Measurement and cardiovascular relevance of partial agonist activity (PAA) involving beta 1- and beta 2-adrenoceptors.
In the normal heart the ratio of beta 1/beta 2-receptors in both atria and ventricles is about 75:25; in the failing heart the ratio is about 60:40. Stimulation of either beta 1- or beta 2-receptors results in a positive chronotropic and inotropic response. In the periphery, with the exception of lipolysis, renin release, control of intraocular pressure and intestinal relaxation, beta 2-related activity predominates. The nature of the beta 2-receptor is being unravelled and it has now been cloned. The beta-receptor antagonist is 'anchored' via disulfide bonding. Subsequent events involve the regulatory protein guanine nucleotide which couples the receptor to adenylate cyclase. beta-receptor density may by up- or down-regulated. beta-stimulation down-regulates (uncouples and internalizes or sequestrates) and beta-antagonism up-regulates beta-receptor numbers, but the functional implications of such changes are not always clear. A partial agonist occupies a receptor site and competitively inhibits the full agonist (e.g. noradrenaline). A partial agonist differs from a full agonist in that maximal response of a tissue is less. When background sympathetic activity is absent or very low a partial agonist will act as an agonist, e.g. increase heart rate, but when background tone is high the partial agonist will behave functionally as an antagonist, e.g. decrease heart rate. In animals partial agonist activity (PAA) can be assessed in many ways. In the catecholamine-depleted (reserpine or syrosingopine), vagotomized or pithed, intact animal beta-activity can be assessed via changes in heart rate, cardiac contractility and atrioventricular conduction. Isolated organs can also be used such as atria, papillary muscle, tracheal, mesenteric artery and uterine preparations. The choice of animal is important as marked species differences in response can occur. In man assessing PAA is difficult due to the presence of an intact sympathetic system: the problem can be overcome by autonomic blockade of constrictor and vagal reflexes with prazosin, clonidine and atropine but leaving the beta-receptor mediated responses unimpaired. beta 1- and beta 2-selective PAA can also be gauged via an increased sleeping heart rate (basal sympathetic tone) in the presence and absence of a beta 1- and beta 2-selective antagonist. beta 1-selective PAA can also cause an increase in resting systolic blood pressure, beta 2-selective PAA may be further assessed by a fall in DBP, increased blood flow, fall in peripheral resistance or increased finger tremor.(ABSTRACT TRUNCATED AT 400 WORDS)
Cruickshank
J M
JM
Cardiac Department, Wythenshawe Hospital, Manchester, U.K.
D000318:Adrenergic beta-Agonists; D000319:Adrenergic beta-Antagonists / Q000009:adverse effects / Q000494:pharmacology*; D000818:Animals; D002319:Cardiovascular System / Q000187:drug effects*; D006439:Hemodynamics / Q000187:drug effects; D006801:Humans; D011943:Receptors, Adrenergic, beta / Q000502:physiology
D000318:Adrenergic beta-Agonists; D000319:Adrenergic beta-Antagonists; D011943:Receptors, Adrenergic, beta