Abstract
Norepinephrine (NE) induces a sigmoidal dose-response curve for perfusion pressure and a bell-shaped curve for oxygen consumption (VO2) in the constant-flow perfused hindlimb of Wistar rats. These effects are now described in spontaneously hypertensive rats (SHR) and age-matched Wistar-Kyoto rats (WKY). In SHR, the pressure curve was shifted left- and upward whereas the VO2curve was shifted left- but downward, when compared with WKY. In the presence of 10 μM propranolol, prazosin (2.5 nM) shifted the pressure and VO2 curves much more than yohimbine (0.1 μM) to the right in both strains and its effects were greater in SHR, suggesting that these effects were mediated largely by alpha-1 receptors, particularly in SHR. In the presence of propranolol plus yohimbine, the pressure curve was markedly shifted to the right by both the selective alpha-1A-antagonist 5-methylurapidil (3.3 nM), and by the alpha-1D antagonist BMY 7378 (0.1 μM) or SK&F 105854 (2 μM) in SHR but not in WKY. With respect to the VO2 curve, 5-methylurapidil attenuated the descending limb without affecting the ascending limb. Similar effects were also obtained with another alpha-1A antagonist 1 nM KMD-3213 in both SHR and WKY. In contrast, BMY and SK&F markedly inhibited the ascending limb of the VO2 curve. These results indicate that both alpha-1A- and alpha-1D subtypes are functionally up-regulated in SHR muscle vascular bed where the ascending limb of VO2 is predominantly mediated by thealpha-1D at a much lower concentration for NE than the descending limb which is predominantly mediated by thealpha-1A subtype.
Footnotes
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Send reprint requests to: Dr. Ji-Ming Ye, Diabetes Group, The Garvan Institute of Medical Research, 384 Victoria Street, Darlinghurst, Sydney NSW 2010, Australia.
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↵1 This study was supported by the National Health and Medical Research Council of Australia.
- Abbreviations:
- α1-ARs
- alpha-1 adrenoceptors
- NE
- norepinephrine
- VO2
- oxygen consumption
- 5 MU
- 5-methylurapidil
- KMD
- KMD-3213
- CEC
- chloroethylclonidine
- BMY
- BMY 7378
- SK&F
- SK&F 105854
- ANOVA
- analysis of variance
- Received August 27, 1997.
- Accepted April 21, 1998.
- The American Society for Pharmacology and Experimental Therapeutics
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