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Distinct endothelial impairment in coronary microvessels from hypertensive Dahl rats
1Department of Physiology, Medical College of Wisconsin, Milwaukee 53226, USA.
Insights
Hypertension impairs coronary microvessel dilation, with acetylcholine responses preserved while bradykinin and substance P responses are lost. Cytochrome P450 products, not nitric oxide, may mediate these dilations.
Area of Science:
- Cardiovascular Physiology
- Endothelial Function
- Hypertension Research
Background:
- Hypertension is associated with impaired coronary microvascular endothelial dilator function.
- The specific profile and underlying mechanisms of this endothelial dysfunction are not well understood.
Purpose of the Study:
- To compare the dilator responses to acetylcholine (ACH), bradykinin (BKN), and substance P (SP) in coronary microvessels of normotensive (Dahl-NT) and hypertensive (Dahl-HT) rats.
- To investigate the mechanisms mediating these responses, including the roles of nitric oxide, prostacyclin, and cytochrome P450 pathways.
Main Methods:
- Coronary microvessels were isolated from Dahl-NT and Dahl-HT rat left ventricles.
- Vessels were cannulated, pressurized to 80 mm Hg, and internal diameters measured using videomicroscopy.
- Responses to ACH, BKN, and SP were assessed with and without inhibitors of nitric oxide synthase (N-nitro-L-arginine) and prostacyclin (indomethacin), and cytochrome P450 (octadecynoic acid).
Main Results:
- Coronary microvessels from both Dahl-NT and Dahl-HT rats exhibited similar dilator responses to acetylcholine.
- However, only vessels from Dahl-NT rats showed dilator responses to substance P and bradykinin.
- Dilator responses to all tested agents persisted after nitric oxide or prostacyclin inhibition but were blunted by cytochrome P450 inhibition.
Conclusions:
- Hypertensive Dahl rats exhibit a distinct endothelial dysfunction pattern, retaining acetylcholine-induced relaxation while losing responses to substance P and bradykinin.
- A cytochrome P450 metabolite, rather than nitric oxide or prostacyclin, appears to partly mediate vasodilator responses to acetylcholine, substance P, and bradykinin in coronary microvessels.
Abstract:
Hypertension has been linked to an impaired dilator function of the coronary microvascular endothelium in vivo. However, the profile and mechanism of this dysfunction remain obscure. Thus, this study compared diameter responses to acetylcholine (ACH), bradykinin (BKN), and substance P (SP) between coronary microvessels (i.d.=106+/-4 microm) dissected from left ventricles of normotensive and hypertensive Dahl rats (Dahl-NT and Dahl-HT, respectively). Vessels were cannulated and pressurized on glass pipettes at 80 mm Hg, and internal diameters were monitored by videomicroscopy. Coronary microvessels from Dahl-NT and Dahl-HT showed similar dilator responses to ACH (100 pmol/L to 10 micromol/L), with maximal diameter increases of 63+/-5 microm and 63+/-7 microm, respectively (n=31,17). However, only vessels from Dahl-NT showed dilator responses to SP (10 fmol/L to 1 nmol/L) and BKN (100 fmol/L to 10 nmol/L). All dilator responses persisted after N-nitro-L-arginine (10 micromol/L) or indomethacin (10 micromol/L), but were blunted after inhibition of cytochrome P450 by 10 micromol/L octadecynoic acid (n=6-8). These results suggest that: (1) coronary microvessels from Dahl-HT show a unique pattern of endothelial impairment, whereby ACH-induced relaxations persist at a time when dilator responses to SP and BKN are severely blunted, and (2) a cytochrome P450 product, rather than nitric oxide or prostacyclin, may partly mediate the vasodilator responses to ACH, SP and BKN.