Aldosterone impairs coronary adenosine-mediated vasodilation via reduced functional expression of Ca2+-activated K+ channels

Elevated plasma aldosterone (Aldo) levels are associated with greater risk of cardiac ischemic events and cardiovascular mortality. Adenosine-mediated coronary vasodilation is a critical cardioprotective mechanism during ischemia; however, whether this response is impaired by increased Aldo is unclear. We hypothesized that chronic Aldo impairs coronary adenosine-mediated vasodilation via downregulation of vascular K+ channels. Male C57BL/6J mice were treated with vehicle (Con) or subpressor Aldo for 4 wk. Coronary artery function, assessed by wire myography, revealed Aldo-induced reductions in vasodilation to adenosine and the endothelium-dependent vasodilator acetylcholine but not to the nitric oxide donor sodium nitroprusside. Coronary vasoconstriction to endothelin-1 and the thromboxane A2 mimetic U-46619 was unchanged by Aldo. Additional mechanistic studies revealed impaired adenosine A2A, not A2B, receptor-dependent vasodilation by Aldo with a tendency for Aldo-induced reduction of coronary A2A gene expression. Adenylate cyclase inhibition attenuated coronary adenosine dilation but did not eliminate group differences, and adenosine-stimulated vascular cAMP production was similar between Con and Aldo mice. Similarly, blockade of inward rectifier K+ channels reduced but did not eliminate group differences in adenosine dilation whereas group differences were eliminated by blockade of Ca2+-activated K+ (KCa) channels that blunted and abrogated adenosine and A2A-dependent dilation, respectively. Gene expression of several coronary KCa channels was reduced by Aldo. Together, these data demonstrate Aldo-induced impairment of adenosine-mediated coronary vasodilation involving blunted A2A-KCa-dependent vasodilation, independent of blood pressure, providing important insights into the link between plasma Aldo and cardiac mortality and rationale for aldosterone antagonist use to preserve coronary microvascular function. NEW & NOTEWORTHY Increased plasma aldosterone levels are associated with worsened cardiac outcomes in diverse patient groups by unclear mechanisms. We identified that, in male mice, elevated aldosterone impairs coronary adenosine-mediated vasodilation, an important cardioprotective mechanism. This aldosterone-induced impairment involves reduced adenosine A2A, not A2B, receptor-dependent vasodilation associated with downregulation of coronary KCa channels and does not involve altered adenylate cyclase/cAMP signaling. Importantly, this effect of aldosterone occurred independent of changes in coronary vasoconstrictor responsiveness and blood pressure. Listen to this article’s corresponding podcast at https://ajpheart.podbean.com/e/attenuation-of-coronary-adenosine-dilation-by-aldosterone/ .

β-Adrenergic blockade enhances coronary vasoconstrictor response to forehead cooling

Forehead cooling activates the sympathetic nervous system and can trigger angina pectoris in susceptible individuals. However, the effect of forehead cooling on coronary blood flow velocity (CBV) is not well understood. In this human experiment, we tested the hypotheses that forehead cooling reduces CBV (i.e., coronary vasoconstriction) and that this vasoconstrictor effect would be enhanced under systemic β-adrenergic blockade. A total of 30 healthy subjects (age range, 23–79 years) underwent Doppler echocardiography evaluation of CBV in response to 60 s of forehead cooling (1°C ice bag on forehead). A subset of subjects (n = 10) also underwent the procedures after an intravenous infusion of propranolol. Rate pressure product (RPP) was used as an index of myocardial oxygen demand. Consistent with our first hypothesis, forehead cooling reduced CBV from 19.5 ± 0.7 to 17.5 ± 0.8 cm/s ( P < 0.001), whereas mean arterial pressure increased by 11 ± 2 mmHg (P < 0.001). Consistent with our second hypothesis, forehead cooling reduced CBV under propranolol despite a significant rise in RPP. The current studies indicate that forehead cooling elicits a sympathetically mediated pressor response and a reduction in CBV, and this effect is augmented under β-blockade. The results are consistent with sympathetic activation of β-receptor coronary vasodilation in humans, as has been demonstrated in animals.

Nitroso-redox balance in control of coronary vasomotor tone

Reactive oxygen species (ROS) are essential in vascular homeostasis but may contribute to vascular dysfunction when excessively produced. Superoxide anion (O2·−) can directly affect vascular tone by reacting with K+ channels and indirectly by reacting with nitric oxide (NO), thereby scavenging NO and causing nitroso-redox imbalance. After myocardial infarction (MI), oxidative stress increases, favoring the imbalance and resulting in coronary vasoconstriction. Consequently, we hypothesized that ROS scavenging results in coronary vasodilation, particularly after MI, and is enhanced after inhibition of NO production. Chronically instrumented swine were studied at rest and during exercise before and after scavenging of ROS with N-(2-mercaptoproprionyl)-glycine (MPG, 20 mg/kg iv) in the presence or absence of prior inhibition of endothelial NO synthase (eNOS) with Nω-nitro-l-arginine (l-NNA, 20 mg/kg iv). In normal swine, MPG resulted in coronary vasodilation as evidenced by an increased coronary venous O2 tension, and trends toward increased coronary venous O2 saturation and decreased myocardial O2 extraction. These effects were not altered by prior inhibition of eNOS. In MI swine, MPG showed a significant vasodilator effect, which surprisingly was abolished by prior inhibition of eNOS. Moreover, eNOS dimer/monomer ratio was decreased after MI, reflecting eNOS uncoupling. In conclusion, ROS exert a small coronary vasoconstrictor influence in normal swine, which does not involve scavenging of NO. This vasoconstrictor influence of ROS is slightly enhanced after MI. Since inhibition of eNOS abolished rather than augmented the vasoconstrictor influence of ROS in swine with MI, while eNOS dimer/monomer ratio was decreased, our data imply that uncoupled eNOS may be a significant source of O2·− after MI.

Prostanoids suppress the coronary vasoconstrictor influence of endothelin after myocardial infarction

Myocardial infarction (MI) is associated with endothelial dysfunction resulting in an imbalance in endothelium-derived vasodilators and vasoconstrictors. We have previously shown that despite increased endothelin (ET) plasma levels, the coronary vasoconstrictor effect of endogenous ET is abolished after MI. In normal swine, nitric oxide (NO) and prostanoids modulate the vasoconstrictor effect of ET. In light of the interaction among NO, prostanoids, and ET combined with endothelial dysfunction present after MI, we investigated this interaction in control of coronary vasomotor tone in the remote noninfarcted myocardium after MI. Studies were performed in chronically instrumented swine (18 normal swine; 13 swine with MI) at rest and during treadmill exercise. Furthermore, endothelial nitric oxide synthase (eNOS) and cyclooxygenase protein levels were measured in the anterior (noninfarcted) wall of six normal and six swine with MI. eNOS inhibition with Nω-nitro-l-arginine (l-NNA) and cyclooxygenase inhibition with indomethacin each resulted in coronary vasoconstriction at rest and during exercise, as evidenced by a decrease in coronary venous oxygen levels. The effect of l-NNA was slightly decreased in swine with MI, although eNOS expression was not altered. Conversely, in accordance with the unaltered expression of cyclooxygenase-1 after MI, the effect of indomethacin was similar in normal and MI swine. l-NNA enhanced the vasodilator effect of the ETA/B receptor blocker tezosentan but exclusively during exercise in both normal and MI swine. Interestingly, this effect of l-NNA was blunted in MI compared with normal swine. In contrast, whereas indomethacin increased the vasodilator effect of tezosentan only during exercise in normal swine, indomethacin unmasked a coronary vasodilator effect of tezosentan in MI swine both at rest and during exercise. In conclusion, the present study shows that endothelial control of the coronary vasculature is altered in post-MI remodeled myocardium. Thus the overall vasodilator influences of NO as well as its inhibition of the vasoconstrictor influence of ET on the coronary resistance vessels were reduced after MI. In contrast, while the overall prostanoid vasodilator influence was maintained, its inhibition of ET vasoconstrictor influences was enhanced in post-MI remote myocardium.

Transthoracic Doppler echocardiography to noninvasively assess coronary vasoconstrictor and dilator responses in humans

Human studies of coronary circulation are limited because of methodological issues. Recently, a noninvasive transthoracic duplex ultrasound (TTD) technique has emerged as an important tool to measure coronary blood flow velocity (CBV) in conscious humans. We employed two protocols to determine whether noninvasive “native” coronary artery velocity responses to constrictor or dilator stimuli assessed by TTD provide reliable data. In the first protocol, coronary vascular resistance (CVR = diastolic blood pressure/CBV) responses to static handgrip were examined in the left internal mammary artery (LIMA) and native left anterior descending artery (LAD) into which the graft was inserted (patient age 63 ± 3 years). Our prior report documented increased CVR in the LIMA graft during static handgrip (Momen et al., J Appl Physiol 102: 735–739, 2007). We hypothesized that the magnitude of increases in CVR during handgrip would be similar in the LIMA graft and LAD in the same individual. Percent increases in CVR were similar in the LIMA and distal native LAD (27 ± 4% vs. 28 ± 6%). In the second protocol, we studied six patients (age 61 ± 3 years) who underwent cardiac catheterization of the LAD. We compared coronary vasodilator responses to intravenous adenosine infusion (0.14 mg·kg−1·min−1) obtained by intracoronary Doppler guidewire technique and TTD on separate studies. The relative increases in CBV with adenosine obtained by intracoronary Doppler guidewire and TTD were similar (62 ± 10% vs. 65 ± 12%). Noninvasive TTD provides reliable human coronary circulatory constrictor and dilator data.