Pharmacologic and autoradiographic evidence for an up-regulation of kinin B(2) receptors in the spinal cord of spontaneously hypertensive rats.
1. The effects of intrathecally (i.t.) injected kinin B(1) and B(2) receptor agonists and antagonists were measured on mean arterial pressure (MAP) and heart rate (HR) of conscious unrestrained spontaneously hypertensive rats (SHR of 16 weeks old) and age-matched normotensive Wistar Kyoto (WKY). Quantitative in vitro autoradiographic studies were also performed on the thoracic spinal cord of both strains with specific radioligands for B(2) receptors, [(125)I]-HPP-Hoe 140, and B(1) receptors, [(125)I]-HPP-[des-Arg(10)]-Hoe140. 2. Bradykinin (BK) (0.81 - 810 pmol) increased MAP dose-dependently with increases or decreases of HR. The pressor response to BK was significantly greater in SHR. The cardiovascular response to 8.1 pmol BK was reversibly blocked by 81 pmol Hoe 140 (B(2) antagonist) but not by 81 - 810 pmol [des-Arg(10)]-Hoe 140 (B(1) antagonist) in both strains. 3. The B(1) receptor agonist, des-Arg(9)-BK (8100 pmol) produced either no effects or increased MAP with variable effects on HR. These responses were similar in both strains and were reversibly blocked by 81 pmol Hoe 140. Inhibition with 8100 pmol [des-Arg(10)]-Hoe 140 was not specific to B(1) agonist-mediated responses. 4. [(125)I]-HPP-Hoe 140 specific binding sites were predominantly located to superficial laminae of the dorsal horn and were significantly higher in SHR. Low levels of [(125)I]-HPP-[des-Arg(10)]-HOE 140 specific binding sites were found in all laminae of both strains. 5. It is concluded that the hypersensitivity of the cardiovascular response to BK is due to an increased number of B(2) receptors in the spinal cord of SHR and that B(1) receptors are unlikely involved in spinal cardiovascular regulation in SHR.
Cloutier
Frank
F
Department of Physiology, Faculty of Medicine, Université de Montréal C.P. 6128, Succursale centre-ville, Montréal, Québec, Canada, H3C 3J7.
de Sousa Buck
Hudson
H
Ongali
Brice
B
Couture
Réjean
R
D000818:Animals; D000894:Anti-Inflammatory Agents, Non-Steroidal / Q000494:pharmacology; D001345:Autoradiography; D001665:Binding Sites; D001794:Blood Pressure / Q000187:drug effects; D001920:Bradykinin / Q000031:analogs & derivatives* / Q000494:pharmacology; D065168:Bradykinin Receptor Antagonists; D004195:Disease Models, Animal; D006339:Heart Rate / Q000187:drug effects; D006973:Hypertension / Q000378:metabolism*; D007213:Indomethacin / Q000494:pharmacology; D007705:Kinins / Q000378:metabolism; D008297:Male; D051381:Rats; D011918:Rats, Inbred SHR; D011921:Rats, Inbred WKY; D043783:Receptor, Bradykinin B1; D043782:Receptor, Bradykinin B2; D018002:Receptors, Bradykinin / Q000378:metabolism*; D013116:Spinal Cord / Q000187:drug effects / Q000378:metabolism*; D013909:Thorax; D015854:Up-Regulation
D000894:Anti-Inflammatory Agents, Non-Steroidal; D065168:Bradykinin Receptor Antagonists; D007705:Kinins; D043783:Receptor, Bradykinin B1; D043782:Receptor, Bradykinin B2; D018002:Receptors, Bradykinin; C024626:bradykinin, des-Arg(9)-; D001920:Bradykinin; D007213:Indomethacin