Tyrosine kinase inhibition attenuates vasopressin-induced contraction of mesenteric resistance arteries: alterations in spontaneously hypertensive rats.

Abstract

This study examined the role of tyrosine kinase-dependent signaling pathways in arginine vasopressin (AVP)-induced contractile responses in resistance arteries from spontaneously hypertensive rats (SHR). Systolic blood pressure was measured in conscious 6- and 21-week old SHR and Wistar Kyoto rats (WKY) by tail cuff measurements. Segments of third-order mesenteric arteries (about 200 microm in diameter, 2mm in length) were mounted in a pressurized chamber with the intraluminal pressure maintained at 45 mmHg. Contractile effects of AVP (10-12 to 10-7 mol/l) were determined in the absence and presence of the selective tyrosine kinase inhibitor tyrphostin A23 (10-5 mol/l) and the inactive analogue, tyrphostin A1 (10-5 mol/l). Systolic blood pressure was significantly higher in SHR compared with age-matched WKY (p < 0.01). AVP increased contraction in a dose-dependent manner with significantly greater responses in adult SHR (pD2 = 10.3 +/- 0.06) than age-matched WKY (pD2 = 9.4 +/- 0.04). Tyrphostin A23 shifted the AVP dose response curve to the right in 6- and 21-week WKY and 6-week SHR, but had little effect on AVP-induced responses in 21-week-old SHR. Tyrphostin A1 did not influence contraction in any groups. Protein tyrosine phosphorylation in VSMCs and mesenteric arteries was increased 2-3 fold in 21-week SHR compared with WKY counterparts. AVP significantly increased tyrosine phosphorylation in VSMCs, with enhanced effects in SHR compared with WKY (p < 0.05). These effects were inhibited by tyrphostin A23. Our findings demonstrate that protein tyrosine kinases contribute to AVP-induced contraction of resistance arteries from WKY and SHR during the phase of developing hypertension. These processes do not seem to play an important role in AVP-induced hypercontractility in SHR with established hypertension.