Pharmacokinetics and pharmacodynamics of SB 209670, an endothelin receptor antagonist: Effects on the regulation of renal vascular tone

Abstract

The pharmacokinetics of intravenous SB 209670 appeared to be linear, and infusion resulted in dose-related increases in immunoreactive endothelin-1. The lack of anti-natriuretic effect and the renal vasodilator response observed in this study indicate that SB 209670 does not possess any partial agonist activity. Further, the renal hemodynamic response supported a potential physiologic role for endogenous endothelin in the maintenance of renal vascular tone in humans.

Pharmacokinetics and pharmacodynamics of tezosentan, an intravenous dual endothelin receptor antagonist, following chronic infusion in healthy subjects

“…This confirmed the results of the first clinical study in which doses of 100 mg and higher (infused in 1 h) also induced headache of mild/moderate intensity [9]. A nitrate‐like headache has occurred in healthy subjects treated with other endothelin antagonists [13–15] but was less pronounced in patients [16]. Probably this phenomenon is caused by cerebral vasodilatation, which is in line with the absence of signs of systemic vasodilatation (Figure 2).…”

“…bolus injection of 10 mg kg −1 tezosentan decreased the mean arterial blood pressure in conscious normotensive rats by only 8 mmHg and did not change blood pressure in dogs [8]. Endothelin receptor blockade with the mixed endothelin‐A and ‐B receptor antagonist SB 209670 also showed only a modest contribution of endothelin to basal renal vascular tone in healthy subjects [14].…”

Pathophysiology of contrast medium–induced nephropathy

“…Accordingly, a selective ET-A receptor blockade could prove to be effective in the prevention of CIN. In the study of Freed et al [75] using the unselective blocker, plasma endothelin-1 levels may have increased as shown by a study employing a similar intravenous infusion of the same endothelin receptor antagonist, SB 209670. This increase in endothelin-1 concentration is probably brought about by the ET-B receptor antagonism [76], since one of the ET-B-mediated effects is the attenuation of further endothelin release.…”

Vasodilator effects of the endothelin ETA receptor selective antagonist BMS‐193884 in healthy men

“…The importance of endothelin‐1 (ET‐1) as a physiological mediator of basal vascular tone in vivo in man is indicated by local [1–3] and systemic [2, 4–6] vasodilatation in response to endothelin receptor antagonists (ERAs) in healthy subjects. The potent vasoconstrictor effects of ET‐1 [7, 8], combined with the vasodilator effects of ERAs described in patients with chronic heart failure (CHF) [9], chronic renal failure [10] and hypertension [11–13], suggests a functional role for ET‐1 in the development and maintenance of the increased peripheral vascular resistance associated with these conditions.…”