PubMed · 11028303
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Y Miura. 2000. [Alpha beta-blocker].. https://pubmed.ncbi.nlm.nih.gov/11028303/
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alpha-Calcitonin gene-related peptide (alphaCGRP) is a pleiotropic neuropeptide implicated in a variety of physiological processes. To better understand the biological functions of alphaCGRP, we developed an alphaCGRP-null mouse model using a gene targeting approach. Recordings of mean arterial pressure (MAP) and heart rate (HR) showed that basal MAP and HR were significantly higher in both anesthetized and conscious, unrestrained alphaCGRP-null mice than in corresponding wild-type mice. The elevated MAP in alphaCGRP-null mice was shown to be the result of elevated peripheral vascular resistance by alpha-adrenergic blockade with prazosin and by transthoracic echocardiogram, which revealed no significant differences between alphaCGRP-null and wild-type mice in the stroke volume, fractional shortening, and ejection fraction. Moreover, evaluation of autonomic nervous activity by measuring HR after pretreatment of atropine and/or atenolol and by analyzing arterial baroreceptor reflexes showed sympathetic nervous activity to be significantly elevated in alphaCGRP-null mice; elevated levels of urinary catecholamine metabolites and decreased HR variability in mutant mice were also consistent with that finding. These findings suggest that alphaCGRP contributes to the regulation of cardiovascular function through inhibitory modulation of sympathetic nervous activity.
Congestive heart failure (CHF) is the most devastating cardiac sequella of long-standing hypertension. Recent data from the Antihypertensive and Lipid Lowering Treatment to Prevent Heart Attack Trial (ALLHAT) have shown the risk of CHF to be twice as high with doxazosin than with chlorthalidone. Although some questions remain regarding the diagnosis and mortality of CHF in the doxazosin arm and regarding the risk of dying from malignancy in the diuretic arm of ALLHAT, drugs used to treat hypertension should lower the CHF risk. Therefore, until ironclad safety data are provided, doxazosin, and probably all alpha-blockers, should no longer be used as first-line antihypertensive therapy.
1. Basal whole-limb blood flow and vascular conductance decrease with age in men. We determined whether these age-associated changes in limb haemodynamics are mediated by tonically augmented sympathetic alpha-adrenergic vasoconstriction. 2. Seven young (28 +/- 2 years; mean +/- S.E.M.) and eight older (64 +/- 2 years) healthy, normotensive adult men were studied. Baseline femoral artery blood flow (Doppler ultrasound) and calculated vascular conductance were 29 and 31 % lower, respectively, and vascular resistance was 53 % higher in the older men (all P < 0.001). 3. Local (intra-femoral artery) alpha-adrenergic receptor blockade with phentolamine evoked greater increases in femoral blood flow (105 +/- 11 vs. 60 +/- 6 %) and vascular conductance (125 +/- 13 vs. 66 +/- 7 %), and reductions in vascular resistance (55 +/- 2 vs. 39 +/- 3 %) in the experimental limb of the older compared with the young men (all P < 0.001). As a result, alpha-adrenergic receptor blockade eliminated the significance of the age-associated differences in absolute levels of femoral blood flow (500 +/- 51 vs. 551 +/- 35 ml min(-1)), vascular conductance (6.02 +/- 0.73 vs. 6.33 +/- 0.26 U), and vascular resistance (0.17 +/- 0.03 vs. 0.16 +/- 0.01 U; P = 0.4-0.8, n.s.). Femoral haemodynamics in the control limb were unaffected by phentolamine administration in the contralateral (experimental) limb. Complete alpha-adrenergic receptor blockade was demonstrated by the absence of vasoconstriction in the experimental limb in response to the cold pressor test. Local propranolol was administered to control for any beta-adrenergic effects of phentolamine. Propranolol did not affect haemodynamics in the experimental or control limbs. 4. Our results indicate that the age-related reductions in basal limb blood flow and vascular conductance are mediated largely by chronically elevated sympathetic alpha-adrenergic vasoconstriction. This may have important physiological and pathophysiological implications for the ageing human.