Hemodynamic and beta-adrenergic receptor adaptations during long-term beta-adrenoceptor blockade. Studies with acebutolol, atenolol, pindolol, and propranolol in hypertensive patients.
In an attempt to further clarify the mechanism of the maintenance of the antihypertensive effect of beta-adrenoceptor antagonists, the effects of four antagonists with different ancillary properties (acebutolol, atenolol, pindolol, and propranolol) on systemic and renal hemodynamics, body fluid volumes, hormones, and lymphocyte beta-adrenoceptor density were studied in four groups of 10 hypertensive patients. The patients were observed for 3 weeks during active treatment and for 2 weeks after withdrawal of treatment. At the end of the 3-week treatment period, the four drugs had an equal antihypertensive effect (fall in mean arterial pressure, 10-13%). Although renin activity was suppressed (60-70%) by all four drugs, changes in renin or pretreatment values of renin levels were not correlated with the fall in blood pressure. The drugs had no effect on plasma catecholamine concentrations or body fluid volumes. Despite similar antihypertensive effects among the four drugs, the changes in flow and resistance underlying the fall in blood pressure differed considerably. With pindolol, the fall in blood pressure was associated with a fall in vascular resistance (26 +/- 6%), whereas with propranolol, it was predominantly associated with a fall in cardiac output (11 +/- 7%). No significant changes in vascular resistance or cardiac output occurred with atenolol or acebutolol. The changes in renal blood flow and renal vascular resistance occurred in parallel with the changes in cardiac output and systemic vascular resistance. Plasma epinephrine concentration and pretreatment cardiac chronotropic responsiveness to isoproterenol appeared to be inversely correlated with lymphocyte beta-adrenoceptor density (Bmax) (r = -0.41 and -0.43, respectively). With pindolol, Bmax decreased maximally by 39 +/- 6%, and with propranolol, it increased by 51 +/- 17%. With both drugs, significant changes in Bmax were already present 24 hours after treatment. Furthermore, 1 week after withdrawal of treatment with pindolol, Bmax was still down-regulated, and cardiac chronotropic responsiveness was still decreased, whereas 1 week after withdrawal of propranolol, Bmax was still up-regulated, and cardiac chronotropic responsiveness was still increased. No changes in Bmax occurred with the beta 1-selective antagonists acebutolol and atenolol. Thus, despite an equal antihypertensive effect, the four beta-adrenoceptor antagonists appear to have dissimilar effects on cardiac output, renal blood flow, and lymphocyte beta-adrenoceptors. Changes in cardiac output, the circulating blood volume, or angiotensin-mediated vasoconstriction are factors unlikely to be crucial for the antihypertensive effect of beta-adrenoceptor antagonists. Therefore, interference with vasoconstrictor nerve activity through blockade of either central or peripheral prejunctional beta-adrenoceptors could be an alternative explanation of their blood pressure-lowering potential.
van den Meiracker
A H
AH
Department of Internal Medicine I, University Hospital Dijkzigt, Erasmus University, Rotterdam, The Netherlands.
Man in't Veld
A J
AJ
Boomsma
F
F
Fischberg
D J
DJ
Molinoff
P B
PB
Schalekamp
M A
MA
D000222:Adaptation, Physiological; D000319:Adrenergic beta-Antagonists / Q000627:therapeutic use*; D000328:Adult; D000450:Aldosterone / Q000097:blood; D002395:Catecholamines / Q000097:blood; D006439:Hemodynamics / Q000187:drug effects*; D006801:Humans; D006973:Hypertension / Q000188:drug therapy* / Q000503:physiopathology; D007545:Isoproterenol / Q000627:therapeutic use; D008214:Lymphocytes / Q000378:metabolism; D008297:Male; D008875:Middle Aged; D011943:Receptors, Adrenergic, beta / Q000187:drug effects* / Q000378:metabolism / Q000502:physiology; D012079:Renal Circulation / Q000187:drug effects; D012083:Renin / Q000097:blood; D013997:Time Factors
D000319:Adrenergic beta-Antagonists; D002395:Catecholamines; D011943:Receptors, Adrenergic, beta; D000450:Aldosterone; D012083:Renin; D007545:Isoproterenol