Coronary vascular and myocardial responses to selective hypoxic and/or hypercapnic carotid chemoreceptor stimulation were investigated in constantly ventilated, pentobarbital or urethan-chloralose anesthetized dogs. Bilaterally isolated carotid chemoreceptors were perfused with autologous blood of varying O2 and CO2 tensions via an extracorporeal lung circuit. Systemic gas tensions were unchanged. Effects of carotid chemoreceptor stimulation on coronary vascular resistance, left ventricular dP/dt, and strain-gauge arch output were studied at natural coronary blood flow with the chest closed and during constant-flow perfusion of the left common coronary artery with the chest open. Carotid chemoreceptor stimulation slightly increased left ventricular dP/dt and slightly decreased the strain-gauge arch output, while markedly increasing systemic pressure. Coronary blood flow increased; however, coronary vascular resistance wa.as not affected. These studies show that local carotid body stimulation increases coronary blood flow but has little effect on the myocardium. The increase in coronary blood flow results mainly from an increase in systemic arterial pressure. Thus these data provide little evidence for increased sympathetic activity of the heart during local stimulation of the carotid chemoreceptors with hypoxic and hypercapnic blood.

for the Cooperative Studies Program (CSP) #572 and Million Veteran Program (MVP)IMPORTANCE Serious mental illnesses, including schizophrenia, bipolar disorder, and depression, are heritable, highly multifactorial disorders and major causes of disability worldwide.OBJECTIVE To benchmark the penetrance of current neuropsychiatric polygenic risk scores (PRSs) in the Veterans Health Administration health care system and to explore associations between PRS and broad categories of human disease via phenome-wide association studies.DESIGN, SETTING, AND PARTICIPANTS Extensive Veterans Health Administration's electronic health records were assessed from October 1999 to January 2021, and an embedded cohort of 9378 individuals with confirmed diagnoses of schizophrenia or bipolar 1 disorder were found. The performance of schizophrenia, bipolar disorder, and major depression PRSs were compared in participants of African or European ancestry in the Million Veteran Program (approximately 400 000 individuals), and associations between PRSs and 1650 disease categories based on ICD-9/10 billing codes were explored. Last, genomic structural equation modeling was applied to derive novel PRSs indexing common and disorder-specific genetic factors. Analysis took place from January 2021 to January 2022. MAIN OUTCOMES AND MEASURESDiagnoses based on in-person structured clinical interviews were compared with ICD-9/10 billing codes. PRSs were constructed using summary statistics from genome-wide association studies of schizophrenia, bipolar disorder, and major depression. RESULTSOf 707 299 enrolled study participants, 459 667 were genotyped at the time of writing; 84 806 were of broadly African ancestry (mean [SD] age, 58 [12.1] years) and 314 909 were of broadly European ancestry (mean [SD] age, 66.4 [13.5] years). Among 9378 individuals with confirmed diagnoses of schizophrenia or bipolar 1 disorder, 8962 (95.6%) were correctly identified using ICD-9/10 codes (2 or more). Among those of European ancestry, PRSs were robustly associated with having received a diagnosis of schizophrenia (odds ratio [OR], 1.81 [95% CI, 1.76-1.87]; P < 10 −257 ) or bipolar disorder (OR, 1.42 [95% CI,; P < 10 −295 ). Corresponding effect sizes in participants of African ancestry were considerably smaller for schizophrenia (OR, 1.35 [95% CI,; P < 10 −38 ) and bipolar disorder (OR, 1.16 [95% CI,; P < 10 −10 ). Neuropsychiatric PRSs were associated with increased risk for a range of psychiatric and physical health problems. CONCLUSIONS AND RELEVANCEUsing diagnoses confirmed by in-person structured clinical interviews and current neuropsychiatric PRSs, the validity of an electronic health records-based phenotyping approach in US veterans was demonstrated, highlighting the potential of PRSs for disentangling biological and mediated pleiotropy.

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Reflex vascular responses to local carotid chemoreceptor stimulation with hypoxic-hypercapnic, hypoxic, or hypercapnic blood were investigated in pentobarbitalized dogs. Bilaterally isolated carotid chemoreceptors were perfused via an extracorporeal lung circuit. Oxygen and carbon dioxide tensions of blood perfusing the carotid bodies were altered by ventilating the isolated lung with various O2-CO2 mixtures. Ventilation of the whole animal maintained normal systemic O2 and CO2 tensions. Perfusion pressures of the isolated kidney, ileum, forelimb, gracilis and hindpaw were measured during constant-flow perfusion. Carotid chemoreceptor stimulation with hypoxic-hypercapnic blood before vagotomy increased renal vascular resistance but caused no change in intestinal or forelimb resistance. Following vagotomy, hypoxic-hypercapnic, hypoxic, or hypercapnic carotid body stimulation increased renal, intestinal, and forelimb vascular resistance. Forelimb skin and muscle vascular beds contributed about equally to the increase in forelimb resistance. Gracilis muscle and hindpaw resistance also increased during hypoxic-hypercapnic stimulation after vagotomy.

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