Regulation of the Responsiveness of Vascular Smooth Muscle

1. The aim of this study was to investigate the roles of hypertension, ?2- adrenoceptors and neurotransmission in the regulation of rat blood vessel responses. 2. Experiments were carried out using the tail artery and aorta of spontaneously hypertensive rats (SHR), and comparisons were made with vessels from the normotensive control strain, Wistar Kyoto (WKY). 3. Rings of aorta and proximal tail artery from SHR were heavier than those from WKY, despite being cut to the same length. This indicated a structural difference, so the histology of the vessels was examined using light microscopy. 4. Both the wall thickness and lumen diameter of the aorta were greater in SHR compared to WKY, but there was no difference in wall thickness to lumen ratio. The area of the medial layer was increased in SHR relative to control. 5. There was no difference in the wall thickness of the proximal part of the tail anery between SHR and WKY rats, but the lumen diameter was reduced in SHR relative to control, giving a greater wall thickness to lumen ratio. The media area was decreased in SHR compared to WKY. 6. Wall thickness was increased and lumen diameter decreased in the distal part of the tail artery from SHR compared to WKY, giving a greater wall thickness to lumen ratio. The media area was increased in SHR compared to WKY. 7. Mechanical responses to drugs were investigated in the aorta and proximal tail artery from SHR and compared to responses obtained in vessels from WKY rats, using both isometric tension and perfusion pressure recording. 8. In the aorta, isometric tension responses to the vasoconstrictor phenylephrine (PE; 10-9-3x10-5M) were lower in rings from SHR compared to responses in rings from WKY, with a lower maximum response. There was no difference in the EC50 for PE between SHR and WKY. In contrast, responses to the endothelium-dependent vasodilator carbachol (10-9-3x10-5M) were greater in rings from SHR compared to relaxations in rings from WKY, with a greater maximum response and a lower EC50. Using the endothelium-independent vasodilator sodium nitroprusside (SNP) there was no difference between hypertensive and control rats at the lower end of the concentration-response curve (3x10-11-10-8M). At the higher concentrations (3x10-8-3x10-6M) however, aortic rings from SHR were more responsive to SNP than were rings from WKY rats, with a greater maximum relaxation, although the EC50 was unchanged. There was no difference in the vasorelaxant response to the beta-adrenoceptor agonist isoprenaline (3x10-10-10-5M) between hypertensive and control rats. 9. In tail artery rings, isometric tension responses to PE (10-8-3x10-5M), noradrenaline (NA ; 10-9 - 10-5M) and UK-14,304 (3x10-10 - 3x10-5M) were greater in SHR compared to WKY with an increased maximum response, but there was no difference in the EC50. Yohimbine (50nM) produced a rightward shift in the concentration-response curve to UK-14,304 in tail artery rings from both SHR and WKY rats. 10. In perfused segments of rat tail artery the response to NA was much greater in vessels from SHR than in vessels from WKY. When expressed as a percentage of the maximum response achieved however, responses in vessels from SHR were lower than in those from WKY. 11. The relaxations produced by SNP (3x-10- 3x10-5M) and isoprenaline (10-8 - 10-4M) were lower in tail artery rings from SHR compared to those in rings from WKY. In vessels from hypertensive rats, SNP did not fully relax the PE-induced precontraction, whereas isoprenaline did not fully relax the precontraction in either hypertensive or control rats. Carbachol produced little or no response in either group of rat. 12. The biochemical response underlying NA-induced contraction in the rat tail artery was investigated by measuring accumulation of total inositol phosphates in response to NA. The basal phosphoinositide (PI) hydrolysis was higher in vessels from SHR than in those from WKY, and 10-5M NA, which had produced increased contractile responses, gave a greater stimulation of PI hydrolysis in vessels from hypertensive rats as compared to control. 13. Preliminary experiments were carried out with rats of two different age groups (12-17 weeks and 6-9 weeks). 14. When tail artery segments were cannulated at one end ("single cannulation") and perfused with Krebs solution at a constant rate, the response to NA (10-3 - 100mug) was greater in older rats than in younger rats. The response to field stimulation (Supramaximal voltage 80V, 50 pulses, 0.4ms duration, 0.5-80Hz) tended to be greater in older than in younger rats. (Abstract shortened by ProQuest.)