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Disagreement in the literature about the occurrence of rebound hypertension (hypertensive overshoot) in animal models initiated this investigation. Oral doses of clonidine (0.03 mg kg−1) or guanfacine (0.3 mg kg−1) were administered twice daily during three weeks to groups of normotensive and renal hypertensive rats. Blood pressure and heart rate were measured immediately before and 3 h after the first daily dose, and compared with values obtained from placebo-treated control rats. Treatment with either drug induced large daily fluctuations rather than sustained falls in blood pressure. In the normotensive, but not in the hypertensive groups, the morning blood pressures measured before the first daily dose were significantly elevated over those of the control groups after 9 and 5 days of treatment with clonidine or guanfacine. This elevation persisted for 3 days after drug withdrawal. It is concluded that in the rat the duration of action of both drugs was short, so that twice daily administration of both drugs similarly produced large daily fluctuations rather than sustained falls in blood pressure. Blood pressure rises developed during treatment rather than after withdrawal in normotensive rats only. Therefore, this type of study does not relate well to the human situation and different experimental approaches to this problem are needed.

The effect of digoxin-specific antibody fragments on glycoside-induced mesenteric vasoconstriction were investigated. Digoxin caused a sustained contraction of strips of isolated feline mesenteric artery lasting for several hours, while in anaesthetized cats it produced a significant decrease in blood flow and increase in resistance in the mesenteric artery. In-vitro, digoxin’s contractile effect was inhibited by ‘prophylactic’ addition of antibody to the organ bath, but the clinical use for prophylaxis is not a practical proposition. When the antibodies were added with the contraction of the arterial strip in response to digoxin already established, the tone of the preparation decreased significantly over 3 h, but the effect of the glycoside was not fully reversible. In-vivo, control animals not treated with antibodies developed arrhythmias, mesenteric blood flow fell by more than 50% and resistance increased by more than 80% relative to the initial values. These animals died of ventricular fibrillation before the end of the experiment. Animals treated with digoxin-specific antibody fragments after receiving digoxin injections showed no further decrease in mesenteric blood flow and 90 min after the last dose of digoxin, the flow was recovering and mesenteric resistance decreasing. Furthermore, all the animals that had received antibodies remained in sinus rhythm to the end of the experiment. In view of the latent period to onset of action of the antibodies, valuable time may be lost in impaired mesenteric blood flow. To bridge the gap or, indeed, as primary treatment, calcium antagonists merit consideration; in our experiments mesenteric vasoconstriction was abolished within a few minutes by application of the dihydropyridine calcium antagonist 4-(2,1,3-benzo-oxadiazol-4-yl)-2,6-dimethyl-1,4-dihydropyridine-3,5-dicarboxylic aid, diethyl ester (PY 108–068).

Endralazine (BQ 22–708, Miretilan) and guanfacine (BS 100–141, Estulic) were tested alone and in combination for their effects on blood pressure and heart rate in conscious spontaneously hypertensive rats and conscious normotensive dogs. During combined administration of endralazine and guanfacine to spontaneously hypertensive rats, guanfacine 1 mg kg−1i.v. blocked the tachycardia caused by endralazine, 1 mg kg−1i.v. After oral administration, the tachycardia induced by 0·5 and 1 mg kg−1of endralazine was inhibited dose-dependently by 0·05, 0·1 and 0·5 mg kg−1of guanfacine. The antihypertensive efficacy of endralazine was either unchanged or increased by guanfacine at 0·05-1 mg kg−1.In normotensive conscious dogs, 0·2 mg kg−1i.v. of guanfacine antagonised the tachycardia elicited by 0·3 mg kg−1i.v. of endralazine. The elimination of the endralazine-induced reflex tachycardia by guanfacine suggests that the combination of both drugs could be useful in antihypertensive therapy.

Several Rh(I), Ir(III), and Pt(II) complexes of the chiral P,S-bidentate ligand 2 have been prepared and characterized. Detailed two-dimensional NMR studies show that (i) the boat-type chelate ring and the stereogenic sulfur center can invert rapidly at ambient temperature and (ii) the sulfur donor may dissociate, essentially destroying the chiral pocket. The solid-state structure of [Pt(η³-C3H5)(2)]PF6 (3) has been determined and the sulfur substituent shown to have an axial orientation. The six-membered chelate ring takes up a boatlike conformation. As shown by an X-ray diffraction study for 3, and via incoherent inelastic neutron scattering (IINS) measurements for the Pd analog, 4, the OH group is remote from the metal atom.

We have evaluated the ⁵⁷Fe nuclear magnetic resonance chemical shielding and Mössbauer electric field gradient tensors and their orientations for a cytochrome c model compound as well as for isopropyl isocyanide and carbon monoxy−myoglobin model systems and two simple metalloporphyrins containing bis(pyridine) and bis(trimethylphosphine) ligands, using Kohn−Sham density functional theory. For cytochrome c we used a model Fe(II) porphyrin structure together with a 1-methylimidazole base (to represent His-18) and a dimethyl sulfide molecule (to represent Met-80 in the structure of horse heart ferrocytochrome c), both located at the X-ray coordinates for cyt c Fe(II). For the Mb calculations, we used the coordinates of two recently characterized metalloporphyrins:  (i-PrNC)(1-methylimidazole)(5,10,15,20-tetraphenylporphinato)Fe(II) and (CO)(1-methylimidazole)(5,10,15,20-tetraphenylporphinato)Fe(II), while literature structures were used for the bis-ligand adducts. We used a “locally dense” basis to evaluate the ⁵⁷Fe shieldings and electric field gradients at iron and compared them with the measured chemical shifts and Mössbauer quadrupole splittings, respectively. There is moderately good agreement between theory and experiment for the cytochrome c and Mb ⁵⁷Fe chemical shifts and shielding tensors, and very good (0.10 mm s^-1 rmsd) agreement for the ⁵⁷Fe Mössbauer quadrupole splittings, using the following basis sets and functional:  a Wachters' all electron representation for iron, a 6-311++G(2d) basis for all atoms directly attached to iron, 6-31G* for the second shell and 3-21G* bases for the other more distant atoms, together with a B3LYP hybrid exchange-correlation functional. Extensive tests with other functionals and basis set schemes are also reported. The shift and electric field gradient tensor orientations are generally close to obvious molecular symmetry axes, with the skew of the shielding tensor reversing sign on transition from strong to weak ligand fields. The paramagnetic contribution to shielding overwhelmingly dominates overall shielding and the variations seen between weak ligand field (bis(pyridine), cytochrome c) and strong ligand field (CO, PMe3, i-PrNC) systems. Poor accord between theory and experiment is obtained for the ⁵⁷Fe chemical shifts when MbCO models having highly distorted X-ray geometries are employed, suggesting that the Fe−C−O is close to the porphyrin normal, both in solution and in the solid state.

Summary In the present paper, two experimental models of heart failure, namely hereditary cardiomyopathy in hamsters (BIO 14.6) and cardiac insufficiency due to mild (0.06 μM) isoprenaline overload of rabbit isolated perfused hearts, were compared in terms of resulting alterations at the level of the functionally isolated contractile system of detergent/glycerol treated skinned cardiac fibres. As the main features of Ca activation of tension in these models, the following were found:1.Within the same species (RB hamsters, BIO 14.6 hamsters or rabbits), the Ca sensitivity, measured as pCa for half maximal Ca activation, was invariably higher in left than in right ventricular skinned fibres.2.During the development of hereditary cardiomyopathy (BIO 14.6), maximum Ca-activated tension, measured per unit cross-sectional area, was reduced in an age-dependent manner, without any significant reduction in Ca sensitivity. This effect appeared to be more pronounced in left than in right ventricles.3.In skinned fibres from right or left ventricular papillary muscles from in vitro isoprenaline pretreated rabbit hearts, no significant alteration in the maximum Ca-activated tension (per unit area) was observed in comparison to non-pretreated control hearts, whereas the Ca sensitivity was reduced. Treatment of control or failing heart skinned fibres with cAMP showed no additivity to the Ca desensitization induced by isoprenaline pretreatment.4.Skinned fibres from isoprenaline pretreated left ventricular rabbit hearts showed a higher susceptibility to the Ca sensitizing effect of APP 201-533 than fibres from unpretreated control hearts.

Detailed crystallographic and NMR measurements are reported for several Pd(II) allyl complexes containing chiral ferrocene-based phosphinopyrazole ligands, CpFe{η⁵-C5H3(1-CH(CH3)(NN&dbd;C(R¹CH&dbd;CR²)-2-PPh2)}, 1. Relative to similar BINAP, CHIRAPHOS, and diphosphine JOSIPHOS analogs, the major isomer of the β-pinene allyl complex [Pd(η³-C10H15)(1a)]CF3SO3, 2, R¹ = R² = H, shows a surprisingly large trans influence for the PPh2 donor moiety, based on ¹³C data. The solid-state structure for 2 shows normal bond lengths, although there are indications that the allyl adjusts its position due to the relatively large P,N ligand. The solid- and solution-state structures of [Pd(η³-PhCHCHCHPh)(1g)]PF6, 3g, R¹ = adamantyl and R² = H (99% ee in the enantioselective allylic amination), show the allyl ligand to be strongly rotated, thus placing the terminal allyl carbon proximate to the pyrazole moiety, significantly below the coordination plane. These structural results suggest that, for the enantioselective catalysis using ligands 1, there is an “early” transition state.

The new chelating P,S-ligands 2,3,4,6-tetra-O-acetyl-1-((2-(diphenylphosphino)benzy)lthio)-β-d-glucopyranose, [(2-Ph2PC6H4CH2)SCHCH(OAc)CH(OAc)CH(OAc)CH(CH2OAc)O, 2] and 2,3,4,6-tetra-O-acetyl-1-((2-(dicyclohexylphosphino)benzyl)thio)-β-d-glucopyranose [(2-Cy2PC6H4CH2)SCHCH(OAc)CH(OAc)CH(OAc)CH(CH2OAc)O,, 3] as well as their (1,3-diphenylallyl)palladium(II) cationic complexes [Pd(η³-PhCHCHCHPh)(2)]PF6, 6, and [Pd(η³-PhCHCHCHPh)(3)]PF6, 7, and one η³-C3H5 complex [Pd(η³-C3H5)(2)]PF6, 5, have been prepared. The solid-state structure of [Pd(η³-C3H5)(2)]PF6, 5, has been determined by X-ray diffraction methods and found to have the S-sugar substituent and one of the P-phenyl rings in pseudo-axial positions on the same side of the P−Pd−S coordination plane. Detailed NMR measurements for 6 reveal the presence of two diastereomeric isomers whereas for 7 four diastereomers are found. 2-D exchange NMR is used to characterize several of the selective equilibria within 6 and 7. On the basis of the observed ee in the enantioselective homogeneous allylic alkylation of 7, it is suggested that the reaction kinetics for the four isomers are not all the same.