β2- and β3-adrenoceptor polymorphisms are related with weight gain and blood pressure elevation over 5 years

AJH–May 2005–VOL. 18, NO. 5, PART 2

POSTERS: Neural Mechanisms and Transmitters

P-555 ACUTE MYOCARDIAL INFARCTION IN PATIENTS WITH HYPERTENSION: ASSOCIATION WITH ADVERSE PROGNOSTIC INDICATORS Andrew J Hogarth, Lee N Graham, Alan F MacKintosh, David ASG Mary. Department of Cardiology, St James’s University Hospital, Leeds, United Kingdom. An impaired baroreceptor reflex sensitivity controlling the heart period through the vagus nerves (BRS) and sympatho-humoral activation following acute myocardial infarction (AMI) represent adverse prognostic indices. The occurrence of AMI in patients with hypertension (HT-AMI) is not unexpected, and has been associated with a greater mortality than that occurring in normotensive subjects (NT-AMI). This study was planned to determine whether HT-AMI patients have a greater central sympathetic output and BRS impairment than NT-AMI patients. We examined 11 HT-AMI, 10 NT-AMI patients 2-4 days following AMI and 10 normal control (NC). The groups were matched according to age, body mass index (BMI) and gender (Table). The two AMI groups were also matched according to heart rate (HR). Muscle sympathetic nerve activity (MSNA) was measured by microneurography from the peroneal nerve and quantified in terms of bursts per 100 cardiac beats (b/100b). BRS was obtained from the Valsalva maneuver as the steepest slope between the RR interval (ms) and systolic pressure (mmHg). Data were expressed as mean ⫾ SEM and summarised in the table below. Mean arterial pressure (MBP) was insignificantly lower in NT-AMI and the HR was higher in NC than NT-AMI (P⬍0.05; ANOVA posttests). MSNA hyperactivity relative to NC was greater in HT-AMI than in NT-AMI (at least P⬍0.05) whilst BRS impairment (at least P⬍0.01) was insignificantly greater in HT-AMI than NT-AMI. These results in patients following AMI indicate that pre-existent hypertension leads to an excessive level of sympathetic activation and BRS impairment, and may at least partly explain the adverse prognosis seen in hypertensive patients following AMI. Table showing data as mean ⴞ SEM for the 3 groups

HT-AMI NT-AMI NC

Number (males)

Age years

BMI kg/m2

HR b/min

MAP mmHg

MSNA b/100b

BRS ms/mmHg

11(8) 10(8) 10(7)

62 ⫾ 2.1 60 ⫾ 2.7 60 ⫾ 2.2

27 ⫾ 1.0 25 ⫾ 0.8 27 ⫾ 1.0

59 ⫾ 2.7 57 ⫾ 1.6 66 ⫾ 2.4

97 ⫾ 4.3 89 ⫾ 2.7 99 ⫾ 1.5

89 ⫾ 3.2 78 ⫾ 3.8 52 ⫾ 4.9

1.7 ⫾ 0.2 2.9 ⫾ 0.5 4.8 ⫾ 0.4

Key Words: Hypertension, Myocardial Infarction, Sympathetic Nerve Activity

P-556 ␤2- AND ␤3-ADRENOCEPTOR POLYMORPHISMS ARE RELATED WITH WEIGHT GAIN AND BLOOD PRESSURE ELEVATION OVER 5 YEARS Kazuko Masuo, Tomohiro Katsuya, Yuxiao Fu, Hiromi Rakugi, Toshio Ogihara, Michael L. Tuck. Human Nuerotransmitter Laboratory, Baker Heart Research Institute, Melbourne, Victoria, Australia; Department of Geriatric Medicine, Osaka University Graduate School of Medicine, Suita city, Osaka, Japan; Endocrinology and Metabolism Division, Sepulveda VA Medical Center and UCLA School of Medicine, Sepulveda, CA. The genes responsible for obesity are also candidate genes for obesityrelated diseases, such as hypertension. Functional polymorphisms in the ␤2- and ␤3-adrenoceptors have been reported to be associated with hypertension and obesity. To clarify the relevance of the ␤-adrenoceptor polymorphisms to weight gain, blood pressure (BP) elevation and sympathetic nerve activity, we studied their association with polymorphisms of ␤2-adrenoceptor genes (Arg16Gly, Gln27Glu) and ␤3-adrenoceptor gene (Trp64Arg). Changes in body weight, BP levels and plasma norepinephrine (NE) levels over 5 years were studied in 160 young, Japanese men, who were nonobese and normotensive at entry. The relationship of these to the ␤-adrenoceptor polymorphisms were also

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investigated. Significant weight gain and BP elevation were defined as ⱖ10% increases over 5 years in BMI or mean BP from entry. The presence of Gly allele of Arg16Gly and Arg allele of Trp64Arg were associated with higher frequencies of weight gain and BP elevation. The subjects carrying Gln allele of Gln27Glu had higher frequency of BP elevation. Significantly higher levels of plasma NE were observed in the subjects with Gly16 allele of Arg16Gly and Gln27 allele of Gln27Glu, who had higher frequency of weight gain and/or BP elevation. These results demonstrate that the polymorphisms of Arg16Gly and Trp64Arg are related with propensity for weight gain and BP elevation, and that the polymorphism of Gln27Glu is linked to BP elevation. The subjects carrying the polymorphisms linked to weight gain and BP elevation have heightened sympathetic activity prior to weight gain and BP elevation, suggesting that ␤-adrenergic receptors polymorphisms associated with heightened sympathetic nerve activity both antedates and predicts the onset of obesity and hypertension. Key Words: Beta-Adrenoceptor Polymorphisms, Hypertension, Obesity

P-557 INHIBITION OF NITRIC OXIDE SYNTHESIS DOES NOT ALTER HYPOGLYCEMIA-INDUCED ACTIVATION OF LUMBAR SYMPATHETIC NERVE ACTIVITY IN RATS Martin S Muntzel, Onyekwere Onwumere, Tawyanna Joseph. Biological Sciences, Lehman College, Bronx, NY. Several studies utilizing nitric oxide (NO) donors or inhibitors of NO synthase have shown that NO generally causes reductions in sympathetic nerve activity (SNA). For example, NO donors usually decrease SNA whereas NO synthase inhibitors produce gradual increases in sympathetic neural output. However, few studies have examined whether NO modulates reflex increases in SNA elicited by sympathoexcitatory stimuli. Given this background, we hypothesized that elevations in SNA, generated by insulin-induced hypoglycemia, would be potentiated by pretreatment with the NO synthase inhibitor, NG-monomethyl-L-arginine (LNMMA). We administered an insulin bolus (30U/kg, i.v.) in urethaneanaesthetized rats receiving either no pretreatment (Insulin group; n ⫽ 8) or after pretreatment with LNMMA (L-NMMA-Insulin group; 0.35 mg/kg/min, i.v.; n ⫽ 13), while measuring blood glucose, mean arterial pressure (MAP), heart rate (HR), and lumbar SNA. We found that insulin caused equivalent blood glucose decreases in the Insulin (from 161⫾14 mg/dl to 63⫾3 mg/dl) and L-NMMA-Insulin (from 170⫾14 mg/dl to 58⫾15 mg/dl) groups. Insulin-induced hypoglycemia caused expected MAP decreases in the Insulin group (from 113⫾11 mmHg to 101⫾14 mmHg) that were abolished and reversed into elevations in the LNMMA-Insulin group (from 106⫾6 mmHg to 112⫾7 mmHg). Hypoglycemia stimulated substantial HR increases that were not different between the Insulin (from 371⫾9 bpm to 428⫾26 bpm) and L-NMMAInsulin (from 369⫾10 bpm to 404⫾21 bpm) groups. Finally, and in contrast to our expectation, increases in SNA to hypoglycemia were not different between the Insulin (273⫾70 % from 100% baseline) and L-NMMA-Insulin (307⫾56 % from 100% baseline) groups. These findings suggest that NO does not modulate increases in lumbar SNA induced by severe hypoglycemic stress. Furthermore, our finding that MAP decreases to hypoglycemia were abolished by L-NMMA indicates that the blood pressure decreases may be secondary to epinephrineinduced activation of beta-2-adrenergic receptors as well as NO-induced vasodilation. Key Words: Blood Pressure, Heart Rate, Insulin