- Email: [email protected]
Angiotensin II receptors in the human heart
International
X
Society
for
Heart
Research
22
POSITIVE IIKJTROPIC RNNPOUSLS IN EYPCFlWYROID RATS Lindsay Brown, Dept Physiology and Pharmacology, Univ of Queensland, Australia. The clinical features of hypothyroidism include distinctive cardiovascular changes. To determine hypothyroidism - induced changes in cardiac responsiveness, Wistar rats were treated from birth with oral methimazole (0.59/l drinking water, M rats); at 10 weeks old, M rats received 85f3 mg methimazole/kg/day (n=26); controls were untreated (C rats). M rats were smaller (166i.9 g; C rats, 421i16g. 1x25) with decreased heart rate CM, 183f8 beats/min; C, 251f5 beats/min) and body temperature (M, 37.0fO.l*C; C, 37.8*O.l'C). Relative to body weight, heart weights were similar in both groups; thyroid gland weights were markedly increased (M, 0.8fO.lmg/kg; C, 0.02f0.002 mg/kg). Positive inotropic responses, determined in isolated left ventricular papillary muscles ("=6-8 for each compound) and given as "eg log EC50 (maximal increase in force), were decreased in M rats: noradrenaline (B,-adrenoceptor agonist); M, 5.79i0.12 (3.Ofl.2m~); C, 6.50&0.13 (3.9f0.4mN); forskolin (adenylate cyclase activator), M, 5.88f0.04 (2.5f0.5mN); C, 6.77f0.12 (3.3*0.3&J); theophylline (phosphodiesterase inhibitor), M, 2.96f0.11 (1.2iO.6mN); C, 4.23f0.13 (3.5*0.2mN). Inotropic responses to phenylephr-"e Were (a,-adrenoceptor agonist) observed only in control rats, (C, 5.30f0.11 (1.5fO.4mN)). Maximal responses to '&Cl, were increased (M,6.2+0.4mN; C, 4.8fO.4m). Thus, chronic hypothyroidism in rats limits access to the contractile reserve of the ventricle while increasing the ability of ventricular muscle to produce force.
23
LABETALOL AND DILEVALOL ARE #,-ADRFJNOCEI’TOR SELECTIVE Sheila A. Doggrell, Department of Pharmacology, School of Medicine., University
ANTAGONISTS
Private Bag 92019, Auckland, New Zealand. Dilevalol is the R,R stereoisomer of labetalol. Labetslol and dilevalol have been classified as nonselective P-blockers (Brittain et al., 1982). I have determined the fl-adrenomptor blocking activity of lalxtalol and dilevalol cm tissues that predominantly contain &- (rat right ventricle, rat left atria) or &-admoceptors (rat aorta, rat portal vein) and the pA, values for lab&M and dilevalol on the guinea-pig left atria, a tissue with &- and &-adremceptors tbat is cmmmmly used in the Thus the effects of labetalol and dilevalol cm the contractile de-on of the potency of drugs at &-adrenoceptom responses of the rat right ventricle. rat left atria, rat portal vein aad guinea-pig let? atria to isoprenaline and on the relaxant mpmsea of the rat aorta to pmcaterol were detemined. The PA, values for labetalol were 8.30 and 8.60 on the rat right ventricle and leti atria and 7.45 and 7.59 on the rat aorta and portal vein, respectively. The PA, values for dilevalol were On tbe guinea-pig left atria the 8.90 and 8.98 on the rat right ventricle and let? atria and 8.25 on the rat aorta, respectively. PA, valuea for lab&M and dilevalol were 7.90 and 8.31, respectively, which is in agreement with the previous study (Brittaia et al., 1982) but does not represent the potency of these dmgs at /3,-adrenoceptors. In conclusion my study illustrates (i) that labetalol and dilevalol are selective &-admmceptor antagonists and (ii) that it is inappropriate to determine the potency of drugs against the mpmse of the guinea-pig left atria to isoprenaline as a measure of &-adrenweptor blocking activity. Brittain, Supported
24
R.T.,
Drew,
G. &Levy,
by the National
Heart
G.P. (1982). Foundation
Br.J.Phamwol.
of New
of Auckland,
77, 105-114
Zealand.
ANGIOTENSIN II RECEPTORS IN TRB HUMAN HEART Lindsay Brown, Catherine Marchant, David McGiffin' and Conrad Sernia, Department of Physiology and Pharmacology, The University of Queensland, and 'The Prince Charles Hospital, Brisbane, Australia. Angiotensin II (AII) activates specific AI1 receptors to cause cardiovascular responses such as vasoconstriction, positive inotropy and chronotropy as well as hypertrophy. We have determined the characteristics of these receptors in the human heart. Right atria1 appendages were obtained from patients undergoing coronary artery bypass graft (CABG, 1x13) or heart transplantation (HT. n=6). Left ventricle was obtained from cardiac transplant patients only. AI1 receptors were characterised (K. and density) in membrane homogenates using analysis of specific'z51-Sar1,11ee-AII binding by the LIGAND iterative program. This ligand bound to one specific high affinity site in atria (K, values: CABG, 1.3f0.2 nM; HT. 0.9i0.2nM; not significant). However, terminal heart disease significantly decreased rightatrialAI1 receptor density (CABG, 35.2f5.3; 14.4f4.0 fmol/mg protein). Receptor density appeared to be age-independent. HT, Ventricular tissue showed markedly fewer AI1 receptors than right atria. The presence of both Type 1 and Type 2 subtypes of AI1 receptors in the human heart was shown by investigations with the Type 1 selective antagonist, DuP 753 (losartan). We conclude that the human heart has high affinity AI1 receptors which are down-regulated in patients with moderate to severe heart failure.
X
Society
for
Heart
Research
22
POSITIVE IIKJTROPIC RNNPOUSLS IN EYPCFlWYROID RATS Lindsay Brown, Dept Physiology and Pharmacology, Univ of Queensland, Australia. The clinical features of hypothyroidism include distinctive cardiovascular changes. To determine hypothyroidism - induced changes in cardiac responsiveness, Wistar rats were treated from birth with oral methimazole (0.59/l drinking water, M rats); at 10 weeks old, M rats received 85f3 mg methimazole/kg/day (n=26); controls were untreated (C rats). M rats were smaller (166i.9 g; C rats, 421i16g. 1x25) with decreased heart rate CM, 183f8 beats/min; C, 251f5 beats/min) and body temperature (M, 37.0fO.l*C; C, 37.8*O.l'C). Relative to body weight, heart weights were similar in both groups; thyroid gland weights were markedly increased (M, 0.8fO.lmg/kg; C, 0.02f0.002 mg/kg). Positive inotropic responses, determined in isolated left ventricular papillary muscles ("=6-8 for each compound) and given as "eg log EC50 (maximal increase in force), were decreased in M rats: noradrenaline (B,-adrenoceptor agonist); M, 5.79i0.12 (3.Ofl.2m~); C, 6.50&0.13 (3.9f0.4mN); forskolin (adenylate cyclase activator), M, 5.88f0.04 (2.5f0.5mN); C, 6.77f0.12 (3.3*0.3&J); theophylline (phosphodiesterase inhibitor), M, 2.96f0.11 (1.2iO.6mN); C, 4.23f0.13 (3.5*0.2mN). Inotropic responses to phenylephr-"e Were (a,-adrenoceptor agonist) observed only in control rats, (C, 5.30f0.11 (1.5fO.4mN)). Maximal responses to '&Cl, were increased (M,6.2+0.4mN; C, 4.8fO.4m). Thus, chronic hypothyroidism in rats limits access to the contractile reserve of the ventricle while increasing the ability of ventricular muscle to produce force.
23
LABETALOL AND DILEVALOL ARE #,-ADRFJNOCEI’TOR SELECTIVE Sheila A. Doggrell, Department of Pharmacology, School of Medicine., University
ANTAGONISTS
Private Bag 92019, Auckland, New Zealand. Dilevalol is the R,R stereoisomer of labetalol. Labetslol and dilevalol have been classified as nonselective P-blockers (Brittain et al., 1982). I have determined the fl-adrenomptor blocking activity of lalxtalol and dilevalol cm tissues that predominantly contain &- (rat right ventricle, rat left atria) or &-admoceptors (rat aorta, rat portal vein) and the pA, values for lab&M and dilevalol on the guinea-pig left atria, a tissue with &- and &-adremceptors tbat is cmmmmly used in the Thus the effects of labetalol and dilevalol cm the contractile de-on of the potency of drugs at &-adrenoceptom responses of the rat right ventricle. rat left atria, rat portal vein aad guinea-pig let? atria to isoprenaline and on the relaxant mpmsea of the rat aorta to pmcaterol were detemined. The PA, values for labetalol were 8.30 and 8.60 on the rat right ventricle and leti atria and 7.45 and 7.59 on the rat aorta and portal vein, respectively. The PA, values for dilevalol were On tbe guinea-pig left atria the 8.90 and 8.98 on the rat right ventricle and let? atria and 8.25 on the rat aorta, respectively. PA, valuea for lab&M and dilevalol were 7.90 and 8.31, respectively, which is in agreement with the previous study (Brittaia et al., 1982) but does not represent the potency of these dmgs at /3,-adrenoceptors. In conclusion my study illustrates (i) that labetalol and dilevalol are selective &-admmceptor antagonists and (ii) that it is inappropriate to determine the potency of drugs against the mpmse of the guinea-pig left atria to isoprenaline as a measure of &-adrenweptor blocking activity. Brittain, Supported
24
R.T.,
Drew,
G. &Levy,
by the National
Heart
G.P. (1982). Foundation
Br.J.Phamwol.
of New
of Auckland,
77, 105-114
Zealand.
ANGIOTENSIN II RECEPTORS IN TRB HUMAN HEART Lindsay Brown, Catherine Marchant, David McGiffin' and Conrad Sernia, Department of Physiology and Pharmacology, The University of Queensland, and 'The Prince Charles Hospital, Brisbane, Australia. Angiotensin II (AII) activates specific AI1 receptors to cause cardiovascular responses such as vasoconstriction, positive inotropy and chronotropy as well as hypertrophy. We have determined the characteristics of these receptors in the human heart. Right atria1 appendages were obtained from patients undergoing coronary artery bypass graft (CABG, 1x13) or heart transplantation (HT. n=6). Left ventricle was obtained from cardiac transplant patients only. AI1 receptors were characterised (K. and density) in membrane homogenates using analysis of specific'z51-Sar1,11ee-AII binding by the LIGAND iterative program. This ligand bound to one specific high affinity site in atria (K, values: CABG, 1.3f0.2 nM; HT. 0.9i0.2nM; not significant). However, terminal heart disease significantly decreased rightatrialAI1 receptor density (CABG, 35.2f5.3; 14.4f4.0 fmol/mg protein). Receptor density appeared to be age-independent. HT, Ventricular tissue showed markedly fewer AI1 receptors than right atria. The presence of both Type 1 and Type 2 subtypes of AI1 receptors in the human heart was shown by investigations with the Type 1 selective antagonist, DuP 753 (losartan). We conclude that the human heart has high affinity AI1 receptors which are down-regulated in patients with moderate to severe heart failure.