Genetic variation in the alpha1B-adrenergic receptor and vascular response.

The alpha1B (α1B)-adrenergic receptors contribute to vasoconstriction in humans. We tested the hypothesis that variation in the ADRA1B gene contributes to interindividual variability and ethnic differences in adrenergic vasoconstriction. We measured dorsal hand vein responses to increasing doses of phenylephrine in 64 Caucasians and 41 African Americans and genotyped 34 ADRA1B variants. We validated findings in another model of catecholamine-induced vasoconstriction, the increase in mean arterial pressure (ΔMAP) during a cold pressor test (CPT). One ADRA1B variant, rs10070745, present in 14 African-American heterozygotes but not in Caucasians, was associated with a lower phenylephrine ED50 (geometric mean (95% confidence interval), 144 (69-299) ng ml-1) compared with 27 African-American non-carriers (208 (130-334) ng ml-1; P=0.015) and contributed to the ethnic differences in ED50. The same variant was also associated with a greater ΔMAP during CPT (P=0.008). In conclusion, ADRA1B rs10070745 was significantly associated with vasoconstrictor responses after adrenergic stimulation and contributed to the ethnic difference in phenylephrine sensitivity.

Genetic variation in the α1A-adrenergic receptor and phenylephrine-mediated venoconstriction.

There is large interindividual variability and ethnic differences in phenylephrine-mediated vasoconstriction. We tested the hypothesis that genetic variation in ADRA1A, the α1A adrenergic receptor gene, contributes to the variability and ethnic differences. We measured local dorsal hand vein responses to increasing doses of phenylephrine in 64 Caucasians and 42 African-Americans and genotyped for 32 ADRA1A single nucleotide polymorphisms. The ED50 ranged from 11 to 5442 ng min(-1), and the Emax ranged from 13.5-100%. The rs574647 variant was associated with a trend towards lower logED50 in each race and in the combined cohort (P=0.008). In addition, rs1079078 was associated with a trend to higher logED50 in each race and in the combined cohort (P=0.011). Neither variant accounted for the ethnic differences in response. None of the ADRA1A haplotypes was associated with the outcomes. In conclusion, ADRA1A variants do not contribute substantially to the marked interindividual variability or ethnic differences in phenylephrine-mediated venoconstriction.

Contrasting effects of vasodilators on blood pressure and sodium balance in the hypertension of autonomic failure.

Supine hypertension, which is very common in patients with autonomic failure, limits the use of pressor agents and induces nighttime natriuresis. In 13 patients with severe orthostatic hypotension due to autonomic failure (7 women, 6 men, 72 +/- 3 yr) and supine hypertension, the effect of 30 mg nifedipine (n = 10) and 0.025 to 0.2 mg/h nitroglycerin patch (n = 11) on supine BP, renal sodium handling, and orthostatic tolerance was determined. Medications were given at 8 p.m.; patients stood up at 8 a.m. Nitroglycerin was removed at 6 a.m. Compared with placebo, nifedipine and nitroglycerin decreased systolic BP during the night by a maximum of 37 +/- 9 and 36 +/- 10 mmHg, respectively (P < 0.01). At 8 a.m., supine systolic BP was 23 +/- 7 mmHg lower with nifedipine than with placebo (P < 0.05), but was similar with nitroglycerin and placebo. Sodium excretion during the night was not reduced with nitroglycerin (0.13 +/- 0.02 mmol/mg creatinine [Cr] versus 0.15 +/- 0.03 mmol/mg Cr with placebo), but it was increased with nifedipine (0.35 +/- 0.06 mmol/mg Cr versus 0.13 +/- 0.02 mmol/mg Cr with placebo, P < 0.05). Nifedipine but not nitroglycerin worsened orthostatic hypotension in the morning. It is concluded that nifedipine and transdermal nitroglycerin are effective in controlling supine hypertension in patients with autonomic failure. However, nifedipine has a prolonged depressor effect and worsens orthostatic hypotension in the morning. The decrease in pressure natriuresis that would be expected with the substantial decrease in BP obtained with nitroglycerin and nifedipine may be offset by a direct effect of both drugs on renal sodium handling.

Raised cerebrovascular resistance in idiopathic orthostatic intolerance: evidence for sympathetic vasoconstriction.

Patients with idiopathic orthostatic intolerance (IOI) exhibit symptoms suggestive of cerebral hypoperfusion and an excessive decrease in cerebral blood flow associated with standing despite sustained systemic blood pressure. In 9 patients (8 women and 1 man aged 22 to 48 years) with IOI, we tested the hypothesis that volume loading (2000 cc normal saline) and alpha-adrenoreceptor agonism improve systemic hemodynamics and cerebral perfusion and that the decrease in cerebral blood flow with head-up tilt (HUT) could be attenuated by alpha-adrenoreceptor blockade with phentolamine. At 5 minutes of HUT, volume loading (-20+/-3.2 bpm) and phenylephrine (-18+/-3.4 bpm) significantly reduced upright heart rate compared with placebo; the effect was diminished at the end of HUT. Phentolamine substantially increased upright heart rate at 5 minutes (20+/-3.7 bpm) and at the end of HUT (14+/-5 bpm). With placebo, mean cerebral blood flow velocity decreased by 33+/-6% at the end of HUT. This decrease in cerebral blood flow with HUT was attenuated by all 3 interventions. We conclude that in patients with IOI, HUT causes a substantial decrease in cerebrovascular blood flow velocity. The decrease in blood flow velocity with HUT can be attenuated with interventions that improve systemic hemodynamics and therefore decrease reflex sympathetic activation. Moreover, alpha-adrenoreceptor blockade also blunts the decrease in cerebral blood flow with HUT but at the price of deteriorated systemic hemodynamics. These observations may suggest that in patients with IOI, excessive sympathetic activity contributes to the paradoxical decrease in cerebral blood flow with upright posture.