Simultaneous two-probe laser Doppler velocimetric assessment of topically applied drugs in rats.

A simple, noninvasive method for the determination of cutaneous blood flow in anesthetized rats is presented. Simultaneous two-probe laser doppler velocimetry is shown to be a useful preclinical tool for the assessment of topically applied drugs.

Pharmacology of BMY 20064, a potent Ca2+ entry blocker and selective alpha 1-adrenoceptor antagonist.

BMY 20064 is a dihydropyridine Ca2+ entry blocker with potent and selective alpha 1-adrenoceptor antagonist properties. The drug was equal in potency to nifedipine as a Ca2+ entry blocker in depolarized smooth muscle preparations. It was less active than nifedipine in antagonizing Ca2+-induced contractions of isolated guinea pig papillary muscles paced at 0.2, 1.0, or 2 Hz. BMY 20064 was a potent (0.1-0.2 X prazosin) and selective alpha 1-adrenoceptor antagonist in radioligand binding assays and in ganglion-blocked anesthetized rats challenged with phenylephrine. BMY 20064 blocked both the K+ and alpha 1-adrenergic agonist-induced increases in 45Ca uptake into rabbit aortic rings. The drug was more effective than nifedipine, prazosin, or combinations of the drugs in preventing ATP depletion of the rat heart during global ischemia. BMY 20064 was a potent antihypertensive agent in normotensive rats and in SHR. BMY 20064 administered intraarterially (i.a.) dilated both femoral and coronary arterial beds of the dog. Hemodynamic changes elicited by BMY 20064 in anesthetized dogs were similar to those induced by nifedipine. BMY 20064 appears to be a more effective myocardial antiischemic agent than nifedipine, prazosin, or combinations of nifedipine and prazosin. A drug of this type may be more efficacious than dihydropyridines in the management of ischemic episodes.

Evaluation of cardiac anoxia and ischemia models in the rat using calcium antagonists.

The effects of severe global ischemia on cardiac high energy phosphate (HEP) stores were investigated in an in vitro rat model. The heart was removed from the rat in this model, sealed in a plastic bag and incubated for varying times and temperatures (20-45 degrees C). The rat, in the in vivo anoxic model, was subjected to cervical dislocation which resulted in respiratory arrest. In both models the hearts were removed and analyzed for HEP at appropriate times following the onset of anoxia or ischemia. Verapamil and nifedipine, administered intravenously 10 minutes before the start of the experiments, preserved HEP stores in both models. The degree of protection provided by the Ca+2 blockers was related to both the dose of drug and the duration of the ischemia/anoxia. Verapamil was more active than nifedipine in both models.

Mode of action of ergonovine on isolated porcine coronary artery: the role of Ca2+.

Coronary vasoconstrictor responses to ergonovine were examined in helical coronary arterial strips of young swine. Both ergonovine and serotonin (5-hydroxytryptamine) produced dose-dependent contractions of the strips. The distal region (less than 1.00 mm outer diameter) of the circumflex coronary artery was most sensitive to the responses of serotonin and ergonovine. Methysergide and nifedipine significantly depressed the contractions induced by ergonovine and serotonin. Atropine, propranolol, and the alpha 1 blocker, prazosin, did not antagonize ergonovine-induced contractions. The ergonovine response may depend entirely upon extracellular Ca2+ while the effect of serotonin may be mediated in part through the mobilization of intracellular Ca2+ stores. Increases in 45Ca2+ cellular contents occurred after ergonovine or serotonin and these increases were blocked by methysergide or nifedipine at concentrations which blocked mechanical responses to the agonist. It is concluded that the contractions of the porcine coronary artery produced by ergonovine and serotonin are as follows: (i) regionally sensitive; (ii) blocked by Ca2+ antagonists and therefore may utilize Ca2+ channels similar to those described in other excitable tissues; (iii) blocked by methysergide. These studies indicate that the major mechanism of ergonovine's action in the porcine coronary artery is through the activation of serotonin receptors on coronary arteries which are, in turn, linked to Ca2+ channels. However, this mechanism of action may be different in an intact animal.

Stereoselective and non-stereoselective effects of D 600 (methoxyverapamil) in smooth muscle preparations.

Mechanical responses in guinea-pig ileal longitudinal, rat vasa deferentia and rat portal vein smooth muscle strips elicited by receptor activation (muscarinic or alpha-adrenergic) or by K+ depolarization were blocked by D 600 (methoxyverapamil). Stereoselectivity was observed with the (-)-enantiomer being more potent than the (+)-enantiomer (the ratio varying from 6 to 180). The tonic (slow) component of response was more sensitive than the phasic (fast) component. D 600 competitively blocked binding of (-)-[3H]QNB and [3H]WB 4101 to muscarinic and alpha-adrenergic receptors respectively, but in marked contrast to the effects on mechanical responses antagonism of ligand binding was non-stereoselective. It is suggested that stereoselectivity of action of D 600 may be a useful criterion to distinguish between its several sites of action.