The structure-activity relationships of a series of 1,4-dihydropyridine Ca2+ channel activators, including Bay K 8644, have been determined by pharmacologic and radioligand binding techniques. Pharmacologic techniques included tension responses and the measurement of pA2 values for nifedipine antagonism of Bay K 8644 responses in guinea pig ileal, rat femoral and rat atrial and papillary muscle preparations. Radioligand binding experiments employed competition against [3H]nitrendipine binding in ileal smooth muscle and rat ventricular membranes and rat brain synaptosomal preparations. The series of compounds was employed as the racemates. Binding affinities were not significantly different between smooth muscle, cardiac muscle and brain preparations and the same rank order of pharmacologic activities is observed in smooth and cardiac muscle, where the effects of the 4-phenyl substituents, o greater than or equal to m greater than p, parallel those observed for 1,4-dihydropyridine antagonists. In the ileal and femoral artery smooth muscle preparations a 1:1 correlation is observed between pharmacologic and radioligand binding affinities. However, in the cardiac muscle preparations, left atrium and papillary muscle, there is an approximately 10-fold difference between the binding affinities and the lower pharmacologic affinities. A similar difference between smooth and cardiac muscle is observed with the pA2 values of 6.97 and 7.06 in atrial and papillary muscle respectively, which are significantly lower than the values of 8.54 and 8.72 measured in ileal and femoral artery respectively. The structure-activity expressions measured for this small series of 1,4-dihydropyridine activators parallel those observed in the larger series of 1,4-dihydropyridine antagonists. This is consistent with proposals that activators and antagonists interact at common binding sites that are components of a voltage-dependent Ca2+ channel.

3-Pyridinecarboxylic acid, 1,4-dihydro-2,6-dimethy↗

PubMedDate not supplied

The interactions of 1,4-dihydropyridines bearing a 2-(2-aminoethylthio)methyl substituent at voltage-dependent Ca2+ channels of smooth muscle, cardiac muscle and neuronal tissues.

The Ca2+ channel antagonistic potencies of tiamdipine [2-(2-aminoethylthio)methyl-3-carboethoxy-5-carbomethoxy-6-m ethyl-4-(3- nitrophenyl)-1,4-dihydropyridine] and nifedipine [2,6-dimethyl-3,5-dicarbomethoxy-4-(2-nitrophenyl)-1,4-dihydrop yri dine] analogs bearing phenyl ring substituents were studied using pharmacologic and radioligand binding techniques. Additionally, analogs of tiamdipine possessing (2-aminoethylthio)methyl-, (2-acetamidoethylthio)methyl- and (2-pyrrolidinylmethylthio)methyl- groups at the C2 position of the 1,4-dihydropyridine ring have been studied. Tiamdipine and nifedipine analogs inhibited K(+)-induced contractile responses in rat tail artery. IC50 values of 4-phenyl ring substituted 2-(2-aminoethylthio)methyl tiamdipine analogs ranged from 10(-7) mol/l to 10(-8) mol/l. However, the corresponding 4-phenyl ring substituted nifedipine analogs covered a wider range of potency from 10(-6) mol/l to 10(-9) mol/l. KI values of the corresponding tiamdipine analogs for the inhibition of specific [3H]PN 200-110 [(+)-[3H]isopropyl-4-(2,1,3-benzoxadiazol-4-yl)-1,4-dihydro-5- methoxycarbonyl-2,6-dimethyl-3-pyridinecarboxylate] binding ranged from 10(-7) mol/l to 10(-9) mol/l in guinea pig ileal and rat heart membranes and rat brain synaptosomes. The two stereoisomers of tiamdipine and its analog 2-(2-acetamidoethylthio)methyl-3-carboethoxy-5-carbomethoxy- 6-methyl-4-(3- nitrophenyl)-1,4-dihydropyridine, and the four stereoisomers of 2-(2-pyrrolidinylmethylthio)methyl-3-carboethoxy-5-carbom eth oxy-6-methyl-4-(3- nitrophenyl)-1,4-dihydropyridine showed high stereoselectivity ratios of approximately (-)/(+) = 100 and 1000 in pharmacologic and binding experiments, respectively. The inhibitory actions of 2-(2-aminoethylthio)methyltiamdipine analogs against K(+)-induced contractile responses in rat tail artery developed very slowly requiring at least 2 h for maximum effect.(ABSTRACT TRUNCATED AT 250 WORDS)

Animals↗

PubMedDate not supplied

Dietary sodium intake: influence on calcium channels and urinary calcium excretion in spontaneously hypertensive rats.

Binding of the 1,4-dihydropyridine [3H]PN200 110 was employed as an index of cardiac Ca2+ channels in normotensive (WKY) and spontaneously hypertensive (SHR) rats during 4 weeks of normal (0.73% NaCl) and high (8% NaCl) sodium diets when the rats were between 20 and 24 weeks of age. Binding site density was not different at the beginning of the study but was increased significantly (P less than 0.01) after 1 week in the SHR on a high sodium diet; this difference was not apparent at 2, 3 or 4 weeks of the diet. During this same period, the urinary Ca2+ excretion in SHR was enhanced significantly (P less than 0.01) and the urinary calcium/sodium ratio was elevated during the high sodium intake period.

Animals↗

PubMedDate not supplied

Angiotensin II receptor antagonism: losartan - sites and mechanisms of action.

This review surveys the basic pharmacology of angiotensin II receptors and their antagonism; reviews the existing clinical experience with losartan, the first approved nonpeptide angiotensin II antagonist; suggests other possible clinical areas for angiotensin II receptor antagonism; and compares angiotensin-converting enzyme inhibition with angiotensin receptor antagonism.

Angiotensin II↗

PubMedDate not supplied

Calcium-channel antagonists: mechanisms of action, vascular selectivities, and clinical relevance.

The calcium-channel antagonists represent three separate structural categories of drugs. They share a common action--the blockade of calcium-ion flow through one specific type of calcium channel. The chemical heterogeneity of these agents is reflected in their pharmacologic and therapeutic diversity. The calcium-channel antagonists enjoy significant use in cardiovascular medicine for the treatment of hypertension, angina, and some cardiac arrhythmias. However, the 1,4-dihydropyridines, the most potent antihypertensive calcium-channel blockers, lack antiarrhythmic properties. The selectivity of action of calcium-channel antagonists rests upon a number of factors, including pathways of calcium mobilization, types of channel activated, state-dependent interactions, and the pathological state of the tissue. An understanding of these factors is important to the rational application of these drugs and to the development of newer agents with different specificities.

Animals↗