Alphonse J. Ingenito

Practical Considerations of the Pharmacology of Angiotensin Receptor Blockers

A review of the drug class of angiotensin receptor blockers (ARBs) as well as the ARBs currently available by prescription in the United States is presented. The importance of angiotensin II production by non‐angiotensin‐converting enzyme (non‐ACE) pathways, particularly human chymase, is discussed. Emphasis is placed on the mechanism of action of ARBs and the different binding kinetics of these agents. Although all ARBs, as a group, block the AT1 receptor, they may differ in the pharmacological characteristics of their binding and be classified as either surmountable or insurmountable antagonists. Mechanisms of surmountable and insurmountable antagonism as well as possible benefits of these blocking characteristics are discussed in relation to the various ARBs. The cardiovascular effects of activation of the two main subtypes of angiotensin receptors (AT1 and AT2) are presented. In addition to their treatment of hypertension, ACE inhibitors are recognized as being effective in the management of heart failure, left ventricular hypertrophy, recurrent myocardial infarctions, and renal disease. ARBs are currently indicated only for the treatment of hypertension; however, in vitro and in vivo pharmacological studies as well as preliminary clinical data suggest that ARBs, like ACE inhibitors, may also provide effective protection against end‐organ damage in these conditions.

Central effects of opioid agonists and naloxone on blood pressure and heart rate in normotensive and hypertensive rats.

1. The central cardiovascular effects of several opioid receptor selective agonists and the nonselective opioid antagonist, naloxone, were studied in anesthetized normotensive control rats, in spontaneously hypertensive rats (SHR), and in foot-shock-stressed rats. 2. Receptor-selective agonists injected into the rostral ventrolateral medulla (RVLM), paraventricular nucleus (PVN), and dorsal hippocampus (dHip) were DAGO (mu), DADLE (delta), and U50,488H (kappa). 3. DAGO and DADLE (3 nM) decreased arterial pressure and heart rate in RVLM and PVN of all rat strains, while U-50,488H (9 nM) had only minimal effects in these areas. 4. In dHip, only DADLE (3 nM) had depressor and bradycardic effects, and then, only in SHR, with DAGO and U50,488H being ineffective in any strain, even at 9 nM. 5. Prior injection of naloxone (10 nM) into the RVLM, PVN and dHip blocked and postinjection reversed the cardiovascular effects of the agonists. Naloxone alone increased blood pressure and heart rate in all three areas, in all rat strains except SHR, suggesting a tonic depressor effect of endogenous opioids. 6. Lack of significant quantitative differences in opioid agonist and antagonist effects between normotensive and hypertensive or stressed rats argues against a role for endogenous brain opioids in experimental hypertension.

Instruction in Clinical Pharmacology: Changes in the Wind

We have presented some views on past, present and potential trends for teaching clinical pharmacology in the medical curriculum. Clinical pharmacology as subject matter in the medical curriculum has been operationally defined for our purposes as: (1) the application of fundamental principles of basic pharmacology to rational drug therapy in humans; and (2) the application of appropriate nuances of the human pharmacology of individual drugs to their use in particular disease states. In terms of improving the results of drug therapy, arguments were advanced for the importance of teaching clinical pharmacology at all levels in the medical curriculum and in postgraduate medical education. The introduction of so many new and potent pharmaceuticals over the past 25 years requires well educated and skilled medical practitioners adept and well versed in the fundamental principles of basic and applied pharmacology, so as to achieve the most prudent, effective and economically sound use of these drugs as possible. This creates a challenge to medical educators, particularly those involved in teaching clinical pharmacology, to devise innovative teaching techniques and curricular changes that foster these goals. In an attempt to address these challenges, we have reviewed some innovative teaching approaches and curricular reforms, both published and unpublished, that have already met with success, and we have also discussed some future trends in teaching both undergraduate and graduate physicians the fundamental principles of rational drug therapy. The challenges and issues involved in these future trends have been identified and will be addressed in subsequent articles in this journal. These will be concerned with teaching clinical pharmacology: (1) in basic medical pharmacology courses; (2) to upperclass medical students; and (3) in continuing medical education programs. Subsequent articles will also deal with new and innovative teaching modalities for clinical pharmacology and with the role of the drug industry in these modalities.

A low hippocampal dynorphin A (1–8) immunoreactivity in spontaneously hypertensive rats

Dynorphin A (1-8)-like immunoreactivity (DN-LI A(1-8] was determined by radioimmunoassay in the brains of age matched spontaneously hypertensive rats (SHR) and two normotensive control groups consisting of Wistar-Kyoto (WKY) and Sprague-Dawley (SD) strain rats. A significantly lower DN-LI A(1-8) was found in the hippocampus and hypothalamus of the SHR compared with the WKY groups. DN-LI A(1-8) was 24% of control WKY levels in hippocampus and 79% of that in WKY hypothalamus at 16 weeks. Similar lower levels of DN-LI A(1-8) were also observed in SHR at 4, 8, and 12 weeks during the development of hypertension when compared with both WKY and SD groups. We failed to find significant differences in brain stem DN levels between the groups. The relationship between the low hippocampal dynorphin levels in SHR and the hypertension is problematical because the differences were present before (4 wks), during (8 and 12 wks) and after (16 wks) its development.

Comparative effects of intrahippocampal injection of dynorphin A(1-8), dynorphin A(1-13), dynorphin A(1-17), U-50,488H, and dynorphin B on blood pressure and heart rate in spontaneously hypertensive and normotensive Wistar-Kyoto rats

We previously demonstrated centrally mediated hypotensive and bradycardic effects of dynorphin A(1-8) (DA1-8) on microinjection into various areas of the hippocampal formation (HF) of both anesthetized and conscious male normotensive and spontaneously hypertensive rats (SHR). The purpose of the present study was to determine whether other dynorphin fragments also had this activity. We microinjected DA1-8, dynorphin A(1-13), dynorphin A(1-17), dynorphin B (DB), and the nonpeptide kappa-opioid agonist U-50,488H into HF areas previously found to react to DA1-8, at doses ranging from 0.05 to 50 nmol. The subjects were male SHR and normotensive Wistar-Kyoto (WKY) rats in which arterial pressure and heart rate were monitored. Dose-related centrally mediated hypotension and bradycardia were found in both strains with all agents used, except for DB, which had no effects. Similarly injected drug vehicle was also without effect. In general, the responses were greater in SHR than in WKY rats. Preinjection of the active HF areas with 2 nmol of nor-binaltorphimine (nor-BNI), a selective kappa-opioid receptor antagonist, which itself had no blood pressure or heart rate effects, abolished both the decrease in blood pressure and heart rate of all dynorphins and U-50,488H. The results demonstrated the equivalent abilities of all the dynorphin fragments studied, except DB, to cause HF-mediated hypotension and bradycardia. The results with U-50,488H and nor-BNI strongly implicate kappa-opiate receptor activation of the HF in these effects.

Cardiovascular Effects of Microinjection of Dynorphin-A(1-8) Into the Hippocampus in Conscious, Spontaneously Hypertensive and Normotensive Wistar-Kyoto Rats

The possibility that the dynorphinergic system in the hippocampal formation (HF) may be implicated in the central regulation of peripheral circulatory activity was examined in chronically catheterized and conscious spontaneously hypertensive rats (SHR) and their normotensive control Wistar-Kyoto (WKY) rats. The ipsilateral microinjection of dynorphin-A(1-8) (DA1-8) at a dose of 10 nmol into the dorsal region of HF, where injection of control saline failed to affect peripheral cardiovascular activities, lowered mean blood pressure (MBP) by 19.2 +/- 1.2 mmHg in WKY and 25.9 +/- 3.2 mmHg in SHR. However, no significant alteration of heart rate (HR) was found in either WKY or SHR following the drug administration. The depressor response to intra-HF DA1-8 was dose-related (0.05 to 50.0 nmol) in the two strains of rats. Intra-HF injection of the kappa opioid receptor antagonist norbinaltorphimine at a dose of 2 nmol, which by itself produced only minimal fluctuations of basal MBP and HR, markedly reversed subsequent reduction of blood pressure induced by intra-HF injection of DA1-8 in both strains of rats. The results indicate that DA1-8 administered into the HF acts on kappa opioid receptors to produce a profound decrease in blood pressure, but not heart rate, in conscious hypertensive and normotensive rats.

DEPRESSOR EFFECT OF KAPPA OPIOID AGONIST ON HYPERTENSION INDUCED BY ISOLATION IN THE RAT

Previous studies by us established that peripheral and hippocampal administration of kappa opioid receptor agonists lowered blood pressure (BP) in the spontaneously hypertensive rat (SHR). The object of the present study was to determine whether U62,066E, a non-peptide kappa agonist, would lower BP in another animal model of hypertension; that produced by isolation of young male rats. After 7 days of isolation had produced a sustained hypertension of approximately 40 mmHg, drug effects were determined in the isolated hypertensive animals and group-housed normotensive rats. Two drug-treated plus vehicle control groups were used as follows: (1) 2 mg/kg intraperitoneally twice daily for 3 days in conscious animals and (2) intrahippocampal injection of from 1 to 10 nmol in animals anesthetized with chloralose and pentobarbital. In group (1) the drug lowered both systolic BP (SBP) and mean BP (MBP) nearly to pre-isolation levels, while having no significant effect on these parameters in group-housed normotensive controls. Heart rate (HR) was not significantly affected by the drug in either sub-group. In group (2) SBP, MBP and HR were reduced in both the isolated hypertensive and group-housed normotensive animals when the drug was given intrahippocampally at 5.0 nmol. The depressor response to intrahippocampal U-62,066E was dose-related in both isolated and grouped rats at doses ranging from 1 to 10 nmol. The findings support our earlier suggestions that the hippocampal kappa opioid system may be somehow involved in cardiovascular regulation and that the non-peptide kappa agonists might make effective antihypertensive drugs.

Dynorphin Receptor Changes in Hippocampus of the Spontaneously Hypertensive Rat

Dynorphin receptor binding sites in hippocampal membrane preparations were assessed in spontaneously hypertensive (SHR) and Wistar-Kyoto (WKY) rats at 4, 8, 12 and 16 weeks of age. At 4 weeks of age, before hypertension is manifested, SHRs had significantly more hippocampal dynorphin receptor binding sites than WKY controls. At 8, 12 and 16 weeks of age, however, when hypertension is seen, SHRs showed significantly fewer hippocampal binding sites than WKY rats. No receptor affinity changes for dynorphin were seen between the two strains of rats at any age. These results suggest that hippocampal receptor changes involving the opioid system may play a role in the central component of blood pressure control.

κ-Opioid receptor antisense oligonucleotide injected into rat hippocampus causes hypertension

Bi-hippocampal microinjection treatment (1 microg per side, twice a day for 5 days) with an antisense phosphorothioate oligodeoxynucleotide antisense oligodeoxynucleotide to the rat kappa-opioid receptor, caused hypertension in normotensive Wistar Kyoto (WKY) rats and increased the blood pressure of spontaneously hypertensive rats (SHR). Systolic blood pressure in WKY rats increased from 121+/-4 to 153+/-6 mm Hg, and in SHR systolic blood pressure increased from 153+/-4 to 183+/-5 mm Hg. Similar results were observed with mean blood pressure, however, there were no changes in heart rate. No significant responses were seen with either vehicle or missense injections. Radioligand binding studies indicated that there was a significant decrease in apparent kappa-opioid receptor density due to antisense oligodeoxynucleotide treatment. The results are in accord with our earlier suggestions that the kappa-opioid system in the hippocampus may have a role in the neural control of blood pressure.

Age-Related Changes in Opioid Peptide Concentrations in Brain and Pituitary of Spontaneously Hypertensive Rats

The relationship of age-dependent changes in concentrations of various opioid peptides in the brain and pituitary to the development of hypertension was studied in the spontaneously hypertensive rat (