Inositolphosphate formation in thoracic and abdominal rat aorta following G q/11 -coupled receptor stimulation

Abstract

Although thoracic and abdominal rat aorta are often used as a classical pharmacological preparation for the assessment of vascular drug effects, little is known on regional differences among these two parts of the aorta with regard to their reaction to Gq/11-coupled receptor activation. Thus, we determined, in rings from thoracic and abdominal aorta from 12-week-old male Wistar rats, the effects of noradrenaline (NA; 10(-8)-10(-4) M), endothelin-1 (ET-1; 10(-10)-10(-6) M) and the thromboxane A2 mimetic U 46619 (10(-8)-10(-5) M) on inositolphoshate (IP) formation (assessed as accumulation of total [3H]IPs in [3H]myoinositol prelabelled rings). NA, ET-1 and U 46619 concentration-dependently increased IP formation; maximum increases were, however, significantly more pronounced in thoracic than in abdominal aorta. Similarly, NA, ET-1 and U 46619 evoked significantly larger maximum contractions in thoracic than in abdominal aorta. NA-induced [3H]IP formation could be inhibited with BMY 7378 (10(-9)-10(-4) M) and with 5-methyl-urapidil (5-MU; 10(-9)-10(-5) M) both exhibiting biphasic concentration-inhibition curves. The pKi-values for BMY 7378 at the high affinity site were in thoracic aorta 8.93+/-0.28 (n=5), and in abdominal aorta 8.76+/-0.35 (n=4) and at the low affinity site 6.45+/-0.2 (thoracic aorta) and 6.55+/-0.27 (abdominal aorta). pKi-Values for 5-MU in thoracic aorta at the high affinity site were 8.25+/-0.34 (n=4), and at the low affinity site 6.61+/-0.39 . In abdominal aorta reliable pKi-values could not be calculated for 5-MU due to a low signal-to-noise ratio. On the other hand, in both preparations the ETA-receptor antagonist BQ-123 (10(-9)-10(-5) M) and the TP-receptor antagonist SQ 29548 (10(-9)-10(-5) M) inhibited ET-1- and U 46619-induced IP formation, respectively, with monophasic concentration-inhibition curves: pKi-values for BQ-123 were: 8.16+/-0.24 (thoracic aorta) and 8.10+/-0.35 (abdominal aorta) and for SQ 29548: 8.2+/-0.3 (thoracic aorta) and 8.5+/-0.3 (abdominal aorta). The amount of immunodetectable Gq/11-protein was similar in both tissues. We conclude that responses to NA, ET-1 and U 46619 (IP formation and contractile force) are larger in thoracic than in abdominal aorta. ET-1 effects on IP formation are mediated by ETA-receptors and U 46619 effects by TP-receptors. NA effects are mediated by alpha1D- and alpha1A-adrenoceptors; alpha1B-adrenoceptors seem to play a minor role.

Noradrenaline-induced contraction of human saphenous vein and human internal mammary artery: involvement of different α-adrenoceptor subtypes

“…From these experiments pK B -values for 5-MU were calculated ranging from 7.2 to 7.5 which are between its affinity at α 1A -(8.63; Michel et al 1995) and α 1B -and α 1D -adrenoceptors (6.97 and 7.31; Michel et al 1995). Involvement of α 1D -adrenoceptors seems to be unlikely because BMY 7378 exhibited only at the rather high concentrations of 3×10 -7 M and 10 -6 M antagonistic effects against NA-induced contraction with pK B -values of 7.0-7.4 which are by far lower than the affinity of BMY 7378 at the α 1D -adrenoceptor (8.2-9.4; Dhein et al 2001). On the other hand, CEC (30 µM, i.e.…”

“…On the other hand, neither prazosin (10 -9 -10 -7 M) nor the α 1A -adrenoceptor-selective antagonist 5-MU (10 -8 M and 10 -7 M) nor the α 1D -adrenoceptor-selective antagonist BMY 7378 (10 -7 M and 10 -6 M) exhibited considerable antagonistic activity against NA-induced contraction although they were used in concentrations 10-to 100-fold higher than their affinities at α 1 -(prazosin pK B 8.5-10; Starke 1981; Hieble et al 1995;Alexander and Peters 1999), α 1A -(5-MU pK B 8.63; Michel et al 1995) or α 1D -adrenoceptors (BMY pK B 8.2-9.4; Dhein et al 2001). Accordingly, a significant contribution of α 1A -or α 1D -adrenoceptors to the contractile action of NA in human saphenous vein is quite unlikely.…”

Changes in α 1 -adrenergic vascular reactivity in monocrotaline-treated rats

“…Several studies have addressed the question of the identity of the α 1 -adrenoceptor subtype mediating constriction in the rat thoracic aorta (e.g. Dhein et al 2001;Hussain and Marshall 1997;Xu and Han 1996). It is now generally accepted that the primary receptor subtype involved is the α 1D -adrenoceptor; however, effects via α 1A -and α 1B -adrenoceptors have also been demonstrated (Testa et al 1995;Fagura et al 1997;Villalobos-Molina and Ibarra 1996).…”

ET-receptor function in relation to blood pressure in spontaneously hypertensive and aortic-banded rats

“…We have recently shown that ET-1 caused [ 3 H]IP formation in rat thoracic and abdominal aorta via stimulation of ET A receptors (Dhein et al 2001). In the present study in rings of thoracic aorta obtained from AOB rats ET-1-induced [ 3 H]IP formation was at all three time points measured (i.e.…”