin II. However, endothelin showed far more long-lasting effects. Endothelin-induced responses consisted of three phases: a rapid and transient depressor phase and then two phases of pressor (transient and long-lasting) response. Nicardipine (0.1 mg/kg), a dihydropyridine Ca 2+ channel blocker, markedly attenuated the slow phase of the pressor response but only slightly attenuated the rapid one. The pressor action of endothelin was not inhibited by continuous infusions of saralasin, which almost abolished the angiotensin II-induced pressor response. Endothelin-induced pressor response was also not attenuated by indomethacin, a prostaglandin synthesis inhibitor. These data provide evidence that endothelin produces a unique, potent, and long-lasting pressor response, which appears to be in part related to the activation of Ca 2+ channels. In 12-week-old spontaneously hypertensive rats (SHR), the maximal pressor response to endothelin was slightly but significantly greater than that in age-matched WKY rats, but the dose dependency of the response was approximately consistent with that in WKY rats. In contrast to the in vivo data, the vasocontractile effect of endothelin on the isolated mesenteric artery was more sensitive in 12-week-old SHR than in WKY rats, despite no differences between SHR and WKY rats at 6 weeks of age. The implication of this inconsistency is discussed. (Hypertension 1989; 14:427-434) T he vascular endothelium is the layer of epithelial cells in direct contact with the blood, and it has recently been recognized to be an important modulator of vascular tonus. Furchgott and Zawadzki 1 first discovered that endothelium is indispensable to relax precontracted vascular strips