Coronary Microvascular Vasodilatory Function: Related Clinical Features and Differences According to the Different Coronary Arteries and Types of Coronary Spasm

Background: In the clinical setting; the microvascular vasodilatory function test (MVFT) with a pressure wire has been used in ischaemia patients with non-obstructive coronary arteries (INOCA), including vasospastic angina (VSA) and microvascular angina (MVA). The exact factors that affect the microvascular vasodilatory function (MVF) in such patients are still unknown. We aimed to identify the factors, including clinical parameters and lesion characteristics, affecting the MVF in such patients. Methods: A total of 53 patients who underwent coronary angiography, spasm provocation tests (SPTs) and MVFTs were enrolled. In the MVFT, the coronary flow reserve (CFR) and index of microcirculatory resistance (IMR) were measured. Of the 53 patients, MVFT data in the left anterior descending coronary artery (LAD) were obtained from 49 patients, and the clinical parameters were checked in all of them. Based on the results of the SPT, coronary spasms were divided into focal spasm, diffuse spasm, and microvascular spasm (MVS). To assess the lesion characteristics influencing MVF, MVFT data were compared according to the types of coronary spasm and coronary vessels in 73 vessels of the 53 patients. Results: In 49 patients who underwent the MVFT in the LAD, the IMR was higher in active smokers (n = 7) than in former smokers (n = 15) and never smokers (n = 27, p < 0.01). In the 73 coronary arteries in this study, the type of coronary spasm did not correlate with the CFR or IMR, whereas a higher IMR were more frequently observed in cases of focal spasm than in cases of diffuse spasm (p = 0.03). In addition, the IMR was higher in the right coronary artery (RCA) than in the LAD (p = 0.02). Conclusion: These results indicate that the smoking status affected the MVF in patients with INOCA, suggesting the possibility of improvement in the MVF by smoking cessation in such patients. In addition, in the assessment of MVF, it may be important to take into account which coronary artery or types of coronary spasm are being evaluated.

AT2R’s (Angiotensin II Type 2 Receptor’s) Role in Cognitive and Cerebrovascular Deficits in a Mouse Model of Alzheimer Disease

Antihypertensive medications targeting the renin-angiotensin system have lowered the incidence and progression of Alzheimer disease. Understanding how these medications function could lead to novel therapeutic strategies. AT4Rs (angiotensin IV receptors) have been associated with angiotensin receptor blockers’ cognitive, cerebrovascular, and neuroinflammatory rescue in Alzheimer disease models. Yet, whether AT4Rs act alone or with AT2Rs remains unknown. Here, we investigated whether AT2Rs contribute to losartan’s benefits and whether chronic AT2R activation could mimic angiotensin receptor blocker benefits in transgenic mice overexpressing familial Alzheimer disease mutations of the human APP (amyloid precursor protein). Losartan-treated mice (10 mg/kg per day, drinking water, 7 months) received intracerebroventricular (1 month) administration of vehicle or AT2R antagonist PD123319 (1.6 nmol/day). PD123319 countered losartan’s benefits on spatial learning and memory, neurovascular coupling, and hampered those on oxidative stress and nitric oxide bioavailability. PD123319 did not oppose losartan’s benefits on short-term memory and vasodilatory function and had no benefit on neuroinflammation or Aβ (amyloid β) pathology. Mice receiving either vehicle or selective AT2R agonist compound 21 (intracerebroventricular: 1 nmol/day, 1 month or drinking water: 10 mg/kg per day, 7 months), showed no improvement in memory, vasodilatory function, or nitric oxide bioavailability. Compound 21 treatment normalized neurovascular coupling, reduced astrogliosis independent of persisting microgliosis, and exacerbated oxidative stress in APP mice. Compound 21 reduced dense core Aβ plaques, but not diffuse plaques or Aβ species. Our findings suggest that targeting AT2Rs is not an ideal strategy for restoring Aβ-related cognitive and cerebrovascular deficits.

P0978THE EFFECTS OF CHRONIC DAPAGLIFLOZIN TREATMENT ON THE RENAL MICROVASCULATURE IN A RAT MODEL OF TYPE 2 DIABETES

Background and Aims Chronic kidney disease (CKD) is an ever-growing concern and CKD associated with diabetes accounted for ∼ 35% of new cases of end-stage renal failure. Clinical trials with insulin-independent sodium-glucose co-transporter 2 (SGLT2) inhibitors not only showed significant improvements in hyperglycemia and thus renal damage, but also reduced the risk of adverse cardiovascular events. Microvessels supply local tissue oxygen demands and are important controllers of regional perfusion. Endothelial dysfunction has been posited to be an important factor driving the pathogenesis of diabetic nephropathy, largely through impaired eNOS activity and thus reduced nitric oxide bioavailability. Thus, we aim to determine the effects of SGLT2 inhibition on vasodilator function in the renal vasculature. We hypothesize that rats chronically treated with dapagliflozin, a SGLT2 inhibitor, improves renal endothelial function and the microvessels are better able to maintain perfusion in response to the inhibition of nitric oxide synthase and prostaglandin blockade. Method Male Zucker fatty diabetic rats (8 wk old), a model of type 2 diabetes, were given daily oral gavage of 1 mg/kg dapagliflozin or its vehicle for up to 22 wks of age (n=6/group). Renal excretory function, glomerular filtration rate (GFR) and indices of renal injury was assessed before treatment and after every 4 wks up until 22 wks of age. GFR was assessed via transcutaneous clearance of FITC-sinistrin. Vasodilator function of the renal microvasculature was assessed via X-ray microangiography. We conducted successive imaging of the microvessels before and during infusion of acetylcholine (ACh) and sodium nitroprusside (SNP) which facilitated the assessment of endothelium dependent and independent dilation respectively. After which, rats were given successive boluses of L-NAME and indomethacin to assess the vasodilatory function of the microvasculature independent of nitric oxide and prostaglandins respectively. These inhibitors were given under the conditions of SNP clamp which allowed for us to titrate the blood pressure to baseline levels. Lastly, we assessed the ability of endothelium hyperpolarizing factors (EDHFs) to maintain microvascular perfusion when SNP infusion ceased and an infusion of ACh commenced while still under the effects of L-NAME and indomethacin. Results As expected, dapagliflozin alleviated hyperglycemia across the treatment period. There was a tendency for dapagliflozin to ameliorate the decline of GFR, although this apparent effect was not statistically significant. Dapagliflozin did not appear to improve indices of renal injury. Treatment with dapagliflozin alleviated polyuria but did not appear to have an impact on urine osmolarity or sodium excretion. The responses (vessel diameter) of renal microvessels to ACh and SNP was greater in dapagliflozin than in vehicle fed rats. The microvessels of vehicle fed rats appeared to undergo relative constriction in response to L-NAME and indomethacin even under the effects of SNP clamp. In contrast, microvessels of dapagliflozin fed rats appeared to be relatively well-perfused after NOS and COX blockade. This suggests that dapagliflozin may improve endothelial dysfunction commonly associated with diabetic nephropathy. Following NOS and COX blockade, ACh was infused in rats to determine the status of vasodilatory function mediated by EDHFs. The microvessels in diabetic rats did not appear to be dilated after infusion of ACh, suggesting that vasodilatory effects of EDHFs on the vasculature is diminished in diabetic rats. Dapagliflozin appeared to improve this effect in that the renal microvessels were dilated even when NOS and COX production was blocked/inhibited. Conclusion Chronic treatment of dapagliflozin may improve endothelial dysfunction and thus retard the progression of diabetic nephropathy in a rat model of type 2 diabetes.

Vasodilatory and vascular mitochondrial respiratory function with advancing age: evidence of a free radically mediated link in the human vasculature

Recognizing the age-related decline in skeletal muscle feed artery (SMFA) vasodilatory function, this study examined the link between vasodilatory and mitochondrial respiratory function in the human vasculature. Twenty-four SMFAs were harvested from young (35 ± 6 yr, n = 9) and old (71 ± 9 yr, n = 15) subjects. Vasodilation in SMFAs was assessed, by pressure myography, in response to flow-induced shear stress, acetylcholine (ACh), and sodium nitroprusside (SNP) while mitochondrial respiration was measured, by respirometry, in permeabilized SMFAs. Endothelium-dependent vasodilation was significantly attenuated in the old, induced by both flow (young: 92 ± 3, old: 45 ± 4%) and ACh (young: 92 ± 3, old: 54 ± 5%), with no significant difference in endothelium-independent vasodilation. Complex I and I + II state 3 respiration was significantly lower in the old (CI young: 10.1 ± 0.8, old: 7.0 ± 0.4 pmol·s−1·mg−1; CI + II young: 12.3 ± 0.6, old: 7.6 ± 0.4 pmol·s−1·mg−1). The respiratory control ratio (RCR) was also significantly attenuated in the old (young: 2.2 ± 0.1, old: 1.1 ± 0.1). Furthermore, state 3 (CI + II) and 4 respiration, as well as RCR, were significantly correlated ( r = 0.49–0.86) with endothelium-dependent, but not endothelium-independent, function. Finally, the direct intervention with mitochondrial-targeted antioxidant (MitoQ) significantly improved endothelium-dependent vasodilation in the old but not in the young. Thus, the age-related decline in vasodilatory function is linked to attenuated vascular mitochondrial respiratory function, likely by augmented free radicals. NEW & NOTEWORTHY In human skeletal muscle feed arteries, the well-recognized age-related fall in endothelium-dependent vasodilatory function is strongly linked to a concomitant fall in vascular mitochondrial respiratory function. The direct intervention with the mitochondrial-targeted antioxidant restored vasodilatory function in the old but not in the young, supporting the concept that exacerbated mitochondrial-derived free radical production is linked to age-related vasodilatory dysfunction. Age-related vasodilatory dysfunction in humans is linked to attenuated vascular mitochondrial respiratory function, likely a consequence of augmented free radical production.

Heterogeneity in the vasodilatory function of individual extremities

Objectives Heterogeneity and homogeneity in the flow-mediated dilation of the human body's individual extremities are not fully understood, and the relationship between flow-mediated dilation and local muscle activity is unclear. We assessed the flow-mediated dilation of four individual extremities and sought to determine the contribution of local muscle activity (evaluated as muscle strength) to the flow-mediated dilation in each extremity. Methods Thirteen healthy young right-handed nonactive males participated. The flow-mediated dilation in the brachial and popliteal arteries at both arms and legs was assessed by ultrasound Doppler. Muscle strength was evaluated as the grip strength and knee extension. Results There was a significant difference in the brachial artery (BA)-FMD values between the subjects' dominant and non-dominant sides (8.0 ± 2.8 vs. 5.5 ± 2.2%, p < 0.05), whereas the two sides showed similar popliteal artery (PA)-FMD values. There was no significant correlation in flow-mediated dilation between the dominant brachial artery and popliteal artery. The BA-FMD was significantly correlated with the grip strength in both upper extremities (dominant: r = 0.562, non-dominant: r = 0.548; p < 0.05, respectively). Conclusion These results demonstrated heterogeneity in the flow-mediated dilation of individual extremities. We observed that local muscle activity can affect the local vascular function. Measurements of vasodilatory function in individual extremities should thus be carefully considered.