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Biomedical subjects

R W Watkins

Publications and source records attributed to R W Watkins.

At least 37 records · Page 2Linked to original sources
PubMed1987

Effects of the antihypertensive dilevalol on large artery compliance in anesthetized dogs.

The present study examined the actions of dilevalol, an antihypertensive beta-adrenoceptor blocker with arterial vasodilator actions, upon aortic compliance (AC) in anesthetized dogs. AC was determined via sonomicrometric determination of the ratio of aortic systolic-diastolic diameters (mm) and arterial pulse pressure (mm Hg). One AC unit (ACU) equals 10(-3) mm/mm Hg. Dilevalol (0.032, 0.1, and 3.2 mg/kg i.v.) significantly (p less than 0.05) increased AC by 1.4 +/- 0.3, 3.7 +/- 1.4, and 4.5 +/- 1.2 ACU, respectively, from basal values of 4.7 +/- 0.4-5.6 +/- 0.4 ACU, while reducing blood pressure by 20 +/- 2, 31 +/- 9, and 41 +/- 10 mm Hg, respectively (p less than 0.05). Increases in AC were not the passive result of altered blood pressure. Proximal mechanical aortic occlusion dropped systolic blood pressure as much as 70 mm Hg without altering AC. Propranolol (0.32 and 1.0 mg/kg) did not significantly change AC, but propranolol pretreatment attentuated dilevalol-induced increases in AC. Pindolol (0.1-1.0 mg/kg i.v.) lowered blood pressure 17 +/- 3 (p less than 0.05) to 34 +/- 7 mm Hg (p less than 0.05), while significantly increasing AC by 1.2 +/- .2 to 2.7 +/- .7 ACU. The data show that dilevalol, unlike propranolol, increases AC substantially at antihypertensive doses. The inhibition of dilevalol-induced AC increases by propranolol illustrates a beta-adrenoceptor agonist activity in large arteries. Since large artery compliance is impaired in hypertension, dilevalol may afford a vasular protective action for known risk factors for evolving systemic arterial disease.

Animals↗
PubMed1987

Effects of spiraprilic acid, an angiotensin converting enzyme inhibitor, on large artery compliance in anesthetized dogs.

The present study examined the actions of spiraprilic acid, a new non-sulfhydryl angiotensin converting enzyme (ACE) inhibitor upon aortic compliance (AC) in anesthetized dogs. Enalaprilic acid was examined for comparative purposes. AC was determined via sonomicrometric determination of the ratio of aortic systolic-diastolic diameter (mm) and arterial pulse pressure (mmHg). One AC unit (ACU) equals 10(-3) mm/mmHg. In non-thiazide pretreated animals, spiraprilic acid (1 mg/kg i.v.), caused a sustained hypotensive response of 21 +/- 3 mmHg (P less than .05). At the same time, aortic systolic and diastolic dimensions were reduced from basal values of 8.17 +/- 0.45 and 7.95 +/- 0.40 mm by 0.19 +/- 0.07 (P less than .05) and 0.29 +/- 0.10 mm (P less than .05), respectively. The aortic systolic-diastolic dimension rose significantly by 0.10 +/- 0.01 mm. Since pulse pressure was unchanged, AC rose from a basal value of 4.6 +/- 0.8 ACU by 1.7 +/- .3 ACU (P less than .05). Similar effects were observed with enalaprilic acid. In dogs pretreated orally with 5 mg/kg hydrochlorothiazide (HCTZ) twice daily for 3 days, spiraprilic and enalaprilic acids caused slightly greater falls in blood pressure (34 +/- 7 and 30 +/- 4 mmHg, respectively) than in nonpretreated dogs. However, the onset of the hypotension effect was more rapid for both ACE inhibitors in HCTZ-pretreated dogs. Effects of spiraprilic and enalaprilic acid upon aortic dimensions were similar to those observed in non-HCTZ pretreated animals. The data illustrate that the ACE inhibitors spiraprilic and enalaprilic acids not only lower blood pressure but also enhance large artery compliance.

Angiotensin-Converting Enzyme Inhibitors↗
PubMed1987

Antihypertensive, hemodynamic and autonomic profile of a new angiotensin converting enzyme inhibitor, SCH 33844 (spirapril).

SCH 33844 is a new, potent and long-acting inhibitor of angiotensin converting enzyme (ACE). Antihypertensive, hemodynamic and autonomic actions of SCH 33844 were examined in the present series of experiments. Oral administration of 0.3-30 mg/kg reduced blood pressure of spontaneously hypertensive rats. The magnitude of the response was significantly enhanced by pretreatment of the animals with hydrochlorothiazide. Blood pressure remained significantly depressed 24 hr following doses of 3 and 10 mg/kg. Administration of SCH 33844 (3 mg/kg) twice daily to nonpretreated rats or once daily to diuretic-pretreated animals for 5 days resulted in a progressive decrease in blood pressure. The compound did not reduce blood pressure in nephrectomized rats demonstrating the dependence of its action on renal renin. SCH 33844 (1-10 mg/kg orally) also produced dose-related decreases in pressure in diuretic-pretreated conscious normotensive dogs. However, only a small fall in pressure occurred in non-pretreated dogs. Hemodynamic actions were examined in anesthetized dogs. SCH 33844 (1 mg/kg i.v.) reduced blood pressure, increased cardiac output and caused a large fall in peripheral resistance. Autonomic actions were assessed in pithed rats. The compound (10 mg/kg orally) tended to decrease pressor responses to sympathetic activation and to i.v. norepinephrine. This profile is probably due, at least in part, to vasorelaxation following suppression of angiotensin II generation. In conclusion, SCH 33844 is a potent, long-lasting antihypertensive agent which reduces peripheral vascular resistance and possesses only slight autonomic effects.

Adrenergic Agonists↗
PubMed1986

AGEPC, a vasodilator phospholipid with profound circulatory actions.

Acetyl-glyceryl-ether-phosphoryl-choline (AGEPC) is a potent platelet activating factor which induces profound circulatory changes. AGEPC is synthesized in a variety of cell types including platelets, neutrophils, macrophages, basophils and endothelial cells. Biological responses include platelet activation, neutrophil activation, release of arachidonic acid metabolites and systemic anaphylaxis. Circulatory responses to AGEPC were evaluated in the present investigation. Intravenous administration of AGEPC (30 micrograms/kg/min) to anesthetized dogs reduced blood pressure, cardiac output, myocardial contractile force, renal blood flow and glomerular filtration. Intracoronary administration of AGEPC (0.3-3 micrograms) reduced blood pressure, coronary blood flow, and myocardial contractile force. Administration of AGEPC into the femoral vascular bed increased femoral artery blood flow. The data suggest that the circulatory response to AGEPC in the dog is complex and depends on the site of administration. The predominant response is hypotension mediated at least in part through myocardial depression. Intramuscular injection of AGEPC (10-30 micrograms/kg) to conscious spontaneously hypertensive rats (SHRs) reduced systemic blood pressure and increased heart rate. In pithed rats, AGEPC decreased pressor responses to sympathetic stimulation, angiotensin II and phenylephrine. Chronotropic responses were unchanged. Thus, antihypertensive doses of AGEPC reduced pressor responsiveness nonspecifically, but do not affect pre- or post-junctional adrenergic mechanisms. High concentrations of AGEPC (100 microM) relaxed phenylephrine contracted rabbit aortic rings. Relaxation was dependent on an intact endothelium. Lyso-GEPC produced similar actions. In light of the low potency of AGEPC and the activity of lyso-GEPC, physiological significance to endothelium dependent relaxation by AGEPC in rabbit aortic rings is unlikely. The physiological role of AGEPC in circulatory homeostasis is unclear at present. AGEPC may play a hypotensive role in some forms of experimental hypertension. In addition, AGEPC may mediate part of the circulatory derangements associated with cardiac anaphylaxis. Lastly, AGEPC may be involved in circulatory control during states of platelet and/or neutrophil activation such as myocardial ischemia and shock.

Animals↗
PubMed1985

Comparative effects of SCH 19927 and timolol on intraocular pressure of conscious rabbits and relative systemic beta-blockade resulting from topical administration.

SCH 19927, the RR isomer of labetalol, has been shown to possess beta-blocking and vasodilator properties. It was compared to timolol for ability to lower intraocular pressure (IOP) in conscious rabbits. Its potential for systemic beta-blockade after topical administration was also assessed. Dose-related reductions in IOP followed topically applied SCH 19927 (0.1-1.0%). Timolol in concentrations less than 0.5% was not effective in lowering IOP. Timolol (0.1 and 0.5%) strongly inhibited tachycardia induced by iv isoproterenol. A 1.0% concentration of SCH 19927 was less effective than 0.5% timolol in inhibiting the isoproterenol-induced tachycardia; 0.1% SCH 19927 caused only minor inhibitory actions. Thus, not only is SCH 19927 at least as potent in lowering IOP in conscious rabbits, its topical administration results in less systemic beta-blockade than does timolol.

Animals↗
PubMed1985

Cardiac, coronary and peripheral vascular effects of acetyl glyceryl ether phosphoryl choline in the anesthetized dog.

Acetyl glyceryl ether phosphoryl choline (AGEPC) is a potent vasodilator, platelet activator and inflammatory agent. The cardiac and peripheral vascular effects of AGEPC were assessed in anesthetized dogs in order to gain additional insight into the mechanism of action of this lipid. Injection of AGEPC (0.1-3.2 micrograms) directly into the femoral vasculature produced a dose-related vasodilation in the innervated and sympathetically denervated hindlimb. Vasodilator responses in the denervated limb were at least as great as those in the innervated limb, which indicates that the response is not due to inhibition of sympathetic vasoconstrictor tone. Vasodilator responses to AGEPC (1 microgram) were not significantly affected by theophylline (5 mg/kg), indomethacin (5 mg/kg) or BW755C (10 mg/kg), which implies that the effect is independent of purinergic P1 receptors, cyclooxygenase products and lipoxygenase products. Intracoronary injection of AGEPC (0.032-3.2 micrograms) reduced blood pressure, myocardial contractile force and coronary blood flow in a dose-related manner. Coronary vascular resistance was unchanged. In contrast, intracoronary injection of another activator of platelets, ADP (10 micrograms), increased blood flow. Responses of blood pressure, heart rate, contractile force and coronary flow to AGEPC were not affected by bilateral vagotomy or hexamethonium, which indicates that they are independent of reflexive mechanisms. Indomethacin attenuated the hypotension and coronary flow reductions to AGEPC. BW755C reduced the hypotensive response. Mechanical reduction of coronary flow by 30 to 40% did not affect blood pressure, heart rate or contractile force, which suggests that AGEPC-induced changes are not secondary to flow reduction. The data suggest that AGEPC produces direct myocardial depression and distinct effects on the coronary and femoral vasculature. The peripheral vascular effects are independent of the autonomic nervous system, purinergic mechanisms and arachidonic acid metabolites, whereas some coronary effects may be mediated through metabolites of arachidonic acid.

4,5-Dihydro-1-(3-(trifluoromethyl)phenyl)-1H-pyraz↗
PubMed1984

Lack of cross-tolerance between disodium cromoglycate and veratrum alkaloids.

We sought to determine if the hypotension and bradycardia caused by disodium cromoglycate (DSC) and veratrine sulfate were due to an action upon a common receptor. Tolerance rapidly developed to the hypotensive and bradycardic action of 10 micrograms/kg iv DSC in anesthetized dogs. Veratrine sulfate 30 micrograms/kg iv given after tolerance had developed to DSC gave falls in blood pressure and heart rate identical to those produced by the alkaloid before DSC tolerance had set in. Thus, no cross-tolerance between DSC and veratrine was observed. This result excludes the possibility of a common site of action for DSC and veratrine.

Animals↗
PubMed1981

Antihypertensive and hemodynamic actions of SCH 19927, the R,R-isomer and labetalol.

SCH 19927, one of the four chiral forms of labetalol, is approximately 4 times as potent as a beta adrenergic receptor blocker as the parent racemate, but is only one-third as potent in blocking alpha receptors. The present report describes its antihypertensive and hemodynamic actions. SCH 19927 and labetalol lowered blood pressure in hypertensive rats and dogs. SCH 19927 was somewhat more effective at lower doses, but the two agents produced comparable responses at higher doses. Both reduced blood pressure and peripheral resistance and increased cardiac output in anesthetized dogs. Intraarterial injection in to the femoral vascular bed, either in the presence or absence of neurogenic vasoconstrictor tone, resulted in dose-related vasodilatation. In contrast, alpha blockers, e.g., phentolamine and prazosin, are essentially devoid of vasodilator activity in denervated beds. It is concluded that vasodilatation is largely responsible for the antihypertensive response to labetalol and particularly to SCH 19927. SCH 19927 is a potentially useful agent which would be expected to reduce pressure in humans by two complementary mechanisms, beta blockade and vasodilatation. It should possess less orthostatic potential than labetalol.

Animals↗
PubMed1980

Contraction velocity analysis of norepinephrine and angiotensin-II activation of vascular smooth muscle.

The contractile response of vascular smooth muscle is known to consist of fast and slow components of contraction. We investigated the effect of norepinephrine and angiotensin-II on these functional properties of vascular smooth muscle in a quantitative fashion by analyzing the velocity of isometric tension development in rabbit aortic strips as a function of time. Basic premises for contraction velocity analysis are: (1) tension development is proportional to agonist concentration and relates to the amount of calcium fixed by the contractile proteins; (2) the rate of tension development (Qt) reflects the rate calcium is mobilized; (3) the rate at which calcium is made available relates to agonist concentration; (4) calcium is available from internal and external sites; (5) the calcium source)s) activated are characteristic of the mechanism of action of a particular agonist, and (6) the source of calcium activated is identifiable. Aortic strips were contracted maximally with norepinephrine and the velocity of contraction found to decrease with time according to the empirical expression Qt = phi 1e-phi 2t + theta 1e-the 2t. Experiments in calcium-free medium served to identify the tonic component of norepinephrine-induced contraction as the second term while angiotensin demonstrated only one term (phasic) which was independent of extracellular calcium. Strips contracted with different concentrations of norepinephrine or angiotensin showed dose-dependent actions on these functional properties of vascular smooth muscle as revealed by their effects on the contraction velocity parameters. An expression describing the contribution of each component to total tension developed was derived by integrating the above expression to give Qtot = phi 1 (1--e-phi 2tmax)/phi 2 + theta 1 (1--e-theta 2tmax)/theta 2. The contribution of each component to total tension development was donse-dependent and their sum gave the total tension observed experimentally with norepinephrine. For angiotensin, the first term of the preceeding expression gave the observed tension response. It is concluded that contraction velocity analysis affords a new approach for studying the effects of vasoactive agents on the functional properties of vascular smooth muscle.

Angiotensin II↗
PubMed1980

Effects of competitive antagonists on phasic and tonic components of vascular smooth muscle contraction.

Phasic and tonic components of contraction are functional properties of vascular smooth muscle reflecting, respectively, release of intracellular calcium and utilization of extracellular calcium. Recently, it has been appreciated that different agonists may manifest discrete actions on these functional properties of vascular smooth muscle. We have analyzed the contractile response of rabbit aortic strips in response to maximal effective concentrations of the agonists norepinephrine, angiotensin II and acetylcholine in the absence and presence of their specific antagonists: phentolamine, saralasin and atropine in order to determine the actions of the antagonists on these functional properties of vascular smooth muscle. When contractions produced by norepinephrine or acetylcholine were plotted as ln velocity vs. time, characteristic curves described by a two-term function Qt = phi 1e-phi 2t + theta 1e-theta 2t were found (Qt = velocity at any time t: phi 1 and theta 1 are velocity of contraction at zero time for phasic and tonic components; phi 2 and theta 2 are contraction velocity constants for their respective components of contraction). The first term represents the phasic component and the second term the tonic component of contraction. The contraction velocity parameters were different for norepinephrine and acetylcholine. Angiotension II-induced contractions gave velocity curves described by a single term, i.e. phasic component of contraction. Phentolamine blocked completely the tonic component and the decreased tension achieved with norepinephrine was completely accounted for by inhibition of the tonic contribution to total tension development. Atropine completely blocked acetylcoholine's tonic component and also attenuated slightly the phasic component. Saralasin reduced angiotensin II-induced tension development and contraction velocity analysis suggested a non-competitive action. We conclude that competitive antagonists may exert distinct actions on the phasic and tonic components of vascular smooth muscle contraction.

Acetylcholine↗
PubMed1977

A total internal-reflection technique for the examination of protein adsorption.

A total internal-reflection fluorescence (TIRF) technique for examining protein adsorption at solid-liquid interfaces is described. For the representative case of adsorption of bovine gamma-globulin onto silicone rubber, the applicability of the technique to serveral important aspects of protein adsorption phenomena is demonstrated. Specifically, in addition to the tightly adsorbed protein layer observed herein and previously by maany others, the presence of a loosely adsorbed protein layer was also noted under conditions of either static or flowing protein solutions. Taking advantage of the continuous real-time measurements possible with TIRF, a rate constant for the protein adsorption step during laminar flow was estimated at both 25 and 37 degrees C. These results serve to demonstrate that the TIRF technique represents a significant and versatile new tool for the study of protein adsorption phenomena.

Adsorption↗