Haemodynamic effects of the calcium facilitator Bay K-8644 in rats following vascular calcium overload.
1. The haemodynamic effects of the Ca2+ facilitator Bay K-8644 (Bay) were studied in a model of calcinosis induced by acute treatment with vitamin D3 and nicotine administration over 4 days with 13 days of recovery. 2. Calcium content of the left ventricular myocardium increased 8-9 fold, while aortic Ca2+ levels increased up to 12-fold in treated animals. There were minimal changes in the ECG and no change in the level of plasma alpha-hydroxy-butyrate-dehydrogenase, a cardiac specific enzyme which increases during ischaemia. Significant increases in pulse pressure (PP) were seen in anaesthetized and conscious calcinotic rats, with no increase in cardiac output index (DABF) or systemic vascular resistance. However, aortic rigidity (AORI) was significantly elevated in the calcinotic group under anaesthesia. 3. In both control and calcinotic rats, pressor responses to i.v. Bay were exclusively mediated by an increase in aortic blood flow (DABF) as lower body vascular resistance (TLBVR) did not change. The increase in DABF at low doses (0.1-1 microgram kg-1) of Bay probably resulted from an increase in venous return induced by the agonist, as Bay had little effect on cardiac contractility over this dose range (as estimated by left ventricular dp/dtmax) and did not cause tachycardia. At higher doses (10-1000 micrograms kg-1), Bay significantly increased LV dp/dt. Bay caused dose-related increases in AORI in pithed calcinotic rats, but a decrease in AORI in control animals. 4. The calcinosis model, which incorporates a recovery period to obviate the acute effects of nicotine and/or vitamin D3 treatment, results in long-term tissue calcium accumulation.(ABSTRACT TRUNCATED AT 250 WORDS)
Chillon
J M
JM
Faculté des Sciences Pharmaceutiques et Biologiques, Université de Nancy, France.
Gellotte
M
M
Ferrandon
P
P
Lartaud
I
I
Martin
D
D
Armstrong
J M
JM
Atkinson
J
J
Hicks
P E
PE
D001498:3-Pyridinecarboxylic acid, 1,4-dihydro-2,6-dimethyl-5-nitro-4-(2-(trifluoromethyl)phenyl)-, Methyl ester / Q000494:pharmacology*; D000758:Anesthesia; D000818:Animals; D002118:Calcium / Q000378:metabolism / Q000502:physiology*; D002762:Cholecalciferol / Q000494:pharmacology; D003655:Decerebrate State; D006439:Hemodynamics / Q000187:drug effects*; D007527:Isoenzymes; D007770:L-Lactate Dehydrogenase / Q000378:metabolism; D008297:Male; D009131:Muscle, Smooth, Vascular / Q000187:drug effects*; D009538:Nicotine / Q000494:pharmacology; D051381:Rats; D017208:Rats, Wistar
D007527:Isoenzymes; D002762:Cholecalciferol; D009538:Nicotine; D001498:3-Pyridinecarboxylic acid, 1,4-dihydro-2,6-dimethyl-5-nitro-4-(2-(trifluoromethyl)phenyl)-, Methyl ester; D007770:L-Lactate Dehydrogenase; D002118:Calcium