Cardiovascular and Cerebrovascular Morbidity in Patients with Urolithiasis: An Epidemiological Approach Based on Hospitalization Burden Data from 1997 to 2021.

Background: Patients with kidney stones (KSFs) are known to have a heightened risk of coronary heart disease (CHD) or stroke. The objective of the present study was to describe the natural history of these complications through the longitudinal analysis of the hospitalizations due to kidney stones in Spain from 1997 to 2021. Methods: A retrospective longitudinal observational study was developed based on nationwide hospitalization data (minimum basic data base). Three different analyses were carried out. In the first step, the prevalence of coronary or cerebrovascular events in kidney stone hospitalizations was compared with the hospitalization burden of CHD or strokes related to the general population. In the second step, a survival analysis of the kidney stones-hospitalized patients using the Kaplan-Meier method was conducted. In the third step, a Cox regression was used to assess the influence of the classical comorbidities in the development of the lithiasic patients-cardiovascular disease. Results: Kidney stone-hospitalized patients exhibit a significantly higher risk of CHD (OR = 14.8 CI95%: 14.7-14.9) and stroke (OR = 6.7 CI95%: 6.6-6.8) compared to the general population across in all age groups, although they had less cardiovascular risk factors. A total of 9352 KSFs (1.5%) developed a coronary event within an average time of 78.8 months. A total of 2120 KSFs (0.33%) suffered a stroke in an average time of 71.1 months. Diabetes, hypertension, hyperlipidemia, and being overweight were identified as risk factors for developing CHD and stroke using a univariate and multivariate analysis. Conclusions: Our study confirms previous studies in which kidney stones must be considered as a risk factor for developing CHD or cerebrovascular disease. Preventive strategies should target patients with kidney stones and classical risk cardiovascular factors to mitigate modifiable conditions associated with cardiovascular diseases.

Activation of mitoKATP channels induces penile vasodilation and inhibits mitochondrial respiration and ROS production: Role of NO.

OBJECTIVE: Mitochondrial ATP-sensitive K+ (mitoKATP) channels are involved in neuronal and cardiac protection from ischemia and oxidative stress. Penile erection is a neurovascular event mediated by relaxation of the erectile tissue via nitric oxide (NO) released from nerves and endothelium. In the present study, we investigated whether mitoKATP channels play a role in the control of penile vascular tone and mitochondrial dynamics, and the involvement of NO. METHODS: The effect of the selective mitoKATP activator BMS191095 was examined on vascular tone, on mitochondrial bioenergetics by real-time measurements with Agilent Seahorse and on ROS production by MitoSOX fluorescence in freshly isolated microarteries. RESULTS: BMS191095 and diazoxide relaxed penile arteries, BMS191095 being one order of magnitude more potent. BMS191095-induced relaxations were reduced by mechanical endothelium removal and by inhibitors of the nitric oxide synthase (NOS) and PI3K enzymes. The NO-dependent component of the relaxation to BMS191095 was impaired in penile arteries from insulin resistant obese rats. The blockers of mitoKATP channel 5-HD, sarcolemma KATP (sarcKATP) channel glibenclamide, and large conductance Ca2+-activated K+ (BKCa) channel iberiotoxin, inhibited relaxations to BMS191095 and to the NO donor SNAP. BMS191095 reduced the mitochondrial bioenergetic profile of penile arteries and attenuated mitochondrial ROS production. Blockade of endogenous NO impaired and exogenous NO mimicked, respectively, the inhibitory effects of BMS191095 on basal respiration and oxygen consumed for ATP synthesis. Exogenous NO exhibited dual inhibitory/stimulatory effects on mitochondrial respiration. CONCLUSIONS: These results demonstrate that selective activation of mitoKATP channels causes penile vasodilation, attenuates ROS production and inhibits mitochondrial respiration in part by releasing endothelial NO. These mechanisms couple blood flow and metabolism in penile arterial wall and suggest that activation of vascular mitoKATP channels may protect erectile tissue against ischemic injury.

Calcium handling coupled to the endothelin ETA and ETB receptor-mediated vasoconstriction in resistance arteries: Differential regulation by PI3K, PKC and RhoK.

Abnormal endothelin-1 (ET-1) activity is involved in the pathogenesis of vascular diseases such as essential and pulmonary arterial hypertension, coronary artery disease, and cerebrovascular disease, blockade of ET receptors having shown efficacy in clinical assays and experimental models of hypertension. Augmented Ca2+ influx and changes in Ca2+ sensitization associated with arterial vasoconstriction underlie increased systemic vascular resistance in hypertension. Since peripheral resistance arteries play a key role in blood pressure regulation, we aimed to determine here the specific Ca2+ signaling mechanisms linked to the ET receptor-mediated vasoconstriction in resistance arteries and their selective regulation by protein kinase C (PKC), Rho kinase (RhoK), the phosphatidylinositol 3-kinase (PI3K) and the mitogen-activated protein kinase (MAPK). ET-1-induced contraction was mediated by the endothelin ETA receptor with a minor contribution of vascular smooth muscle (VSM) endothelin ETB receptors. ET receptor activation elicited Ca2+ mobilization from intracellular stores, extracellular Ca2+ influx and Ca2+ sensitization associated with contraction in resistance arteries. Vasoconstriction induced by ET-1 was largely dependent on activation of canonical transient receptor potential channel 3 (TRPC3) and extracellular Ca2+ influx through nifedipine-sensitive voltage-dependent Ca2+ channels. PI3K inhibition reduced intracellular Ca2+ mobilization and Ca2+ entry without altering vasoconstriction elicited by ET-1, while PKC has dual opposite actions by enhancing Ca2+ influx associated with contraction, and by inhibiting Ca2+ release from intracellular stores. RhoK was a major determinant of the enhanced sensitivity of the contractile filaments underlying ET-1 vasoconstriction, with also a modulatory positive action on Ca2+ influx and intracellular Ca2+ release. Augmented RhoK and PKC activities are involved in vascular dysfunction in hypertension and vascular complications of insulin-resistant states, and these kinases are thus potential pharmacological targets in vascular diseases in which the ET pathway is impaired.