Impaired hemodynamics and endothelial vasomotor function via endoperoxide-mediated vasoconstriction in the carotid artery of spontaneously hypertensive rats

Abstract

The fact that endothelium removal increases diameter and compliance in the common carotid artery (CCA) of spontaneously hypertensive rats (SHR) and that improving CCA endothelium-dependent vasorelaxation has been shown to normalize a reduced systolic blood flow through the SHR CCA compared with normotensive Wistar-Kyoto rats (WKY) suggests that endothelial vasomotor dysfunction may be linked to altered large artery hemodynamics in hypertension. The experiments herein were designed to further investigate WKY and SHR CCA hemodynamics and endothelium-dependent vasomotor functions. It was hypothesized that CCA blood flow and conductance would be reduced throughout the cardiac cycle in SHR and that endothelium-dependent contractile activity would impair SHR CCA vasorelaxation. We report that mean, maximal systolic, and diastolic blood flow was reduced in SHR vs. WKY CCA, as was vascular conductance. Pressure was augmented in SHR CCA and accompanied by late systolic flow augmentation so that total flow during systole was indeed no different between strains, possibly explained by earlier lower body wave reflection. While ACh stimulation in isolated precontracted WKY CCA caused a robust nitric oxide (NO)-mediated vasorelaxation, endothelium-dependent, cyclooxygenase (COX)-mediated contractile activity stimulated by high ACh concentration impaired NO- and non-NO/non-COX-mediated vasorelaxation in precontracted SHR CCA. In quiescent CCA, this endothelium-dependent contractile response was COX-1 and thromboxane-prostanoid receptor mediated and modulated by the availability of NO. These data collectively suggest that endothelium-dependent, COX-mediated endoperoxide signaling in the CCA of SHR may elicit vasoconstriction, which could shift the mechanical properties of this conduit artery and contribute to reduced CCA blood flow in vivo.

Altered hemodynamics, endothelial function, and protein expression occur with aortic coarctation and persist after repair

“…Distal arteries of the CoA group continued to show endothelial dysfunction, but no differences between corrected and control groups were present. While endothelial dysfunction in the proximal arteries of untreated CoA rabbits is in agreement with spontaneously hypertensive animal models (16,28,38), the data presented from corrected rabbits are the first to demonstrate endothelial dysfunction in coarctation despite the restoration of normal BP using a chronic animal model mimicking treatment. Importantly, researchers investigating tissue specimens for viability often consider rabbit arteries exhibiting Ͻ50% relaxation to be nonfunctional (41), and maximum ACh relaxation from CoA and corrected rabbits in the present study was 17% and 32%, respectively, underscoring the severity of this dysfunction.…”

“…The vascular endothelium is dynamic, serving to sense WSS and regulate vasomotor tone via the release of dilatory substances as well as anti-inflammatory agents to maintain vascular health. Impaired vasorelaxation through endothelial nitric oxide (NO) release, known as "endothelial dysfunction," is a characteristic effect of hypertension in human and animal models including prior CoA models (16,38). Along with vasorelaxation, arterial constriction mediated by arterial SM may also play a role in the adaptive response of arteries to hypertension, as alterations in the resting and active contractile force of elastic conduit arteries, such as the thoracic aorta and carotid arteries, may indicate atherogenic changes in stiffness (23).…”

Endothelium-dependent vasorelaxation to the AMPK activator AICAR is enhanced in aorta from hypertensive rats and is NO and EDCF dependent

“…7), contributing to the responsiveness of SHR E ϩ rings at lower AICAR concentrations. Furthermore, conduit vessels from SHR exhibit higher levels of eNOS protein content expression than those from WKY (see RESULTS) (14,24), presenting a more abundant target for AMPK stimulation and NO generation and thus possibly contributing to greater sensitivity and enhanced NO-mediated relaxation observed in SHR aortic rings. In the vascular smooth muscle, signaling through mechanisms such as the Ca 2ϩ sensitization that are responsible for regulating contraction is upregulated in aorta from SHR versus WKY (30,42).…”

“…Before all experiments, body mass was recorded and rats were anesthetized by pentobarbital sodium injection (50 -65 mg/kg ip; Vetoquinol N.-A., Lavaltrie, QC, Canada). To confirm blood pressure levels in SHR and WKY, a subset of anesthetized animals from each group were instrumented for mean arterial pressure and heart rate measurements by inserting a Mikro-Tip Pressure Transducer catheter (Millar Instruments, Houston, TX) into the left common carotid artery (14,23). Data were collected as previously described (14,23).…”

“…The lowest dosages of AICAR and CC capable of generating maximal functional effects were chosen based on pilot experiments (data not shown). Rings were then exposed to increasing concentrations of ACh to elicit endothelium-dependent, COX-EDCF-mediated contractions as previously described (13,14).…”